CA3207513A1 - Crystalline solids of mek inhibitor n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and uses thereof - Google Patents

Crystalline solids of mek inhibitor n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and uses thereof Download PDF

Info

Publication number
CA3207513A1
CA3207513A1 CA3207513A CA3207513A CA3207513A1 CA 3207513 A1 CA3207513 A1 CA 3207513A1 CA 3207513 A CA3207513 A CA 3207513A CA 3207513 A CA3207513 A CA 3207513A CA 3207513 A1 CA3207513 A1 CA 3207513A1
Authority
CA
Canada
Prior art keywords
crystalline form
fluoro
difluoro
dihydroxypropoxy
phenylamino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CA3207513A
Other languages
French (fr)
Inventor
Kristin Patterson
Jiping Liu
Ricky Wayne Couch
Peter Gregory Varlashkin
Mai Li
Yonghong Gan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SpringWorks Therapeutics Inc
Original Assignee
SpringWorks Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SpringWorks Therapeutics Inc filed Critical SpringWorks Therapeutics Inc
Publication of CA3207513A1 publication Critical patent/CA3207513A1/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The present disclosure relates to: a) crystalline forms of N-((R)-2,3-dihydroxypropoxy)- 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b) pharmaceutical compositions comprising one or more crystalline forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide, and, optionally, one or more pharmaceutically acceptable carriers; c) methods of treating a tumor a cancer, or a Rasopathy disorder by administering one or more crystalline forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide to a subject in need thereof; and methods of producing essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)- benzamide.

Description

CRYSTALLINE SOLIDS OF MEK INHIBITOR N-((R)-2,3-DIHYDROXYPROPDXY)-3,4-DIFLUOR0-2-(2-FLUOR0-4-IODO-PHENYLAMINO)-BENZAMIDE AND USES THEREOF
FIELD OF THE INVENTION
[0001] The present disclosure relates to: a) methods of synthesizing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b) crystalline forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; c) pharmaceutical compositions comprising one or more crystalline forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and, optionally, one or more pharmaceutically acceptable carriers; and d) methods of treating a tumor, a cancer, or a Rasopathy disorder by administering one or more crystalline forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide to a subject in need thereof.
BACKGROUND
[0002] N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide ("mirdametinib", or "PD-0325901") is a small molecule drug which has been designed to inhibit mitogen-activated protein kinase kinase 1 ("MEK1") and mitogen-activated protein kinase kinase 2 ("MEK2"). MEK1 and MEK2 are proteins that play key roles in the mitogen-activated protein kinase ("MAPK") signaling pathway. The MAPK
pathway is critical for cell survival and proliferation, and overactivation of this pathway, has been shown to lead to tumor development and growth. Mirdametinib is a highly potent and specific allosteric non-ATP-competitive inhibitor of MEK1 and MEK2.
By virtue of its mechanism of action, mirdametinib leads to significantly inhibited phosphorylation of the extracellular regulated MAP kinases ERK1 and ERK2, thereby leading to impaired growth of tumor cells both in vitro and in vivo. In addition, evidence indicates that inflammatory cytokine-induced increases in MEK/ERK activity contribute to the inflammation, pain, and tissue destruction associated with rheumatoid arthritis and other inflammatory diseases.

WO 2022/177557 _ 2 _ 100031 Crystal forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide have been described previously. W02002/006213 describes crystalline Forms land II. U.S. Patent No. 7,060,856 ("the '856 patent") describes a method of producing Form IV. The '856 patent indicates that the material produced by this method was greater than 90% Form IV (The '856 patent, Example 1). The '856 patent also states that the differential scanning calorimetry ("DSC") of the material produced shows an onset of melting at 110 C as well as a small peak with an onset at 117 C, consistent with the material being a mixture of two forms.
100041 WO 2006/134469 ("the '469 PCT publication") also describes a method of synthesizing N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The '469 PCT publication reports the method yields a product conforming to the polymorphic Form IV disclosed in U.S. Patent Application No.

10/969,681 which issued as the '856 patent.
100051 Differences in the characteristics of different polymorphic forms can lead to differences in the effective dose or physical properties affecting processability of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide caused by differences in solubility or bioavailability. Thus, there is a need for compositions of polymorphic forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, for use in treatment of a tumor, a cancer, or a Rasopathy disorder.
BRIEF DESCRIPTION OF THE FIGURES
100061 FIG. IA is a X-ray powder diffraction pattern ("XRPD") corresponding to essentially pure crystalline Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
100071 FIG. 1B is a thermogravimetric analysis thermogram ("TGA") and a differential scanning calorimetry thermogram ("DSC") corresponding to essentially pure crystalline Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
100081 FIG. 2A is a X-ray powder diffraction pattern ("XRPD") corresponding to crystalline Form V.
- 3 -[0009] FIG. 2B is a thermogravimetric analysis thermogram ("TGA") and a differential scanning calorimetry thermogram ("DSC") corresponding to crystalline Form V.
[0010] FIG. 3A is an XRPD corresponding to crystalline Form VI.
[0011] FIG. 3B is a DSC and a TGA corresponding to crystalline Form VI.
[0012] FIG. 4A is an XRPD corresponding to crystalline Form VII.
[0013] FIG. 4B is a DSC and a TGA corresponding to crystalline Form VII.
100141 FIG. 5A is an XRPD corresponding to crystalline Form VIII.
[0015] FIG. 5B is a DSC and a TGA corresponding to crystalline Form VIII.
[0016] FIG. 6A is an XRPD corresponding to crystalline Form IX.
100171 FIG. 6B is a DSC and a TGA corresponding to crystalline Form IX.
[0018] FIG. 7A is an XRPD corresponding to crystalline Form X.
[0019] FIG. 7B is a DSC and a TGA corresponding to crystalline Form X.
[0020] FIG. 8A is an XRPD corresponding to crystalline Form XI.
[0021] FIG. 8B is a DSC and a TGA corresponding to crystalline Form XI.
[0022] FIG. 9A is an XRPD corresponding to crystalline Form XII.
[0023] FIG. 9B is a DSC and a TGA corresponding to crystalline Form XII.
[0024] FIG. 10A is an XRPD corresponding to crystalline Form XIII.
[0025] FIG. 10B is a DSC and a TGA corresponding to crystalline Form XIII.
[0026] FIG. 11A is an XRPD corresponding to crystalline Form XIV
overlaid with an XRPD corresponding to crystalline Form IV.
[0027] FIG. 11B is a DSC and a TGA corresponding to crystalline Form XIV.
[0028] FIG. 12A is an XRPD corresponding to crystalline Form XV.
100291 FIG. 12B is a DSC and a TGA corresponding to crystalline Form XV.
[0030] FIG. 13A is an XRPD corresponding to crystalline Form XVI.
[0031] FIG. 13B is a DSC and a TGA corresponding to crystalline Form XVI.
[0032] FIG. 14A is an XRPD corresponding to crystalline Form XVII.
[0033] FIG. 14B is a DSC and a TGA corresponding to crystalline Form XVII.
[0034] FIG. 15A is an XRPD corresponding to crystalline Form XVIII.
[0035] FIG. 15B is a DSC and a TGA corresponding to crystalline Form XVIII.
[0036] FIG. 16A is an XRPD corresponding to crystalline Form XIX.
[0037] FIG. 16B is a DSC and a TGA corresponding to crystalline Form XIX.
[0038] FIG. 17A is an XRPD corresponding to crystalline Form XX.
[0039] FIG. 17B is a DSC and a TGA corresponding to crystalline Form XX.
- 4 -[0040] FIG. 18A is an XRPD corresponding to crystalline Form XXI.
100411 FIG. 18B is a DSC and a TGA corresponding to crystalline Form XXI.
100421 FIG. 19A is an XRPD corresponding to crystalline Form XXII.
100431 FIG. 19B is a DSC and a TGA corresponding to crystalline Form XXII.
100441 FIG. 20A is an XRPD corresponding to crystalline Form XXIII.
100451 FIG. 20B is a DSC and a TGA corresponding to crystalline Form XXIII.
100461 FIG. 21A is an XRPD corresponding to crystalline Form XXIV.
100471 FIG. 21B is a DSC and a TGA corresponding to crystalline Form XXIV.
100481 FIG. 22A is an XRPD corresponding to amorphous mirdametinib.
100491 FIG. 22B is a DSC and a TGA corresponding to amorphous mirdametinib.
BRIEF SUMMARY OF THE INVENTION
Crystalline Forms and Amorphous Solids 100501 The present disclosure features useful compositions and methods to treat disorders whereby aberrant MEK1 or MEK2 activity is implicated, e.g., a cancer, a tumor, or a Rasopathy disorder, such as neurofibromatosis type 1, in a subject in need thereof. In some aspects, the present disclosure features novel polymorphic forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and methods of producing them using pure Form IV, which is substantially free of contaminating forms, e.g., Form I.
100511 In some aspects, the present disclosure features novel methods of synthesizing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the methods of synthesizing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein are useful in producing pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
100521 In some aspects, the methods and compositions described herein are useful in treating patients who struggle to swallow whole capsules or tablets, e.g., pediatric patients or subjects suffering from dysphagia, such as patients with esophageal cancer, Parkinson's disease, amyotrophic lateral sclerosis, stroke, achalasia, or esophageal narrowing.
- 5 -[0053] In some aspects, the present disclosure provides a crystalline form of N-((R)-2,3-di hy droxyprop oxy)-3 ,4-difluoro-2-(2-fluoro-4 odo-ph enyl amino)-b enzami de of Formula (I) H
6F1 N, I , (I), selected from the group consisting of:
a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.4 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta;
b) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.9 0.2, 7.2 0.2, and 21.2 0.2 degrees two theta;
c) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.3 0.2, 10.6 0.2, and 16.1 0.2 degrees two theta;
d) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.4 0.2, 10.7 0.2, and 18.7 0.2 degrees two theta;
e) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 6.7 0.2, 13.5 0.2, and 22.2 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 10.6 0.2, 19.6 0.2, and 24.8 0.2 degrees two theta;
g) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.5 0.2, 6.9 0.2, and 10.1 0.2 degrees two theta;
- 6 -h) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 10.1 0.2, 17.3 0.2, and 22.6 0.2 degrees two theta;
i) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 4.6 0.2, 5.1 0.2, and 14.6 0.2 degrees two theta;
j) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 4.6 0.2, 23.4 0.2, and 25.2 0.2 degrees two theta;
k) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.5 0.2, 14.7 0.2, and 20.9 0.2 degrees two theta;
1) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 6.0 + 0.2, 17.1 + 0.2, and 20.61 0.2 degrees two theta;
m) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.9 + 0.2, 10.1 + 0.2, and 15.5 + 0.2 degrees two theta;
n) a crystalline form of N-((R)-2,3 -di hydroxyprop oxy)-3 ,4-di uoro-2-(2-fluoro-4-iodo-phenylamino)-b enzamide characterized by an XRPD pattern having peaks at 4.6 0.2, 10.7 0.2, and 15.9 0.2 degrees two theta;
o) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 10.2 0.2, 11.6 0.2, and 20.0 0.2 degrees two theta;
1)) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 7.8 0.2, 14.0 0.2, and 17.1 0.2 degrees two theta;
cl) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.5 0.2, 8.2 0.2, and 16.7 0.2 degrees two theta;
r) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 7.2 0.2, 21.7 0.2, and 29.1 0.2 degrees two theta;
- 7 -s) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.4 0.2, 9.7 0.2, and 10.7 0.2 degrees two theta; and t) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 7.2 0.2, 20.6 0.2, and 23.0 0.2 degrees two theta.
100541 In some aspects, the crystalline form of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks 5.4 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta.
In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks 5.4 0.2, 12.5 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 2A.
100551 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.7 wt% between about 35 C and about 100 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de exhibits a DSC thermogram that has an endotherm onset at about 77 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 95 C. In some aspects, the crystalline form of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 77 C and a second endotherm onset at about 95 C.
In some aspects, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile substantially as shown in FIG. 2B; and/or b) a DSC profile substantially as shown in FIG. 2B.
100561 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form V.
100571 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de is characterized by an XRPD
- 8 -pattern haying peaks at 5.9 0.2, 7.2 0.2, and 21.2 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.9 0.2, 7.2 0.2, 9.3 0.2, and 21.2 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
3A.
100581 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.4 wt% between about 25 C and about 125 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 41 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 70 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 109 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 41 C and an endotherm onset at about 70 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 41 C and an endotherm onset at about 109 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has an endotherm onset at about 70 C and an endotherm onset at about 109 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 41 C, a second endotherm onset at about 70 C, and a third endotherm onset at about 109 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 3B; and/or b) a DSC
profile substantially as shown in FIG. 3B.
100591 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is Form VI.
- 9 -[0060] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 5.3 0.2, 10.6 0.2, and 16.1 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.3 0.2, 10.6 0.2, 13.9 0.2, and 16.1 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 4A.
100611 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 5.2 wt% between about 40 C and about 120 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 85 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endothermic event at about 110 'C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has a first endotherm onset at about 85 C and a second endothermic event at about 110 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile substantially as shown in FIG. 4B; and/or b) a DSC profile substantially as shown in FIG. 4B.
[0062] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VII.
[0063] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 5.4 0.2, 10.7 0.2, and 18.7 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4 0.2, 10.7 + 0.2, 18.7 + 0.2, and 23.9 + 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-
- 10 -phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 5A.
100641 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 3.3 wt% between about 40 C and about 112 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 81 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 110 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has a first endotherm onset at about 81 C and a second endotherm onset at about 110 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile substantially as shown in FIG. 5B; and/or b) a DSC profile substantially as shown in FIG.
5B.
100651 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VIII.
100661 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 6.7 0.2, 13.5 0.2, and 22.2 0.2 degrees two theta. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 6.7 0.2, 8.0 0.2, 13.5 0.2, and 22.2 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 6A.
100671 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 4.6 wt% between about 28 C and about 128 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 84 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-
- 11 -phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 107 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has an endotherm onset at about 114 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 84 C and an endotherm onset at about 107 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 84 C and an endotherm onset at about 114 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has an endotherm onset at about 107 C and an endotherm onset at about 114 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 84 C, a second endotherm onset at about 107 C, and a third endotherm onset at about 114 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 6B; and/or b) a DSC
profile substantially as shown in FIG. 6B.
[0068] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form IX.
[0069] In some aspects, the crystalline form of N-((R)-2,3-dihy droxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 10.6 0.2, 19.6 0.2, and 24.8 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 10.6 0.2, 19.6 0.2, and 24.8 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 7A.
[0070] In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.9 wt% between about 40 C and about 115 C. In some aspects, the crystalline form of
- 12 -N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 89 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 7B; and/or b) a DSC profile substantially as shown in FIG. 7B.
[0071] In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form X.
[0072] In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 5.5 0.2, 6.9 0.2, and 10.1 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern haying peaks at 5.5 0.2, 6.9 0.2, 10.1 0.2, and 19.2 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 8A.
[0073] In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 7.6 wt% between about 40 C and about 175 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 69 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 104 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has a first endotherm onset at about 69 C and a second endotherm onset at about 104 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile substantially as shown in FIG. 8B; and/or b) a DSC profile substantially as shown in FIG.
8B.
[0074] In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XI.
- 13 -[0075] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 10.1 0.2, 17.3 0.2, and 22.6 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.1 0.2, 17.3 0.2, 21.5 0.2, and 22.6 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 9A.
100761 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 8.5 wt% between about 40 C and about 160 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 72 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 109 'C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has a first endotherm onset at about 72 C and a second endotherm onset at about 109 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile substantially as shown in FIG. 9B; and/or b) a DSC profile substantially as shown in FIG.
9B.
100771 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XII.
100781 In some aspects, the crystalline form of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 4.6 0.2, 5.1 0.2, and 14.6 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 0.2, 5.1 + 0.2, 6.41 0.2, and 14.61 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
10A.
- 14 -[0079] In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 3.1 wt% between about 20 C and about 100 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 55 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 109 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has a first endotherm onset at about 55 C and a second endotherm onset at about 109 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile substantially as shown in FIG. 10B; and/or b) a DSC profile substantially as shown in FIG. 10B.
[0080] In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIII.
100811 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 4.6 0.2, 23.4 0.2, and 25.2 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 0.2, 23.4 0.2, 25.2 0.2, and 30.6 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 11A.
100821 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 0.15 wt% between about 40 C and about 150 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about ii 1 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 11B; and/or b) a DSC profile substantially as shown in FIG. 11B.
- 15 -[0083] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIV.
[0084] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 5.5 0.2, 14.7 0.2, and 20.9 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 14.7 0.2, 20.9 0.2, and 26.6 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 12A.
[0085] In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 3.8 wt% between about 40 C and about 150 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 104 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 12B; and/or b) a DSC profile substantially as shown in FIG. 12B.
[0086] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XV.
[0087] In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 6.0 0.2, 17.1 0.2, and 20.6 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 6.0 0.2, 12.8 0.2, 17.1 0.2, and 20.6 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 13A.
[0088] In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.1 wt% between about 40 C and about 150 C. In some aspects, the crystalline form of
- 16 -N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 74 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 102 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has an endotherm onset at about 114 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 74 C and an endotherm onset at about 102 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 74 C and an endotherm onset at about 114 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has an endotherm onset at about 102 C and an endotherm onset at about 114 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 74 C, a second endotherm onset at about 102 C, and a third endotherm onset at about 114 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 13B, and/or b) a DSC
profile substantially as shown in FIG. 13B.
100891 In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVI.
100901 In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern haying peaks at 5.9 0.2, 10.1 0.2, and 15.5 0.2 degrees two theta. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.9 0.2, 10.1 0.2, 11.7 0.2, and 15.5 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 14A.
- 17 -[0091] In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.7 wt% between about 40 C and about 100 C. In some aspects, crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 89 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 14B; and/or b) a DSC profile substantially as shown in FIG. 14B.
[0092] In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVII.
[0093] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 4.6 0.2, 10.7 0.2, and 15.9 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 +
0.2, 10.7 0.2, 15.9 0.2, and 19.6 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 15A.
[0094] In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 1.6 wt% between about 30 C and about 150 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 83 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 15B; and/or b) a DSC profile substantially as shown in FIG. 15B.
[0095] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVIII.
[0096] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 10.2 0.2, 11.6 0.2, and 20.0 0.2 degrees two theta. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
- 18 -iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.2 + 0.2, 11.6 0.2, 17.1 + 0.2, and 20.0 + 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 16A.
[0097] In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 1.85 wt% between about 23 C and about 92 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 69 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 98 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 115 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 69 'V and an endotherm onset at about 98 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de exhibits a DSC thermogram that has an endotherm onset at about 69 C and an endotherm onset at about 115 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has an endotherm onset at about 98 C and an endotherm onset at about 115 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 69 C, a second endotherm onset at about 98 C, and a third endotherm onset at about 115 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 16B; and/or b) a DSC
profile substantially as shown in FIG. 16B.
[0098] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIX.
- 19 -[0099] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 7.8 0.2, 14.0 0.2, and 17.1 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.8 0.2, 14.0 0.2, 15.6 0.2, and 17.1 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 17A.
101001 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.6 wt% between about 29 C and about 126 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 77 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 92 'C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 110 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 77 C and an endotherm onset at about 92 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 77 C and an endotherm onset at about 110 C. In some aspects, the crystalline form of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has an endotherm onset at about 92 C and an endotherm onset at about 110 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 77 C, a second endotherm onset at about 92 C, and a third endotherm onset at about 110 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is
- 20 -characterized by: a) a TGA profile substantially as shown in FIG. 17B; and/or b) a DSC
profile substantially as shown in FIG. 17B.
101011 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XX.
101021 In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 5.5 0.2, 8.2 0.2, and 16.7 0.2 degrees two theta. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 8.2 0.2, 16.7 0.2, and 17.7 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 18A.
101031 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 14.1 wt% between about 30 C and about 110 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram has an endotherm onset at about 52 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 90 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 52 C and a second endotherm onset at about 90 C.
In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 18B; and/or b) a DSC profile substantially as shown in FIG. 18B.
101041 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXI.
101051 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 7.2 0.2, 21.7 0.2, and 29.1 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-
- 21 -iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2 0.2, 18.6 + 0.2, 21.7 + 0.2, and 29.1 10.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 19A.
[0106] In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 13.8 wt% between about 26 C and about 135 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 65 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 89 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 102 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 65 C and an endotherm onset at about 89 C. In some aspects, the crystalline form of N-((R)-2,3 -di hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl ami no)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 65 C
and an endotherm onset at about 102 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 89 C and an endotherm onset at about 102 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has a first endotherm onset at about 65 C, a second endotherm onset at about 89 C, and a third endotherm onset at about 102 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 19B; and/or b) a DSC
profile substantially as shown in FIG. 19B.
[0107] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXII.
- 22 -[0108] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 5.4 0.2, 9.7 0.2, and 10.7 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4 0.2, 6.5 0.2, 9.7 0.2, and 10.7 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
20A.
[0109] In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 4.4 wt% between about 27 C and about 137 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 81 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 101 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has a first endotherm onset at about 81 C and a second endotherm onset at about 101 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile substantially as shown in FIG. 20B; and/or b) a DSC profile substantially as shown in FIG. 20B.
101101 In some aspects, the crystalline form of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXIII.
[0111] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 7.2 0.2, 20.6 0.2, and 23.0 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2 0.2, 9.5 0.2, 20.6 0.2, and 23.0 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 21A.
- 23 -[0112] In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 1.2 wt% between about 30 C and about 119 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 104 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 21B; and/or b) a DSC profile substantially as shown in FIG. 21B.
[0113] In some aspects, the crystal form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXIV.
[0114] In some aspects, the present disclosure provides an amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) ' H 7 OH N
I

[0115] In some aspects, the amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern substantially as shown in FIG. 22A.
[0116] In some aspects, the amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile substantially as shown in FIG. 22B; and/or b) a DSC profile substantially as shown in FIG. 22B.
[0117] In some aspects, the XRPD pattern is generated using a PANALYTICAL X'Pert Pro diffractometer using Ni-filtered Cu Ka (45 kV/40 mA) radiation and a step size of 0.03 20 with a X'CELERATOR Real Time Multi-Strip detector, configured (a) on the incidental beam side as follows: variable divergence slits (10 mm irradiated length), 0.04 rad Soller slits, fixed anti-scatter slit (0.50 ), and 10 mm beam mask, and (b) on the diffracted beam side as follows: variable anti-scatter slit (10 mm observed length) and 0.04 rad Soller slit or a BRUKER D8 ADVANCETM system using Cu Ka (40 kV/40
- 24 -mA) radiation and a step size of 0.03 20 with a LYNXEYE detector, configured (a) on the incidental beam side as follows: Goebel mirror, mirror exit slit (0.2 mm), 2.5 Soller slit, beam knife, and (b) on the diffracted beam side as follows: anti-scatter slit (8 mm) and 2.5 Soller slit; wherein samples are mounted flat on zero-background Si wafers. In some aspects, the DSC pattern is generated using a TA Instruments Q100 or differential scanning calorimeter at a rate of temperature increase of about 15 C/min.
Pharmaceutical Composition [0118] In some aspects, the present disclosure is directed to a pharmaceutical composition (e.g., capsule, tablet, powder, granules, minitablets, or pellets) comprising a crystalline form or amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein and one or more pharmaceutically acceptable carriers.
[0119] In some aspects, the pharmaceutical composition is for oral administration. In some aspects, the pharmaceutical composition is a solid dosage form. In some aspects, the pharmaceutical composition is a capsule, tablet (e.g., dispersible tablet or orodispersible tablet), powder (e.g., dispersible powder), granules (e.g., dispersible granules), minitablets (e.g., dispersible minitablets), or pellets (e.g., dispersible pellets). In some aspects, the pharmaceutical composition is a tablet (e.g., dispersible tablet or orodispersible tablet) or a capsule.
101201 In some aspects, the pharmaceutical composition is a capsule. In some aspects, the capsule comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows:
(a) about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
(b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt%
of one or more lubricants; and (e) a gelatin capsule which encapsulates components (a)-(d). In some aspects, the capsule comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more
- 25 -diluents; (c) about 3.5 wt/wt% to about 6 wt/vv-t% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) a gelatin capsule which encapsulates components (a)-(d).
101211 In some aspects, the capsule comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or more lubricants; and (e) a gelatin capsule which encapsulates components (a)-(d). In some aspects, the capsule comprises about 2 mg of NAR)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows:
(a) about 0.25 wt/wt% to about 1.5 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
(b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) a gelatin capsule which encapsulates components (a)-(d).
101221 In some aspects, the capsule comprises about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; and (d) a gelatin capsule which encapsulates components (a)-(c). In some aspects, the capsule comprises about 5 mg of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
and (d) a gelatin capsule which encapsulates components (a)-(c).
- 26 -[0123] In some aspects, the pharmaceutical composition is a tablet. In some aspects, the tablet comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the tablet is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
(b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; and (d) 0 wt/wt% to about 5 wt/wt% of one or more lubricants. In some aspects, the tablet comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the tablet is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; and (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
[0124] In some aspects, the tablet comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the tablet is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; and (d) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
In some aspects, the tablet comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the tablet is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
and (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
[0125] In some aspects, the tablet comprises about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the tablet is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98
- 27 -wt/wt% of one or more diluents; and (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants. In some aspects, the tablet comprises about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the tablet is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; and (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants.
101261 In some aspects, the pharmaceutical composition is for oral administration. In some aspects, the pharmaceutical composition is dispersible orodispersible.
101271 In some aspects, the pharmaceutical composition is a tablet, a powder, granules, minitablets, or pellets (also called beads).
101281 In some aspects, the pharmaceutical composition is a powder. In some aspects, the pharmaceutical composition is a dispersible powder. In some aspects, a capsule or sachet comprises the dispersible powder.
101291 In some aspects, the pharmaceutical composition is in the form of granules. In some aspects, the granules are dispersible granules. In some aspects, a capsule or sachet comprises the dispersible granules.
101301 In some aspects, the pharmaceutical composition is in the form of minitablets. In some aspects, the minitablets are dispersible minitablets. In some aspects, a capsule or sachet comprises the dispersible minitablets.
101311 In some aspects, the pharmaceutical composition is in the form of pellets. In some aspects, the pellets are dispersible pellets. In some aspects, a capsule or sachet comprises the dispersible pellets.
101321 In some aspects, the pharmaceutical composition is a tablet. In some aspects, the tablet is a dispersible tablet. In some aspects, the tablet is an orodispersible tablet.
101331 In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the pharmaceutical composition is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
(b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to
- 28 -about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt%
of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
101341 In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the pharmaceutical composition is as follows: (a) about 0.2 wt/wt% to about 1.5 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
(b) about 75 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 3 wt/wt% to about 8 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
101351 In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.1 mg to about 20 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the pharmaceutical composition is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de;
(b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt%
of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
101361 In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules,
- 29 -dispersible minitablets, or dispersible pellets comprises about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets comprises about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
101371 In some aspects, at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate. In some aspects, at least one of the diluents is microcrystalline cellulose.
101381 In some aspects, at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid. In some aspects, at least one of the disintegrants is croscarmellose sodium.
101391 In some aspects, at least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors including but not limited to, grape flavoring, bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry flavoring. In some aspects, at least one of the flavoring agents is grape flavoring.
101401 In some aspects, at least one of the sweeteners is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame. In some aspects, at least one of the sweeteners is sucralose.
101411 In some aspects, at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc. In some aspects, at least one of the lubricants is magnesium stearate.
- 30 -Methods of Treatment 101421 In some aspects, the present disclosure provides a method of treating a tumor, a cancer, or a Rasopathy disorder comprising administering to a subject in need of such treatment a pharmaceutical composition (e.g., capsule, tablet, powder, granules, minitablets, or pellets) described herein.
101431 In some aspects, the present disclosure provides use of a pharmaceutical composition (e.g., capsule, tablet, powder, granules, minitablets, or pellets) described herein for the manufacture of a medicament for treating a tumor, a cancer, or Rasopathy disorder.
101441 In some aspects, the tumor is a neurofibroma. In some aspects, the tumor is a neurofibroma associated with Neurofibromatosis Type 1. In some aspects, the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, or malignant peripheral nerve sheath tumor. In some aspects, the tumor is plexiform neurofibroma.
101451 In some aspects, the subject has been diagnosed with a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
101461 In some aspects, the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum. In some aspects, the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia. In some aspects, the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia. In some aspects, the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-
- 31 -small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.
101471 In some aspects, the subject bears a mutation or other aberration in one or more genes for which the mutation or other aberration causes a gain or loss of function characteristic of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
101481 In some aspects, an individual dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as more than one capsule, more than one tablet (e.g., dispersible tablet), more than one dose of powder (e.g., dispersible powder), more than one dose of granules (e.g., dispersible granules), more than one dose of minitablets (e.g., dispersible minitablets), more than one dose of pellets (e.g., dispersible pellets), or a combination thereof.
101491 In some aspects, the pharmaceutical composition is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets, wherein the pharmaceutical composition is dispersed in a potable liquid prior to administration to the subject. For example, a dose of 3 mg of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide can be administered as two dispersible tablets ¨ one containing 2 mg and the other containing 1 mg or as three dispersible tablets each containing 1 mg. As another example, a dose of 1.5 mg of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide can be administered as two dispersible dosage forms ¨ one dispersible tablet containing 1 mg and a separate unit of dispersible powder containing 0.5 mg or as three units of dispersible powder each containing 0.5 mg.
101501 In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 20 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed mg. In some aspects, the NAR)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 6 mg.
In some aspects, the N-((R)-2,3-di hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-
- 32 -phenylamino)-benzamide is administered in a total daily dose that does not exceed 2 mg.
In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 1 mg.
101511 In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 0.1 mg to about 20 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 0.5 mg. In some aspects, the total daily dose of the N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 1 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 2 mg. In some aspects, the total daily dose of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 4 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 6 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is about 8 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered about 20 mg.
101521 In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is administered two times daily.
101531 In some aspects, the total daily dose of the N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.1 mg to about 10 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.5 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 1 mg each. In some aspects, the total daily dose of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 2 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 3 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 4 mg each. In some aspects, the total daily
- 33 -dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 10 mg each.
101541 In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.1 mg to about 20 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.5 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 1 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 2 mg. In some aspects, the total daily dose of the N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 4 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 8 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is administered once daily at a dose of about 10 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 20 mg.
101551 In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 20 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg. In some aspects, the N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 6 mg.
In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 4 mg.
In some aspects, the N-((R)-2,3-di hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-
- 34 -phenylamino)-benzamide is administered in a total daily dose that does not exceed 2 mg.
In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 1 mg.
[0156] In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 days in which the total daily dose is administered; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 consecutive days in which the total daily dose is administered;
followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
[0157] In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 days in which the total daily dose is administered and (ii) 2 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 consecutive days in which the total daily dose is administered and (ii) 2 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
[0158] In some aspects, the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.
[0159] In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising 28 days in which the total daily dose is administered.
[0160] In some aspects, the subject experiences dysphagia. In some aspects, the subject experiences dysphagia caused by one or more of: disease of the nervous system, muscle
- 35 -weakening, developmental disability, stroke, injury, anatomical defect, cancer, treatment for cancer, allergic reaction, dementia, memory loss, or cognitive decline.
101611 In some aspects, the subject is a pediatric subject.
Methods of Preparing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and Essentially Pure Form IV
101621 Novel methods of producing NAR)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) HO
H
OH
(0, that comprise reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent that is 1-propylphosphonic anhydride ("T3P to obtain 901 Acetonide, as shown in Scheme I below are disclosed herein.
Scheme 1 __\\_cr cy /
__r..NH 0 0õ)0.NH2 + 110 T3P
NI

(IPGA) MW 147.17 PD-0315209 (FIPFA) MW 393.10 901 Acetonide MW 522.26 101631 In some aspects, the T3P is in solution. In some aspects, T3P is provided as a solution in ethyl acetate.
101641 In some aspects, the method of producing essentially pure Form IV N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) comprises (a) reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent that is T3P to obtain 901 Acetonide; and (b) treating 901 Acetonide with acid to form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, as shown in Scheme II below.
- 36 -Scheme II
+ HO 0 F H
H
00, -(5 N
NH2 0 1.1 F I
(IPGA) PD-0315209 F
MW 147.17 (FIPFA) MW 393.10 901 Acetonide MW 522.26 _ _ "acid'' H H
HOO-N 0 ,---......--., ,N

H F HO . 0 F
H
OH N
0 0 -...- OH N so --, _____ F I F I
F F
Mirdametinib (PD-0325901) Crude PD-0325901 M
MW 482.20 W 482.20 101651 In some aspects, the synthesis for essentially pure crystalline Form IV of N-((R)-2,3-dihy droxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) comprises the reaction set forth according to Scheme III.
- 37 -Scheme III

F H
*0 H
N T3P , , _ F
F I
ON.)-0,,NH2 + 110 0 (50% in Et0Ac) .---6 H
N
i-Pr2NEt la 101 ._ PD-0337792 F THF, toluene F I
(IPGA) PD-0315209 MTBE, aq. NaOH F
MW 147.17 (FIPFA) 901 Acetonide MW 393.10 MW 522.26 aq. HCI
toluene, ACN
H H

HOO' H

H F F Et0H
-OH N
1401 0 . F I Et0H OH N ________ .
water I* 110 F I
F F
Mirdametinib Crude PD-0325901 (PD-0325901) MW 482.20 MW 482.20 101661 In some aspects, the synthesis for essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) is as shown below in Scheme IV.

n >
o u, r., o ,i u, , u, 9, 4, Scheme IV
Step 1 0 N

N
tj !A

!A
-o, xxO MW 163.13 ______________________________________________________________ 0o . i)---0 J, , N)-- 0 C
\0H
0.

_ MW: 132.16 MW: 264.22 MW: 277.28 MW: 147.17 (S)-Glycerol Acetonide PF-03714421 PD-0333760 P0-( IPGAP ) ( IPGA ) Step 2 .

L.) ,6 F + so F N
oo _____________________________________________________________ ,... 40 40 .
F F
I
F I F
MW: 176.09 MW: 237.02 MW:
393.10 0315209 Step 3 , ( FIPFA ) Step 4 ¨
H H
H

H F /-..õõ,,..N 0 F t 0. i u n OH N
40 10 ..,_ OH N
I-7, cp N
= 40 4 /..'.-C) AI N la F I F I
igr F lir I
ts.) F F
F
O' MW: 482.20 MW: 482.20 MW: 522.26 oo Crude P0-0325901 w x ( Mirdametinib ) ( 901 Acetonide ) [0167] In some aspects, the methods provided herein provide a crystalline composition that is essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide that contains < 0.2% of dimeric impurity PF-F
HN

Exact Mass: 856.93 101681 In some aspects, the crystalline composition contains about 0.05% to about 0.19%
by weight of dimeric impurity PF-00191189. In some aspects, the crystalline composition contains no detectable amount of dimeric impurity PF-00191189.
Definitions 101691 To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.
101701 Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
101711 In this specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise.
The terms "a"
(or "an"), as well as the terms "one or more," and "at least one" can be used interchangeably herein. In certain aspects, the term "a" or "an" means "single." In other aspects, the term "a" or "an" includes "two or more" or "multiple."
101721 Furthermore, "and/or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other.
Thus, the term "and/or" as used in a phrase such as "A and/or B" herein is intended to include "A and B,"

"A or B," "A" (alone), and "B" (alone). Likewise, the term "and/or" as used in a phrase such as "A, B, and/or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A
(alone); B
(alone); and C (alone).
101731 The terms "mirdametinib" and "PD-0325901" refer to the single enantiomer N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
101741 The term "subject" refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject"
and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
101751 The term "pediatric" refers to a human subject under the age of 21 years at the time of treatment. The term "pediatric" can be further divided into various subpopulations including- neonates (from birth through the first 28 days of life); infants (29 days of age to less than two years of age); children (two years of age to less than 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). See, e.g., Berhman R E, Kliegman R, Arvin A M, Nelson W E.
Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996;
Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery M
D, First L R. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.
Younger pediatric patients in particular, such as neonates, infants and young children, can have difficulty swallowing whole capsules or tablets.
101761 The term "dispersible" as used herein refers to a composition (e.g., a tablet, powder, granules, minitablets, or pellets (also known as "beads") which disintegrates and/or dissolves when combined with water or another potable liquid (e.g., a non-water beverage), or a subject's own saliva when placed in the subject's mouth, with or without the addition of agitation or temperature modification. In some aspects, the dispersible composition disintegrates or dissolves within 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute after being combined with water or another potable liquid. Such disintegration or dissolution need not be complete. For example, a dispersible tablet may dissolve almost entirely, but some undissolved particulate matter may remain.
101771 The term "orodispersible- refers to a composition which is capable of dissolving or disintegrating in a subject's mouth (i.e., dissolving or disintegrating in a subject's saliva) if administered orally, without a requirement of first dissolving or disintegrating in a separate container.
101781 As used herein, the terms "treat," "treated," and "treating"
mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or obtain beneficial or desired clinical results. Thus, those in need of treatment include those already diagnosed with or suspected of having the disorder. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of a condition, disorder, or disease; stabilized (i.e., not worsening) state of condition, disorder, or disease; delay in onset or slowing of condition, disorder, or disease progression; amelioration of the condition, disorder, or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient, or enhancement or improvement of condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects.
Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. The term "therapeutically effective amount" is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of a disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
[0179] In certain aspects, a subject is successfully "treated" for a tumor, according to the methods described herein if the patient shows one or more of the following: a reduction in the size of the tumor; relief of one or more symptoms associated with the specific tumor;
a reduction in the volume of the tumor; improvement in quality of life;
increased progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), a decrease in progressive disease (PD), an increased time to progression (TTP), or any combination thereof. In some aspects, nationally or internationally accepted standards of treatment outcomes in a given tumor can be used to determine whether an effective amount of mirdametinib meets any of these particular endpoints (e.g., CR, PFS, PR).

101801 In certain aspects, a subject is successfully "treated" for cancer, e.g., lung cancer or ovarian cancer, according to the methods disclosed herein if the patient shows one or more of the following: a reduction in the number of or complete absence of cancer cells;
relief of one or more symptoms associated with the specific cancer; reduced morbidity and mortality; improvement in quality of life; increased progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (1\SFS), complete response (CR), minimal residual disease (MRD), partial response (PR), stable disease (SD), a decrease in progressive disease (PD), an increased time to progression (TTP), or any combination thereof In some aspects, nationally or internationally accepted standards of treatment outcomes in a given cancer can be used to determine whether an effective amount of mirdametinib meets any of these particular endpoints (e.g., CR, PFS, PR).
101811 The terms "pharmaceutically acceptable carrier,"
"pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient"
refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid excipient, solvent, or encapsulating material. In one aspect, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See Remington: The Science and Practice of Pharmacy, 21' Edition, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, (incorporated herein by reference). Excipients can include, for example:
antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, calcium sulfate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.
101821 The term "pharmaceutical composition," as used herein, represents a composition containing a compound described herein formulated with one or more pharmaceutically acceptable excipients (carriers), and can be manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet (e.g., dispersible tablet), powder (e g , dispersible powder) capsule, granules, minitablets, pellets, caplet, gelcap, or syrup) 101831 The terms "about" or "approximately" means within a range of an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In some aspects, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In some aspects, the term "about" or "approximately" means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length.
101841 As used herein, the term "administration" refers to the administration of a composition (e.g., a compound or a preparation that includes a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) can be by any appropriate route, such as one described herein.
101851 The term "solvate" refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
Where the solvent includes ethanol, the compound can be an ethanol solvate.
101861 The term "crystalline," as used herein, refers to a solid-state form which consists of orderly arrangement of structural units. Different crystalline forms of the same compound, or a salt, hydrate, or solvate thereof, arise from different packing of the molecules in the solid-state, which results in different crystal symmetries and/or unit cell parameter. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. See, e.g., Remington'.s' Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA, 173 (1990); lhe United States Pharmacopeia, 23rd ed., 1843-1844 (1995) (incorporated herein by reference).
101871 Crystalline forms are commonly characterized by X-ray powder diffraction (XRPD). An XRF'D pattern of reflections (peaks, typically expressed in degrees 2-theta) is commonly considered a fingerprint of a particular crystalline form. The relative intensities of the XRPD peaks can widely vary depending on, inter alia, the sample preparation technique, crystal size distribution, filters, the sample mounting procedure, and the particular instrument employed. In some instances, new peaks may be observed or existing peaks may disappear, depending on the type of instrument or the settings. In some instances, any particular peak in an XRPD pattern may appear as a singlet, doublet, triplet, quartet, or multiplet, depending on the type of instrument or the settings, the sensitivity of the instrument, measuring conditions, and/or purity of the crystalline form.
In some instances, any particular peak in an XRPD may appear in a symmetric shape or in an asymmetric shape, e.g., having a shoulder. Moreover, instrument variation and other factors can affect the 2-theta values. A skilled artisan understanding these variations is capable of discriminating or ascertaining the defining features or characteristics of a particular crystal form using XRPD, as well as using other known physicochemical techniques.
101881 The term "anhydrate" as applied to a compound refers to a crystalline form wherein the compound contains no structural water within the crystal lattice.
101891 As used herein, the term "essentially pure" with respect to Form IV means that the composition comprising Form IV contains no detectable amount of another polymorphic form (e.g., Form I or Form II), as determined by observing no detectable differences in an XRPD and/or DSC pattern between a single Form IV crystal and the crystalline composition of N4(R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. However, "essentially pure" Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de can include impurities, such as, but not limited to, synthetic reactants or by-products generated during the chemical synthesis.
101901 As used herein, the term "aberration- as applied to a gene refers to a mutation, chromosomal loss or fusion, epigenetic chemical modification, or other event which alters the sequence, level of expression, or processed mRNA sequence associated with a gene relative to the sequence, level of expression, or processed mRNA sequence associated with the wild-type gene.
101911 It is understood that wherever aspects are described herein with the language "comprising," otherwise analogous aspects described in terms of "consisting of' and/or "consisting essentially of" are also provided.
101921 The details of one or more aspects are set forth in the description below. Other features, objects, and advantages will be apparent from the description and from the claims.
DETAILED DESCRIPTION OF THE INVENTION
101931 Novel crystalline forms and amorphous solids of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide are described herein.
Pharmaceutical compositions (e.g., capsules, tablets, dispersible and non-dispersible dosage forms) and methods to treat a patient in need of therapeutic administration of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide are also described herein. Additionally, a novel method of producing a pure composition of crystalline Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is described herein.
Crystalline Forms and Amorphous Solids 101941 The present disclosure relates in part to novel crystalline forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. As with all pharmaceutical compounds and compositions, the chemical and physical properties of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide are important in its commercial development. These properties include, but are not limited to: (1) packing properties such as molar volume, bulk density and hygroscopicity, (2) thermodynamic properties such as melting temperature, vapor pressure and solubility, (3) kinetic properties such as dissolution rate and stability (including stability at ambient conditions, especially to moisture and under storage conditions), (4) surface properties such as surface area, wettability, interfacial tension and shape, (5) mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend;
and (6) filtration properties. These properties can affect, for example, the processing and storage of the compound and pharmaceutical compositions comprising the compound.

[0195] In some aspects, the present disclosure provides a crystalline form of N-((R)-2,3-dihy droxypropoxy)-3 ,4-difluoro-2-(2-fluoro-44 odo-phenylamino)-b enzami de of Formula (I) HOONO H r OH
selected from the group consisting of:
a) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.4 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta;
b) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.9 0.2, 7.2 0.2, and 21.2 0.2 degrees two theta;
c) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.3 + 0.2, 10.6 + 0.2, and 16.1 + 0.2 degrees two theta;
d) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.4 0.2, 10.7 0.2, and 18.7 0.2 degrees two theta;
e) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 6.7 0.2, 13.5 0.2, and 22,2 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 10.6 0.2, 19.6 0.2, and 24.8 0.2 degrees two theta;
g) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.5 0.2, 6.9 0.2, and 10.1 0.2 degrees two theta;
h) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 10.1 0.2, 17.3 0.2, and 22.6 0.2 degrees two theta;

i) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 4.6 0.2, 5.1 0.2, and 14.6 0.2 degrees two theta;
j) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 4.6 0.2, 23.4 0.2, and 25.2 0.2 degrees two theta;
k) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.5 0.2, 14.7 0.2, and 20.9 0.2 degrees two theta;
1) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 6.0 0.2, 17.1 0.2, and 20.6 0.2 degrees two theta;
m) a crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.9 0.2, 10.1 0.2, and 15.5 0.2 degrees two theta;
n) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 4.6 0.2, 10.7 0.2, and 15.9 0.2 degrees two theta;
o) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 10.2 0.2, 11.6 0.2, and 20.0 0.2 degrees two theta;
P) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 7.8 0.2, 14.0 0.2, and 17.1 0.2 degrees two theta;
cl) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.5 0.2, 8.2 0.2, and 16.7 0.2 degrees two theta;
r) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 7.2 0.2, 21.7 0.2, and 29.1 0.2 degrees two theta;
s) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.4 0.2, 9.7 0.2, and 10.7 0.2 degrees two theta; and t) a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 7.2 0.2, 20.6 0.2, and 23.0 0.2 degrees two theta.
101961 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks 5.4 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta.
In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks 5.4 +
0.2, 12.5 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 2A.
101971 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.7 wt% between about 35 C and about 100 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 77 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 95 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 77 C and a second endotherm onset at about 95 C.
In some aspects, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile substantially as shown in FIG. 2B; and/or b) a DSC profile substantially as shown in FIG. 2B.
101981 In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form V.
101991 In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD
pattern having peaks at 5.9 0.2, 7.2 0.2, and 21.2 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.9 0.2, 7.2 0.2, 9.3 0.2, and 21.2 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
3A.
102001 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.4 wt% between about 25 C and about 125 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 41 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 70 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 109 C. In some aspects, the crystalline form of N-((R)-2,3 -di hydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-4-i odo-phenyl am i no)-benzami de exhibits a DSC thermogram that has an endotherm onset at about 41 C and an endotherm onset at about 70 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 41 C and an endotherm onset at about 109 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has an endotherm onset at about 70 C and an endotherm onset at about 109 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 41 C, a second endotherm onset at about 70 C, and a third endotherm onset at about 109 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 3B; and/or b) a DSC
profile substantially as shown in FIG. 3B.
102011 In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VI.
102021 In some aspects, the crystalline form of N-((R)-2,3-dihy droxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern haying peaks at 5.3 0.2, 10.6 0.2, and 16.1 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern haying peaks at 5.3 0.2, 10.6 0.2, 13.9 0.2, and 16.1 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 4A.
102031 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 5.2 wt% between about 40 C and about 120 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 85 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endothermic event at about 110 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has a first endotherm onset at about 85 C and a second endothermic event at about 110 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile substantially as shown in FIG. 4B; and/or b) a DSC profile substantially as shown in FIG. 4B.
102041 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VII.
102051 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 5.4 1 0.2, 10.7 1 0.2, and 18.7 1 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4 0.2, 10.7 0.2, 18.7 0.2, and 23.9 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 5A.
102061 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 3.3 wt% between about 40 C and about 112 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 81 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 110 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has a first endotherm onset at about 81 C and a second endotherm onset at about 110 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile substantially as shown in FIG. 5B; and/or b) a DSC profile substantially as shown in FIG.
5B.
102071 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VIII.
102081 In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 6.7 0.2, 13.5 0.2, and 22.2 0.2 degrees two theta. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 6.7 0.2, 8.0 0.2, 13.5 0.2, and 22.2 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 6A.
102091 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 4.6 wt% between about 28 C and about 128 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 84 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 107 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de exhibits a DSC
thermogram that has an endotherm onset at about 114 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 84 C and an endotherm onset at about 107 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 84 C and an endotherm onset at about 114 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has an endotherm onset at about 107 C and an endotherm onset at about 114 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 84 C, a second endotherm onset at about 107 C, and a third endotherm onset at about 114 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 6B; and/or b) a DSC
profile substantially as shown in FIG. 6B.
102101 In some aspects, the crystalline form of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is Form IX
102111 In some aspects, the crystalline form of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 10.6 0.2, 19.6 0.2, and 24.8 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern haying peaks at 5.5 0.2, 10.6 0.2, 19.6 0.2, and 24.8 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 7A.
102121 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.9 wt% between about 40 C and about 115 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de exhibits a DSC thermogram that has an endotherm onset at about 89 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 7B; and/or b) a DSC profile substantially as shown in FIG. 7B.
102131 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form X.
102141 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 5.5 0.2, 6.9 0.2, and 10.1 0.2 degrees two theta. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 6.9 0.2, 10.1 0.2, and 19.2 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 8A.
[0215] In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 7.6 wt% between about 40 C and about 175 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 69 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 104 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has a first endotherm onset at about 69 C and a second endotherm onset at about 104 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile substantially as shown in FIG. 8B; and/or b) a DSC profile substantially as shown in FIG.
8B.
[0216] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XI.
[0217] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 10.1 0.2, 17.3 0.2, and 22.6 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.1 0.2, 17.3 0.2, 21.5 0.2, and 22.6 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 9A.
[0218] In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 8.5 wt% between about 40 C and about 160 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 72 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 109 C. In some aspects, the crystalline form of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has a first endotherm onset at about 72 C and a second endotherm onset at about 109 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile substantially as shown in FIG. 9B; and/or b) a DSC profile substantially as shown in FIG.
9B.
102191 In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XII.
102201 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 4.6 0.2, 5.1 0.2, and 14.6 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern haying peaks at 4.6 0.2, 5.1 0.2, 6.4 0.2, and 14.6 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
10A.
102211 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 3.1 wt% between about 20 C and about 100 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de exhibits a DSC thermogram that has an endotherm onset at about 55 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 109 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has a first endotherm onset at about 55 C and a second endotherm onset at about 109 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile substantially as shown in FIG. 10B; and/or b) a DSC profile substantially as shown in FIG. 10B.
102221 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIII.
[0223] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 4.6 0.2, 23.4 0.2, and 25.2 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 0.2, 23.4 0.2, 25.2 0.2, and 30.6 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in 11A.
[0224] In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 0.15 wt% between about 40 C and about 150 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 111 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 11B; and/or b) a DSC profile substantially as shown in FIG. 11B.
[0225] In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIV.
[0226] In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 5.5 0.2, 14.7 0.2, and 20.9 0.2 degrees two theta. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 14.7 0.2, 20.9 0.2, and 26.6 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 12A.
[0227] In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 3.8 wt% between about 40 C and about 150 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 104 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 12B; and/or b) a DSC profile substantially as shown in FIG. 12B.
102281 In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XV.
102291 In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 6.0 + 0.2, 17.1 + 0.2, and 20.6 + 0.2 degrees two theta. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 6U
0.2, 12.8 0.2, 17.1 0.2, and 20.6 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 13A.
102301 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.1 wt% between about 40 C and about 150 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 74 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 102 C. In some aspects, the crystalline form of NAR)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has an endotherm onset at about 114 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 74 C and an endotherm onset at about 102 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 74 C and an endotherm onset at about 114 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has an endotherm onset at about 102 C and an endotherm onset at about 114 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 74 C, a second endotherm onset at about 102 C, and a third endotherm onset at about 114 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 13B; and/or b) a DSC
profile substantially as shown in FIG. 13B.
102311 In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVI.
102321 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 19 02, 10 1 02, and 115 01 degrees two theta In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern haying peaks at 5.9 0.2, 10.1 0.2, 11.7 0.2, and 15.5 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 14A.
102331 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.7 wt% between about 40 C and about 100 C. In some aspects, crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 89 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 14B; and/or b) a DSC profile substantially as shown in FIG. 14B.
102341 In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVII.
102351 In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern haying peaks at 4.6 0.2, 10.7 0.2, and 15.9 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern haying peaks at 4.6 0.2, 10.7 0.2, 15.9 0.2, and 19.6 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 15A.
[0236] In some aspects, the TGA exhibits that the crystalline form of NAR)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 1.6 wt% between about 30 C and about 150 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 83 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 15B; and/or b) a DSC profile substantially as shown in FIG. 15B.
[0237] In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVIII.
[0238] In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 10.2 0.2, 11.6 0.2, and 20.0 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.2 0.2, 11.6 0.2, 17.1 0.2, and 20.0 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 16A.
[0239] In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 1.85 wt% between about 23 C and about 92 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 69 C. In some aspects, the crystalline form of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 98 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 115 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 69 C and an endotherm onset at about 98 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 69 C and an endotherm onset at about 115 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has an endotherm onset at about 98 C and an endotherm onset at about 115 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 69 C, a second endotherm onset at about 98 C, and a third endotherm onset at about 115 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG 16B; and/or b) a DSC
profile substantially as shown in FIG. 16B.
102401 In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIX.
102411 In some aspects, the crystalline form of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 7.8 0.2, 14.0 0.2, and 17.1 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.8 0.2, 14.0 0.2, 15.6 0.2, and 17.1 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 17A.
102421 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.6 wt% between about 29 C and about 126 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de exhibits a DSC thermogram that has an endotherm onset at about 77 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 92 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 110 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 77 C and an endotherm onset at about 92 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 77 C and an endotherm onset at about 110 C. In some aspects, the crystalline form of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has an endotherm onset at about 92 C and an endotherm onset at about 110 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 77 C, a second endotherm onset at about 92 C, and a third endotherm onset at about 110 C In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 17B, and/or b) a DSC
profile substantially as shown in FIG. 17B.
102431 In some aspects, the crystalline form of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XX.
102441 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 5.5 0.2, 8.2 0.2, and 16.7 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 +
0.2, 8.2 + 0.2, 16.7 + 0.2, and 17.7 + 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 18A.
102451 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de loses about 14.1 wt% between about 30 C and about 110 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram has an endotherm onset at about 52 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 90 C. In some aspects, the crystalline form of NAR)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 52 C and a second endotherm onset at about 90 C.
In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 18B; and/or b) a DSC profile substantially as shown in FIG. 18B.
102461 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXI.
102471 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 7.2 0.2, 21.7 0.2, and 29.1 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2 0.2, 18.6 0.2, 21.7 0.2, and 29.1 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 19A.
102481 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 13.8 wt% between about 26 C and about 135 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 65 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 89 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 102 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de exhibits a DSC thermogram that has an endotherm onset at about 65 C and an endotherm onset at about 89 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 65 C and an endotherm onset at about 102 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has an endotherm onset at about 89 C and an endotherm onset at about 102 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 65 C, a second endotherm onset at about 89 C, and a third endotherm onset at about 102 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 19B; and/or b) a DSC
profile substantially as shown in FIG. 19B.
102491 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXII.
102501 In some aspects, the crystalline form of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 5.4 0.2, 9.7 0.2, and 10.7 0.2 degrees two theta. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4 0.2, 6.5 0.2, 9.7 0.2, and 10.7 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
20A.
102511 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 4.4 wt% between about 27 C and about 137 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 81 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 101 C. In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC
thermogram that has a first endotherm onset at about 81 C and a second endotherm onset at about 101 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile substantially as shown in FIG. 20B; and/or b) a DSC profile substantially as shown in FIG. 20B.

102521 In some aspects, the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXIII.
102531 In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern having peaks at 7.2 0.2, 20.6 0.2, and 23.0 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2 0.2, 9.5 + 0.2, 20.6 + 0.2, and 23.0 + 0.2 degrees two theta. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 21A.
102541 In some aspects, the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de loses about 1.2 wt% between about 30 C and about 119 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 104 C. In some aspects, the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA profile substantially as shown in FIG. 21B; and/or b) a DSC profile substantially as shown in FIG. 21B.
102551 In some aspects, the crystal form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXIV.
102561 In some aspects, the present disclosure provides an amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) HOONO , OH N
= F
(I).
102571 In some aspects, the amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD

pattern substantially as shown in FIG. 22A.

102581 In some aspects, the amorphous form of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by: a) a TGA
profile substantially as shown in FIG. 22B; and/or b) a DSC profile substantially as shown in FIG. 22B.
102591 In some aspects, the XRPD pattern is generated using a PANALYTICAI?) X'Pert Pro diffractometer using Ni-filtered Cu Ka (45 kV/40 mA) radiation and a step size of 0.03 20 with a X'CELERATOR Real Time Multi-Strip detector, configured (a) on the incidental beam side as follows: variable divergence slits (10 mm irradiated length), 0.04 rad Soller slits, fixed anti-scatter slit (0.50 ), and 10 mm beam mask, and (b) on the diffracted beam side as follows: variable anti-scatter slit (10 mm observed length) and 0.04 rad Soller slit or a BRUKER D8 ADVANCETM system using Cu Ka (40 kV/40 mA) radiation and a step size of 0.03 20 with a LYNX:EYE detector, configured (a) on the incidental beam side as follows- Goebel mirror, mirror exit slit (0.2 mm), 2.5 Soller slit, beam knife, and (b) on the diffracted beam side as follows: anti-scatter slit (8 mm) and 2.5 Soller slit; wherein samples are mounted flat on zero-background Si wafers. In some aspects, the DSC pattern is generated using a TA Instruments Q100 or differential scanning calorimeter at a rate of temperature increase of about 15 C/min.
Pharmaceutical Compositions 102601 In some aspects, the present disclosure provides a pharmaceutical composition comprising a crystalline form or amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein and one or more pharmaceutically acceptable carriers.
102611 In some aspects, the desired crystalline form or amorphous solid comprises less than 10% by weight total of one or more other crystalline forms and/or amorphous solid.
In some aspects, the desired crystalline form or amorphous solid comprises less than 9%
by weight total of one or more other crystalline forms and/or amorphous solid.
In some aspects, the desired crystalline form or amorphous solid comprises less than 8% by weight total of one or more other crystalline forms and/or amorphous solid. In some aspects, the desired crystalline form or amorphous solid comprises less than 7% by weight total of one or more other crystalline forms and/or amorphous solid. In some aspects, the desired crystalline form or amorphous solid comprises less than 6% by weight total of one or more other crystalline forms and/or amorphous solid. In some aspects, the desired crystalline form or amorphous solid comprises less than 5% by weight total of one or more other crystalline forms and/or amorphous solid. In some aspects, the desired crystalline form or amorphous solid comprises less than 4% by weight total of one or more other crystalline forms and/or amorphous solid. In some aspects, the desired crystalline form or amorphous solid comprises less than 3% by weight total of one or more other crystalline forms and/or amorphous solid. In some aspects, the desired crystalline form or amorphous solid comprises less than 2% by weight total of one or more other crystalline forms and/or amorphous solid. In some aspects, the desired crystalline form or amorphous solid comprises less than 1% by weight total of one or more other crystalline forms and/or amorphous solid. In some aspects, the desired crystalline form or amorphous solid comprises less than 0.5% by weight total of one or more other crystalline forms and/or amorphous solid. In some aspects, the desired crystalline form or amorphous solid comprises less than 0.4% by weight total of one or more other crystalline forms and/or amorphous solid In some aspects, the desired crystalline form or amorphous form is essentially pure of other crystalline forms and/or amorphous solid.
102621 In some aspects, the pharmaceutical composition is for oral administration. In some aspects, the pharmaceutical composition is a solid dosage form. In some aspects, the pharmaceutical composition is a capsule, tablet (e.g., dispersible tablet), powder (e.g., dispersible powder), granules (e.g., dispersible granules), minitablets (e.g., dispersible minitablets), or pellets (e.g., dispersible pellets). In some aspects, the pharmaceutical composition (e.g., a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets) further comprises one or more pharmaceutically acceptable carriers. In some aspects, the pharmaceutical composition is for oral administration. In some aspects, the pharmaceutical composition is orodispersible.
102631 In some aspects, the potable liquid is water, milk or a juice (e.g., orange juice or apple juice). In some aspects, the potable liquid is water. In some aspects, the potable liquid is a juice.
102641 In some aspects, the pharmaceutical composition is a tablet, a powder, granules, minitablets, or pellets.
102651 In some aspects, the pharmaceutical composition is a powder. In some aspects, the powder is a dispersible powder. In some aspects, a capsule or sachet comprises the dispersible powder.

102661 In some aspects, the pharmaceutical composition is in the form of granules. In some aspects, the granules are dispersible granules. In some aspects, a capsule or sachet comprises the dispersible granules.
102671 In some aspects, the pharmaceutical composition is in the form of minitablets. In some aspects, the minitablets are dispersible minitablets. In some aspects, a capsule or sachet comprises the dispersible minitablets.
102681 In some aspects, the pharmaceutical composition is in the form of pellets. In some aspects, the pellets are dispersible pellets. In some aspects, a capsule or sachet comprises the dispersible pellets.
102691 In some aspects, the pharmaceutical composition is a tablet. In some aspects, the tablet is a dispersible tablet. In some aspects, the dispersible tablet is an orodispersible tablet.
102701 In some aspects, the pharmaceutical composition comprises about 0 1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 0.5 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 1 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 2 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 3 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de. In some aspects, the pharmaceutical composition comprises about 4 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 5 mg of the crystalline composition of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.

[0271] In some aspects, the pharmaceutical composition comprises about 0.1 wt/wt% to about 7 wt/wt% of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 0.1 wt/wt% to about 5 wt/wt%
of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2 wt/wt%, about 2.1 wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5 wt/wt%, about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about wt/wt%, about 3.1 wt/wt%, about 3.2 wt/wt%, about 3.3 wt/wt%, about 3.4 wt/wt%, about 3.5 wt/wt%, about 3.6 wt/wt%, about 3.7 wt/wt%, about 3.8 wt/wt%, about 3.9 wt/wt%, about 4 wt/wt%, about 4.1 wt/wt%, about 4.2 wt/wt%, about 4.3 wt/wt%, about 4.4 wt/wt%, about 4.5 wt/wt%, about 4.6 wt/wt%, about 4.7 wt/wt%, about 4.8 wt/wt%, about 4.9 wt/wt%, about 5 wt/wt%, about 5.1 wt/wt%, about 5.2 wt/wt%, about 5.3 wt/wt%, about 5.4 wt/wt%, about 5.5 wt/wt%, about 5.6 wt/wt%, about 5.7 wt/wt%, about 5.8 wt/wt%, about 5.9 wt/wt%, about 6 wt/wt%, about 6.1 wt/wt%, about 6.2 wt/wt%, about 6.3 wt/wt%, about 6.4 wt/wt%, about 6.5 wt/wt%, about 6.6 wt/wt%, about 6.7 wt/wt%, about 6.8 wt/wt%, about 6.9 wt/wt%, or about 7 wt/wt% of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 0.5 wt/wt% of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl ami no)-benzami de. In some aspects, the pharmaceutical composition comprises about 0.8 wt/wt% of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de.
102721 In some aspects, the pharmaceutical composition comprises one or more diluents.
In some aspects, the pharmaceutical composition comprises about 50 wt/wt% to about 98 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition comprises about 70 wt/wt% to about 98 wt/wt% of one or more diluent. In some aspects, the pharmaceutical composition comprises about 85 wt/wt% to about 95 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition comprises about 50 wt/wt%, about 51 wt/wt%, about 52 wt/wt%, about 53 wt/wt%, about 54 wt/wt%, about 55 wt/wt%, about 56 wt/wt%, about 57 wt/wt%, about 58 wt/wt%, about 59 wt/wt%, about 60 wt/wt%, about 61 wt/wt%, about 62 wt/wt%, about 63 wt/wt%, about 64 wt/wt%, about 65 wt/wt%, about 66 wt/wt%, about 67 wt/wt%, about 68 wt/wt%, about 69 wt/wt%, about 70 wt/wt%, about 71 wt/wt%, about 72 wt/wt%, about 73 wt/wt%, about 74 wt/wt%, about 75 wt/wt%, about 76 wt/wt%, about 77 wt/wt%, about 78 wt/wt%, about 79 wt/wt%, about 80 wt/wt%, about 81 wt/wt%, about 82 wt/wt%, about 83 wt/wt%, about 84 wt/wt%, about 85 wt/wt%, about 86 wt/wt%, about 87 wt/wt%, about 88 wt/wt%, about 89 wt/wt%, about 90 wt/wt%, about 91 wt/wt%, about 92 wt/wt%, about 93 wt/wt%, about 94 wt/wt%, about 95 wt/wt%, about 96 wt/wt%, about 97 wt/wt%, or about 98 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition comprises about 90 wt/wt% of one or more diluents In some aspects, the pharmaceutical composition comprises about 93 wt/wt% of one or more diluents.
102731 In some aspects, at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate. In some aspects, at least one of the diluents is microcrystalline cellulose.
102741 In some aspects, the pharmaceutical composition comprises about 50 wt/wt% to about 98 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 70 wt/wt% to about 95 wt/wt% microcrystalline cellulose.
In some aspects, the pharmaceutical composition comprises about 85 wt/wt % to about 95 wt/wt % microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 50 wt/wt%, about 51 wt/wt%, about 52 wt/wt%, about 53 wt/wt%, about 54 wt/wt%, about 55 wt/wt%, about 56 wt/wt%, about 57 wt/wt%, about 58 wt/wt%, about 59 wt/wt%, about 60 wt/wt%, about 61 wt/wt%, about 62 wt/wt%, about 63 wt/wt%, about 64 wt/wt%, about 65 wt/wt%, about 66 wt/wt%, about 67 wt/wt%, about 68 wt/wt%, about 69 wt/wt%, about 70 wt/wt %, about 71 wt/wt %, about 72 wt/wt %, about 73 wt/wt %, about 74 wt/wt %, about 75 wt/wt %, about 76 wt/wt %, about wt/wt %, about 78 wt/wt %, about 79 wt/wt %, about 80 wt/wt %, about 81 wt/wt %, about 82 wt/wt %, about 83 wt/wt %, about 84 wt/wt %, about 85 wt/wt %, about wt/wt %, about 87 wt/wt %, about 88 wt/wt %, about 89 wt/wt %, about 90 wt/wt %, about 91 wt/wt%, about 92 wt/wt%, about 93 wt/wt%, about 94 wt/wt%, about 95 wt/wt %, about 96 wt/wt%, about 97 wt/wt%, or about 98 wt/wt % microcrystalline cellulose.
In some aspects, the pharmaceutical composition comprises about 90 wt/wt%
microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 93 wt/wt% microcrystalline cellulose.
102751 In some aspects, the pharmaceutical composition comprises about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants. In some aspects, the pharmaceutical composition comprises about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants.
In some aspects, the pharmaceutical composition comprises about 1.0 wt/wt%, about LI
wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2.0 wt/wt%, about 2.1 wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5 wt/wt%, about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about 3.0 wt/wt%, about 11 wt/wt%, about 12 wt/wt%, about 3.3 wt/wt%, about 3.4 wt/wt%, about 3.5 wt/wt%, about 3.6 wt/wt%, about 3.7 wt/wt%, about 3.8 wt/wt%, about 3.9 wt/wt%, about 4.0 wt/wt%, about 4.1 wt/wt%, about 4.2 wt/wt%, about 4.3 wt/wt%, about 4.4 wt/wt%, about 4.5 wt/wt%, about 4.6 wt/wt%, about 4.7 wt/wt%, about 4.8 wt/wt%, about 4.9 wt/wt%, about 5.0 wt/wt%, about 5.1 wt/wt%, about 5.2 wt/wt%, about 5.3 wt/wt%, about 5.4 wt/wt%, about 5.5 wt/wt%, about 5.6 wt/wt%, about 5.7 wt/wt%, about 5.8 wt/wt%, about 5.9 wt/wt%, about 6.0 wt/wt%, about 6.1 wt/wt%, about 6.2 wt/wt%, about 6.3 wt/wt%, about 6.4 wt/wt%, about 6.5 wt/wt%, about 6.6 wt/wt%, about 6.7 wt/wt%, about 6.8 wt/wt%, about 6.9 wt/wt%, about 7.0 wt/wt%, about 7.1 wt/wt%, about 7.2 wt/wt%, about 7.3 wt/wt%, about 7.4 wt/wt%, about 7.5 wt/wt%, about 7.6 wt/wt%, about 7.7 wt/wt%, about 7.8 wt/wt%, about 7.9 wt/wt%, about 8.0 wt/wt%, about 8.1 wt/wt%, about 8.2 wt/wt%, about 8.3 wt/wt%, about 8.4 wt/wt%, about 8.5 wt/wt%, about 8.6 wt/wt%, about 8.7 wt/wt%, about 8.8 wt/wt%, about 8.9 wt/wt%, about 9.0 wt/wt%, about 9.1 wt/wt%, about 9.2 wt/wt%, about 9.3 wt/wt%, about 9.4 wt/wt%, about 9.5 wt/wt%, about 9.6 wt/wt%, about 9.7 wt/wt%, about 9.8 wt/wt%, about 9.9 wt/wt%, or about 10.0 wt/wt% of one or more disintegrants. In some aspects, the pharmaceutical composition comprises about 5 wt/wt% of one or more disintegrants.
102761 In some aspects, at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid. In some aspects, at least one of the disintegrants is croscarmellose sodium. In some aspects, the disintegrant is croscarmellose sodium. In some aspects, the pharmaceutical composition comprises about 1 wt/wt % to about 10 wt/wt % croscarmellose sodium. In some aspects, the pharmaceutical composition comprises about 3.5 wt/wt % to about 6 wt/wt % croscarmellose sodium. In some aspects, the pharmaceutical composition comprises about 1.0 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2.0 wt/wt%, about 2.1 wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5 wt/wt%, about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about 3.0 wt/wt%, about 3.1 wt/wt%, about 3.2 wt/wt%, about 3.3 wt/wt%, about 3.4 wt/wt%, about 3.5 wt/wt %, about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %, about 3.9 wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt%, about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %, about 5 wt/wt %, about 5.1 wt/wt %, about 5.2 wt/wt %, about 5.3 wt/wt %, about 5.4 wt/wt %, about 5.5 wt/wt %, about 5.6 wt/wt %, about 5.7 wt/wt %, about 5.8 wt/wt %, about 5.9 wt/wt %, about 6.0 wt/wt %, about 6.1 wt/wt%, about 6.2 wt/wt%, about 6.3 wt/wt%, about 6.4 wt/wt%, about 6.5 wt/wt%, about 6.6 wt/wt%, about 6.7 wt/wt%, about 6.8 wt/wt%, about 6.9 wt/wt%, about 7.0 wt/wt%, about 7.1 wt/wt%, about 7.2 wt/wt%, about 7.3 wt/wt%, about 7.4 wt/wt%, about 7.5 wt/wt%, about 7.6 wt/wt%, about 7.7 wt/wt%, about 7.8 wt/wt%, about 7.9 wt/wt%, about 8.0 wt/wt%, about 8.1 wt/wt%, about 8.2 wt/wt%, about 8.3 wt/wt%, about 8.4 wt/wt%, about 8.5 wt/wt%, about 8.6 wt/wt%, about 8.7 wt/wt%, about 8.8 wt/wt%, about 8.9 wt/wt%, about 9.0 wt/wt%, about 9.1 wt/wt%, about 9.2 wt/wt%, about 9.3 wt/wt%, about 9.4 wt/wt%, about 9.5 wt/wt%, about 9.6 wt/wt%, about 9.7 wt/wt%, about 9.8 wt/wt%, about 9.9 wt/wt%, or about 10.0 wt/wt% croscarmellose sodium. In some aspects, the pharmaceutical composition comprises about 5 wt/wt %
croscarmellose sodium.
102771 In some aspects, the pharmaceutical composition comprises 0 wt/wt % to about 5 wt/wt % of one or more lubricants. In some aspects, the pharmaceutical composition comprises about 0.1 wt/wt % to about 5 wt/wt % of one or more lubricants. In some aspects, the pharmaceutical composition comprises 0 wt/wt % to about 2 wt/wt %
of one or more lubricants. In some aspects, the pharmaceutical composition comprises about 0.1 wt/wt % to about 2 wt/wt % of one or more lubricants. In some aspects, the pharmaceutical composition comprises 0 wt/wt %, about 0.1 wt/wt %, about 0.2 wt/wt %, about 0.3 wt/wt %, about 0.4 wt/wt %, about 0.5 wt/wt %, about 0.6 wt/wt %, about 0.7 wt/wt %, about 0.8 wt/wt %, about 0.9 wt/wt %, about 1 wt/wt %, about 1.1 wt/wt %, about 1.2 wt/wt %, about 1.3 wt/wt %, about 1.4 wt/wt %, about 1.5 wt/wt %, about 1.6 wt/wt %, about 1.7 wt/wt %, about 1.8 wt/wt %, about 1.9 wt/wt %, about 2 wt/wt %, about 2.1 wt/wt %, about 2.2 wt/wt %, about 2.3 wt/wt %, about 2.4 wt/wt %, about 2.5 wt/wt %, about 2.6 wt/wt %, about 2.7 wt/wt %, about 2.8 wt/wt %, about 2.9 wt/wt %, about 3.0 wt/wt %, about 3.1 wt/wt %, about 3.2 wt/wt %, about 3.3 wt/wt %, about 3.4 wt/wt %, about 3.5 wt/wt %, about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %, about 3.9 wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt %, about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %, or about 5.0 wt/wt % of one or more lubricants. In some aspects, the pharmaceutical composition comprises about 1 wt/wt % of one or more lubricants.
102781 In some aspects, at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc. In some aspects, at least one of the lubricants is magnesium stearate. In some aspects, the lubricant is magnesium stearate. In some aspects, the pharmaceutical composition comprises 0 wt/wt % to about 5 wt/wt % of magnesium stearate. In some aspects, the pharmaceutical composition comprises about 0.1 wt/wt % to about 5 wt/wt %
of magnesium stearate. In some aspects, the pharmaceutical composition comprises 0 wt/wt % to about 2 wt/wt % of magnesium stearate. In some aspects, the pharmaceutical composition comprises about 0.1 wt/wt % to about 2 wt/wt % of magnesium stearate. In some aspects, the pharmaceutical composition comprises 0 wt/wt %, about 0.1 wt/wt %, about 0.2 wt/wt %, about 0.3 wt/wt %, about 0.4 wt/wt %, about 0.5 wt/wt %, about 0.6 wt/wt %, about 0.7 wt/wt %, about 0.8 wt/wt %, about 0.9 wt/wt %, about 1 wt/wt %, about 1.1 wt/wt %, about 1.2 wt/wt %, about 1.3 wt/wt %, about 1.4 wt/wt %, about 1.5 wt/wt %, about 1.6 wt/wt %, about 1.7 wt/wt %, about 1.8 wt/wt %, about 1.9 wt/wt %, about 2 wt/wt %, about 2.1 wt/wt %, about 2.2 wt/wt %, about 2.3 wt/wt %, about 2.4 wt/wt %, about 2.5 wt/wt %, about 2.6 wt/wt %, about 2.7 wt/wt %, about 2.8 wt/wt %, about 2.9 wt/wt %, about 3.0 wt/wt %, about 3.1 wt/wt %, about 3.2 wt/wt %, about 3.3 wt/wt %, about 3.4 wt/wt %, about 3.5 wt/wt %, about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %, about 3.9 wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt %, about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %, or about 5.0 wt/wt %
magnesium stearate. In some aspects, the pharmaceutical composition comprises 0 wt/wt % magnesium stearate. In some aspects, the pharmaceutical composition comprises about 0.1 wt/wt % magnesium stearate. In some aspects, the pharmaceutical composition comprises about 1 wt/wt % magnesium stearate.
102791 In some aspects, the pharmaceutical composition comprises 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents. In some aspects, the pharmaceutical composition comprises 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents. In some aspects, the pharmaceutical composition comprises 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1 6 wt/wt%, about 1 7 wt/wt%, about 1 8 wt/wt%, about 1 9 wt/wt%, about wt/wt%, about 2.1 wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5 wt/wt%, about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about 3.0 wt/wt%, about 3.1 wt/wt%, about 3.2 wt/wt%, about 3.3 wt/wt%, about 3.4 wt/wt%, about 3.5 wt/wt%, about 3.6 wt/wt%, about 3.7 wt/wt%, about 3.8 wt/wt%, about 3.9 wt/wt%, about 4.0 wt/wt%, about 4.1 wt/wt%, about 4.2 wt/wt%, about 4.3 wt/wt%, about 4.4 wt/wt%, about 4.5 wt/wt%, about 4.6 wt/wt%, about 4.7 wt/wt%, about 4.8 wt/wt%, about 4.9 wt/wt%, or about 5.0 wt/wt% of one or more flavoring agents. In some aspects, the pharmaceutical composition comprises about 2 wt/wt% of one or more flavoring agents.
102801 In some aspects, at least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors including but not limited to, grape flavoring, bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry flavoring. In some aspects, at least one of the flavoring agents is grape flavoring. In some aspects, the pharmaceutical composition comprises 0 wt/wt%
to about 5.0 wt/wt% grape flavoring. In some aspects, the pharmaceutical composition comprises 0 wt/wt% to about 2.5 wt/wt% grape flavoring. In some aspects, the pharmaceutical composition comprises 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2 wt/wt%, about 2.1 wt/wt%, about 2.2 wt/wt%, about 2.3 wt/wt%, about 2.4 wt/wt%, about 2.5 wt/wt%, about 2.6 wt/wt%, about 2.7 wt/wt%, about 2.8 wt/wt%, about 2.9 wt/wt%, about 3.0 wt/wt%, about 3.1 wt/wt%, about 3.2 wt/wt%, about 3.3 wt/wt%, about 3.4 wt/wt%, about 3.5 wt/wt%, about 3.6 wt/wt%, about 3.7 wt/wt%, about 3.8 wt/wt%, about 3.9 wt/wt%, about 4.0 wt/wt%, about 4.1 wt/wt%, about 4.2 wt/wt%, about 4.3 wt/wt%, about 4.4 wt/wt%, about 4.5 wt/wt%, about 4.6 wt/wt%, about 4.7 wt/wt%, about 4.8 wt/wt%, about 4.9 wt/wt%, or about 5.0 wt/wt% grape flavoring. In some aspects, the pharmaceutical composition comprises about 2 wt/wt% grape flavoring.
102811 In some aspects, the pharmaceutical composition comprises 0 wt/wt% to about 5 wt/wt% of one or more sweeteners. In some aspects, the pharmaceutical composition comprises 0 wt/wt% to about 2 wt/wt% of one or more sweeteners In some aspects, the pharmaceutical composition comprises 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2 wt/wt%, about 2.1 wt/wt %, about 2.2 wt/wt %, about 2.3 wt/wt %, about 2.4 wt/wt %, about 2.5 wt/wt %, about 2.6 wt/wt %, about 2.7 wt/wt %, about 2.8 wt/wt %, about 2.9 wt/wt %, about 3.0 wt/wt %, about 3.1 wt/wt %, about 3.2 wt/wt %, about 3.3 wt/wt %, about 3.4 wt/wt %, about 3.5 wt/wt %, about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %, about 3.9 wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt %, about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %, or about 5.0 wt/wt % of one or more sweeteners. In some aspects, the pharmaceutical composition comprises about 1 wt/wt% of one or more sweeteners.
102821 In some aspects, at least one of the sweeteners is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame. In some aspects, at least one of the sweeteners is sucralose. In some aspects, the sweetener is sucralose. In some aspects, the pharmaceutical composition comprises 0 wt/wt% to about 5 wt/vv-t% sucralose.
In some aspects, the pharmaceutical composition comprises 0 wt/wt% to about 2 wt/wt%
sucralose. In some aspects, the pharmaceutical composition comprises 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2 wt/wt%, about 2.1 wt/wt %, about 2.2 wt/wt %, about 2.3 wt/wt %, about 2.4 wt/wt %, about 2.5 wt/wt %, about 2.6 wt/wt %, about 2.7 wt/wt %, about 2.8 wt/wt %, about 2.9 wt/wt %, about 3.0 wt/wt %, about 3.1 wt/wt %, about 3.2 wt/wt %, about 3.3 wt/wt %, about 3.4 wt/wt %, about 3.5 wt/wt %, about 3.6 wt/wt %, about 3.7 wt/wt %, about 3.8 wt/wt %, about 3.9 wt/wt %, about 4.0 wt/wt %, about 4.1 wt/wt %, about 4.2 wt/wt %, about 4.3 wt/wt %, about 4.4 wt/wt %, about 4.5 wt/wt %, about 4.6 wt/wt %, about 4.7 wt/wt %, about 4.8 wt/wt %, about 4.9 wt/wt %, or about 5.0 wt/wt %
sucralose. In some aspects, the pharmaceutical composition comprises about 1 wt/wt%
sucralose.
102831 In some aspects, the pharmaceutical composition is a capsule In some aspects, the capsule comprises about 1 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 5 wt/wt% of one or more lubricants; and (e) a gelatin capsule which encapsulates components (a)-(d).
102841 In some aspects, the capsule comprises about 1 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows:
(a) about 0.25 wt/wt% to about 1.5 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) a gelatin capsule which encapsulates components (a)-(d).
102851 In some aspects, the capsule comprises about 2 mg of one or more crystalline or amorphous forms of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows:
(a) about 0.1 wt/wt% to about 7 wt/wt% of the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt%
of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or more lubricants; and (e) a gelatin capsule which encapsulates components (a)-(d).
102861 In some aspects, the capsule comprises about 2 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows:
(a) about 0.25 wt/wt% to about 1.5 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) a gelatin capsule which encapsulates components (a)-(d). In some aspects, the capsule comprises about 3 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de described herein, wherein each component of the capsule is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 5 wt/wt% of one or more lubricants; and (e) a gelatin capsule which encapsulates components (a)-(d).
102871 In some aspects, the capsule comprises about 3 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt% to about L5 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) a gelatin capsule which encapsulates components (a)-(d). In some aspects, the capsule comprises about 4 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 5 wt/wt% of one or more lubricants; and (e) a gelatin capsule which encapsulates components (a)-(d).
102881 In some aspects, the capsule comprises about 4 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows:
(a) about 0.25 wt/wt% to about 1.5 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) a gelatin capsule which encapsulates components (a)-(d).
102891 In some aspects, the capsule comprises about 5 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows:
(a) about 2.5 wt/wt% to about 7.0 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt%
of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
and (d) a gelatin capsule which encapsulates components (a)-(c).
102901 In some aspects, the capsule comprises about 5 mg of one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows:
(a) about 2.5 wt/wt% to about 7.0 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt%
of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
and (d) a gelatin capsule which encapsulates components (a)-(c).
102911 In some aspects, the pharmaceutical composition is a tablet (e.g., dispersible tablet). In some aspects, the tablet is a dispersible tablet. In some aspects, the tablet (e.g., dispersible tablet) comprises about 0.5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the tablet (e.g., dispersible tablet) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about wt/wt% of one or more lubricants.
102921 In some aspects, the tablet (e.g., dispersible tablet) comprises about 0.5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the tablet (e.g., dispersible tablet) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt-13/0 of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
102931 In some aspects, the tablet (e.g., dispersible tablet) comprises about 1 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the tablet (e.g., dispersible tablet) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
102941 In some aspects, the tablet (e.g., dispersible tablet) comprises about 1 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the tablet (e.g., dispersible tablet) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents;
(c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants 102951 In some aspects, the tablet (e.g, dispersible tablet) comprises about 2 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the tablet (e.g., dispersible tablet) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
102961 In some aspects, the tablet (e.g, dispersible tablet) comprises about 2 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the tablet (e.g., dispersible tablet) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) 0 wt/we/0 to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants 102971 In some aspects, the tablet (e.g., dispersible tablet) comprises about 3 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the tablet (e.g., dispersible tablet) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
102981 In some aspects, the tablet (e.g., dispersible tablet) comprises about 3 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the tablet (e.g., dispersible tablet) is as follows: (a) about 0.5 wt/wt% to about 1 .2 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
102991 In some aspects, the tablet (e.g., dispersible tablet) comprises about 4 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the tablet (e.g, dispersible tablet) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103001 In some aspects, the tablet (e.g., dispersible tablet) comprises about 4 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the tablet (e.g, dispersible tablet) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more di sintegrants; (d) 0 wt/wt% to about 2 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
103011 In some aspects, the tablet (e.g., dispersible tablet) comprises about 5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the tablet (e.g., dispersible tablet) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103021 In some aspects, the tablet (e.g., dispersible tablet) comprises about 5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the tablet (e.g., dispersible tablet) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.

[0303] In some aspects, the tablet (e.g., dispersible tablet) comprises about 0.1 mg to about 5 mg of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible in a potable liquid; and wherein each component of the pharmaceutical composition is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners;
and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103041 In some aspects, the tablet (e.g., dispersible tablet) comprises about 0.1 mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible in a potable liquid; and wherein each component of the pharmaceutical composition is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners;
and (0 about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
103051 In some aspects, the tablet (e.g., dispersible tablet) is dissolved in a potable liquid before administration. In some aspects, the potable liquid is water, milk or a juice (e.g., orange juice or apple juice). In some aspects, the potable liquid is water. In some aspects, the potable liquid is a juice. In some aspects, the tablet is orodispersible in a subject's saliva.
103061 In some aspects, the pharmaceutical composition is a powder (e.g., dispersible powder). In some aspects, the powder (e.g., dispersible powder) is a dispersible powder.
In some aspects, a capsule or sachet comprises the dispersible powder. In some aspects, the powder (e.g., dispersible powder) comprises about 0.5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the powder (e.g., dispersible powder) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
(b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt%
of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0307] In some aspects, the powder (e.g., dispersible powder) comprises about 0.5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the powder (e.g., dispersible powder) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/vv-t% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
[0308] In some aspects, the powder (e.g., dispersible powder) comprises about 1 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the powder (e.g., dispersible powder) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0309] In some aspects, the powder (e.g., dispersible powder) comprises about 1 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de described herein, and wherein each component of the powder (e.g., dispersible powder) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/vv-t% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.

[0310] In some aspects, the powder (e.g, dispersible powder) comprises about 2 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the powder (e.g., dispersible powder) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103111 In some aspects, the powder (e.g, dispersible powder) comprises about 2 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the powder (e.g., dispersible powder) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
10M21 In some aspects, the powder (e.g., dispersible powder) comprises about 3 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the powder (e.g., dispersible powder) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103131 In some aspects, the powder (e.g., dispersible powder) comprises about 3 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the powder (e.g., dispersible powder) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/vv-t% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
103141 In some aspects, the powder (e.g., dispersible powder) comprises about 4 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the powder (e.g, dispersible powder) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103151 In some aspects, the powder (e.g., dispersible powder) comprises about 4 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the powder (e.g, dispersible powder) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/vv-t% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (t) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
103161 In some aspects, the powder (e.g., dispersible powder) comprises about 5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the powder (e.g., dispersible powder) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103171 In some aspects, the powder (e.g., dispersible powder) comprises about 5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the powder (e.g., dispersible powder) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
103181 In some aspects, the powder (e g , dispersible powder) comprises about 0.1 mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible in a potable liquid; and wherein each component of the pharmaceutical composition is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners;
and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103191 In some aspects, the powder (e.g., dispersible powder) comprises about 0.1 mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible in a potable liquid; and wherein each component of the pharmaceutical composition is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners;
and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
103201 In some aspects, the powder (e.g., dispersible powder) is dissolved in a potable liquid before administration. In some aspects, the potable liquid is water, milk or a juice (e.g., orange juice or apple juice). In some aspects, the potable liquid is water. In some aspects, the potable liquid is a juice. In some aspects, the powder is orodispersible in a subject's saliva.
103211 In some aspects, the pharmaceutical composition is in the form of granules (e.g., dispersible granules). In some aspects, the granules (e.g., dispersible granules) are dispersible granules. In some aspects, a capsule or sachet comprises the dispersible granules. In some aspects, the granules (e.g., dispersible granules) comprise about 0.5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the granules (e.g., dispersible granules) is as follows: (a) about 0.1 wt/wt%
to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103221 In some aspects, the granules (e.g., dispersible granules) comprise about 0.5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the granules (e.g., dispersible granules) is as follows: (a) about 0.5 wt/wt%
to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (t) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
103231 In some aspects, the granules (e.g., dispersible granules) comprise about 1 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de described herein, and wherein each component of the granules (e.g., dispersible granules) is as follows: (a) about 0.1 wt/wt%
to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103241 In some aspects, the granules (e.g., dispersible granules) comprise about 1 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the granules (e.g., dispersible granules) is as follows: (a) about 0.5 wt/wt%
to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
103251 In some aspects, the granules (e g, dispersible granules) comprise about 2 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the granules (e.g., dispersible granules) is as follows: (a) about 0.1 wt/wt%
to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103261 In some aspects, the granules (e.g, dispersible granules) comprise about 2 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the granules (e.g., dispersible granules) is as follows: (a) about 0.5 wt/wt%
to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
103271 In some aspects, the granules (e.g., dispersible granules) comprise about 3 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the granules (e.g., dispersible granules) is as follows: (a) about 0.1 wt/wt%
to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 -wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103281 In some aspects, the granules (e.g., dispersible granules) comprise about 3 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the granules (e.g., dispersible granules) is as follows: (a) about 0.5 wt/wt%
to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
103291 In some aspects, the granules (e.g., dispersible granules) comprise about 4 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the granules (e.g, dispersible granules) is as follows: (a) about 0.1 wt/wt%
to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103301 In some aspects, the granules (e.g., dispersible granules) comprise about 4 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the granules (e.g, dispersible granules) is as follows: (a) about 0.5 wt/wt%
to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
103311 In some aspects, the granules (e.g., dispersible granules) comprise about 5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the granules (e.g., dispersible granules) is as follows: (a) about 0.1 wt/wt%
to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103321 In some aspects, the granules (e.g., dispersible granules) comprise about 5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the granules (e.g., dispersible granules) is as follows: (a) about 0.5 wt/wt%
to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/vv-t% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/vv-t% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
103331 In some aspects, the granules (e.g., dispersible granules) comprise about 0.1 mg to about 5 mg of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible in a potable liquid; and wherein each component of the pharmaceutical composition is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners;
and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.

[0334] In some aspects, the granules (e.g., dispersible granules) comprise about 0.1 mg to about 5 mg of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible in a potable liquid; and wherein each component of the pharmaceutical composition is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners;
and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
103351 In some aspects, the granules (e.g., dispersible granules) are dissolved in a potable liquid before administration. In some aspects, the potable liquid is water, milk or a juice (e g , orange juice or apple juice) In some aspects, the potable liquid is water In some aspects, the potable liquid is a juice. In some aspects, the granules are orodispersible in a subject's saliva.
103361 In some aspects, the pharmaceutical composition is in the form of minitablets (e.g., dispersible minitablets). In some aspects, the minitablets are dispersible minitablets. In some aspects, the minitablets (e.g., dispersible minitablets) comprise about 0.5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the minitablets (e.g., dispersible minitablets) is as follows:
(a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt%
of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/vv-t% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103371 In some aspects, the minitablets (e.g., dispersible minitablets) comprise about 0.5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the minitablets (e.g., dispersible minitablets) is as follows:
(a) about 0.5 wt/wt% to about 1.2 wt/vv-t% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt%
of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;

(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt%
to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
[0338] In some aspects, the minitablets (e.g., dispersible minitablets) comprise about 1 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the minitablets (e.g., dispersible minitablets) is as follows:
(a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/vv-t%
of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0339] In some aspects, the minitablets (e.g., dispersible minitablets) comprise about 1 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the minitablets (e.g., dispersible minitablets) is as follows:
(a) about 0.5 wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt%
of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/vv-t% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/vv-t% of one or more lubricants.
[0340] In some aspects, the minitablets (e.g, dispersible minitablets) comprise about 2 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de described herein, and wherein each component of the minitablets (e.g., dispersible minitablets) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.

[0341] In some aspects, the minitablets (e.g, dispersible minitablets) comprise about 2 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the minitablets (e.g., dispersible minitablets) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
103421 In some aspects, the minitablets (e.g., dispersible minitablets) comprise about 3 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the minitablets (e.g., dispersible minitablets) is as follows:
(a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt%
of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103431 In some aspects, the minitablets (e.g., dispersible minitablets) comprise about 3 mg of a crystalline or amorphous form of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the minitablets (e.g., dispersible minitablets) is as follows:
(a) about 0.5 wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt%
of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt%
to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
103441 In some aspects, the minitablets (e.g., dispersible minitablets) comprise about 4 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the minitablets (e.g, dispersible minitablets) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt%
of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103451 In some aspects, the minitablets (e.g., dispersible minitablets) comprise about 4 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the minitablets (e.g, dispersible minitablets) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt%
of one or more diluents; (c) about 3 5 wt/wt% to about 6 wt/wt% of one or more di sintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt%
to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
103461 In some aspects, the minitablets (e.g., dispersible minitablets) comprise about 5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the minitablets (e.g., dispersible minitablets) is as follows:
(a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt%
of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (t) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103471 In some aspects, the minitablets (e.g., dispersible minitablets) comprise about 5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the minitablets (e.g., dispersible minitablets) is as follows:
(a) about 0.5 wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt%
of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt%
to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/vv-t% of one or more lubricants.
103481 In some aspects, the minitablets (e.g., dispersible minitablets) comprise about 0.1 mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible in a potable liquid; and wherein each component of the pharmaceutical composition is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners;
and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103491 In some aspects, the minitablets (e g , dispersible minitablets) comprise about 0 1 mg to about 5 mg of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible in a potable liquid; and wherein each component of the pharmaceutical composition is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners;
and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
103501 In some aspects, the minitablets (e.g., dispersible minitablets) are dissolved in a potable liquid before administration. In some aspects, the potable liquid is water, milk or a juice (e.g., orange juice or apple juice). In some aspects, the potable liquid is water. In some aspects, the potable liquid is a juice. In some aspects, the minitablets are orodispersible in a subject's saliva.
103511 In some aspects, the pharmaceutical composition is in the form of pellets (e.g., dispersible pellet). In some aspects, the pellets are dispersible pellets. In some aspects, the pellets (e.g., dispersible pellets) comprise about 0.5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the pellets (e.g., dispersible pellets) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners;
and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0352] In some aspects, the pellets (e.g., dispersible pellets) comprise about 0.5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the pellets (e.g., dispersible pellets) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
[0353] In some aspects, the pellets (e.g., dispersible pellets) comprise about 1 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the pellets (e.g., dispersible pellets) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0354] In some aspects, the pellets (e.g., dispersible pellets) comprise about 1 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the pellets (e.g., dispersible pellets) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.

[0355] In some aspects, the pellets (e.g, dispersible pellets) comprise about 2 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the pellets (e.g., dispersible pellets) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (0 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103561 In some aspects, the pellets (e.g, dispersible pellets) comprise about 2 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the pellets (e g , dispersible pellets) is as follows- (a) about 05 wt/wt% to about 1 2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/vv-t% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
103571 In some aspects, the pellets (e.g., dispersible pellets) comprise about 3 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the pellets (e.g., dispersible pellets) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more di sintegrants; (d) 0 wt/wt% to about wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103581 In some aspects, the pellets (e.g., dispersible pellets) comprise about 3 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the pellets (e.g., dispersible pellets) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
[0359] In some aspects, the pellets (e.g., dispersible pellets) comprise about 4 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the pellets (e.g, dispersible pellets) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants [0360] In some aspects, the pellets (e.g., dispersible pellets) comprise about 4 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the pellets (e.g, dispersible pellets) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants;
(d) 0 wt/wt% to about 2.5 wt/vv-t% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
[0361] In some aspects, the pellets (e.g., dispersible pellets) comprise about 5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the pellets (e.g., dispersible pellets) is as follows: (a) about 0.1 wt/wt% to about 7 wt/wt%
of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0362] In some aspects, the pellets (e.g., dispersible pellets) comprise about 5 mg of a crystalline or amorphous form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide described herein, and wherein each component of the pellets (e.g., dispersible pellets) is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/vv-t% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/vv-t% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners; and (f) about 0.5 wt/wt% to about 2 wt/wt%
of one or more lubricants.
103631 In some aspects, the pellets (e.g., dispersible pellets) comprise about 0.1 mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible in a potable liquid; and wherein each component of the pharmaceutical composition is as follows- (a) about 0.1 wt/wt% to about 7 wt/wt% of a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 5 wt/wt% of one or more sweeteners;
and (f) 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
103641 In some aspects, the pellets (e.g., dispersible pellets) comprise about 0.1 mg to about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; wherein the pharmaceutical composition is dispersible in a potable liquid; and wherein each component of the pharmaceutical composition is as follows: (a) about 0.5 wt/wt% to about 1.2 wt/wt% of a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) 0 wt/wt% to about 2.5 wt/wt% of one or more flavoring agents; (e) 0 wt/wt% to about 2 wt/wt% of one or more sweeteners;
and (f) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants.
103651 In some aspects, the pellets (e.g., dispersible pellets) are dissolved in a potable liquid before administration. In some aspects, the potable liquid is water, milk or a juice (e.g., orange juice or apple juice). In some aspects, the potable liquid is water. In some aspects, the potable liquid is a juice. In some aspects, the pellets are orodispersible in a subject's saliva.

Methods of Treatment [0366] In some aspects, the present disclosure provides a method of treating a tumor, a cancer, or a Rasopathy disorder comprising administering to a subject in need of such treatment a pharmaceutical composition described herein.
[0367] In some aspects, the tumor is a neurofibroma. In some aspects, the tumor is a neurofibroma associated with Neurofibromatosis Type 1. In some aspects, the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, or malignant peripheral nerve sheath tumor. In some aspects, the tumor is plexiform neurofibroma.
[0368] In some aspects, the subject has been diagnosed with a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
103691 In some aspects, the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum. In some aspects, the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia. In some aspects, the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia. In some aspects, the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.
[0370] In some aspects, the subject bears a mutation or other aberration in one or more genes for which the mutation or other aberration causes a gain or loss of function characteristic of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
103711 In some aspects, an individual dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as more than one capsule, tablet (e.g., dispersible tablet), dose of powder (e.g, dispersible powder), dose of granules (e.g., dispersible granules), dose of minitablets (e.g., dispersible minitablets), dose of pellets (e.g., dispersible pellets), or a combination thereof. For example, a dose of 3 mg of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide can be administered as two capsules ¨ one containing 2 mg and the other containing 1 mg or as three capsules each containing 1 mg. As another example, a dose of 1.5 mg of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide can be administered as two dispersible dosage forms ¨
one dispersible tablet containing 1 mg and a separate unit of dispersible powder containing 0.5 mg or as three units of dispersible powder each containing 0.5 mg.
[0372] In some aspects, if the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is to be administered more than one time a day, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide can be divided so the patient receives different doses at each administration. For example, if the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is to be 2 mg administered two times per day, the patient can receive 0.5 mg (e.g., as one 0.5 mg tablet (e.g., dispersible tablet)) in the morning and 1.5 mg (e.g., as one 0.5 mg dose of powder (e.g., dispersible powder) and one 1 mg capsule) in the evening.
[0373] In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in an amount of about 0.1 mg to about 20 mg per dose of the pharmaceutical compositions described herein. In some aspects, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in an amount of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about U.S
mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg per dose. In some aspects, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in an amount of about 0.5 mg per dose. In some aspects, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in an amount of about 1 mg per dose.
In some aspects, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in an amount of about 2 mg per dose. In some aspects, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in an amount of about 3 mg per dose. In some aspects, one or more crystalline or amorphous forms of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in an amount of about 4 mg per dose. In some aspects, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in an amount of about 5 mg per dose In some aspects, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in an amount of about 10 mg per dose. In some aspects, one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided in an amount of about 20 mg per dose.
103741 In some aspects, the pharmaceutical composition comprising one or more crystalline or amorphous forms of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered one time, two times, three times, or four times per day. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times per day.
103751 In some aspects, the present disclosure provides a method of treating a tumor, a cancer, or a Rasopathy disorder comprising administering to a patient in need of such treatment a pharmaceutical composition described herein, wherein the total daily dose of the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily of about 0.1 mg to about 10 mg each.
103761 In some aspects, the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered via a pharmaceutical composition described herein, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is provided at a total daily dose that does not exceed 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 20 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 15 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 12 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 10 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 6 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 4 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 2 mg. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 1 mg.
103771 In some aspects, the present disclosure provides a method of treating a tumor, a cancer, or a Rasopathy disorder comprising administering to a patient in need of such treatment a pharmaceutical composition described herein, wherein the total daily dose of the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.1 mg to about 20 mg.
103781 In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is administered once daily. In some aspects, the total daily dose of the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.1 mg to about 20 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.5 mg.
In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 1 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 2 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 3 mg. In some aspects, the total daily dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 4 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 5 mg. In some aspects, the total daily dose of the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 6 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 7 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 8 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 9 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 10 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 11 mg.
In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 12 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 13 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 14 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 15 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 16 mg.
In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 17 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 18 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 19 mg. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 20 mg 103791 In some aspects, the total daily dose of the N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.1 mg to about 10 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.25 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.5 mg each.
In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 1 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 2 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 3 mg each. In some aspects, the total daily dose of the NAR)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 4 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 5 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 6 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 7 mg each. In some aspects, the total daily dose of the N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 8 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de is administered two times daily at a dose of about 9 mg each. In some aspects, the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 10 mg each.
103801 In some aspects, the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 days in which the total daily dose is administered; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 consecutive days in which the total daily dose is administered;
followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
103811 In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 days in which the total daily dose is administered and (ii) 2 days in which no N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered. In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 consecutive days in which the total daily dose is administered and (ii) 2 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
103821 In some aspects, the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising 28 days in which the total daily dose is administered.
103831 In some aspects, the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.
103841 In some aspects, the pharmaceutical composition is a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets, and wherein the pharmaceutical composition is dispersed in a potable liquid (e.g., water or a juice (e g , orange juice or apple juice)) prior to administration to the subject 103851 In some aspects, the composition is an orodispersible dosage form (e.g., dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets) which is administered to the subject without first dissolving the dosage form in a separate container.
103861 In some aspects, the subject experiences dysphagia. In some aspects, the subject experiences dysphagia caused by one or more of: disease of the nervous system, muscle weakening, developmental disability, stroke, injury, anatomical defect, cancer, treatment for cancer, allergic reaction, dementia, memory loss, or cognitive decline. In some aspects, the subject has been diagnosed with an autism spectrum disorder. In some aspects, the subject has been diagnosed with a craniofacial disorder. In some aspects, the subject has been diagnosed with myasthenia gravis. In some aspects, the subject has been diagnosed with tardive dyskinesia.
103871 In some aspects, the subject is a pediatric subject In some aspects, the subject is less than 18 years old, less than 17 years old, less than 16 years old, less than 15 years old, less than 14 years old, less than 13 years old, less than 12 years old, less than 11 years old, less than 10 years old, less than 9 years old, less than 8 years old, less than 7 years old, less than 6 years old, less than 5 years old, less than 4 years old, less than 3 years old, less than 2 years old, or less than 1 year old. In some aspects, the subject is 1 year old, 2 years old, 3 years old, 4 years old, 5 years old, 6 years old, 7 years old, 8 years old, 9 years old, 10 years old, 11 years old, 12 years old, 13 years old, 14 years old, 15 years old, 16 years old, or 17 years old. In some aspects, the subject is less than 13 years old. In some aspects, the subject is less than 12 years old. In some aspects, the subject is less than 11 years old. In some aspects, the subject is less than 10 years old. In some aspects, the subject is less than 9 years old. In some aspects, the subject is less than 8 years old. In some aspects, the subject is less than 7 years old. In some aspects, the subject is less than 6 years old. In some aspects, the subject is less than 5 years old. In some aspects, the subject is less than 4 years old. In some aspects, the subject is less than 3 years old. In some aspects, the subject is less than 2 years old. In some aspects, the subject is less than 1 year old. In some aspects, the subject is about 2 to about 18 years old. In some aspects, the subject is about 3 to about 17 years old. In some aspects, the subject is about 4 to about 16 years old. In some aspects, the subject is about 5 to about 15 years old. In some aspects, the subject is about 6 to about 14 years old.
In some aspects, the subject is about 7 to about 13 years old. In some aspects, the subject is about 8 to about 12 years old 103881 In some aspects, the subject is a geriatric subject. In some aspects, the subject is more than 30 years old, more than 35 years old, more than 40 years old, more than 45 years old, more than 50 years old, more than 55 years old, more than 60 years old, more than 65 years old, more than 70 years old, more than 75 years old, more than 80 years old, more than 85 years old, more than 90 years old, more than 95 years old, or more than 100 year old. In some aspects, the subject is more than 50 years old. In some aspects, the subject is more than 60 years old. In some aspects, the subject is more than 70 years old.
In some aspects, the subject is more than 80 years old. In some aspects, the subject is more than 90 years old. In some aspects, the subject is more than 100 years old.
103891 In some aspects, the present disclosure provides use of a pharmaceutical composition described herein for the manufacture of a medicament for treating a cancer, a tumor, or a Rasopathy disorder.
Methods of Preparing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and Essentially Pure Form IV
103901 Novel methods of producing N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) HOONO H

N
F
(I), that comprise reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent that is 1-propylphosphonic anhydride ("T3P") to obtain 901 Acetonide, as shown in Scheme I below, are disclosed herein.
Scheme 1 ,N 0 H2 + 10 T3P

(IPGA) MW 147.17 PD-0315209 (FIPFA) MW 393.10 901 Acetonide MW 522.26 103911 In some aspects, the T3P is in solution. In some aspects, T3P is provided as a solution in ethyl acetate.
103921 In some aspects, the method of producing essentially pure Form IV N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) comprises (a) reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent that is T3P to obtain 901 Acetonide; and (b) treating 901 Acetonide with acid to form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, as shown in Scheme II below.

Scheme II
¨
_ *0 H F

H F
ON,õ1-0.NH2 + N T3P k6 N

F I
(IPGA) PD-0315209 F
MW 147.17 (FIPFA) 901 Acetonide MW 393.10 MW 522.26 ¨
_ 'acid'' H H
HO0.-N 0 õ....,õ _........_ ,N

H

OH N 0 (51-1 _..,_ F I F I
F F
Mirdametinib (PD-0325901) Crude PD-0325901 MW 482.20 MW 482.20 103931 In some aspects, the synthesis for essentially pure crystalline Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) comprises the reaction set forth according to Scheme III.

Scheme III
¨
_ +0 H
N F
T3P 0,.." -H
...---.... ,N

.õ 0 H F
ON.).0,NH2 + 0 0 (50% in Et0Ae) F I
i-Pr2NEt N
__________________________________________________________ . 110 PD-0337792 F THF, toluene F I
(IPGA) PD-0315209 MTBE, aq. NaOH F
MW 147.17 (FIPFA) 901 Acetonide MW 393.10 MW 522.26 aq. HCI
toluene, ACN
H H

HOO'N F HOON ". F
Et0H
H H
61-I N F I Et0H OH N .
_______ 0 0 . _____________________________________ water 0 0 F I
F F
Mirdametinib Crude PD-0325901 (PD-0325901) MW 482.20 MW 482.20 103941 In some aspects, the synthesis for essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) is as shown below in Scheme IV.

n >
o u, r., o ,4 u, , u, 9, 4, Scheme IV
Step 1 0 1 o N
-.) HON . --.1 Pli 0 MW 163.13 !A
00 ,c) ___________________________________________________________ .. ----c) oO,N
0\,1,70H '', 00,NH2 II CF

MW: 132.16 MW: 264.22 MW: 277.28 MW:
147.17 (S)-Glycerol Acetonide PF-03714421 P0-0333760 PD-( IPGAP ) ( IPGA ) Step 2 .

la F
F + I. F N
'8 lµF 40 40 F
I .
F I F
MW: 176.09 MW: 237.02 MW:
393.10 0315209 Step 3 ( FIPFA ) Step 4 -H H
H
HeO'N 0 H F
HO"N!"O'N H 0 F /,,,_/,õN 0 H
F t 0 ; `-' n OH N

OH Nlei _______________ z\-0 t!
Cl)N
---la N ra F I F I
11 V F I1V I o ts.) F F F

MW: 482.20 MW: 482.20 MW: 522.26 oo Crude PD-0325901 w x ( Mirdametinib ) ( 901 Acetonide ) 10395] In some aspects, the methods of preparing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide yields a crystalline composition that is essentially pure Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
103961 In some aspects, the essentially pure Form IV crystalline composition contains <
0.2% of dimeric impurity PF-00191189 141) HN

OH

Exact Mass: 856.93 103971 In some aspects, the essentially pure Form IV crystalline composition contains about 0.05% to about 0.19% by weight of dimeric impurity PF-00191189. In some aspects, the essentially pure Form IV crystalline composition contains about 0.05% to about 0.15% by weight of dimeric impurity PF-00191189. In some aspects, the essentially pure Form IV crystalline composition contains about 0.05% to about 0.10% by weight of dimeric impurity PF-00191189. In some aspects, the essentially pure Form IV
crystalline composition contains no detectable amount of dimeric impurity PF-00191189.
103981 In some aspects, the amount of dimeric impurity PF-00191189 is determined using High Performance Liquid Chromatography ("HPLC"). In some aspects, reversed-phase liquid chromatography using an ultraviolet detector at 275 nm is used.
EXAMPLES
103991 Abbreviations and Acronyms ACN Acetonitrile CC Controlled cooling DCM Dichloromethane DMF N,N-Dimethyl formamide DMSO Dimethyl sulfoxide DSC Differential scanning calorimetry Et0Ac Ethyl acetate Et0H Ethanol Exp Experiment FEV Fast evaporation FIA 2-fluoro-4-idodoaniline FT Fourier Transform GVS Gravimetric Vapor Sorption HC1 Hydrochloric acid HOAc Acetic acid i-Pr2NEt N,N-diisopropylethylamine IPA 2-Propanol IPE Isopropyl ether LiNH2 Lithium amide MeCN Acetonitrile Me0H Methanol MIBK 4-Methyl-2-pentanone min Minutes MTBE Methyl t-butyl ether n/a Not Applicable NaOH Sodium hydroxide NH40H Ammonium hydroxide NHP N-hydroxyphthalimide PLM Polarized light microscopy PXRD Powder X-ray diffraction (also known as XRPD (X-ray powder diffraction) RC Rapid cooling RT Room temperature SAS Solvent-anti solvent SEV Slow evaporation SGA (S)-(+)-2,2-dimethy1-1,3-dioxolane-4-methanol SU Scale Up t-BuOH Tert-butanol TC Temperature cycling T3P 1-propylphosphonic anhydride solution TEA triethylamine Tf20 Trifluoromethanesulfonic anhydride TFBA 2,3,4-trifluorobenzoic acid TFE 2,2,2-Trifluoroethanol TGA Thermogravimetric analyzer TGA-IR Thermogravi metric analysis interfaced with infrared spectrophotometer THF Tetrahydrofuran v/v Volume/volume Example!: Production of Seed Crystals of Form IV
Step 1: Preparation of "Side Chain", PD-0337792 104001 14.4 kg alcohol (chemical purity 99.4%, optical purity 99.6%
enantiomeric excess) was converted to 97.5 kg 9.7% w/w PD-0337792 (IPGA) solution in toluene (overall yield ¨60%). The triflate activation was performed in the 200 L
reactor by maintaining temperatures under ¨20 C during triflic anhydride addition. The resulting activated alcohol was then transferred to a 400 L reactor containing solid N-hydroxypthalimide (NHP) and the reaction was allowed to occur at ambient temperature to completion. The final base de-protection was performed by adding aqueous ammonia (-28% soln, 5 equiv., 34 kg). After reaction completion, water was removed by distillation from toluene, and the resulting solid side product was filtered out to yield the product solution.
Step 2: Preparation of PD-0315209 104011 The process yielded 2L4 kg (99.4% w/w assay), which is 80% of theoretical from starting materials 2,3,4-trifluorobenzoic acid (12 kg, 1 eq.) and 2-fluoro-4-iodoaniline (16.4 kg, 1.02 eq.) with lithium amide base (5 kg, 3.2 eq.). The reaction was initiated by adding 5% of total solution of TFBA and FIA into lithium amide slurry at 50 C. This reaction demonstrated a minimal initiation period of ¨10 minutes, which was observed by color change and slight exotherm. The remaining TFBA/FIA solution in THF was slowly added through a pressure can in an hour while maintaining the reaction temperatures within 45-55 C. There was no appreciable pressure rise (due to ammonia gas release) observed during the entire operation.
Step 3: Preparation of PD-0325901 104021 A modification was made to the CDI charging to mitigate potential gas generation. Two equal portions of CDI were added into solid FIPFA before and after solvent addition (through a shot loader). The timing between the two solid CDI
additions (4.6 kg each) should not exceed 30 minutes. Then two intermediate filter cakes were dissolved with ethanol. The excess ethanol was distilled and replaced with toluene to approximately 5% v/v ethanol prior to PD-0325901 recrystallization. Lab studies suggested that the crystallization from toluene and acetonitrile and recrystallization from ethanol in toluene would not be able to reduce impurities which is essential for the polymorph transformation. The presence of a dimeric impurity (PF-00191189) at a level greater than 0.2% has been known to result in the formation of undesired polymorph.

HN

z OH

Exact Mass: 856.93 [0403] The crude crystallization from the final reaction mixture reduced dimeric impurity PF-00191189 to approximately 1.9% and the subsequent recrystallization further reduced it to approximately 0.4%. As a consequence, undesired polymorphs were produced. The DSC patterns indicated two different melting points ¨80 C (low melt Form II) and ¨117 C (Form I). Also during the processing, the solids crystallized at a much lower temperature than expected (actual ¨10 C, expected ¨40 C). It is suspected that the unsuccessful recrystallization is due to a change in the solvent composition as a result of incomplete drying of the crude. Drying of the crude wet cake prior to ethanol dissolution was stopped after about 36 hours when the crude product was ¨28 kg (26 kg theoretical).
Polymorph Transformation [0404] Approximately 7.4 kg of PD-0325901 (mixed polymorphs) from the final Et0H/Water crystallization and precipitated materials from the earlier Et0H/Toluene filtrate were taken forward to the polymorph transformation. Both crops were separately dried in the filter until constant weights and each was dissolved in Et0H. The combined Et0H solution was analyzed by TIPLC and resulted in an estimated amount of 16.4 kg PD-0325901. The recrystallization was started after removing Et0H via vacuum distillation and adjusting the solvent composition to about 5% Et0H in Toluene at 65 C
(i.e., Et0H is added dropwise at 65 C until complete solids dissolution).
[0405] A slow 4-hour cooling ramp to 5 C followed by 12 h stirring was performed to ensure satisfactory results. The resulting slurry was filtered and again it was completely dried in the filter until constant weight (approximately 3 days). The purified solid showed 99.8% pure PD-0325901 with not detected level of dimeric impurity PF-00191189.

[0406] The dried solid (15.4 kg) was re-dissolved in exactly 4 volumes of Et0H (62 L) off of the filter, transferred to the reactor and precipitated by a slow (-3 h) water addition (308 L) at 30-35 C, cooled to 20 C and stirred for 12 h. The DSC analysis of a slurry sample taken at 2 h shows the solids to be completely Form IV (desired polymorph).
104071 21.4 kg PD-0315209, 9.7 kg CDI (1.05 equiv.), 91 kg solution of 9.7% PD-0337792 in Toluene (1.1 equiv.) were used and resulted in 12.74 kg of PD-(assay 99.4%, 100% Form IV, Yield ¨ 48%).
Example 2: Assay/Impurities and Identification of PD-0325901 104081 PD-0325901 is separated from process impurities and degradants by reversed-phase liquid chromatography with UV detection at 275 nm Identification of PD-0325901 is performed by obtaining either an infrared or proton NMR spectrum, in addition to the HPLC retention time. For purity evaluation, process impurities and degradants are identified by their characteristic relative retention times and quantitated by area normalization.
104091 Chromatographic Conditions: Agilent Zorbax SB C18, 5 p.m, 4.6 x 250 mm (or equivalent); flow rate is 1.0 mL/min; column temperature is 30 C; detector wavelength is 275 nm; diluent is 50/50 acetonitrile/water; mobile phase A is 0.1%
trifluoroacetic acid (TFA) in water; mobile phase B is methanol; and the gradient conditions below.
The assay is determined against a reference standard and reported on an anhydrous, solvent free basis. Quantification of specified and unspecified impurities is reported by area percent. Total impurities is the sum of all impurities present above the reporting threshold of 0.05%.
Time (minutes) 0 15 40 45 46 % mobile phase B 70 70 100 100 70 Example 3: Improved Process for Preparation of Form IV
104101 As described in Example 1, synthetic methods of producing mirdametinib as Form IV produced Form IV with dimeric impurity PF-00191189, and further steps were required to transform the product into essentially pure Form IV without undesired polymorphs Form I and Form II. Therefore, it was necessary to develop a method of producing essentially pure Form IV without additional processing steps.

Mirdametinib Manufacturing Process 104111 The route is a convergent four step synthesis with six chemical steps overall, using the proposed starting materials (S)-( )-2,2-dimethy1-1,3-dioxolane-4-methanol (SGA), 2,3,4-trifluorobenzoic acid (TFBA), 2-fluoro-4-idodoaniline (FIA), and N-hydroxyphthalimide (NRP). The final step (Step 4) provides essentially pure Form IV of mirdametinib.

n >
o L.
r., o -.1 u, ,--u, r, o r, 9' 4, Scheme for Preparation of Mirdametinib :

Step I
t,) 1 t,) I--L
.,1 .,1 Pli - HO-N NHP _ --..1 OOH Tf20 NI-0 MW 163.13 0 ON)C), ,,C
NH4OH 00.,NH2 (S)-(+)-2,2-dimethy1-1,3- TEA II CF3 0 toluene, TEA 0 dioxolane-4-methanol toluene toluene PD-0337792 (SGA) (S)-glycerol acetonide (IPGA) triflate P0-0333760 MW 132.16 - -(IPGAP) MW 147.17 MW 264.22 MW 277.28 Step 2 0 T3P --, I. F
H F
(50% in Et0Ac) -.I
(01 ______________________________________________________________________ .
N i-Pr2NEt F
F LiNH2 + THF, MTBE
. 110 THF, toluene F
F I
I toluene, aq. HCI MTBE, aq. NaOH
2,3,4-trifluoro-benzoic acid 2-fluoro-4-iodoaniline F
(TFBA) (FIA) MW 176.09 MW 237.02 (FIPFA) MW 393.10 Step 3 Step 4 ¨ ¨
H H
H
,N 0,N 0 aq. HCI ., --,,.......õ, , N 0 F
"0 HO . 0 F HO , 0 F
0 H n H H toluene, ACN
F OH 40 N s Et0H _____________________ OH si N io 110 110 ci) water Et0H F
F I I
F F
F r.) CB
Mirdametinib 901 Acetonide Crude P0-0325901 oc (P0-0325901) MW 522.26 ca MW 482.20 XMW 482.20 - - 1-L

[0412] Step 1 (Preparation of PD-0337792 (IPGA)): A clean, dry 100-gallon reactor was charged with toluene (139.3 kg, 8 volumes) and (S)-(+)-2,2-Dimethy1-1,3-dioxolane-4-methanol (SGA; 20.0 kg, 1.0 equivalents). Triethylamine (18.8 kg, 1.22 equivalents) was charged to the reactor. The reactor contents were agitated and cooled to -10 10 C.
Trifluoromethanesulfonic anhydride (43.5 kg, 1.02 equivalents) was added to a clean 50-L round bottom flask under nitrogen then cooled to a temperature of < -10 'C.
The cooled trifluoromethanesulfonic anhydride was slowly transferred to the 100-gallon reactor while maintaining the internal temperature at -10 + 10 C. The reaction mixture was agitated at -10 10 C for 30 minutes. Reaction monitoring by TLC indicated the conversion to be complete. While maintaining the internal temperature at -10 10 C, anhydrous toluene (99.8 kg, 5.75 volumes) was charged to the reactor followed by N-hydroxyphthalimide (26.4 kg, 1.07 equivalents). The contents were warmed to 20 5 C then agitated at this temperature for at least 5 hours, until the triflate intermediate was not detectable by TLC
The reaction mixture was split into two equal portions. Each toluene solution was quenched with USP purified water (66 kg, 6.7 volumes). The toluene solution was then washed twice with USP purified water (66 kg, 6.7 volumes).
104131 The toluene solutions were recombined in a 100-gallon reactor.
The organic solution was treated with 28% ammonium hydroxide solution (41.5 kg, 7.8 equivalents).
The contents were heated to 35 5 C then agitated for not less than ("NLT") 12 hours.
Upon reaction completion, the lower, aqueous phase was removed. The toluene solution was dried via azeotropic distillation of toluene. The toluene solution was then concentrated to minimum stir volume. The concentrated solution was filtered to remove by-product solids. The cake was washed with toluene and the filtrates were combined.
Assay of the toluene solution indicated 8.6 kg (36.7% yield) of PD-0337792 (IPGA) was present.
104141 Step 2 (Preparation of PD-0315209): A clean, dry 100-gallon reactor was purged with nitrogen then charged with lithium amide (LiNH2, 8.8 kg, 3,4 equivalents) followed by tetrahydrofuran (THF, 56.8 kg, 3.2 volumes). The mixture was cooled to 10 then additional TI-IF (15.1 kg, 0.85 volumes) was charged to the reactor, followed by a solution of 2,3,4-trifluorobenzoic acid (TFBA, 20.0 kg, 1.0 equivalent) in THF
(26.4 kg, 1.15 volumes). The reaction mixture was heated to NMT ("not more than") 50 C.
A
solution of 2-flouro-4-iodoaniline (FIA, 27.5 kg, 1.02 equivalents) in THF
(17.8 kg, 1 volumes) was added portion wise to the reactor, maintaining the batch temperature at NMT 50 C and stirring for 1 hour between additions. After completing the additions, the reaction mixture stirred for an additional 3 hours at 50 10 C. Upon reaction completion, the mixture was cooled to NMT 10 C then quenched with USP
purified water (120.3 kg, 6 volumes). The reaction mixture was distilled to approximately 30 gallons after which methyl t-butyl ether (MTBE, 118.6 kg, 8 volumes) was added. The MTBE solution was then quenched with 2M hydrochloric acid solution (89.5 kg) to a pH
= 7. The aqueous phase was then removed. The MTBE solution was filtered through celite then washed twice with 5% brine solution (104.1 kg, 5.2 volumes) followed by 1M
hydrochloric acid solution (77.4 kg). The MTBE solution was solvent swapped with toluene followed by volume adjustment to approximately 50 gallons. This mixture was heated to 75 5 C for 1 hour then cooled to 20 5 C and stirred for 1 hour. The product was filtered, washed with toluene (68.1 kg, -4 volumes), then dried under vacuum at 40 C to obtain 25.2 kg of PD-0315209 (56.4% yield).
104151 Step 3 (Preparation of crude PD-0325901): A clean, dry 100-gallon reactor was purged with nitrogen then charged with PD-0315209 (18.0 kg, 1 equivalent) and THF
(113.0 kg, 7 volumes). The mixture was cooled to 5 5 C. N,N-diisopropylethylamine (15.1 kg, 2.55 equivalents) was charged maintaining the temperature NIVIT 25 C. The mixture was cooled to 5 5 C then stirred for 10 minutes. PD-0337792 solution in toluene (121.7 kg total, 1.3 equivalents) was charged to the reactor at 5 5 C, followed by 50% T3P in ethyl acetate (42.0 kg, 1.45 equivalents). The reaction mixture stirred at 5 C for NLT 3 hours. An additional charge of N,N-dii sopropylethylamine (1.9 kg, 0.3 equivalents) and 50% T3P in ethyl acetate (4.1 kg, 0.15 equivalents) were made to advance the coupling to completion. The reaction was reverse quenched into a 5% sodium hydroxide solution (50 kg), followed by washing with 5% brine (55.4 kg). The organic solution was concentrated then solvent swapped with toluene. Acetonitrile (43.0 kg, 2.4 volumes) was added to the reactor followed by 2M hydrochloric acid (117.6 kg, 5.1 equivalents). The mixture stirred at 25 5 C until reaction completion after 16 hours The bottom aqueous was removed then the reaction mixture was washed with 5%
brine (75.2 kg). The organic phase was concentrated then solvent swapped with toluene to an appropriate volume. The mixture was then heated to 75 5 C for 30 minutes then slowly cooled to 20 C. The solids were filtered then washed with toluene (31.1 kg, 1.7 volumes) 104161 The crude solids were charged back to the 100-gallon reactor, followed by 5%
ethanol in toluene (170.0 kg). The mixture was heated to 75 5 C for 60 minutes to achieve a solution then slowly cooled to 20 C. The solids were filtered then washed twice with toluene (31 kg, 1.7 volumes). The wet cake was dried under vacuum at 45 C
to obtain 8.2 kg of crude PD-0325901 (37.1% yield).
104171 Step 4 (Preparation of Essentially Pure Form Ifr' Mirdametinib):
A clean, dry 100-gallon reactor was purged with nitrogen then charged with USP Purified Water (164.1 kg, 20 volumes) followed by ethanol (200 proof, 20.8 kg, 3.25 volumes).
The solution was heated to 35 5 C. In a separate vessel, crude PD-0325901 (8.1 kg, 1 equivalent) was dissolved in ethanol (200 proof, 40.5 kg, 6.3 volumes). A
portion of this solution (14.4 kg) was added to the 100-gallon reactor over 60 minutes. PD-Form IV seeds as prepared in Example 1 (82.6 g, 1%wt) was added to the reactor to facilitate precipitation. The remainder of the crude PD-0325901/ethanol solution (34.3 kg) was added to the reactor over 90 minutes as the mixture stirred at 35 + 5 C. The reactor contents continued to stir at 35 5 C for 5.5 hours then were slowly cooled to 20 C. The solids were then filtered, washed with USP purified water (16 5 kg, 2 volumes), then dried under vacuum at 45 C for 16 hours. The dried solids were screened through a 10-mesh sieve to obtain 5.7 kg PD-0325901 Form IV (70.4% yield).
104181 An XRPD pattern for essentially pure Form IV used herein is shown in FIG. 1A.
TGA and DSC analysis of essentially pure Form IV used herein are shown in FIG.
1B.
Example 4: Approximate Kinetic Solubility 104191 Solubility of mirdametinib prepared by Example 3 was assessed in 30 solvents.
The solubility was visually estimated at room temperature (RT; ¨23 C) by dosing small aliquots of solvent into a fixed amount of solid (-10 mg) until the dissolution point or a maximum volume (1.8 mL) was reached. Samples that contained undissolved solids at RT were heated to 40 C for 1 hour and the dissolution was assessed visually.
The solubility data are shown below in Table 1.
Table 1 Solvent v/v Solubility (mg/mL)at Solubility(mg/mL) ( ) RT (23 C) at 1 Ethanol/Water (9:1 v/v) >
424 n/a 2 MeCN/water (8:2 v/v) >
412 n/a 3 MeCN/Water (7:3 v:v) >408 n/a 4 Dioxane >408 n/a DMF (dimethylformamide) > 408 n/a 6 2-Propanol:water (9:1 v/v) > 400 n/a 7 Acetone > 400 n/a 8 Tetrahydrofuran (THY) > 396 n/a 9 Acetic acid (HOAc) > 388 n/a Dimethyl sulfoxide (DMSO) > 388 n/a 11 Methanol (Me0H) > 380 nia 12 Ethanol/Toluene (9:1) 210 - 420 n/a 13 Ethanol 208 -416 n/a 14 1-Propanol 101 - 202 n/a 2-Propanol (IPA) 98 - 196 n/a 16 2-Methyl-2-Butanol 97 - 194 n/a 17 Ethyl Acetate (Et0Ac) 48 - 95 n/a 18 M1BK (4-methyl-2-pentanone) 48 - 95 n/a 19 Acetonitrile (MeCN) 19 - 49 n/a Nitromethane 10-20 n/a 21 Dimethylcarbonate (DMC) 10-19 n/a 22 Trifluoroethanol (TFE) 7-12 n/a 23 Tert-butanol (t-BuOH) 6-10*
n/a 24 MTBE (methyl-t-butyl ether) <6 > 6 Dichloromethane (DCM) <6 > 6 26 Cyclohexane <6 <6 27 Chloroform <6 <6 28 Isopropyl ether (IPE) <6 <6 29 Toluene <6 <6 Water <6 <6 n/a ¨ not applicable *solubility determined at 30 C
Example 5: Comprehensive Crystal-Form Screening 104201 About 450 crystallization experiments were performed using the mirdametinib prepared in Example 3 to identify novel polymorphs and solvates/hydrates of mirdametinib. The description of crystallization methods and solid-state forms of the input materials are described here.
Crystallization Modes 104211 Four main types of crystallization modes were employed in the screening study:
Slurry equilibration:
o Isothermal at 5, 25, and 50 C for 48-72 hours o Thermocycling between 40-5 C (in one-hour periods) for 48 hours Rapid and controlled cooling of clarified solutions of mirdametinib:
o Controlled cooling from 50 C to 5 C at a rate of 0.1 C/min with one hour hold every 5 C followed by hold at 5 C for 5 days, followed by hold at -20 C (for remaining solutions) for 6 to 9 days o Rapid cooling from 50 C to -20 C at an uncontrolled rate followed by hold at -20 C for 4 to 14 days Rapid and slow evaporation of clarified solutions of mirdametinib:
o Slow evaporation over up to 30 days at ambient conditions o Rapid evaporation for up to 3 days at reduced pressure at ambient temperature Addition of antisolvent to saturated and clarified mirdametinib solutions at room temperature:
o Rapid anti solvent addition and stirring at ambient temperature for up to days Crystallization Experimental # Exps. Description Input Forms Mode Mode Slurry of mirdametinib stirred Thermo-cycled 48 while cycling temperature Amorphous between 5-40 C for 48 hours Isothermal at Slurry of excess mirdametinib Elevated 48 Amorphous stirred at 50 C for 48 hours Temperature Slurry Isothermal at Slurry of excess mirdametinib Ambient 48 Amorphous stirred at 25 C for >48 hours Temperature Isothermal at Slurry of excess mirdametinib Low 48 Amorphous stirred at 5 C for 72 hours Temperature Mirdametinib solution equilibrated at ¨50 C, filtered, cooled at 0.1 C/min to 5 C with Controlled 48 1 hour hold every 5 C and hold Form IV
Cooling days at 5 C, followed by -Solution 20 C storage for 6-9 days for Cooling remaining solutions Mirdametinib solution equilibrated at ¨50 C, filtered, Rapid Cooling 48 Form IV
crash cooled to -20 C and hold 4-14 days at -20 C
Solution of mirdametinib Solution Fast 48 equilibrated at ambient is filtered Form IV
Evaporation Evaporation and rapidly evaporated under reduced pressure at ambient temperature Solution of mirdametinib Slow equilibrated at ambient is slowly Form IV
Evaporation evaporated over up to 30 days at ambient conditions Solution Rapid (but Precipitation of the mirdametinib Antisolvent dropwise) 48 from saturated solution induced Form IV
Addition Addition by the addition of an antisolvent.
Slurry of Toluene Solvate in Water/Ethanol Spiked with Process Solvent Toluene to Evaluate Solvate Risk Experiments to in Mirdametinib Process.
Evaluate Solvate Risk, Vacuum-Oven Drying of Focused Vacuum-Oven Important Solvates and Hydrates Various Experiments Drying, to Determine Stability.
Desolvation/
Dehydration by Desolvation/Dehydration by Heating Heating of Important Solvates Experiments and Hydrates to Investigate Potential New Non-Solvated Forms Total 443 Example 6: Amorphous Material Preparation and Experiments [0422] Amorphous mirdametinib was prepared on a 100 mg scale by rapid evaporation under reduced pressure (Genevac vacuum centrifuge) of 100 mg/mL solutions of the mirdametinib in methanol and THF (A-1 and A-2, respectfully).
[0423] Solutions of mirdametinib (100 mg/mL) were prepared in methanol and THE, and each solution was divided into three equal parts to be used for 1) open at RI
stability evaluation, 2) closed at RI stability evaluation, and 3) closed at -20 C
stability evaluation. Observations after rapid evaporation revealed that the samples from methanol were mostly dry, glassy materials, and the samples from THE were mostly sticky, dark amber gums.
104241 PXRD analyses of all six samples (three from both methanol and THF) following rapid evaporation indicated an amorphous state. Other analyses (e.g. PLM, TGA-1R, DSC) were performed on one sample from each solvent. Following initial analyses, one sample from each solvent was stored at RI in an open vial, at RI in a capped vial, and at -20 C in a capped vial.
[0425] PXRD and PLM analyses after one day showed no crystallization in A-la (open at RI), and A-lb (capped at RI) from methanol. A-lc (capped at -20 C) was not analyzed.

[0426]
PXRD and PLM analyses after one day showed crystallization to Form IV
in A-2a (open at RT) from THF. A-2b (capped at RT) and A-2c (capped at -20 C) were not analyzed.
104271 Since amorphous mirdametinib (A-1) was successfully prepared at 100 mg scale by rapid evaporation at reduced pressure from a methanol solution, this method was used to prepare vials containing amorphous material for use as the input material for slurry-ripening experiments in the screen.
Amorphous Mirdametinib Experiments Experiment Procedure Results A-1: Combined 299.8 mg of mirdametinib with 3 mL of Amorphous A-1 methanol and stirred for 1 hour yielding a solution.
Filtered the solution through 2 p.m PTFE filter to clarify.
(after 1 day at ambient) Pipetted 900 ILIL of A-1 above into 3 separate 2 mL vials: A-la, A-lb, and A-1c. Rapidly evaporated the solvent under reduced pressure in a vacuum centrifuge (GeneVac ) for 20 hours.
Products were mostly glassy with a thin film of dark amber on bottom.
PXRD and PLM analyses of all 3 samples indicated they were initially amorphous. Analyzed A-la by PLM, TGA-IR, and DSC.
DSC data was consistent with an amorphous state. TGA-IR
showed 1.3% wt. water and Me0H evolved upon heating to 200 "C.
PXRD and PLM analyses of A-la, after one day open at RT
indicated an amorphous state.
A-2 A-2: Combined 298.9 mg of mirdametinib with 3 mL of THF
and Form IV
stirred for 1 hour yielding a solution. Filtered the solution through 2 p.m PTFE filter to clarify.
(after 1 day at ambient) Pipetted 900 juL of A-2 above into 3 separate 2 mL vials: A-2a, A-2b, and A-2c. Rapidly evaporated the solvent under reduced pressure in a vacuum centrifuge (GeneVac ) for 20 hours.
Product was a dark amber clear gum with some glassy material on top.
PXRD and PLM analyses of all three samples indicated they were initially amorphous. Analyzed A-2a by PLM and TGA-IR.
TGA-IR showed 7.8% wt. water and THF evolved upon heating to 200 C. PXRD and PLM analyses of A-2a after one day open at RT showed crystallization to the supplied Form IV.

Characterization of Amorphous Material (A-1) 104281 PXRD and PLM analyses indicated the material was non-crystalline. DSC
analysis showed no melting endotherm up to 200 C, which is consistent with an amorphous phase. TGA-IR analysis showed about 1.3% wt. loss of water and methanol upon heating from 26-200 C. Amorphous mirdametinib was physically stable in both open and closed vials for at least 24 hours at RT.
Example 7: Results of Crystal-Form Screen 104291 The crystal-form screen consisted of about 450 crystallization experiments covering crystalline and amorphous input materials, and various crystallization modes, solvents, and temperatures.
104301 Four hydrates (designated Forms VI, XIII, XIX and XX) were observed and appear to be novel forms. Water activity experiments conducted between non-solvated Form IV and two stable hydrates (Forms VI and XIX) indicated that Form IV is more stable at water activities (aw) 0.6 ¨ 0.99 than hydrate Forms VI and XIX.
104311 Fifteen solvates (designated Forms V, VII-XII, XV-XVIII, and XXI-XXIV) observed included process-related toluene (Form V), toluene/MIBK (Form VIII), and unstable toluene (Form IX) solvates.
104321 Mirdametinib/process solvent conversion studies involving stirring the toluene solvate (Form V) in 1.1/0.5 (v/v) water/ethanol at RT with varying amounts of added toluene indicated that if crude mirdametinib from toluene/ethanol was the pure toluene solvate, controlling toluene levels going into the final crystallization could be critical However, if the crude API is mostly Form IV with lesser amounts of the toluene solvate, it may not be as critical to monitor toluene levels in the crude mirdametinib.

n >
o 1. .
r . , o r . , o r . , 9' 4, Summary of Slurry-Ripening and Evaporative Screening Results kµ.) Amorph Amorph Amorph Amorph Fast Slow o # Solvent Solvent kµ.) Evap Evap t.).
i--, 1 water C C A R A
Ethanol A A -4 2 water:ethanol (80:20 v/v) A A
A A ethanol:water (95:5 v/v) A C !A
!A

3 water:ethanol (90:10 v/v) A A
A A ethanol:water (90:10 v/v) A C
4 water:ethanol (95:5 v/v) A A A
A ethanol:water (80:20 v/v) A C
watermethanol (95:5 v/v) A A A
ethanol:toluene (90:10 v/v) A A
6 water:THF (95:5 ITN) A A A A
ethanol:toluene (50:50 v/v) A A
7 water:dimethylformamide (95:5 v/v) A A A A
ethanol:TFE (90:10 v/v) A A
8 water:dioxane (95:5) A A A A
ethanol:DMF (80:20 v/v) A A
9 water:acetone (95:5 v/v) A A A
A ethanol:dimethylcarbonate (70:30 v/v) A A
water:2-propanol (99:1 v/v) C C R A A
Acetone A A
11 cyclohexane A A A A
acetone:water (95:5 v/v) A A
12 chloroform A A A A
acetone:water (90:10 v/v) A C
13 isopropyl ether (IPE) D D D A D
acetone:water (80:20 v/v) A A 1 14 toluene X B F B
acetone:dichloromethane (90:10 v/v) X A
toluene:ethanol (95:5 v/v) B B B
acetone:chloroform (90:10 v/v) X , 16 toluene:ethanol (85:15 v/v) B B
B acetone:isopropyl ether (90:10 v/v) X A
17 toluene:acetone (80:20 v/v) A B
B B acetone:tetrahydrofuran (50:50 v/v) A A
18 toluene:4-methyl-2-pentanone (80:20 v/v) E F B
B acetone:nitromethane (70:30 v/v) N A
19 toluene:ethyl acetate (80:20 v/v) B B F B
acetone:methyl-t-butyl ether (90:10 v/v) A A
toluene:2-propanol (80:20 v/v) F B A acetone:DMF
(80:20 v/v) A 2 21 dimethylcarbonate:ethanol (95:5 NW) A A A
Acetonitrile A A
22 trifluoroethanol (TFE) A A A
acetonitrile:water (90:10 v/v) A A
23 MTBE (methyl-t-butyl ether) G A G
acetonitrile:water (80:20 v/v) A C
24 acetonitrile A A A
acetonitrile:water (70:30 v/v) C
acetonitrile:toluene (50:50 v/v) B B B B
acetonitrile:DMSO (80:20 v/v) 2 ro n 26 acetontrile:isopropyl ether (50:50 v/v) A A A
acetonitrile:DMF (80:20 v/v) A 2 27 acetontrile:dichloromethane (50:50 v/v) A A
Methanol A A
cp 28 dichloromethane:methanol (80:20 v/v) A
methananitromethane (80:20 v/v) A C iµ.) o 29 dichloromethane:tetrahydrofuran (80:20 v/v) A A
methanol:methyl acetate (50:50 v/v) A C 1--, C---, dichloromethane:ethanol (80:20 v/v) J 2-propanol A A
oc 31 isopropyl ether:methanol (80:20 v/v) A J 2-propanolloluene (90:10 v/v) A A w oc 32 isopropyl ether:tetrahydrofuran (80:20 v/v) J 2-propanol:cyclohexane (90:10 v/v) A A 1--, n >
o L.
r., o ,4 u, , u, r., o r., 9' 4, Amorph Amorph Amorph Amorph Fast Slow # Solvent Solvent Evap Evap 0 33 chloroform:2-propanol (60:40 v/v) J
2-propanol: dichloromethane (90:10 v/v) A A tµ.) o 34 chloroform:dimethylformamide (90:10 v/v) A J 2-propanol:chloroform (90:10 v/v) A A tµ.) t.).
35 dichloromethane 2-propanol (60:40 v/v) J 2-methy1-2-butanol 0 0 i--, 36 dichloromethane:DMSO (90:10 v/v) A
A ethyl acetate:dimethyl formamide (70:30 v/v) A 2 !A
!A
37 heptane A A A
ethyl acetate A A --.1
38 heptane:ethyl acetate (50:50 v/v) A A A A methyl acetate A A
39 heptane:2-propanol (80:20 v/v) A A A A
4-methyl-2-pentanone (MIBK) A Q
40 heptane:tetrahydrofuran (90:10 v/v) A
A A A J tetrahydrofuran (THF) A
41 heptane:2-butanone (80:20 v/v) A A A A
tetrahydrofurarrwater (90:10 v/v) A A
42 cyclohexane:acetone (90:10 v/v) A A A A
tetrahydrofuran:2-butanol (90:10 v/v) A A
43 cyclohexane:2-butanone (90:10 v/v) A
A A M tetrahydrofuran:cyclohexane (90:10 v/v) A A
44 trifluoroethanol (TFE):ethanol (95:5 v/v) A J J
dioxane:water (90:10 v/v) A A
45 trifluoroethanol (TFE):ethanol (90:10 v/v) A J A
dioxane:toluene (90:10 v/v) A A
46 nitromethane A A A
dioxane:toluene (80:20 v/v) A A
47 nitromethane:1-propanol (95:5 v/v) A
A A dioxane:dichloromethane (90:10 v/v) A A .
48 dimethylcarbonate (DMC) A A
dioxane:cyclohexane (90:10 v/v) A A
-...1 A Form IV Non-solvated Form IV N Form XVI Poorly crystalline Nitromethane solvate .
B Form V Toluene solvate 0 Form XVII 2-Methyl-2-Butanol solvate C Form VI Hydrate P Form XVIII
Chloroform/Water solvate D Form VII IPE or IPE/Water solvate Q Form II Non-solvated Form II
E Form VIII TolueneNIIBK solvate R Form XIX Hydrate F Form IX Unstable Toluene solvate S Form XX
Hydrate (unstable) G Form X MTBE/Water solvate T Form XXI 2-Methyl-2-Butanol solvate 2 (unstable) H Form XI Chloroform/IPA solvate U Form XXII IPE or IPE/Water solvate 2 I Form XII IPA solvate (isostructural to Form XI) V Form XXIII Cyclohexane/Et0Ac solvate J Form I Non-solvated Form I W Form XIV IPE
Solvate (unstable to desolvation) it K Form X111 Hydrate X Amorphous n L Form XIV Transient Non-solv. form (similar to Form No Solid IV) cp tµ.) o M Form XV Cyclohexane solvate ts.) 1¨, Notes:
C---, 1¨, 1. Some extra peaks of unknown transient form observed. Some conversion to Form IV observed at ambient conditions. oc w 2. Sample was a solution after 30 days of evaporation.
oc 1¨, 3. Sample was a solution after 11 days mixing.

n >
o 1. .
r . , o r . , o r . , 9' 4, Summary of Cooling and Solvent-Antisolvent Screening Results k..) # Solvent RC CC # Solvent Anti-Solvent SAS o kµ.) t.).
1 water:ethanol (60:40 v/v) C A C 1 ethanol water A i--, 2 water:ethanol (50:50 v/v) A C 2 ethanol toluene 3 --I
!A
!A
3 water:ethanol (40:60 v/v) 3 ethanol cyclohexane 3 -4 4 watermethanol (40:60 v/v) R A 4 ethanol chloroform 3 water:THF (50:50 v/v) C 5 ethanol IPE 3 6 water:dimethylformamide (50:50 v/v) 6 MIBK toluene F
7 water:dioxane (50:50) 7 MIBK cyclohexane A
8 water:acetone (50:50 v/v) 8 MIBK chlorofoim 3 9 2-propanol I I 9 cyclohexane 10 MeCN water A
11 chloroform 11 MeCN
toluene 3 12 isopropyl ether (IPE) 12 MeCN cyclohexane 3 13 toluene 13 MeCN
chloroform 3 .
14 toluene:ethanol (70:30 v/v) B 14 MeCN DCM 3 t'-::) toluene:ethanol (80:20 v/v) B B 15 MeCN IPE
3 oo 16 toluene:ethanol (90:10 v/v) B B 16 Et0Ac toluene A -- .
17 toluene:acetone (70:30 v/v) 17 Et0Ac cyclohexane V
18 toluene:4-methyl-2-pentanone (50:50 v/v) E
18 Et0Ac chloroform A
19 toluene:ethyl acetate (50:50 v/v) 19 Et0Ac IPE D
toluene:2-propanol (50:50 v/v) 20 Et0Ac DCM 3 21 dimethylcarbonate:ethanol (70:30 v/v) A
22 trifluoroethanol (TFE): ethanol (70:30 v/v) A
A
23 MTBE (methyl-t-butyl ether):2-propanol (50:50 v/v) 24 acetonitrile S S
acetonitrile:toluene (50:50 v/v) it 26 acetontrile:isopropyl ether (50:50 v/v) A D W n 27 acetontrile:dichloromethane (50:50 v/v) S
28 dicliloromethane:methanol (80:20 v/v) cp k.) o 29 dichloromethane:tetrahydrofuran (80:20 v/v) I-.
dichloromethane:ethanol (80:20 v/v) C---, 1--, 31 isopropyl ether:methanol (80:20 v/v) w 32 isopropyl ethertetrahydrofuran (80:20 v/v) oo I-.
33 chloroform:2-propanol (60:40 v/v) H H

n >
o L.
r., o ,4 u, , u, r., o r., 9' 4, # Solvent RC CC # Solvent Anti-Solvent SAS

34 chloroform:dimethylformamide (90:10 v/v) o 35 dichloromethane:2-propanol (40:60 viv) iµ.) t.).
36 dichloromethane:dimethyl sulfoxide (50:50 vAT) i--, 37 methyl acetate --I
Pli 38 heptane:ethyl acetate (50:50 v/v) A
Pli --I
39 heptane:2-propanol (50:50 v/v) I I
40 heptane:tetrahydrofuran (50:50 v/v) 41 heptane:2-butanone (50:50 v/v) A A
42 cyclohexane:acetone (40:60 v/v) 43 cyclohexane:2-butanone (40:60 v/v) 44 MIBK (4-methyl-2-pentanone) 45 Ethyl Acetate (Et0Ac) 46 2-methyl-2-butanol T T
47 nitromethane:1-propanol (40:60 v/v) 48 dimethylcarbonate (DMC) A 1 A 1 , A Form IV Non-solvated Form IV N Form XVI Poorly crystalline Nitromethane solvate B Form V Toluene solvate 0 Form XVII 2-Methyl-2-Butanol solvate ' C Form VI Hydrate P Form XVIII
Chloroform! Water solvate D Form VII IPE or IPE/Water solvate Q Form II Non-solvated Form II
E Form VIII Toluene/MIBK solvate R Form XIX
Hydrate F Form IX Unstable Toluene solvate S Form XX
Hydrate (unstable) G Form X MTBE/Water solvate T Form XXI 2-Methyl-2-Butanol solvate 2 (unstable) H Form XI Chloroform/IPA solvate U Form XXII IPE
or IPE/Water solvate 2 I Form XII IPA solvate (isostructural to Form XI) V
Form XXIII Cyclohexane/Et0Ac solvate J Form I Non-solvated Form I W Form XXIV IPE
Solvate (unstable to desolvation) K Form XIII Hydrate X Amorphous ro n Form XIV Transient Non-solv. form (similar to Form No Solid L
IV) Cl) M Form XV Cyclohexane solvate iµ.) o Notes:
1--, C---, 1. Some extra peaks of unknown transient form observed. Some conversion to Form IV observed at ambient conditions.
oc 2. Sample was a solution after 30 days of evaporation. w oc 3. Sample was a solution after 11 days mixing. 1--, Example 8: Description of the Obtained Crystal Forms of Mirdametinib [0433] The following sections deserig117be and summarize the physical properties of each of the crystal forms observed for mirdametinib.
Transient Non-Solvated Form XIV
[04341 The characterization data for Form XIV, a transient non-solvated form very similar to Form IV, are presented in FIG. 12A and FIG. 12B. PXRD and PLM
analysis indicates that the material is crystalline. DSC analysis shows a single sharp endotherm with onset at about 111 C (AH= 85.6 J/g). TGA-IR analysis shows about 0.15%
wt. loss to 150 C, indicating a non-solvated form. Form XIV was found to convert to Form IV
within four days at ambient conditions. Form XIV was not scaled up to be used for further studies (e.g. relative stability studies).
Toluene Solvate Form V
[04351 The characterization data for Form V, a process-relevant toluene solvate, are presented in FIG. 3A and FIG. 3B. PXRD and PLM analysis indicates that the material is crystalline. DSC analysis shows two overlapping endotherms with onsets at about 77 C
(AH= 44.3 J/g) and about 95 C (AH= 33.2 J/g). TGA-1R analysis shows about 2.7% wt.
(0.15 eq) loss of toluene upon heating to 100 C and about 4.7% wt. (0.26 eq) total loss of toluene upon heating to 185 C, indicating a solvated form. Form V was found to be stable at ambient conditions for > 10 days. Form V was scaled up to be used for focused studies around the mirdametinib crystallization process.
Preparation of Form V
[0436] Mirdametinib (308.0 mg) was dissolved in 3.0 mL of methanol and the solution was filtered through a 0.2 tim PTFE filter. The solution was rapidly evaporated under reduced pressure (GeneVac0) overnight to yield amorphous material. Toluene (150 tiL) and a stir disc was added to the amorphous product and the mixture was stirred at 25 C
for 35 min. Seeds ( --1 mg) were added, and the sample was stirred at 25 C
for 23 hours.
The damp solids were dried in a nitrogen flow chamber for 3 hours. The batch weight was about 212 mg, and the yield was about 69% wt. of Form V.

Form VIII (Toluene/MIBK Solvate) [0437] The characterization data for Form VIII, a toluene/MIBK solvate, are presented FIG. 6A and FIG. 6B. PXRD and PLM analysis indicates that the material is crystalline.
DSC analysis shows a broad endotherm with onset at about 81 C (AH= 67.1 J/g) followed by a small broad endotherm with onset at about 110 C (AH= 7.1 J/g).
TGA-IR
analysis shows about 3.3% wt. loss of toluene and MIBK upon heating to 112 C
and about 0.8% wt. additional loss of toluene and MIBK upon heating from 112 to 150 C, indicating a solvated form. Form VIII was stable at ambient conditions for > 2 days. Form VIII was not scaled up for further studies (e.g., focused studies around the mirdametinib crystallization process).
Unstable Toluene Solvate Form IX
[0438] The characterization data for Form IX, an unstable toluene solvate, are presented in FIG. 7A and FIG. 7B. PXRD and PLM analysis indicates that the material is crystalline. DSC analysis shows a broad endotherm with onset at about 84 C
(AH= 17.1 J/g), an endotherm at about 107 C (AH=12.4 J/g), and a sharper endotherm with onset at about 114 C (AH= 39.6 J/g). TGA-IR analysis shows about 4.6% wt. loss of toluene upon heating to 128 C, indicating a solvated form. Form IX exhibited significant conversion toward Form IV after 20 hours at ambient conditions. Form IX was not scaled up for further studies (e.g. focused studies around the mirdametinib crystallization process).
Hydrate Form VI
[0439] The characterization data for Form VI, a hydrate, are presented in FIG. 4A and FIG. 4B. PXRD and PLM analysis indicates that the material is crystalline. DSC
analysis shows three broad endotherms with onsets at about 41 C (AH= 11.4 J/g), about (AH= 48.1 J/g), and about 109 C (AH= 21.3 J/g). TGA-IR analysis shows about 2.4% wt.
(0.7 eq) loss of water upon heating to 125 C, indicating a hydrated form.
Form VI was found to be stable for > 2 weeks in solid-state at ambient conditions. Form VI
was scaled up to be used for water activity studies between non-solvated Form IV and the stable hydrates.

Preparation of Form VI/ Form IV Mixture [0440] Mirdametinib (120.8 mg) was dissolved in 1.0 mL of methanol. The solution was filtered through a 0.2 lam PTFE filter and rapidly evaporated under reduced pressure (GeneVac8) overnight. Water (1.0 mL) and a stir disc were added to the dry solids, followed by seeds (-0.1 mg). The suspension was mixed at 25 C for 24 hours, and the solids were isolated by vacuum-filtration. The batch weight was about 58 mg, and the yield was an about 48% wt. of a mixture of Form VI and Form IV.
Hydrate Form IX
[04411 The characterization data for Form IX, a hydrate, are presented in FIG. 7A and FIG. 7B. PXRD and PLM analysis indicates that the material is crystalline and contains some Form IV. DSC analysis shows two broad endotherms with onsets at about 55 C
(AH= 66.8 J/g) and about 109 C (AH= 25.5 J/g). TGA-lR analysis shows about 3.1% wt.
(0.9 eq) loss of water upon heating to 100 C, indicating a hydrated form.
Form IX was observed only once (as phase-pure) during screening, and it was observed to slowly convert to Form IV in solid-state at ambient conditions. Form IX was not scaled up for further studies (e.g., water activity studies).
Hydrate Form XIX
[04421 The characterization data for Form XIX, a hydrate, are presented in FIG. 17A and FIG. 17B. PXRD and PLM analysis indicates that the material is crystalline.
DSC
analysis shows a broad endotherm with onset at about 69 C (AH= 28.5 J/g), followed by an exotherm with onset at about 98 C (AH= 13.5 J/g), and a sharp endotherm with onset at about 115 C (AH= 59.6 J/g). TGA-IR analysis shows about 1.85% wt. (0.5 eq) loss of water upon heating to 92 C, indicating a hydrated form. Form XIX was found to be stable in a capped vial for > 2 weeks. Form XIX was scaled up to be used for water activity studies between non-solvated Form IV and the stable hydrates.
Preparation of Form XIX
[04431 Mirdametinib (about 497 mg) was dissolved in 3.0 mL of water:Me0H (40:60 v/v) by mixing at 50 C for 10 min. The solution was filtered hot through a 0.2 lam PTFE
filter into a second vial at 50 C. The solution was rapidly cooled to -20 C, and seeds (1-2 mg) were added and dispersed by swirling. After 30 min., the product was a thick paste, so 1.0 mL more solvent was added, and the suspension cooled at -20 C for 30 min. The solids in the cold suspension were isolated by vacuum-filtration, then allowed to air dry for 16 hours. The batch weight was about 278 mg, and the yield was about 56%
wt. of Form XIX.
Hydrate Form XX
[0444] The characterization data for Form XX, a hydrate, are presented in FIG. 18A and FIG. 18B. PXRD and PLM analysis indicates that the material is crystalline.
DSC
analysis shows three broad endotherms with onsets at about 77 C (AH= 29.0 J/g), about 92 C (AH= 9.8 J/g) and about 110 C (AH= 6.8 J/g). TGA-IR analysis shows about 2.6%
wt. (0.7 eq) loss of mostly water with a small amount of acetonitrile upon heating to 126 C, indicating a hydrated form. TGA-IR analysis of a second less-crystalline sample of Form XX showed only water evolved upon heating. Form XX was found to convert to Form IV within 10 days at ambient conditions. Form XX was not scaled up for further studies (e.g., water activity studies).
Other Non-Process Related Solvates (Forms VII, X-XII, XV-XVIII, XXI-XXIV) [0445]
A summary of the non-process related solvates (Forms VII, X-XII, XV-XVIII, and XXI-XXIV) is shown in Table 2. The characterization data for these solvates are shown in FIGs. 5A-5B, 8A-8B, 9A-9B, 10A-10B, 13A-13B, 14A-14B, 15A-15B, 16A-16B, 19A-19B, 20A-20B, 21A-21B, and 22A-22B.
Table 2 - Summary of Non-Process Solvates DSC Endotherm Form Nature of Solvate Onsets (approximate TGA-IR Data (Wt. Loss) C) VII IPE or IPE/water 85, 110 5.2% isopropyl ether X MTBE/water 89 (2 merged) 2.9% MTBE and water XI Chloroform/IPA 69, 104 7.6% chloroform and IPA

8.5% IPA (low sample , quantity) XV Cyclohexane 104 3.8% (0.2 eq.) cyclohexane XVI Nitromethane (poorly 74, 102 21% (0.2 eq.) crystalline) (2 merged), 114 nitromethane XVII 2-Methyl-2-Butanol 89 2.7% (0.15 eq.) 2-methyl-2- butanol XVIII Likely Chloroform 83 1.6% chloroform and water 2-Methyl-2-Butanol 52 (overlap of two), 90 14.1% (0.9 eq.) 2-methyl-(converts to Form IV) 2-butanol XXII IPE or IPE/water 65, 89, 102 13.8% isopropyl ether and water XXIII Cyclohexane/Et0Ac 81, 101 4.4% cyclohexane and Et0Ac XXIV IPE or IPE/water 104 (multiple 1.2% isopropyl ether and overlapping endotherms) water [0446] PXRD, TGA, and DSC data for each form presented herein are shown in FIGs.
2A-2B, 3A-3B, 4A-4B, 5A-5B, 6A-6B, 7A-7B, 8A-8B, 9A-9B, 10A-10B, 11A-11B, 12A-12B, 13A-13B, 14A-14B, 15A-15B, 16A-16B, 17A-17B, 18A-18B, 19A-19B, 20A-20B, 21A-21B, 22A-22B, and 23A-23B.
Example 9: Water Activity Studies of Hydrates at 23 C
[0447]
Water activity studies of the stable hydrated Forms VI and XIX were conducted to determine their relative thermodynamic stabilities. The studies were conducted at 23 C
in various water/ethanol mixtures to provide water activities (aw) from 0.6 ¨
0.99. The water activity range includes the approximate water activity of the current final isolation step of the mirdametinib manufacturing process. Saturated suspensions were prepared by stirring an excess of mirdametinib in the test solvents for 16 hours. The suspensions were filtered and transferred onto mixtures containing equivalent amounts of Form VI and Form XIX.
[0448] The suspensions were stirred at the target temperatures, sampled at three and five days and analyzed by PXRD. The results are summarized below and show that all experiments produced Form IV. The hydrates may be kinetically favored at higher water activities.
Example 10: Drying of Certain Forms Via Vacuum Oven [0449]
Drying studies for certain forms were conducted overnight in a vacuum oven at 45 C. After drying, samples were equilibrated to RT for 10 min. and analyzed by PXRD at about 70% ambient lab humidity. The results are summarized below.
= Form V (Toluene Solvate): Remained unchanged.

= Form VI (Hydrate): Partially converted to Form A.
= Form XIII (Hydrate): Form XIII/Form IV mixture converted to Form IV.
= Form XIX (Hydrate): Remained unchanged.
[0450] Desolvation/dehydration studies of certain forms were conducted in a TGA pan with loose lid at a heating rate of 15 C/min from 25 to 100 C with a 5 min.
hold at 100 C. Samples were air-cooled to RT on the TGA and analyzed by PXRD if crystalline. The results are summarized below.
= Form V (Toluene Solvate): After cooling, observed sample to be molten and transparent dark amber in appearance (melted and solidified in molten, amorphous state, possible decomposition).
= Form VI (Hydrate): After cooling, observed sample to be molten and transparent dark amber in appearance (melted and solidified in molten, amorphous state, possible decomposition).
= Form XIX (Hydrate): After cooling, observed sample to be very slightly sticky, but solid particles (not melted). PXRD indicated Form I.
Example 11: Toluene-Spiked Slurry Studies [0451] The process-relevant toluene solvate (Form V) was stirred in water:ethanol (1.1/0.5 v/v) overnight at RT with varying amounts of added toluene. The suspensions were filtered, and solids analyzed by PXRD. The results are summarized below.
= With no added toluene, Form V converted to phase-pure Form IV.
= With 0.5% added toluene (relative to mirdametinib weight), Form V
converted to mostly Form IV with some lesser amount of Form V.
= With 1% and 2% added toluene, higher relative amounts of Form V were observed, but difficult to distinguish between 1% and 2% toluene, since PXRD
data was qualitative and variable.
[0452] The results of the toluene-spiked slurry studies suggest that if crude mirdametinib from toluene/ethanol was the pure toluene solvate, controlling toluene levels going into the final crystallization would be critical. However, if the crude mirdametinib is mostly Form IV with lesser amounts of the toluene solvate, it may not be as critical to monitor toluene levels in the crude mirdametinib.

Example 12: Single Crystal X-Ray Diffraction Analysis of Form IV
[0453] A suitable single Form IV crystal was analyzed using a Bruker D8 Venture Photon II CPAD diffractometer equipped with a CuKa INCOATEC Imus micro-focus source (X = 1.54178 A). The simulated PXRD pattern was calculated from the low temperature (100 K) structure and room temperature (298 K, 25 C) unit cell parameters shown below. Unit cell at room temperature was initially determined by Difference Vectors method based on 235 reflections harvested from 151, 10 diffraction frames. Unit cell parameters were subsequently refined during data integration by Saint (Bruker (2020). SAINT. Data Reduction Software) and are based on 903 reflections recorded between 19.1 and 1.1 A resolution. The simulated pattern was consistent with an experimental Form IV pattern as shown in FIG. 1A.
Table 3: Initially Determined Unit Cell Parameters at Room Temperature a[A] b[A] c[A] an V[A3]
27.080(2) 27.080(2) 4.6971(5) 90 90 90 3444.5(8) Table 4: Form IV Crystal Data and Structure Refinement Crystal system Tetragonal Space group P41 a/A 26.9861(4) b/A 26.9861(4) c/A 4.66600(10) cdo 90 Volume/A3 3398.01(12) pcalcg/cm3 1.885 Wmm-1 15.351 F(000) 1888 Example 13: Capsule Formulations Formulation Composition 1 mg 2 mg 5 mg Ingredient mg/cap (w/w) mg/cap (w/w) mg/cap (w/w) Mirdametinib a 0.77 1 0.77 2 5.26 5 Microcrystalline Cellulose b 93.23 121.2 93.23 242.4 89.74 85.25 Croscarmellose sodium 5 6.5 5 13 5 4.75 Magnesium Stearate 1 1.3 1 2.6 0 0 Total 100 130 100 260 100 95 Size #3 Size #1 Size #2 Capsule Shells HG HG HG
capsules capsules capsules HG = Hard Gelatin a Based on a theoretical potency of 1.000. Actual quantity may be adjusted based on the actual potency.
b Quantity of microclystalline cellulose may be adjusted for slight potency changes of PD-0325901.
Example 14: Dispersible Tablets Formulation Composition 0.5 mg 1.0 mg Ingredient mg/ta %
mg/tab (w/w) b (w/w) Mirdametinib a 0.75 0.50 0.75 1.00 Microcrystalline Cellulose b 90.52 60.60 90.52 121.20' Croscarmellose sodium 4.85 3.25 4.85 6.50 Grape flavor 1.94 1.30 1.94 2.60 Sucralose 0.97 0.65 0.97 1.30 Magnesium Stearate 0.97 0.65 0.97 1.30 Total 100.0 66.95 100.0 133.90 a = Based on theoretical potency of 1.000. Quantity may be adjusted based on the actual potency.
b = Quantity of microcrystalline cellulose may be adjusted for slight potency changes of mirdametinib c = Excipients are present at the same mg/unit as the 1 mg capsule [0454] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.
[0455] While the invention has been described in connection with specific aspects thereof, it will be understood that invention is capable of further modifications and this application is intended to cover any variations, uses, or adaptations following, in general, the principles and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and can be applied to the essential features hereinbefore set forth, and follows in the scope of the claimed.
[0456] In addition to the various embodiments described herein, the present disclosure includes the following embodiments numbered El through E275. This list of embodiments is presented as an exemplary list and the application is not limited to these embodiments.
[0457] El. A crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (1) HOON
OH
F I
(I), selected from the group consisting of:
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern haying peaks at 5.4 0.2, 17.5 + 0.2, and 22.8 + 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.9 0.2, 7.2 0.2, and 21.2 0.2 degrees two theta;
a crystalline form of N-((R)-2,3 -di hydroxypropoxy)-3,4 -di fluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.3 0.2, 10.6 0.2, and 16.1 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern haying peaks at 5.4 0.2, 10.7 0.2, and 18.7 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern haying peaks at 6.7 0.2, 13.5 0.2, and 22.2 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 10.6 0.2, 19.6 0.2, and 24.8 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.5 1 0.2, 6.9 0.2, and 10.1 0.2 degrees two theta;

a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 10.1 0.2, 17.3 0.2, and 22.6 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 4.6 0.2, 5.1 0.2, and 14.6 0.2 degrees two theta;
a crystalline form of N-((R)-2,3 -di hydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 4.6 0.2, 23.4 0.2, and 25.2 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.5 0.2, 14.7 0.2, and 20.9 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 6.0 0.2, 17.1 0.2, and 20.6 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.9 +
0.2, 10.1 0.2, and 15.5 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 4.6 +
0.2, 10.7 0.2, and 15.9 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 10.2 0.2, 11.6 0.2, and 20.0 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 7.8 0.2, 14.0 0.2, and 17.1 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.5 0.2, 8.2 0.2, and 16.7 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 7.2 0.2, 21.7 + 0.2, and 29.1 + 0.2 degrees two theta;

a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern haying peaks at 5.4 0.2, 9.7 0.2, and 10.7 0.2 degrees two theta; and a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 7.2 0.2, 20.6 0.2, and 23.0 0.2 degrees two theta.
[0458] E2. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks 5.4 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta.
[0459] E3. The crystalline form of E2, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks 5.4 0.2, 12.5 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta.
[0460] E4. The crystalline form of E2 or E3, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.7 wt% between about 35 C and about 100 C.
[0461] E5. The crystalline form of any one of E2-E4, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 77 C.
[0462] E6. The crystalline form of any one of E2-E5, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 95 C.
[0463] E7. The crystalline form of any one of E2-E6, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 77 C and a second endotherm onset at about 95 C.
[04641 E8. The crystalline form of any one of E2-E7, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 2A.
[0465] E9. The crystalline form of any one of E2-E8, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de is characterized by:

a) a TGA profile substantially as shown in FIG. 2B; and/or b) a DSC profile substantially as shown in FIG. 2B.
[0466] E10. The crystalline form of any one of E2-E9, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form V.
[0467] El 1. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is characterized by an XRPD pattern having peaks at 5.9 0.2, 7.2 0.2, and 21.2 0.2 degrees two theta.
[0468] E12. The crystalline form of Ell, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.9 0.2, 7.2 0.2, 9.3 0.2, and 21.2 0.2 degrees two theta.
[0469] E13. The crystalline form of Ell or E12, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.4 wt% between about 25 C and about 125 C.
[0470] E14. The crystalline form of any one of El 1-E13, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 41 C.
[0471] E15. The crystalline form of any one of Ell-E14, wherein the crystalline form of N-((R)-2,3 -di hydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 70 C.
[0472] E16. The crystalline form of any one of Ell-E15, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 109 C.
[0473] E17. The crystalline form of any one of Ell-E16, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 41 'V, a second endotherm onset at about 70 C, and a third endotherm onset at about 109 C.
[0474] E18. The crystalline form of Ell-E17, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 3A.

[0475] E19. The crystalline form of Ell-E18, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 3B; and/or b) a DSC profile substantially as shown in FIG. 3B.
[0476] E20. The crystalline form of any one of El 1-E1 9, wherein the crystalline form of N-((R)-2,3 -di hydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-4-i odo-phenyl ami no)-benzamide is Form VI.
[0477] E21. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.3 0.2, 10.6 0.2, and 16.1 0.2 degrees two theta.
[0478] E22. The crystalline form of E21, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.3 0.2, 10.6 0.2, 13.9 0.2, and 16.1 0.2 degrees two theta.
[0479] E23. The crystalline form of E21 or E22, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 5.2 wt% between about 40 C and about 120 C.
[0480] E24. The crystalline form of any one of E21-E23, wherein the crystalline form of N-((R)-2,3 -di hydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzamide exhibits a DSC thermogram that an endotherm onset at about 85 C.
[0481] E25. The crystalline form of any one of E21-E24, wherein the crystalline form of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 110 C.
[0482] E26. The crystalline form of any one of E21-E25, wherein the crystalline form of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 85 'V
and a second endotherm onset at about 110 C.
[0483] E27. The crystalline form of any one of E21-E26, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de is characterized by an XRPD pattern substantially as shown in FIG.
4A.

[0484] E28. The crystalline form of any one of E21-E27, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 4B; and/or b) a DSC profile substantially as shown in FIG. 4B.
[0485] E29. The crystalline form of any one of E21-E28, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl ami no)-benzamide is Form VII.
[0486] E30. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4 0.2, 10.7 0.2, and 18.7 0.2 degrees two theta.
[0487] E31. The crystalline form of E30, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4 0.2, 10.7 0.2, 18.7 0.2, and 23.9 0.2 degrees two theta.
[0488] E32. The crystalline form of E30 or E31, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 3.3 wt% between about 40 C and about 112 C.
[0489] E33. The crystalline form of any one of E30-E32, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 81 C.
[0490] E34. The crystalline form of any one of E30-E33, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 110 C.
[0491] E35. The crystalline form of any one of E30-E34, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 81 'V
and a second endotherm onset at about 110 C.
[0492] E36. The crystalline form of any one of E30-E35, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de is characterized by an XRPD pattern substantially as shown in FIG.
5A.

[0493] E37. The crystalline form of any one of E30-E36, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 5B; and/or b) a DSC profile substantially as shown in FIG. 5B.
[0494] E38. The crystalline form of any one of E30-E37, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl ami no)-benzamide is Form VIII.
[0495] E39. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 6.7 0.2, 13.5 0.2, and 22.2 0.2 degrees two theta.
[0496] E40. The crystalline form of E39, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 6.7 0.2, 8.0 0.2, 13.5 0.2, and 22.2 0.2 degrees two theta.
[0497] E41. The crystalline form of E39 or E40, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 4.6 wt% between about 28 C and about 128 C.
[0498] E42. The crystalline form of any one of E39-E41, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 84 C.
[0499] E43. The crystalline form of any one of E39-E42, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 107 C.
[0500] E44. The crystalline form of any one of E39-E43, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 114 C.
[0501] E45. The crystalline form of any one of E39-E44, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 84 'V, a second endotherm onset at about 107 C, and a third endotherm onset at about 114 C.

[0502] E46. The crystalline form of any one of E39-E45, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
6A.
[0503] E47. The crystalline form of any one of E39-E46, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de is characterized by:
a) a TGA profile substantially as shown in FIG. 6B; and/or b) a DSC profile substantially as shown in FIG. 6B.
[0504] E48. The crystalline form of any one of E39-E47, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form IX.
[0505] E49. The crystalline of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.6 0.2, 19.6 0.2, and 24.8 0.2 degrees two theta.
[0506] E50. The crystalline of E49, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 10.6 0.2, 19.6 0.2, and 24.8 0.2 degrees two theta.
[0507] E51. The crystalline form of E49 or E50, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.9 wt% between about 40 C and about 115 C.
[0508] E52. The crystalline form of any one of E49-E51, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 89 C.
[0509] E53. The crystalline form of any one of E49-E52, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
7A.
[0510] E54. The crystalline form of any one of E49-E53, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 7B; and/or b) a DSC profile substantially as shown in FIG. 7B.

[0511] E55. The crystalline form of any one of E49-E54, wherein the crystalline form of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form X.
[0512] E56. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 6.9 0.2, and 10.1 0.2 degrees two theta.
[0513] E57. The crystalline form of E56, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 6.9 0.2, 10.1 0.2, and 19.2 0.2 degrees two theta.
[05141 E58. The crystalline form of E56 or E57, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 7.6 wt% between about 40 C and about 175 C.
[0515] E59. The crystalline form of any one of E56-E58, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 69 C.
[0516] E60. The crystalline form of any one of E56-E59, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 104 C.
[0517] E61. The crystalline form of any one of E56-E60, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about and a second endotherm onset at about 104 C.
[0518] E62. The crystalline form of any one of E56-E61, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
8A.
[05191 E63. The crystalline form of any one of E56-E62, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 8B; and/or b) a DSC profile substantially as shown in FIG. 8B.

[0520] E64. The crystalline form of any one of E56-E63, wherein the crystalline form of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-b enzami de is Form XI.
[0521] E65. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.1 0.2, 17.3 0.2, and 22.6 0.2 degrees two theta.
[0522] E66. The crystalline form of E65, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.1 0.2, 17.3 0.2, 21.5 0.2, and 22.6 0.2 degrees two theta.
[0523] E67. The crystalline form of E65 or E66, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 8.5 wt% between about 40 C and about 160 C.
[0524] E68. The crystalline form of any one of E65-E67, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 72 C.
[0525] E69. The crystalline form of any one of E65-E68, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 109 C.
[0526] E70. The crystalline form of any one of E65-E69, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about and a second endotherm onset at about 109 C.
[0527] E71. The crystalline form of any one of E65-E70, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
9A.
[0528] E72. The crystalline form of any one of E65-E71, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 9B; and/or b) a DSC profile substantially as shown in FIG. 9B.

[0529] E73. The crystalline form of any one of E65-E72, wherein the crystalline form of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-b enzami de is Form XII.
[0530] E74. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 0.2, 5.1 0.2, and 14.6 0.2 degrees two theta.
[0531] E75. The crystalline form of E74 wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 0.2, 5.1 0.2, 6.4 0.2, and 14.6 0.2 degrees two theta.
[0532] E76. The crystalline form of E74 or E75, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 3.1 wt% between about 20 C and about 100 C.
[0533] E77. The crystalline form of any one of E74-E76, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 55 C.
[0534] E78. The crystalline form of any one of E74-E77, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 109 C.
[0535] E79. The crystalline form of any one of E74-E78, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about and a second endotherm onset at about 109 C.
[0536] E80. The crystalline form of any one of E74-E79, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
10A.
[0537] E81. The crystalline form of any one of E74-E80, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 10B; and/or b) a DSC profile substantially as shown in FIG. 10B.

[05381 E82. The crystalline form of any one of E74-E81, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIII.
[0539] E83. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 0.2, 23.4 0.2, and 25.2 0.2 degrees two theta.
[05401 E84. The crystalline form of E83, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 0.2, 23.4 0.2, 25.2 0.2, and 30.6 0.2 degrees two theta.
[05411 E85. The crystalline form of E83 or E84, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 0.15 wt% between about 40 C and about 150 C.
[0542] E86. The crystalline form of any one of E83-E85, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 111 C.
[05431 E87. The crystalline form of any one of E83-E86, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
11A.
[05441 E88. The crystalline form of any one of E83-E87, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 11B; and/or b) a DSC profile substantially as shown in FIG. 11B.
[0545] E89. The crystalline form of any one of E83-E88, wherein the crystalline form of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-b enzami de is Form XIV.
[0546] E90. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 14.7 0.2, and 20.9 0.2 degrees two theta.

[0547] E91. The crystalline form of E90, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 14.7 0.2, 20.9 0.2, and 26.6 + 0.2 degrees two theta.
[0548] E92. The crystalline form of E90 or E91, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 3.8 wt% between about 40 C and about 150 C.
[0549] E93. The crystalline form of any one of E90-E92, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 104 C.
[0550] E94. The crystalline form of any one of E90-E93, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
12A.
[0551] E95. The crystalline form of any one of E90-E94, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 12B; and/or b) a DSC profile substantially as shown in FIG. 12B.
[0552] E96. The crystalline form of any one of E90-E95, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de is Form XV.
[0553] E97. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 6.0 0.2, 17.1 0.2, and 20.6 0.2 degrees two theta.
[0554] E98. The crystalline form of E97, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 6.0 0.2, 12.8 0.2, 17.1 0.2, and 20.6 0.2 degrees two theta.
[0555] E99. The crystalline form of E97 or E98, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.1 wt% between about 40 C and about 150 C.

[0556] E100. The crystalline form of any one of E97-E99, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 74 C.
[0557] E101. The crystalline form of any one of E97-E100, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de exhibits a DSC thermogram that has an endotherm onset at about 102 C.
[0558] E102. The crystalline form of any one of E97-E101, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 114 C.
[0559] E103. The crystalline form of any one of E97-E102, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 74 'V, a second endotherm onset at about 102 C, and a third endotherm onset at about 114 C.
[0560] E104. The crystalline form of any one of E97-E103, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
13A.
[0561] E105. The crystalline form of any one of E97-E104, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 13B; and/or b) a DSC profile substantially as shown in FIG. 13B.
[0562] E106. The crystalline form of any one of E97-E105, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVI.
[0563] E107. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.9 0.2, 10.1 0.2, and 15.5 0.2 degrees two theta.
[0564] E108. The crystalline form of E107, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.9 0.2, 10.1 0.2, 11.7 0.2, and 15.5 0.2 degrees two theta.

[0565] E109. The crystalline form of E107 or E108, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.7 wt% between about 40 C and about 100 C.
[0566] E110. The crystalline form of any one of E107-E109, wherein crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 89 C.
[0567] El 11. The crystalline form of any one of El 07-El 10, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
14A.
[0568] E112. The crystalline form of any one of E107-E111, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 14B; and/or b) a DSC profile substantially as shown in FIG. 14B.
[0569] E113. The crystalline form of any one of E107-E112, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVII.
[0570] E114. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 + 0.2, 10.7 + 0.2, and 15.9 + 0.2 degrees two theta.
[0571] E115. The crystalline form of E114, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 0.2, 10.7 0.2, 15.9 0.2, and 19.6 0.2 degrees two theta.
[0572] E116. The crystalline form of E114 or E115, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 1.6 wt% between about 30 C and about 150 C.
[0573] E117. The crystalline form of any one of E114-E116, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 83 C.

[0574] E118. The crystalline form of any one of E114-E117, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
15A.
[0575] E119. The crystalline form of any one of E114-E118, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 15B; and/or b) a DSC profile substantially as shown in FIG. 15B.
[0576] E120. The crystalline form of any one of E114-E119, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVIII.
[05771 E121. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.2 0.2, 11.6 0.2, and 20.0 0.2 degrees two theta.
[0578] E122. The crystalline form of E121, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.2 0.2, 11.6 0.2, 17.1 0.2, and 20.0 0.2 degrees two theta.
[0579] E123. The crystalline form of E121 or E122, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 1.85 wt% between about 23 C and about 92 C.
[0580] E124. The crystalline form of any one of E121-E123, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 69 C.
[0581] E125. The crystalline form of any one of E121-E124, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 98 C.
[0582] E126. The crystalline form of any one of E121-E125, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 115 C.
[0583] E127. The crystalline form of any one of E121-E126, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 69 C, a second endotherm onset at about 98 C, and a third endotherm onset at about 115 'C.
[0584] E128. The crystalline form of any one of E121-E127, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
16A.
[0585] E129. The crystalline form of any one of E121-E128, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 16B; and/or b) a DSC profile substantially as shown in FIG. 16B.
[0586] E130. The crystalline form of any one of E121-E129, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIX.
[0587] E131. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.8 0.2, 14.0 0.2, and 17.1 0.2 degrees two theta.
[0588] E132. The crystalline form of E131, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.8 + 0.2, 14.0 + 0.2, 15.6 +
0.2, and 17.1 0.2 degrees two theta.
[0589] E133. The crystalline form of E131 or E132, wherein the TGA
exhibits that the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.6 wt% between about 29 C and about 126 C.
[0590] E134. The crystalline form of any one of E131-133, wherein the crystalline form of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 77 C.
[05911 E135. The crystalline form of any one of E131-E134, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 92 C.
[0592] E136. The crystalline form of any one of E131-E135, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 110 C.

[0593] E137. The crystalline form of any one of E131-E136, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 77 C, a second endotherm onset at about 92 C, and a third endotherm onset at about 110 C.
[0594] E138. The crystalline form of any one of E131-E137, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
17A.
[0595] El 39. The crystalline form of any one of E131-E138, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 17B; and/or b) a DSC profile substantially as shown in FIG. 17B.
[0596] E140. The crystalline form of any one of E131-E139, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XX.
[0597] E141. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 8.2 0.2, and 16.7 0.2 degrees two theta.
[0598] E142. The crystalline form of E141, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is characterized by an XRPD pattern having peaks at 5.5 0.2, 8.2 0.2, 16.7 0.2, and 17.7 0.2 degrees two theta.
[0599] E143. The crystalline form of E141 or E142, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 14.1 wt% between about 30 C and about 110 C.
[0600] E144. The crystalline form of any one of E141-E143, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 52 C.
[0601] E145. The crystalline form of any one of E141-E144, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 90 C.

[0602] E146. The crystalline form of any one of E141-E145, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about and a second endotherm onset at about 90 C.
[0603] E147. The crystalline form of any one of E141-E146, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
18A.
[0604] E148. The crystalline form of any one of E141-E147, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 18B; and/or b) a DSC profile substantially as shown in FIG. 18B.
[0605] E149. The crystalline form of any one of E141-E148, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXI.
[0606] E150. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2 0.2, 2L7 0.2, and 29.1 0.2 degrees two theta.
[0607] E151. The crystalline form of E150, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is characterized by an XRPD pattern having peaks at 7.2 0.2, 18.6 0.2, 21.7 0.2, and 29.1 0.2 degrees two theta.
[0608] E152. The crystalline form of E150 or E151, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 13.8 wt% between about 26 C and about 135 C.
[0609] E153. The crystalline form of any one of E150-E152, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 65 C.
[0610] E154. The crystalline form of any one of E150-E153, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 89 C.

[0611] E155. The crystalline form of any one of E150-E154, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 102 C.
[0612] E156. The crystalline form of any one of E150-E155, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 65 C, a second endotherm onset at about 89 C, and a third endotherm onset at about 102 C.
[0613] E157. The crystalline form of any one of E150-E156, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
19A.
[0614] E158. The crystalline form of any one of E150-E157, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 19B; and/or b) a DSC profile substantially as shown in FIG. 19B.
[0615] E159. The crystalline form of any one of E150-E158, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXII.
[0616] E160. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4 0.2, 9.7 0.2, and 10.7 0.2 degrees two theta.
[0617] E161. The crystalline form of E160, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4 0.2, 6.5 0.2, 9.7 0.2, and 10.7 0.2 degrees two theta.
[0618] E162. The crystalline form of E160 or E161, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 4.4 wt% between about 27 C and about 137 C.
[0619] E163. The crystalline form of any one of E160-E162, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 81 C.

[0620] E164. The crystalline form of any one of E160-E163, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 101 C.
[0621] E165. The crystalline form of any one of E160-E164, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about and a second endotherm onset at about 101 C.
[0622] E166. The crystalline form of any one of E160-E165, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG.
20A.
[0623] E167. The crystalline form of any one of E160-E166, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 20B; and/or b) a DSC profile substantially as shown in FIG. 20B.
[0624] E168. The crystalline form of any one of E160-E167, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXIII.
[0625] E169. The crystalline form of El, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2 0.2, 20.6 0.2, and 23.0 0.2 degrees two theta.
[0626] E170. The crystalline form of E169, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2 0.2, 9.5 0.2, 20.6 0.2, and 23.0 0.2 degrees two theta.
[0627] E171. The crystalline form of E169 or E170, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 1.2 wt% between about 30 C and about 119 C.
[0628] E172. The crystalline form of any one of E169-E171, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 104 C.

[0629] E173. The crystalline form of any one of E169-E172, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRF'D pattern substantially as shown in FIG.
21A.
[0630] E174. The crystalline form of any one of E169-E173, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 21B; and/or b) a DSC profile substantially as shown in FIG. 21B.
[0631] E175. The crystalline form of any one of E169-E174, wherein the crystal form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXIV.
[06321 E176. Amorphous solid of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) HOO N
OH H
N
(I).
[0633] E177. The amorphous solid of claim 176, wherein the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 22A.
[0634] E178. The amorphous solid of E176 or E177, wherein the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 22B; and/or b) a DSC profile substantially as shown in FIG. 22B.
[0635] El 79. A pharmaceutical composition comprising: the crystalline form of any one of claims 1-175 or the amorphous solid of any one of claims 176-178; and one or more pharmaceutically acceptable carriers.
[0636] E180. The pharmaceutical composition of E179, wherein the crystalline form or the amorphous solid comprises less than 10% by weight total of one or more other crystalline forms and/or amorphous solid.

[0637] E181. The pharmaceutical composition of E179, wherein the crystalline form or the amorphous solid comprises less than 5% by weight total of one or more other crystalline forms and/or amorphous solid.
[0638] E182. The pharmaceutical composition of E179, wherein the crystalline form or the amorphous solid comprises less than 2% by weight total of one or more other crystalline forms and/or amorphous solid.
[0639] E183. The pharmaceutical composition of E179, wherein the crystalline form or the amorphous solid comprises less than 1% by weight total of one or more other crystalline forms and/or amorphous solid.
[0640] E184. The pharmaceutical composition of E179, wherein the crystalline form or the amorphous solid comprises less than 0.5% by weight total of one or more other crystalline forms and/or amorphous solid.
[0641] E185. The pharmaceutical composition of E179, wherein the crystalline form or the amorphous solid comprises less than 0.1% by weight total of one or more other crystalline forms and/or amorphous solid.
[0642] E186. The pharmaceutical composition of any one of E179-E185, wherein the pharmaceutical composition is for oral administration.
[0643] E187. The pharmaceutical composition of any one of E179-E186, wherein the pharmaceutical composition is a solid dosage form.
[0644] E188. The pharmaceutical composition of any one of E179-E187, wherein the pharmaceutical composition is a capsule, tablet, powder, granules, minitablet, or pellet.
[0645] E189. The pharmaceutical composition of E188, wherein the pharmaceutical composition is a capsule.
[0646] E190. The pharmaceutical composition of E189, wherein the capsule comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows:
a) about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d) 0 wt/wt% to about 5 wt/wt% of one or more lubricants; and e) a gelatin capsule which encapsulates components a-d.

[0647] E191. The pharmaceutical composition of E189, wherein the capsule comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows:
a) about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de;
b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants, d) 0 wt/wt% to about 5 wt/wt% of one or more lubricants; and e) a gelatin capsule which encapsulates components a-d.
[0648] E192. The pharmaceutical composition of E189, wherein the capsule comprises about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows:
a) about 2.5 wt/wt% to about 7.0 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; and d) a gelatin capsule which encapsulates components a-c.
[0649] E193. The pharmaceutical composition of any one of E190-E192, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate.
[0650] E194. The pharmaceutical composition of E193, wherein at least one of the diluents is microcrystalline cellulose.
[0651] E195. The pharmaceutical composition of any one of E190-E194, wherein at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid.
[0652] E196. The pharmaceutical composition of E195, wherein at least one of the disintegrants is croscarmellose sodium.
[0653] E197. The pharmaceutical composition of any one of E190-E196, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
[0654] E198. The pharmaceutical composition of E197, wherein at least one of the lubricants is magnesium stearate.
[0655] E199. The pharmaceutical composition of E188, wherein the pharmaceutical composition is a tablet.
[0656] E200. The pharmaceutical composition of E199, wherein the tablet is a dispersible tablet.
[0657] E201. The pharmaceutical composition of E200, wherein the dispersible tablet comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible tablet is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0658] E202. The pharmaceutical composition of E200, wherein the dispersible tablet comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible tablet is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.

[0659] E203. The pharmaceutical composition of E201 or E202, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate.
[0660] E204. The pharmaceutical composition of E203, wherein at least one of the diluents is microcrystalline cellulose.
[0661] E205. The pharmaceutical composition of any one of E201-E204, wherein at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid.
[0662] E206. The pharmaceutical composition of E205, wherein at least one of the disintegrants is croscarmellose sodium.
[0663] E207. The pharmaceutical composition of any one of E201-E206, wherein at least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors including but not limited to, grape flavoring, bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry flavoring.
[0664] E208. The pharmaceutical composition of E207, wherein at least one of the flavoring agents is grape flavoring.
[0665] E209. The pharmaceutical composition of any one of E201-E208, wherein at least one sweetener of the dispersible tablet is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame.
[0666] E210. The pharmaceutical composition of E209, wherein the sweetener is sucralose.
[0667] E211. The pharmaceutical composition of any one of E201-E210, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
[0668] E212. The pharmaceutical composition of E211, wherein at least one of the lubricants is magnesium stearate.

[0669] E213. The pharmaceutical composition of any one of E199-E212, wherein the tablet is an orodispersible tablet.
[0670] E214. The pharmaceutical composition of E188, wherein the pharmaceutical composition is a powder.
[0671] E215. The pharmaceutical composition of E214, wherein the powder is a dispersible powder.
[0672] E216. The pharmaceutical composition of E215, wherein the dispersible powder comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible powder is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0673] E217. The pharmaceutical composition of E215, wherein the dispersible powder comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible powder is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0674] E218. The pharmaceutical composition of E216 or E217, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate.
[0675] E219. The pharmaceutical composition of E218, wherein at least one of the diluents is microcrystalline cellulose.
[0676] E220. The pharmaceutical composition of any one of E216-E219, wherein at least one of the di sintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycol ate, crospovi done, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid.
[0677] E221. The pharmaceutical composition of E220, wherein at least one of the disintegrants is croscarmellose sodium.
[0678] E222. The pharmaceutical composition of any one of E216-E221, wherein at least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors including but not limited to, grape flavoring, bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry flavoring.
[0679] E223. The pharmaceutical composition of E222, wherein at least one of the flavoring agents is grape flavoring.
[0680] E224. The pharmaceutical composition of any one of E216-E223, wherein at least one sweetener of the dispersible powder is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame.
[0681] E225. The pharmaceutical composition of E224, wherein the sweetener is sucralose.
[0682] E226. The pharmaceutical composition of any one of E216-E225, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
[0683] E227. The pharmaceutical composition of E226, wherein at least one of the lubricants is magnesium stearate.
[0684] E228. The pharmaceutical composition of any one of E215-E227, wherein the powder is an orodispersible powder.

[0685] E229. The pharmaceutical composition of E188, wherein the pharmaceutical composition is granules.
[0686] E230. The pharmaceutical composition of E229, wherein the granules are dispersible granules.
[0687] E231. The pharmaceutical composition of E230, wherein the dispersible granules comprise about 0.5 mg of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible granules is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0688] E232. The pharmaceutical composition of E230, wherein the dispersible granules comprise about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible granules is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0689] E233. The pharmaceutical composition of E231 or E232, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate.

[0690] E234. The pharmaceutical composition of E233, wherein at least one of the diluents is microcrystalline cellulose.
[0691] E235. The pharmaceutical composition of any one of E231-E234, wherein at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid.
[0692] E236. The pharmaceutical composition of E235, wherein at least one of the disintegrants is croscarmellose sodium.
[0693] E237. The pharmaceutical composition of any one of E231-E236, wherein at least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors including but not limited to, grape flavoring, bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry flavoring.
[0694] E238. The pharmaceutical composition of E237, wherein at least one of the flavoring agents is grape flavoring.
[0695] E239. The pharmaceutical composition of any one of E231-E238, wherein at least one sweetener of the dispersible granules is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame.
[0696] E240. The pharmaceutical composition of E239, wherein the sweetener is sucralose.
[0697] E241. The pharmaceutical composition of any one of E231-E240, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
[0698] E242. The pharmaceutical composition of E241, wherein at least one of the lubricants is magnesium stearate.
[0699] E243. The pharmaceutical composition of any one of E229-E242, wherein the granules are orodispersible granules.
[0700] E244. The pharmaceutical composition of E188, wherein the pharmaceutical composition is a minitablet.

[0701] E245. The pharmaceutical composition of E244, wherein the minitablets are dispersible minitablets.
[0702] E246. The pharmaceutical composition of E245, wherein the dispersible minitablets comprise about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible minitablets is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0703] E247. The pharmaceutical composition of E245, wherein the dispersible minitablets comprise about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible minitablets is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of NAR)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0704] E248. The pharmaceutical composition of E246 or E247, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate.
[0705] E249. The pharmaceutical composition of E248, wherein at least one of the diluents is microcrystalline cellulose.

[0706] E250. The pharmaceutical composition of any one of E246-E249, wherein at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid.
[0707] E251. The pharmaceutical composition of E250, wherein at least one of the di sintegrants is croscarmellose sodium.
[0708] E252. The pharmaceutical composition of any one of E246-E251, wherein at least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors including but not limited to, grape flavoring, bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry flavoring.
[0709] E253. The pharmaceutical composition of E252, wherein at least one of the flavoring agents is grape flavoring.
[0710] E254. The pharmaceutical composition of any one of E246-E253, wherein at least one sweetener of the dispersible minitablets is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame.
[0711] E255. The pharmaceutical composition of E254, wherein the sweetener is sucralose.
[0712] E256. The pharmaceutical composition of any one of E246-E255, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
[0713] E257. The pharmaceutical composition of E256, wherein at least one of the lubricants is magnesium stearate.
[0714] E258. The pharmaceutical composition of any one of E244-E257, wherein the minitablets are orodispersible minitablets.
[0715] E259. The pharmaceutical composition of E188, wherein the pharmaceutical composition is a pellet.
[0716] E260. The pharmaceutical composition of E259, wherein the pellets are dispersible pellets.

[0717] E261. The pharmaceutical composition of E260, wherein the dispersible pellets comprise about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible pellets is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0718] E262. The pharmaceutical composition of E260, wherein the dispersible pellets comprise about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible pellets is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more di sintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
[0719] E263. The pharmaceutical composition of E261 or E262, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate.
[0720] E264. The pharmaceutical composition of E263, wherein at least one of the diluents is microcrystalline cellulose.
[0721] E265. The pharmaceutical composition of any one of E261-E264, wherein at least one of the di sintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid.
[0722] E266. The pharmaceutical composition of E265, wherein at least one of the disintegrants is croscarmellose sodium.
[0723] E267. The pharmaceutical composition of any one of E261-E266, wherein at least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors including but not limited to, grape flavoring, bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry flavoring.
[0724] E268. The pharmaceutical composition of E267, wherein at least one of the flavoring agents is grape flavoring.
[0725] E269. The pharmaceutical composition of any one of E261-E268, wherein at least one sweetener of the dispersible pellets is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame.
[0726] E270. The pharmaceutical composition of E269, wherein the sweetener is sucralose.
[0727] E271. The pharmaceutical composition of any one of E261-E270, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
[0728] E272. The pharmaceutical composition of E271, wherein at least one of the lubricants is magnesium stearate.
[0729] E273. The pharmaceutical composition of any one of E259-E272, wherein the pellets are orodispersible pellets.
[0730] E274. A method of treating a tumor, cancer, or Rasopathy disorder comprising administering to a subject in need of such treatment the pharmaceutical composition of any one of E179-E273.
[0731] E275. The method of E274, wherein the tumor is a neurofibroma.
[0732] E276. The method of E274 or E275, wherein the tumor is a neurofibroma associated with Neurofibromatosis Type 1.

[0733] E277. The method of any one of claims E274-E276, wherein the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, and malignant peripheral nerve sheath tumor.
[0734] E278. The method of E277, wherein the tumor is plexiform neurofibroma.
[0735] E279. The method of any one of E274-E278, wherein the subject has been diagnosed with a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
[0736] E280. The method of any one of E274-E279, wherein the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum.
[0737] E281. The method of E280, wherein the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.
[0738] E282. The method of E280, wherein the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.
[0739] E283. The method of E280, wherein the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.
[0740] E284. The method of any one of E274-E283, wherein the subject bears a mutation or other aberration in one or more genes for which the mutation or other aberration causes a gain or loss of function characteristic of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
[0741] E285. The method of any one of E274-E284, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 20 mg.
[0742] E286. The method of any one of E274-E284, wherein the N-((R)-2,3-di hydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-4-i odo-phenyl ami n o)-b en zami de is administered in a total daily dose that does not exceed 10 mg.
[0743] E287. The method of any one of E274-E284, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg.
[07441 E288. The method of any one of E274-E284, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 6 mg.
[0745] E289. The method of any one of E274-E288, wherein the total daily dose of the N-((R)-2,3 -dihydroxypropoxy)-3 ,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-b enzami de is administered once daily.
[0746] E290. The method of E289, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.1 mg to about 20 mg.
[0747] E291. The method of E290, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3 ,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-b enzami de is administered once daily at a dose of about 0.5 mg.
[0748] E292. The method of E290, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 1 mg.
[0749] E293. The method of E290, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 2 mg.
[0750] E294. The method of E290, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 4 mg.

[0751] E295. The method of E290, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 6 mg.
[0752] E296. The method of E290, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3 ,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-b enzami de is administered once daily at a dose of about 8 mg.
[0753] E297. The method of E290, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 20 mg.
[0754] E298. The method of any one of E274-E288, wherein the total daily dose of the N-((R)-2,3 -dihydroxypropoxy)-3 ,4-difluoro-2-(2-fluoro-44 odo-phenylamino)-b enzami de is administered two times daily.
[0755] E299. The method of E298, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.1 mg to about 10 mg each.
[0756] E300. The method of E298, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.5 mg each.
[0757] E301. The method of E298, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 1 mg each.
[0758] E302. The method of E298, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 2 mg each.
[0759] E303. The method of E298, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 3 mg each.
[07601 E304. The method of E298, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 4 mg each.
[0761] E305. The method of E298, wherein the total daily dose of the N-((R)-2,3-di hydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-4-i odo-phenyl ami n o)-b en zami de is administered two times daily at a dose of about 10 mg each.

[0762] E306. The method of any one of E274-E305, wherein an individual dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as more than one capsule, more than one tablet, more than one dose of dispersible powder, more than one dose of granules, more than one dose of minitablets, more than one dose of pellets, or a combination thereof.
[0763] E307. The method of any one of E274-E306, wherein the pharmaceutical composition is a dispersible tablet, a dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets, and wherein the dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets is dispersed in a potable liquid prior to administration to the subject.
[0764] E308. The method of E307, wherein the subject experiences dysphagia caused by one or more of: disease of the nervous system, muscle weakening, developmental disability, stroke, injury, anatomical defect, cancer, treatment for cancer, allergic reaction, dementia, memory loss, or cognitive decline.
[0765] E309. The method of E307 or E308, wherein the subject is a pediatric subject.
[0766] E310. The method of any one of E274-E309, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 days in which the total daily dose is administered; and (b) 7 days in which no N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
[0767] E311. The method of any one of E274-E309, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 consecutive days in which the total daily dose is administered; followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
[0768] E312. The method of any one of E274-E309, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 days in which the total daily dose is administered and (ii) 2 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.

[0769] E313. The method of any one of E274-E309, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 consecutive days in which the total daily dose is administered and (ii) 2 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is administered.
[0770] E314. The method of any one of E310-E313, wherein the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.
[0771] E315. Use of the pharmaceutical composition of any one of E179-E273 for the manufacture of a medicament for treating a tumor, cancer, or Rasopathy disorder.
[0772] E316. The use of E315, wherein the tumor is a neurofibroma.
[0773] E317. The use of E315 or E316, wherein the tumor is a neurofibroma associated with Neurofibromatosis Type 1.
[0774] E318. The use of any one of E315-E317, wherein the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, and malignant peripheral nerve sheath tumor.
[0775] E319. The use of E318, wherein the tumor is plexiform neurofibroma.
[0776] E320. The use of any one of E315-E319, wherein the subject has been diagnosed with a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
[0777] E321. The use of any one of E315-E320, wherein the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum.

[0778] E322. The use of E321, wherein the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.
[0779] E323. The use of E321, wherein the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macrogl obulinemi a.
[0780] E324. The use of E321, wherein the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.
[0781] E325. The use of any one of E315-E324, wherein the subject bears a mutation or other aberration in one or more genes for which the mutation or other aberration causes a gain or loss of function characteristic of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, BRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
[0782] E326. The use of any one of E315-E325, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 20 mg.
[0783] E327. The use of any one of E315-E325, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 10 mg.
[0784] E328. The use of any one of E315-E325, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg.
[0785] E329. The use of any one of E315-E325, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 6 mg.
[07861 E330. The use of any one of E315-E329, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily.
[0787] E331. The use of E330, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de is administered once daily at a dose of about 0.1 mg to about 20 mg.

[0788] E332. The use of E331, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.5 mg.
[0789] E333. The use of E331, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3 ,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-b enzami de is administered once daily at a dose of about 1 mg.
[0790] E334. The use of E331, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 2 mg.
[0791] E335. The use of E331, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 4 mg.
[0792] E336. The use of E331, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 6 mg.
[0793] E337. The use of E331, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 8 mg.
[0794] E338. The use of E331, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 20 mg.
[0795] E339. The use of any one of E315-E329, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily.
[0796] E340. The use of E339, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.1 mg to about 10 mg each.
[0797] E341. The use of E340, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.5 mg each.
[0798] E342. The use of E340, wherein the total daily dose of the N-((R)-2,3-di hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl ami n o)-b en zami de is administered two times daily at a dose of about 1 mg each.

[07991 E343. The use of E340, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 2 mg each.
[0800] E344. The use of E340, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 3 mg each.
[08011 E345. The use of E340, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 4 mg each.
[0802] E346. The use of E340, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 10 mg each.
[08031 E347. The use of any one of E315-E346, wherein an individual dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as more than one capsule, more than one tablet, more than one dose of dispersible powder, more than one dose of granules, more than one dose of minitablets, more than one dose of pellets, or a combination thereof.
[08041 E348. The use of any one of E315-E347, wherein the pharmaceutical composition is a dispersible tablet, a dispersible powder, dispersible granules, a dispersible minitablet, or a dispersible pellet, and wherein the dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets is dispersed in a potable liquid prior to administration to the subject.
[0805] E349. The use of E348, wherein the subject experiences dysphagia caused by one or more of: disease of the nervous system, muscle weakening, developmental disability, stroke, injury, anatomical defect, cancer, treatment for cancer, allergic reaction, dementia, memory loss, or cognitive decline.
[0806] E350. The use of E348 or E349, wherein the subject is a pediatric subject.
[08071 E351. The use of any one of E315-E350, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 days in which the total daily dose is administered; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-4-i odo-phenyl am i no)-benzami de is administered.

[0808] E352. The use of any one of E315-E350, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 consecutive days in which the total daily dose is administered; followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
[0809] E353. The use of any one of E315-E350, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 days in which the total daily dose is administered and (ii) 2 days in which no N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
[0810] E354. The use of any one of E315-E350, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 consecutive days in which the total daily dose is administered and (ii) 2 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
[0811] E355. The use of any one of E351-E354, wherein the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.
[0812] E356. A method of producing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) 0, N H F
OH N
F
(I), the method comprising reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent 1-propylphosphonic anhydride (T3P) to obtain 901 Acetonide as shown in Scheme 1:
Scheme 1 ,N 0 00,N H2 + T3P
I. PD-0337792 (IPGA) .
(FIPFA) MW 393.10 901 Acetonide MW 522.26 [0813] E357. The method of E356, wherein the 1-propylphosphonic anhydride is in solution.
[0814] E358. The method of E356 or E357, wherein the 1-propylphosphonic anhydride is provided as a solution in ethyl acetate.
[0815] E359. The method of E356, wherein the method of producing N-((R)-2,3-dihydroxypropoxy)-3,4-ditluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I), comprises a) reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent that is 1-propylphosphonic anhydride (T3P) to obtain 901 Acetonide;
and b) treating 901 Acetonide with acid to form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide as shown in Scheme II:

Scheme II

õN 0 0õ3Ø,NH2 10 T3P

(IPGA) PD-0315209 MW 147.17 (FIPFA) MW 393.10 901 Acetonide MW 522.26 "acid"

H F

Mirdametinib (PD-0325901) Crude P0-0325901 M
MW 482.20 W 482.20 [0816] E360. The method of E356, wherein the method of producing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) HOON
H
OHLL N
F I
(I), comprises:
reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent to obtain 901 Acetonide; and treating 901 Acetonide with acid to form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-tluoro-4-iodo-phenylamino)-benzamide according to Scheme III:

Scheme III

F H
H õ,---.......õõ--., ,N 0 F
F I 110 (50% in Et0AG) ,,..)--C-N
NH2 + i-Pr2NEt la 01 ___________________________________________________________ i.-PD-0337792 F THF, toluene F I
(IPGA) PD-0315209 MTBE, aq. NaOH F
MW 147.17 (FIPFA) 901 Acetonide MW 393.10 MW 522.26 aq. HCI
toluene, ACN
H H

,N õN 0 EtOH
- - -OH N
110 0 Et0H OH N
water 4 ________ F I F I
F F
Mirdametinib Crude PD-0325901 (PD-0325901) MW 482.20 MW 482.20 [0817] E361. A crystalline composition that is essentially pure Form IV N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide prepared by the method of any one of E356-E360.
[0818] E362. The crystalline composition of E361, wherein the crystalline composition contains < 0.2% of dimeric impurity PF-00191189.
I
el F F

OH N
la 0 F I
F

Exact Mass: 856.93 [0819] E363. The crystalline composition of E361 or E362, wherein the crystalline composition contains about 0.05% to about 0.19% by weight of dimeric impurity PF-00191189.
[0820] E364. The crystalline composition of any one of E361-E363, wherein the crystalline composition contains no detectable amount of dimeric impurity PF-00191189.

Claims (364)

WHAT IS CLAIMED IS:
1. A crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) F
OH
I
F I
(I), selected from the group consisting of:
a cry stalline form of N-((R)-2,3 -dihy droxy prop oxy)-3,4-difl uoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.4 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta;
a crystalline form of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.9 0.2, 7.2 0.2, and 21.2 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.3 0.2, 10.6 0.2, and 16.1 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.4 +
0.2, 10.7 0.2, and 18.7 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 6.7 0.2, 13.5 0.2, and 22.2 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 10.6 +
0.2, 19.6 0.2, and 24.8 0.2 degrees two theta;

a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.5 0.2, 6.9 0.2, and 10.1 0.2 degrees two theta;
a crystalline form of N -((R)-2,3 -di hydroxyprop oxy)-3,4 -difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 10.1 0.2, 17.3 0.2, and 22.6 0.2 degrees two theta;
a crystalline form of N-((R)-2,3 -di hydroxypropoxy)-3,4-di fluoro-2-(2-fluoro-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 4.6 0.2, 5.1 0.2, and 14.6 0.2 degrees two theta;
a cry stalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern haying peaks at 4.6 0.2, 23.4 0.2, and 25.2 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern haying peaks at 5.5 0.2, 14.7 0.2, and 20.9 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern haying peaks at 6.0 0.2, 17.1 0.2, and 20.6 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern haying peaks at 5.9 0.2, 10.1 0.2, and 15.5 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern haying peaks at 4.6 0.2, 10.7 0.2, and 15.9 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern haying peaks at 10.2 0.2, 11.6 0.2, and 20.0 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern haying peaks at 7.8 0.2, 14.0 0.2, and 17.1 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de characterized by an XRPD pattern haying peaks at 5.5 0.2, 8.2 0.2, and 16.7 0.2 degrees two theta;

a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 7.2 0.2, 21.7 0.2, and 29.1 0.2 degrees two theta;
a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 5.4 0.2, 9.7 0.2, and 10.7 0.2 degrees two theta; and a crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide characterized by an XRPD pattern having peaks at 7.2 0.2, 20.6 0.2, and 23.0 0.2 degrees two theta.
2. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks 5.4 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta.
3. The crystalline form of claim 2, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks 5.4 0.2, 12.5 0.2, 17.5 0.2, and 22.8 0.2 degrees two theta.
4. The crystalline form of claim 2 or claim 3, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.7 wt% between about 35 C and about 100 C.
5. The crystalline form of any one of claims 2-4, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 77 C.
6. The crystalline form of any one of claims 2-5, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 95 C.
7. The crystalline form of any one of claims 2-6, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 77 C and a second endotherm onset at about 95 C.
8. The crystalline form of any one of claims 2-7, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 2A.
9. The crystalline form of any one of claims 2-8, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 2B; and/or b) a DSC profile substantially as shown in FIG. 2B.
10. The crystalline form of any one of claims 2-9, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form V.
11. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.9 0.2, 7.2 + 0.2, and 21.2 0.2 degrees two theta.
12. The crystalline form of claim 11, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.9 0.2, 7.2 0.2, 9.3 0.2, and 21.2 0.2 degrees two theta.
13. The crystalline form of claim 11 or claim 12, wherein the TGA
exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.4 wt% between about 25 C and about 125 C.
14. The crystalline form of any one of claims 11-13, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 41 C.
15. The crystalline form of any one of claims 11-14, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 70 C.
16. The crystalline form of any one of claims 11-15, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 109 C.
17. The crystalline form of any one of claims 11-16, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 41 C, a second endotherm onset at about 70 C, and a third endotherm onset at about 109 C.
18. The crystalline form of claim 11-17, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 3A.
19. The crystalline form of claim 11-18, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 3B; and/or b) a DSC profile substantially as shown in FIG. 3B.
20. The crystalline form of any one of claims 11-19, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VI.
21. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.3 0.2, 10.6 0.2, and 16.1 0.2 degrees two theta.
22. The crystalline form of claim 21, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.3 0.2, 10.6 0.2, 13.9 0.2, and 16.1 + 0.2 degrees two theta.
23. The crystalline form of claim 21 or claim 22, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 5.2 wt% between about 40 C and about 120 C.
24. The crystalline form of any one of claims 21-23, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that an endotherm onset at about 85 C.
25. The crystalline form of any one of claims 21-24, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 110 C.
26. The crystalline form of any one of claims 21-25, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 85 C and a second endotherm onset at about 110 C.
27. The crystalline form of any one of claims 21-26, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 4A.
28. The crystalline form of any one of claims 21-27, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 4B; and/or b) a DSC profile substantially as shown in FIG. 4B.
29. The crystalline form of any one of claims 21-28, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VII.
30. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de i s characterized by an XRPD pattern having peaks at 5.4 0.2, 10.7 0.2, and 18.7 0.2 degrees two theta.
31. The crystalline form of claim 30, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4 0.2, 10.7 0.2, 18.7 0.2, and 23.9 0.2 degrees two theta.
32. The crystalline form of claim 30 or claim 31, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 3.3 wt% between about 40 C and about 112 C.
33. The crystalline form of any one of claims 30-32, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 81 C.
34. The crystalline form of any one of claims 30-33, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 110 C.
35. The crystalline form of any one of claims 30-34, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 81 C and a second endotherm onset at about 110 C.
36. The crystalline form of any one of claims 30-35, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 5A.
37. The crystalline form of any one of claims 30-36, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 5B; and/or b) a DSC profile substantially as shown in FIG. 5B.
38. The crystalline form of any one of claims 30-37, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VIII.
39. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 6.7 0.2, 13.5 0.2, and 22.2 0.2 degrees two theta.
40. The crystalline form of claim 39, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 6.7 0.2, 8.0 0.2, 13.5 0.2, and 22.2 0.2 degrees two theta.
41. The crystalline form of claim 39 or claim 40, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 4.6 wt% between about 28 C and about 128 C.
42. The crystalline form of any one of claims 39-41, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 84 C.
43. The crystalline form of any one of claims 39-42, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 107 C.
44. The crystalline form of any one of claims 39-43, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 114 C.
45. The crystalline form of any one of claims 39-44, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 84 C, a second endotherm onset at about 107 C, and a third endotherm onset at about 114 C.
46. The crystalline form of any one of claims 39-45, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 6A.
47. The crystalline form of any one of claims 39-46, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 6B; and/or b) a DSC profile substantially as shown in FIG. 6B.
48. The crystalline form of any one of claims 39-47, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form IX.
49. The crystalline of claim 1, wherein the crystalline form of NAR)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.6 0.2, 19.6 0.2, and 24.8 0.2 degrees two theta.
50. The crystalline of claim 49, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 10.6 0.2, 19.6 0.2, and 24.8 + 0.2 degrees two theta.
51. The crystalline form of claim 49 or claim 50, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.9 wt% between about 40 'V and about 115 C.
52. The crystalline form of any one of claims 49-51, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 89 C.
53. The crystalline form of any one of claims 49-52, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 7A.
54. The crystalline form of any one of claims 49-53, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 7B; and/or b) a DSC profile substantially as shown in FIG. 7B.
55. The crystalline form of any one of claims 49-54, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form X.
56. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 6.9 0.2, and 10.1 0.2 degrees two theta.
57. The crystalline form of claim 56, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 6.9 0.2, 10.1 0.2, and 19.2 + 0.2 degrees two theta.
58. The crystalline form of claim 56 or claim 57, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 7.6 wt% between about 40 C and about 175 C.
59. The crystalline form of any one of claims 56-58, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 69 C.
60. The crystalline form of any one of claims 56-59, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 104 C.
61. The crystalline form of any one of claims 56-60, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 69 C and a second endotherm onset at about 104 C.
62. The crystalline form of any one of claims 56-61, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 8A.
63. The crystalline form of any one of claims 56-62, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 8B; and/or b) a DSC profile substantially as shown in FIG. 8B.
64. The crystalline form of any one of claims 56-63, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XI.
65. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de i s characterized by an XRPD pattern having peaks at 10.1 0.2, 17.3 0.2, and 22.6 0.2 degrees two theta.
66. The crystalline form of claim 65, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.1 0.2, 17.3 0.2, 21.5 0.2, and 22.6 0.2 degrees two theta.
67. The crystalline form of claim 65 or claim 66, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 8.5 wt% between about 40 C and about 160 C.
68. The crystalline form of any one of claims 65-67, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 72 C.
69. The crystalline form of any one of claims 65-68, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 109 C.
70. The crystalline form of any one of claims 65-69, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 72 C and a second endotherm onset at about 109 C.
71. The crystalline form of any one of claims 65-70, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 9A.
72. The crystalline form of any one of claims 65-71, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 9B; and/or b) a DSC profile substantially as shown in FIG. 9B.
73. The crystalline form of any one of claims 65-72, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XII.
74. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 0.2, 5.1 0.2, and 14.6 0.2 degrees two theta.
75. The crystalline form of claim 74 wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 0.2, 5.1 0.2, 6.4 0.2, and 14.6 0.2 degrees two theta.
76. The crystalline form of claim 74 or claim 75, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 3.1 wt% between about 20 C and about 100 C.
77. The crystalline form of any one of claims 74-76, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 55 C.
78. The crystalline form of any one of claims 74-77, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 109 C.
79. The crystalline form of any one of claims 74-78, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 55 C and a second endotherm onset at about 109 C.
80. The crystalline form of any one of claims 74-79, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 10A.
81. The crystalline form of any one of claims 74-80, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 10B; and/or b) a DSC profile substantially as shown in FIG. 10B.
82. The crystalline form of any one of claims 74-81, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIII.
83. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 0.2, 23.4 0.2, and 25.2 0.2 degrees two theta.
84. The crystalline form of claim 83, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 0.2, 23.4 0.2, 25.2 0.2, and 30.6 + 0.2 degrees two theta.
85. The crystalline form of claim 83 or claim 84, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 0.15 wt% between about 40 `V and about 150 'C.
86. The crystalline form of any one of claims 83-85, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 111 C.
87. The crystalline form of any one of claims 83-86, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 11A.
88. The crystalline form of any one of claims 83-87, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 11B; and/or b) a DSC profile substantially as shown in FIG. 11B.
89. The crystalline form of any one of claims 83-88, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIV.
90. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 14.7 0.2, and 20.9 0.2 degrees two theta.
91. The crystalline form of claim 90, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 14.7 0.2, 20.9 0.2, and 26.6 + 0.2 degrees two theta.
92. The crystalline form of claim 90 or claim 91, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 3.8 wt% between about 40 `V and about 150 'C.
93. The crystalline form of any one of claims 90-92, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 104 C.
94. The crystalline form of any one of claims 90-93, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 12A.
95. The crystalline form of any one of claims 90-94, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 12B; and/or b) a DSC profile substantially as shown in FIG. 12B.
96. The crystalline form of any one of claims 90-95, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XV.
97. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 6.0 0.2, 17.1 0.2, and 20.6 0.2 degrees two theta.
98. The crystalline form of claim 97, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 6.0 0.2, 12.8 0.2, 17.1 0.2, and 20.6 + 0.2 degrees two theta.
99. The crystalline form of claim 97 or claim 98, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.1 wt% between about 40 `V and about 150 'C.
100. The crystalline form of any one of claims 97-99, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 74 C.
101. The crystalline form of any one of claims 97-100, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 102 C.
102. The crystalline form of any one of claims 97-101, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotheim onset at about 114 C.
103. The crystalline form of any one of claims 97-102, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 74 C, a second endotherm onset at about 102 C, and a third endotherm onset at about 114 C.
104. The crystalline form of any one of claims 97-103, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 13A.
105. The crystalline form of any one of claims 97-104, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 13B; and/or b) a DSC profile substantially as shown in FIG. 13B.
106. The crystalline form of any one of claims 97-105, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVI.
107. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl ami no)-benzami de i s characterized by an XRPD pattern having peaks at 5.9 0.2, 10.1 0.2, and 15.5 0.2 degrees two theta.
108. The crystalline form of claim 107, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.9 0.2, 10.1 0.2, 11.7 0.2, and 15.5 0.2 degrees two theta
109. The crystalline form of claim 107 or claim 108, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.7 wt% between about 40 C and about 100 C.
110. The crystalline form of any one of claims 107-109, wherein crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 89 C.
111. The crystalline form of any one of claims 107-110, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 14A.
112. The crystalline form of any one of claims 107-111, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 14B; and/or b) a DSC profile substantially as shown in FIG. 14B.
113. The crystalline form of any one of claims 107-112, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVII.
114. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl ami no)-benzami de i s characterized by an XRPD pattern having peaks at 4.6 0.2, 10.7 0.2, and 15.9 0.2 degrees two theta.
115. The crystalline form of claim 114, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 4.6 0.2, 10.7 0.2, 15.9 0.2, and 19.6 0.2 degrees two theta.
116. The crystalline form of claim 114 or claim 115, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 1.6 wt% between about 30 C and about 150 C.
117. The crystalline form of any one of claims 114-116, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 83 C.
118. The crystalline form of any one of claims 114-117, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 15A.
119. The crystalline form of any one of claims 114-118, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 15B; and/or b) a DSC profile substantially as shown in FIG. 15B.
120. The crystalline form of any one of claims 114-119, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVIII.
121. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de i s characterized by an XRPD pattern having peaks at 10.2 0.2, 11.6 0.2, and 20.0 0.2 degrees two theta.
122. The crystalline form of claim 121, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 10.2 0.2, 11.6 0.2, 17.1 0.2, and 20.0 0.2 degrees two theta.
123. The crystalline form of claim 121 or claim 122, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 1.85 wt% between about 23 C and about 92 C.
124. The crystalline form of any one of claims 121-123, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 69 C.
125. The crystalline form of any one of claims 121-124, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 98 C.
126. The crystalline form of any one of claims 121-125, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 115 C.
127. The crystalline form of any one of claims 121-126, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 69 C, a second endotherm onset at about 98 `V, and a third endotherm onset at about 115 'C.
128. The crystalline form of any one of claims 121-127, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 16A.
129. The crystalline form of any one of claims 121-128, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 16B; and/or b) a DSC profile substantially as shown in FIG. 16B.
130. The crystalline form of any one of claims 121-129, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIX.
131. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.8 0.2, 14.0 0.2, and 17.1 0.2 degrees two theta.
132. The crystalline form of claim 131, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.8 0.2, 14.0 0.2, 15.6 0.2, and 17.1 0.2 degrees two theta.
133. The crystalline form of claim 131 or claim 132, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 2.6 wt% between about 29 C and about 126 C.
134. The crystalline form of any one of claims 13 1-133, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 77 C.
135. The crystalline form of any one of claims 13 1-134, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 92 C.
136. The crystalline form of any one of claims 131-135, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 110 C.
137. The crystalline form of any one of claims 13 1-136, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de exhibits a DSC thermogram that has a first endotherm onset at about 77 C, a second endotherm onset at about 92 C, and a third endotherm onset at about 110 C.
138. The crystalline form of any one of claims 131-137, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 17A.
139. The crystalline form of any one of claims 131-138, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 17B; and/or b) a DSC profile substantially as shown in FIG. 17B.
140. The crystalline form of any one of claims 131-139, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XX.
141. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 8.2 0.2, and 16.7 0.2 degrees two theta.
142. The crystalline form of claim 141, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.5 0.2, 8.2 0.2, 16.7 0.2, and 17.7 0.2 degrees two theta.
143. The crystalline form of claim 141 or claim 142, wherein the TGA exhibits that the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 14.1 wt% between about 30 C and about 110 C.
144. The crystalline form of any one of claims 141-143, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 52 C.
145. The crystalline form of any one of claims 141-144, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 90 C.
146. The crystalline form of any one of claims 141-145, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 52 C and a second endotherm onset at about 90 C.
147. The crystalline form of any one of claims 141-146, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 18A.
148. The crystalline form of any one of claims 141-147, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 18B; and/or b) a DSC profile substantially as shown in FIG. 18B.
149. The crystalline form of any one of claims 141-148, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenylamino)-benzami de is Form XXI.
150. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2 0.2, 21.7 0.2, and 29.1 0.2 degrees two theta.
151. The crystalline form of claim 150, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2 0.2, 18.6 0.2, 21.7 0.2, and 29.1 0.2 degrees two theta.
152. The crystalline form of claim 150 or claim 151, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 13.8 wt% between about 26 C and about 135 C.
153. The crystalline form of any one of claims 150-152, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 65 C.
154. The crystalline form of any one of claims 150-153, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 89 C.
155. The crystalline form of any one of claims 150-154, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 102 C.
156. The crystalline form of any one of claims 150-155, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 65 C, a second endotherm onset at about 89 C, and a third endotherm onset at about 102 C.
157. The crystalline form of any one of claims 150-156, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 19A.
158. The crystalline form of any one of claims 150-157, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 19B; and/or b) a DSC profile substantially as shown in FIG. 19B.
159. The crystalline form of any one of claims 150-158, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXII.
160. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4 0.2, 9.7 0.2, and 10.7 0.2 degrees two theta.
161. The crystalline form of claim 160, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 5.4 0.2, 6.5 0.2, 9.7 0.2, and 10.7 + 0.2 degrees two theta.
162. The crystalline form of claim 160 or claim 161, wherein the TGA exhibits that the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 4.4 wt% between about 27 `V and about 137 'C.
163. The crystalline form of any one of claims 160-162, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 81 C.
164. The crystalline form of any one of claims 160-163, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 101 C.
165. The crystalline form of any one of claims 160-164, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has a first endotherm onset at about 81 C and a second endotherm onset at about 101 C.
166. The crystalline form of any one of claims 160-165, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 20A.
167. The crystalline form of any one of claims 160-166, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 20B; and/or b) a DSC profile substantially as shown in FIG. 20B.
168. The crystalline form of any one of claims 160-167, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXIII.
169. The crystalline form of claim 1, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2 0.2, 20.6 0.2, and 23.0 0.2 degrees two theta.
170. The crystalline form of claim 169, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern having peaks at 7.2 0.2, 9.5 0.2, 20.6 0.2, and 23.0 0.2 degrees two theta.
171. The crystalline form of claim 169 or claim 170, wherein the TGA exhibits that the crystalline form of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide loses about 1.2 wt% between about 30 C and about 119 C.
172. The crystalline form of any one of claims 169-171, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide exhibits a DSC thermogram that has an endotherm onset at about 104 C.
173. The crystalline form of any one of claims 169-172, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 21A.
174. The crystalline form of any one of claims 169-173, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 21B; and/or b) a DSC profile substantially as shown in FIG. 21B.
175. The crystalline form of any one of claims 169-174, wherein the crystal form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXIV.
176. Amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) N
OH N
(I).
177. The amorphous solid of claim 176, wherein the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRPD pattern substantially as shown in FIG. 22A.
178. The amorphous solid of claim 176 or claim 177, wherein the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by:
a) a TGA profile substantially as shown in FIG. 22B; and/or b) a DSC profile substantially as shown in FIG. 22B.
179. A pharmaceutical composition comprising:
the crystalline form of any one of claims 1-175 or the amorphous solid of any one of claims 176-178; and one or more pharmaceutically acceptable carriers.
180. The pharmaceutical composition of claim 179, wherein the crystalline form or the amorphous solid comprises less than 10% by weight total of one or more other crystalline forms and/or amorphous solid.
181. The pharmaceutical composition of claim 179, wherein the crystalline form or the amorphous solid comprises less than 5% by weight total of one or more other crystalline forms and/or amorphous solid.
182. The pharmaceutical composition of claim 179, wherein the crystalline form or the amorphous solid comprises less than 2% by weight total of one or more other crystalline forms and/or amorphous solid.
183. The pharmaceutical composition of claim 179, wherein the crystalline form or the amorphous solid comprises less than 1% by weight total of one or more other crystalline forms and/or amorphous solid.
184. The pharmaceutical composition of claim 179, wherein the crystalline form or the amorphous solid comprises less than 0.5% by weight total of one or more other crystalline forms and/or amorphous solid.
185. The pharmaceutical composition of claim 179, wherein the crystalline form or the amorphous solid comprises less than 0.1% by weight total of one or more other crystalline forms and/or amorphous solid.
186. The pharmaceutical composition of any one of claims 179-185, wherein the pharmaceutical composition is for oral administration.
187. The pharmaceutical composition of any one of claims 179-186, wherein the pharmaceutical composition is a solid dosage form.
188. The pharmaceutical composition of any one of claims 179-187, wherein the pharmaceutical composition is a capsule, tablet, powder, granules, minitablet, or pellet.
189. The pharmaceutical composition of claim 188, wherein the pharmaceutical composition is a capsule.
190. The pharmaceutical composition of claim 189, wherein the capsule comprises about 1 mg of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows:
a) about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzami de;
b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants, d) 0 wt/wt% to about 5 wt/wt% of one or more lubricants; and e) a gelatin capsule which encapsulates components a-d.
191. The pharmaceutical composition of claim 189, wherein the capsule comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows:
a) about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d) 0 wt/wt% to about 5 wt/wt% of one or more lubricants; and e) a gelatin capsule which encapsulates components a-d.
192. The pharmaceutical composition of claim 189, wherein the capsule comprises about 5 mg of N-((R)-2,3 -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows:
a) about 2.5 wt/wt% to about 7.0 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylarnino)-benzamide;
b) about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants; and d) a gelatin capsule which encapsulates components a-c.
193. The pharmaceutical composition of any one of claims 190-192, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate.
194. The pharmaceutical composition of claim 193, wherein at least one of the diluents is microcrystalline cellulose.
195. The pharmaceutical composition of any one of claims 190-194, wherein at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid.
196. The pharmaceutical composition of claim 195, wherein at least one of the disintegrants is croscarmellose sodium.
197. The pharmaceutical composition of any one of claims 190-196, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
198. The pharmaceutical composition of claim 197, wherein at least one of the lubricants is magnesium stearate.
199 The pharmaceutical composition of claim 188, wherein the pharmaceutical composition is a tablet.
200. The pharmaceutical composition of claim 199, wherein the tablet is a dispersible tablet.
201. The pharmaceutical composition of claim 200, wherein the dispersible tablet comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible tablet is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of NAR)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more di sintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
202. The pharmaceutical composition of claim 200, wherein the dispersible tablet comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible tablet is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
203. The pharmaceutical composition of claim 201 or claim 202, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate.
204. The phannaceutical composition of claim 203, wherein at least one of the diluents is microcrystalline cellulose.
205. The pharmaceutical composition of any one of claims 201-204, wherein at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid.
206. The pharmaceutical composition of claim 205, wherein at least one of the disintegrants is croscarmellose sodium.
207. The pharmaceutical composition of any one of claims 201-206, wherein at least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors including but not limited to, grape flavoring, bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry flavoring.
208. The pharmaceutical composition of claim 207, wherein at least one of the flavoring agents is grape flavoring.
209. The pharmaceutical composition of any one of claims 201-208, wherein at least one sweetener of the dispersible tablet is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame.
210. The pharmaceutical composition of claim 209, wherein the sweetener is sucralose.
211. The pharmaceutical composition of any one of claims 201-210, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
212. The pharmaceutical composition of claim 211, wherein at least one of the lubricants is magnesium stearate.
213. The pharmaceutical composition of any one of claims 199-212, wherein the tablet is an orodispersible tablet.
214. The pharmaceutical composition of claim 188, wherein the pharmaceutical composition is a powder.
215. The pharmaceutical composition of claim 214, wherein the powder is a dispersible powder.
216. The pharmaceutical composition of claim 215, wherein the dispersible powder comprises about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible powder is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
217. The pharmaceutical composition of claim 215, wherein the dispersible powder comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible powder is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;

e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
218. The pharmaceutical composition of claim 216 or claim 217, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate.
219. The pharmaceutical composition of claim 218, wherein at least one of the diluents is microcrystalline cellulose.
220. The pharmaceutical composition of any one of claims 216-219, wherein at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid.
221. The pharmaceutical composition of claim 220, wherein at least one of the disintegrants is croscarmellose sodium.
222. The pharmaceutical composition of any one of claims 216-221, wherein at least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors including but not limited to, grape flavoring, bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry flavoring.
223. The pharmaceutical composition of claim 222, wherein at least one of the flavoring agents is grape flavoring.
224. The pharmaceutical composition of any one of claims 216-223, wherein at least one sweetener of the dispersible powder is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame.
225. The pharmaceutical composition of claim 224, wherein the sweetener is sucralose.
226. The pharmaceutical composition of any one of claims 216-225, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
227. The pharmaceutical composition of claim 226, wherein at least one of the lubricants is magnesium stearate.
228. The pharmaceutical composition of any one of claims 215-227, wherein the powder is an orodispersible powder.
229. The pharmaceutical composition of claim 188, wherein the pharmaceutical composition is granules.
230. The pharmaceutical composition of claim 229, wherein the granules are dispersible granules.
231. The pharmaceutical composition of claim 230, wherein the dispersible granules comprise about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible granules is as follows:
a about 0 1 wt/wt% to about 7 wt/wt% of the crystalline fornri or the amorphous solid of N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;

e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
232. The pharmaceutical composition of claim 230, wherein the dispersible granules comprise about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible granules is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
233. The pharmaceutical composition of claim 231 or claim 232, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate.
234. The pharmaceutical composition of claim 233, wherein at least one of the diluents is microcrystalline cellulose.
235. The pharmaceutical composition of any one of claims 231-234, wherein at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid.
236. The pharmaceutical composition of claim 235, wherein at least one of the disintegrants is croscarmellose sodium.
237. The pharmaceutical composition of any one of claims 231-236, wherein at least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors including but not limited to, grape flavoring, bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry flavoring.
238. The pharmaceutical composition of claim 237, wherein at least one of the flavoring agents is grape flavoring.
239. The pharmaceutical composition of any one of claims 231-238, wherein at least one sweetener of the dispersible granules is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame.
240. The pharmaceutical composition of claim 239, wherein the sweetener is sucralose.
241. The pharmaceutical composition of any one of claims 231-240, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
242. The pharmaceutical composition of claim 241, wherein at least one of the lubricants is magnesium stearate.
243. The pharmaceutical composition of any one of claims 229-242, wherein the granules are orodispersible granules.
244. The pharmaceutical composition of claim 188, wherein the pharmaceutical composition is a minitablet.
245. The pharmaceutical composition of claim 244, wherein the minitablets are dispersible minitablets.
246. The pharmaceutical composition of claim 245, wherein the dispersible minitablets comprise about 0.5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible minitablets is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
247. The pharmaceutical composition of claim 245, wherein the dispersible minitablets comprise about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible minitablets is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of NAR)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
248. The phannaceuti cal composition of claim 246 or claim 247, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate.
249. The pharmaceutical composition of claim 248, wherein at least one of the diluents is microcrystalline cellulose.
250. The pharmaceutical composition of any one of claims 246-249, wherein at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid.
251. The pharmaceutical composition of claim 250, wherein at least one of the disintegrants is croscarmellose sodium.
252. The pharmaceutical composition of any one of claims 246-251, wherein at least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors including but not limited to, grape flavoring, bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry flavoring.
253. The pharmaceutical composition of claim 252, wherein at least one of the flavoring agents is grape flavoring.
254. The pharmaceutical composition of any one of claims 246-253, wherein at least one sweetener of the dispersible minitablets is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame.
255. The pharmaceutical composition of claim 254, wherein the sweetener is sucralose.
256. The pharmaceutical composition of any one of claims 246-255, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
257. The pharmaceutical composition of claim 256, wherein at least one of the lubricants is magnesium stearate.
258. The pharmaceutical composition of any one of claims 244-257, wherein the minitablets are orodispersible minitablets.
259. The pharmaceutical composition of claim 188, wherein the pharmaceutical composition is a pellet.
260. The pharmaceutical composition of claim 259, wherein the pellets are dispersible pellets.
261. The pharmaceutical composition of claim 260, wherein the dispersible pellets comprise about 0.5 mg of N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible pellets is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl amino)-benzami de;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;
c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
262. The pharmaceutical composition of claim 260, wherein the dispersible pellets comprise about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, and wherein each component of the dispersible pellets is as follows:
a. about 0.1 wt/wt% to about 7 wt/wt% of the crystalline form or the amorphous solid of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
b. about 50 wt/wt% to about 98 wt/wt% of one or more diluents;

c. about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants;
d. 0 wt/wt% to about 5 wt/wt% of one or more flavoring agents;
e. 0 wt/wt% to about 5 wt/wt% of one or more sweeteners; and f. 0 wt/wt% to about 5 wt/wt% of one or more lubricants.
263. The pharmaceutical composition of claim 261 or claim 262, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, sorbitol, xylitol, sucrose, pregelatinized starch, calcium sulfate, calcium carbonate, starch, and dibasic calcium phosphate.
264. The pharmaceutical composition of claim 263, wherein at least one of the diluents is microcrystalline cellulose
265. The pharmaceutical composition of any one of claims 261-264, wherein at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, starch, pregelatinized starch, low substituted hydroxypropyl cellulose, and alginic acid.
266. The pharmaceutical composition of claim 265, wherein at least one of the disintegrants is croscarmellose sodium.
267. The pharmaceutical composition of any one of claims 261-266, wherein at least one of the flavoring agents is selected from the group consisting of natural or synthetic flavors including but not limited to, grape flavoring, bubble gum flavoring, caramel flavoring, orange flavoring, lemon flavoring, strawberry flavoring, raspberry flavoring, mint flavoring, peppermint flavoring, grapefruit flavoring, pineapple flavoring, pear flavoring, peach flavoring, vanilla flavoring, banana flavoring, or cherry flavoring.
268. The pharmaceutical composition of claim 267, wherein at least one of the flavoring agents is grape flavoring.
269. The pharmaceutical composition of any one of claims 261-268, wherein at least one sweetener of the dispersible pellets is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame.
270. The pharmaceutical composition of claim 269, wherein the sweetener is sucralose.
271. The pharmaceutical composition of any one of claims 261-270, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glycerol dibehenate, stearic acid, hydrogenated vegetable oil, calcium stearate, zinc stearate, beeswax, colloidal silicon dioxide, and talc.
272. The pharmaceutical composition of claim 271, wherein at least one of the lubricants is magnesium stearate.
273. The pharmaceutical composition of any one of claims 259-272, wherein the pellets are orodispersible pellets.
274. A method of treating a tumor, cancer, or Rasopathy disorder comprising administering to a subject in need of such treatment the pharmaceutical composition of any one of claims 179-273.
275. The method of claim 274, wherein the tumor is a neurofibroma.
276. The method of claim 274 or 275, wherein the tumor is a neurofibroma associated with Neurofibromatosis Type 1.
277. The method of any one of claims 274-276, wherein the tumor is selected from the group con si sti ng of cutaneous neurofibroma, pl exi form neurofibroma, optic pathway gl i om a , low grade glioma, high grade glioma, and malignant peripheral nerve sheath tumor.
278. The method of claim 277, wherein the tumor is plexiform neurofibroma.
279. The method of any one of claims 274-278, wherein the subject has been diagnosed with a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
280. The method of any one of claims 274-279, wherein the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer, chol angi ocarcinom a, urotheli al cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum.
281. The method of claim 280, wherein the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.
282. The method of claim 280, wherein the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.
283. The method of claim 280, wherein the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.
284. The method of any one of claims 274-283, wherein the subject bears a mutation or other aberration in one or more genes for which the mutation or other aberration causes a gain or loss of function characteristic of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
285. The method of any one of claims 274-284, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 20 mg.
286. The method of any one of claims 274-284, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 10 mg.
287. The method of any one of claims 274-284, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg.
288. The method of any one of claims 274-284, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 6 mg.
289. The method of any one of claims 274-288, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is administered once daily.
290. The method of claim 289, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.1 mg to about 20 mg
291 The method of claim 290, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.5 mg.
292. The method of claim 290, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 1 mg.
293. The method of claim 290, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 2 mg.
294. The method of claim 290, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 4 mg.
295. The method of claim 290, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 6 mg.
296. The method of claim 290, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 8 mg.
297. The method of claim 290, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 20 mg.
298. The method of any one of claims 274-288, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily.
299 The method of claim 298, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.1 mg to about 10 mg each.
300. The method of claim 298, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.5 mg each.
301. The method of claim 298, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 1 mg each.
302. The method of claim 298, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 2 mg each.
303. The method of claim 298, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 3 mg each.
304. The method of claim 298, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 4 mg each.
305. The method of claim 298, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is administered two times daily at a dose of about 10 mg each.
306. The method of any one of claims 274-305, wherein an individual dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as more than one capsule, more than one tablet, more than one dose of dispersible powder, more than one dose of granules, more than one dose of minitablets, more than one dose of pellets, or a combination thereof.
307. The method of any one of claims 274-306, wherein the pharmaceutical composition is a dispersible tablet, a dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets, and wherein the dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets is dispersed in a potable liquid prior to administration to the subject.
308. The method of claim 307, wherein the subject experiences dysphagia caused by one or more of: disease of the nervous system, muscle weakening, developmental disability, stroke, injury, anatomical defect, cancer, treatment for cancer, allergic reaction, dementia, memory loss, or cognitive decline.
309. The method of claim 307 or claim 308, wherein the subject is a pediatric subject.
310. The method of any one of claims 274-309, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 days in which the total daily dose is administered; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
311. The method of any one of claims 274-309, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 consecutive days in which the total daily dose is administered; followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
312. The method of any one of claims 274-309, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 days in which the total daily dose is administered and (ii) 2 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
313. The method of any one of claims 274-309, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 consecutive days in which the total daily dose is administered and (ii) 2 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
followed by (b) 7 consecutive days in which no N4R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
314. The method of any one of claims 310-313, wherein the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.
315. Use of the pharmaceutical composition of any one of claims 179-273 for the manufacture of a medicament for treating a tumor, cancer, or Rasopathy disorder.
316. The use of claim 315, wherein the tumor is a neurofibroma.
317. The use of claim 315 or 316, wherein the tumor is a neurofibroma associated with Neurofibromatosis Type 1.
318. The use of any one of claims 315-317, wherein the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, and malignant peripheral nerve sheath tumor.
319. The use of claim 318, wherein the tumor is plexiform neurofibroma.
320. The use of any one of claims 315-319, wherein the subject has been diagnosed with a Rasopathy disorder selected from the group consisting of neurofibromatosis type 1, neurofibromatosis type 2, cardio-facio-cutaneous syndrome, Costello syndrome, Legius syndrome, Noonan syndrome, and Noonan syndrome with multiple lentigines.
321. The use of any one of claims 315-320, wherein the cancer is selected from the group consisting of skin cancer, malignant peripheral nerve sheath cancer, leukemia, lymphoma, sti ocyti c neopl asm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer, cholangiocarcinoma, urothelial cancer, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, pancreatic cancer, melanoma, hepatocellular cancer, biliary tract cancer, and serous carcinoma of the peritoneum.
322. The use of claim 321, wherein the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.
323. The use of claim 321, wherein the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia.
324. The use of claim 321, wherein the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.
325. The use of any one of claims 315-324, wherein the subject bears a mutation or other aberration in one or more genes for which the mutation or other aberration causes a gain or loss of function characteristic of certain cancers, wherein the mutation or other aberration in one or more genes is a mutation or other aberration in one or more of KRAS, NRAS, BRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2.
326. The use of any one of claims 315-325, wherein the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 20 mg.
327. The use of any one of claims 315-325, wherein the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 10 mg.
328. The use of any one of claims 315-325, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 8 mg.
329. The use of any one of claims 315-325, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered in a total daily dose that does not exceed 6 mg.
330. The use of any one of claims 315-329, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide i s administered once daily.
331. The use of claim 330, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.1 mg to about 20 mg.
332. The use of claim 331, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-i odo-phenyl amino)-benzami de is administered once daily at a dose of about 0.5 mg.
333. The use of claim 331, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 1 mg.
334 The use of claim 331, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 2 mg.
335. The use of claim 331, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 4 mg.
336. The use of claim 331, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 6 mg.
337. The use of claim 331, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 8 mg.
338. The use of claim 33 l, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 20 mg.
339. The use of any one of claims 315-329, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide i s administered two times daily.
340. The use of claim 339, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3 ,4-di fluoro-2-(2-fluoro-4-i odo-phenyl am i n o)-b enzami de i s admini stered two times daily at a dose of about 0.1 mg to about 10 mg each.
341. The use of claim 340, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 0.5 mg each.
342 The use of claim 340, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 1 mg each.
343. The use of claim 340, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 2 mg each.
344. The use of claim 340, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 3 mg each.
345. The use of claim 340, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 4 mg each.
346. The use of claim 340, wherein the total daily dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered two times daily at a dose of about 10 mg each.
347. The use of any one of claims 315-346, wherein an individual dose of the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered as more than one capsule, more than one tablet, more than one dose of dispersible powder, more than one dose of granules, more than one dose of minitablets, more than one dose of pellets, or a combination thereof.
348. The use of any one of claims 315-347, wherein the pharmaceutical composition is a dispersible tablet, a dispersible powder, dispersible granules, a dispersible minitablet, or a dispersible pellet, and wherein the dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets is dispersed in a potable liquid prior to administration to the subject.
349. The use of claim 348, wherein the subject experiences dysphagia caused by one or more of: disease of the nervous system, muscle weakening, developmental disability, stroke, injury, anatomical defect, cancer, treatment for cancer, allergic reaction, dementia, memory loss, or cognitive decline.
350. The use of claim 348 or claim 349, wherein the subject is a pediatric subject.
351. The use of any one of claims 315-350, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 days in which the total daily dose is administered;
and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
352. The use of any one of claims 315-350, wherein the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) 21 consecutive days in which the total daily dose is administered;
followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
353. The use of any one of claims 315-350, wherein the N#R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 days in which the total daily dose is administered and (ii) 2 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; and (b) 7 days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
354. The use of any one of claims 315-350, wherein the N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered on a 28-day dosing cycle comprising: (a) three 7-day periods each comprising (i) 5 consecutive days in which the total daily dose is administered and (ii) 2 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;
followed by (b) 7 consecutive days in which no N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
355. The use of any one of claims 351-354, wherein the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.
356. A method of producing NAR)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) HOO N
OH N
F, I
(I), the method comprising reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent 1-propylphosphonic anhydride (T3P) to obtain 901 Acetonide as shown in Scheme 1:
Scheme 1 ,N
0 z 0 + T3P

(IPGA) MW 147.17 PD-0315209 (FIPFA) MW 393.10 901 Acetonide MW 522.26 =
357. The method of claim 356, wherein the 1-propylphosphonic anhydride is in solution.
358. The method of claim 356 or 357, wherein the 1-propylphosphonic anhydride is provided as a solution in ethyl acetate.
359. The method of claim 356, wherein the method of producing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I), comprises a) reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent that is 1-propylphosphonic anhydride (T3P) to obtain 901 Acetonide;
and b) treating 901 Acetonide with acid to form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide as shown in Scheme II:

Scheme II

0,0,N H2 + Si T3P ______ k N

(IPGA) PD-0315209 MW 147.17 (FIPFA) 901 Acetoni MW 393.10 de MW 522.26 "acid"
, 0 OH 1.1 OH = N =Mirdametinib (PD-0325901) Crude PD-0325901 M
MW 482.20 W 482.20
360. The method of claim 356, wherein the method of producing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (I) e5H N
F I
(I), comprises:
reacting PD-0315209 (FIPFA) and PD-0337792 (IPGA) with a coupling reagent to obtain 901 Acetonide; and treating 901 Acetonide with acid to form N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide according to Scheme III:

Scheme III
_ _ F H

L, F
0,0, 01 + 101 (50% in Et0Ac) =---`5 H
N
NH2 i-Pr2NEt F I ______________________ la 1.1 PD-0337792 F THF, toluene F
I
(IPGA) PD-0315209 MTBE, aq. NaOH F
MW 147.17 (FIPFA) 901 Acetonide MW 393.10 MW 522.26 ¨ _ aq. HCI
toluene, ACN
H H
õ....--...õ_õ--..., ,N 0 Et0H

F
H
N Et0H (5H H
N
water 110 0 F I F I
F F
Mirdametinib Crude PD-(PD-0325901) MW 482.20 MW 482.20 =
361. A crystalline composition that is essentially pure Form IV N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide prepared by the method of any one of claims 356-360.
362. The crystalline composition of claim 361, wherein the crystalline composition contains <
0.2% of dimeric impurity PF-00191189.
I
el F F

HO-0"-N 0 F

F I
F

Exact Mass: 856.93
363. The crystalline composition of claim 361 or claim 362, wherein the crystalline composition contains about 0.05% to about 0.19% by weight of dimeric impurity PF-00191189.
364. The crystalline composition of any one of claims 361-363, wherein the crystalline composition contains no detectable amount of dimeric impurity PF-00191189.
CA3207513A 2021-02-17 2021-02-17 Crystalline solids of mek inhibitor n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and uses thereof Pending CA3207513A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2021/018381 WO2022177557A1 (en) 2021-02-17 2021-02-17 Crystalline solids of mek inhibitor n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and uses thereof

Publications (1)

Publication Number Publication Date
CA3207513A1 true CA3207513A1 (en) 2022-08-25

Family

ID=74860569

Family Applications (1)

Application Number Title Priority Date Filing Date
CA3207513A Pending CA3207513A1 (en) 2021-02-17 2021-02-17 Crystalline solids of mek inhibitor n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and uses thereof

Country Status (10)

Country Link
EP (1) EP4294526A1 (en)
JP (1) JP2024509759A (en)
KR (1) KR20230147139A (en)
CN (1) CN117083264A (en)
AR (1) AR124911A1 (en)
AU (1) AU2021428512A1 (en)
CA (1) CA3207513A1 (en)
IL (1) IL305078A (en)
TW (1) TW202302526A (en)
WO (1) WO2022177557A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023223205A1 (en) 2022-05-17 2023-11-23 Teva Pharmaceuticals International Gmbh Solid state forms of mirdametinib and process for preparation thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EE05450B1 (en) 2000-07-19 2011-08-15 Warner-Lambert Company Oxygenated esters of 4-iodophen laminobenzh droxamic acids, their crystalline forms and pharmaceutical compositions and their use
MXPA06004363A (en) 2003-10-21 2006-06-14 Warner Lambert Co Polymorphic form of n-[(r)-2, 3-dihydroxy -propoxy]-3, 4-difluoro-2 -(2-fluoro-4 -iodophenylamino) -benzamide.
WO2006134469A1 (en) 2005-06-14 2006-12-21 Warner-Lambert Company Llc Methods of preparing mek inhibitor
US11066358B1 (en) * 2021-02-17 2021-07-20 Warner-Lambert Company Llc Compositions of essentially pure form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof
US11084780B1 (en) * 2021-02-17 2021-08-10 Springworks Therapeutics, Inc. Crystalline solids of MEK inhibitor N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof

Also Published As

Publication number Publication date
EP4294526A1 (en) 2023-12-27
KR20230147139A (en) 2023-10-20
WO2022177557A1 (en) 2022-08-25
AR124911A1 (en) 2023-05-17
IL305078A (en) 2023-10-01
AU2021428512A1 (en) 2023-09-21
TW202302526A (en) 2023-01-16
JP2024509759A (en) 2024-03-05
CN117083264A (en) 2023-11-17

Similar Documents

Publication Publication Date Title
US11427534B1 (en) Solids of MEK inhibitor N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and uses thereof
US11312700B2 (en) Aryl cyclopropyl-amino-isoquinolinyl amide compounds
NZ545578A (en) Gamma-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it
TW201000471A (en) Trisubstituted 1,2,4-triazoles
EP2991999A1 (en) Co-crystals of dapagliflozin
CA3207513A1 (en) Crystalline solids of mek inhibitor n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and uses thereof
EP2800747A1 (en) Polymorphs of perampanel
US11571402B2 (en) Dispersible formulations of N-((R)-2,3-dihydroxypropoly)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof
US20090292025A1 (en) Novel crystalline forms of armodafinil and preparation thereof
US20130059872A1 (en) Polymorphs of alogliptin benzoate
US6713491B2 (en) Heterocyclic derivatives
AU2012300841C1 (en) Novel crystal form
CA3207271A1 (en) Dispersible formulations of n-((r)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof
JP7194828B2 (en) crystalline salt of corridarmin
US20220089550A1 (en) Crystalline forms of (s)-2-(7-cyano-1h-benzimidazol-1 yl)-n-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}acetamide
JP3222051B2 (en) 6-methoxy-1H-benzotriazole-5-carboxamide derivative
CN116419757A (en) Amorphous melanocortin-4 receptor agonists
KR20100101405A (en) Method of preparing non-crystalline (+)-lansoprazole and (+)-lansoprazole alcoholate used therein
AU2010353051A1 (en) Polymorphs of alogliptin benzoate