WO2022177557A1 - Solides cristallins d'inhibiteur de mek n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide et utilisations associées - Google Patents

Solides cristallins d'inhibiteur de mek n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide et utilisations associées Download PDF

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WO2022177557A1
WO2022177557A1 PCT/US2021/018381 US2021018381W WO2022177557A1 WO 2022177557 A1 WO2022177557 A1 WO 2022177557A1 US 2021018381 W US2021018381 W US 2021018381W WO 2022177557 A1 WO2022177557 A1 WO 2022177557A1
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WIPO (PCT)
Prior art keywords
crystalline form
dihydroxypropoxy
difluoro
fluoro
phenylamino
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PCT/US2021/018381
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English (en)
Inventor
Kristin Patterson
Jiping Liu
Ricky Wayne Couch
Peter Gregory Varlashkin
Mai Li
Yonghong Gan
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Springworks Therapeutics, Inc.
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Priority to PCT/US2021/018381 priority Critical patent/WO2022177557A1/fr
Priority to CN202180095459.2A priority patent/CN117083264A/zh
Priority to AU2021428512A priority patent/AU2021428512A1/en
Priority to JP2023549993A priority patent/JP2024509759A/ja
Priority to EP21710829.9A priority patent/EP4294526A1/fr
Priority to CA3207513A priority patent/CA3207513A1/fr
Priority to IL305078A priority patent/IL305078A/en
Priority to KR1020237031522A priority patent/KR20230147139A/ko
Priority to TW111105779A priority patent/TW202302526A/zh
Priority to ARP220100336A priority patent/AR124911A1/es
Publication of WO2022177557A1 publication Critical patent/WO2022177557A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • 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

Definitions

  • 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.
  • Mirdametinib is a highly potent and specific allosteric non-ATP-competitive inhibitor of MEK1 and MEK2.
  • 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.
  • 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.
  • 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.
  • 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.
  • FIG.1A 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.
  • 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.
  • FIG.2A is a X-ray powder diffraction pattern ("XRPD”) corresponding to crystalline Form V.
  • FIG.2B is a thermogravimetric analysis thermogram (“TGA”) and a differential scanning calorimetry thermogram (“DSC”) corresponding to crystalline Form V.
  • FIG.3A is an XRPD corresponding to crystalline Form VI.
  • FIG.3B is a DSC and a TGA corresponding to crystalline Form VI.
  • FIG.4A is an XRPD corresponding to crystalline Form VII.
  • FIG.4B is a DSC and a TGA corresponding to crystalline Form VII.
  • FIG.5A is an XRPD corresponding to crystalline Form VIII.
  • FIG.5B is a DSC and a TGA corresponding to crystalline Form VIII.
  • FIG.6A is an XRPD corresponding to crystalline Form IX.
  • FIG.6B is a DSC and a TGA corresponding to crystalline Form IX.
  • FIG.7A is an XRPD corresponding to crystalline Form X.
  • FIG.7B is a DSC and a TGA corresponding to crystalline Form X.
  • FIG.8A is an XRPD corresponding to crystalline Form XI.
  • FIG.8B is a DSC and a TGA corresponding to crystalline Form XI.
  • FIG.9A is an XRPD corresponding to crystalline Form XII.
  • FIG.9B is a DSC and a TGA corresponding to crystalline Form XII.
  • FIG.10A is an XRPD corresponding to crystalline Form XIII.
  • FIG.10B is a DSC and a TGA corresponding to crystalline Form XIII.
  • FIG.11A is an XRPD corresponding to crystalline Form XIV overlaid with an XRPD corresponding to crystalline Form IV.
  • FIG.11B is a DSC and a TGA corresponding to crystalline Form XIV.
  • FIG.12A is an XRPD corresponding to crystalline Form XV.
  • FIG.12B is a DSC and a TGA corresponding to crystalline Form XV.
  • FIG.13A is an XRPD corresponding to crystalline Form XVI.
  • FIG.13B is a DSC and a TGA corresponding to crystalline Form XVI.
  • FIG.14A is an XRPD corresponding to crystalline Form XVII.
  • FIG.14B is a DSC and a TGA corresponding to crystalline Form XVII.
  • FIG.15A is an XRPD corresponding to crystalline Form XVIII.
  • FIG.15B is a DSC and a TGA corresponding to crystalline Form XVIII.
  • FIG.16A is an XRPD corresponding to crystalline Form XIX.
  • FIG.16B is a DSC and a TGA corresponding to crystalline Form XIX.
  • FIG.17A is an XRPD corresponding to crystalline Form XX.
  • FIG.17B is a DSC and a TGA corresponding to crystalline Form XX.
  • FIG.18A is an XRPD corresponding to crystalline Form XXI.
  • FIG.18B is a DSC and a TGA corresponding to crystalline Form XXI.
  • FIG.19A is an XRPD corresponding to crystalline Form XXII.
  • FIG.19B is a DSC and a TGA corresponding to crystalline Form XXII.
  • FIG.20A is an XRPD corresponding to crystalline Form XXIII.
  • FIG.20B is a DSC and a TGA corresponding to crystalline Form XXIII.
  • FIG.21A is an XRPD corresponding to crystalline Form XXIV.
  • FIG.21B is a DSC and a TGA corresponding to crystalline Form XXIV.
  • FIG.22A is an XRPD corresponding to amorphous mirdametinib.
  • FIG.22B is a DSC and a TGA corresponding to amorphous mirdametinib.
  • 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.
  • 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.
  • the present disclosure features novel methods of synthesizing N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • 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.
  • 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.
  • dysphagia such as patients with esophageal cancer, Parkinson’s disease, amyotrophic lateral sclerosis, stroke, achalasia, or esophageal narrowing.
  • the present disclosure provides a crystalline form of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (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,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form V.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VI.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VIII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form IX.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form X.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XI.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIV.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XV.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVI.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVIII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIX.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 and an endotherm onset at about 110 °C.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XX.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXI.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXIII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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) (I).
  • 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.
  • 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.
  • the XRPD pattern is generated using a PANALYTICAL ® X'Pert Pro diffractometer using Ni-filtered Cu K ⁇ (45 kV/40 mA) radiation and a step size of 0.03° 2 ⁇ 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 ® ADVANCE TM system using Cu K ⁇ (40 kV/40 mA) radiation and a step size of 0.03° 2 ⁇ with a LYNXEYE TM detector, configured (a) on the incidental
  • the DSC pattern is generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a rate of temperature increase of about 15°C/min.
  • a pharmaceutical composition e.g., capsule, tablet, powder, granules, minitablets, or pellets
  • the pharmaceutical composition is for oral administration.
  • the pharmaceutical composition is a solid dosage form.
  • 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).
  • the pharmaceutical composition is a tablet (e.g., dispersible tablet or orodispersible tablet) or a capsule. [0120] In some aspects, the pharmaceutical composition is a capsule.
  • 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)
  • 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 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
  • 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 (
  • 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 0.25 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 (
  • 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).
  • 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 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).
  • the pharmaceutical composition is a tablet.
  • 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 w
  • 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.
  • 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-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.
  • 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.
  • 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 wt/wt% of one or more diluents; and (c) about 1 wt/wt% to about 10 wt/wt% of one or more disintegrants.
  • 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.
  • the pharmaceutical composition is for oral administration. In some aspects, the pharmaceutical composition is dispersible orodispersible. [0127] In some aspects, the pharmaceutical composition is a tablet, a powder, granules, minitablets, or pellets (also called beads). [0128] 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. [0129] 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.
  • 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. [0131] 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. [0132] 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.
  • 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 about 10 wt/wt% of one or more disintegrants
  • 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
  • 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-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 disintegr
  • 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.
  • 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.
  • the pharmaceutical composition that is a dispersible tablet, dispersible powder, dispersible granules, 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.
  • 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.
  • 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.
  • At least one of the diluents is microcrystalline cellulose.
  • 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.
  • 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.
  • at least one of the flavoring agents is grape flavoring.
  • 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.
  • 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.
  • 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.
  • a pharmaceutical composition e.g., capsule, tablet, powder, granules, minitablets, or pellets
  • 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.
  • the tumor is a neurofibroma.
  • the tumor is a neurofibroma associated with Neurofibromatosis Type 1.
  • 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.
  • the tumor is plexiform neurofibroma.
  • 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.
  • 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.
  • the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.
  • 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.
  • 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.
  • 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.
  • 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.
  • tablet e.g., dispersible tablet
  • powder e.g., dispersible powder
  • granules e.g., dispersible granules
  • minitablets e.g., dispersible minitablets
  • pellets e.g., dispersible pellets
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 2 mg.
  • 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.
  • 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.
  • 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 N-((R)-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.
  • the total daily dose of N-((R)-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.
  • 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.
  • 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.
  • 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 0.5 mg each.
  • 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 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.
  • 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.
  • 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. [0154] 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.
  • 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.
  • 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.
  • 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. 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.
  • 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 20 mg.
  • 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 10 mg.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.
  • 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.
  • 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.
  • 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 [0162] Novel methods of producing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide of Formula (I) (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.
  • FRPFA PD-0315209
  • IPGA 1-propylphosphonic anhydride
  • the T3P is in solution. In some aspects, T3P is provided as a solution in ethyl acetate.
  • 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.
  • 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- 00191189 [0168] 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 [0169] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.
  • the term “a” or “an” means “single.” In other aspects, the term “a” or “an” includes “two or more” or “multiple.” [0172] 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).
  • mirdametinib and PD-0325901 refer to the single enantiomer N- ((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
  • 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.
  • primate e.g., human
  • cow, sheep, goat horse
  • dog cat
  • rabbit rat
  • patient e.g., human
  • human cow
  • sheep goat
  • horse dog
  • cat rabbit
  • rat e.g., human
  • patient e.g., monkey
  • patient e.g., a mammalian subject
  • 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)).
  • 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
  • adolescents (12 years of age through 21 years of age (up to, but not including, the twenty- second birthday)).
  • Berhman R E Kliegman R, Arvin A M, Nelson W E. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996
  • Rudolph A M et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002
  • Avery M D First L R. Pediatric Medicine, 2nd Ed.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • PFS progression-free survival
  • DFS disease-free survival
  • OS overall survival
  • MFS metastasis-free survival
  • CRC complete response
  • MRD minimal residual disease
  • PR partial response
  • SD stable disease
  • PD progressive disease
  • TTP time to progression
  • 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 (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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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
  • composition 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).
  • 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.
  • 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.
  • 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.
  • crystalline 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.
  • Crystalline forms are commonly characterized by X-ray powder diffraction (XRPD).
  • XRPD X-ray powder diffraction
  • An XRPD pattern of reflections 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.
  • 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.
  • any particular peak in an XRPD may appear in a symmetric shape or in an asymmetric shape, e.g., having a shoulder.
  • instrument variation and other factors can affect the 2-theta values.
  • anhydrate as applied to a compound refers to a crystalline form wherein the compound contains no structural water within the crystal lattice.
  • 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 N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide.
  • another polymorphic form e.g., Form I or Form II
  • “essentially pure” Form IV of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide can include impurities, such as, but not limited to, synthetic reactants or by-products generated during the chemical synthesis.
  • 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.
  • compositions e.g., capsules, tablets, dispersible and non-dispersible dosage forms
  • 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.
  • 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.
  • 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.
  • the present disclosure provides a crystalline form of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide of Formula (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,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form V.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. [0201] 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form VIII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form IX.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form X.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XI.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIV.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XV.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVI.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XVIII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XIX.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 and an endotherm onset at about 110 °C.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XX.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXI.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXIII.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the crystal form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro- 2-(2-fluoro-4-iodo-phenylamino)-benzamide is Form XXIV.
  • 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) (I).
  • 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.
  • 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.
  • the XRPD pattern is generated using a PANALYTICAL ® X'Pert Pro diffractometer using Ni-filtered Cu K ⁇ (45 kV/40 mA) radiation and a step size of 0.03° 2 ⁇ 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 ® ADVANCE TM system using Cu K ⁇ (40 kV/40 mA) radiation and a step size of 0.03° 2 ⁇ with a LYNXEYE TM detector, configured (a) on the incidental
  • the DSC pattern is generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a rate of temperature increase of about 15°C/min.
  • Pharmaceutical Compositions [0260] 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. [0261] 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.
  • 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.
  • 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.
  • 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. [0262] In some aspects, the pharmaceutical composition is for oral administration. In some aspects, the pharmaceutical composition is a solid dosage form.
  • 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).
  • the pharmaceutical composition e.g., a dispersible tablet, dispersible powder, dispersible granules, dispersible minitablets, or dispersible pellets
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is for oral administration.
  • the pharmaceutical composition is orodispersible.
  • 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.
  • the pharmaceutical composition is a tablet, a powder, granules, minitablets, or pellets. [0265] 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. [0266] In some aspects, the pharmaceutical composition is in the form of granules. In some aspects, the granules are dispersible granules.
  • a capsule or sachet comprises the dispersible granules.
  • 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. [0268] 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. [0269] 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.
  • 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.
  • 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.
  • 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)-benzamide.
  • 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.
  • 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.
  • 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%,
  • 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-phenylamino)-benzamide. 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)-benzamide. [0272] In some aspects, the pharmaceutical composition comprises one or more diluents.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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
  • the pharmaceutical composition comprises about 90 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 93 wt/wt% microcrystalline cellulose. [0275] 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.
  • 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/w
  • the pharmaceutical composition comprises about 5 wt/wt% of one or more disintegrants.
  • 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.
  • at least one of the disintegrants is croscarmellose sodium.
  • the disintegrant is croscarmellose sodium.
  • the pharmaceutical composition comprises about 1 wt/wt % to about 10 wt/wt % croscarmellose sodium.
  • 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
  • the pharmaceutical composition comprises about 5 wt/wt % croscarmellose sodium. [0277] 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.
  • 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 %
  • the pharmaceutical composition comprises about 1 wt/wt % of one or more lubricants.
  • 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.
  • at least one of the lubricants is magnesium stearate.
  • the lubricant is magnesium stearate.
  • the pharmaceutical composition comprises 0 wt/wt % to about 5 wt/wt % of magnesium stearate.
  • 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.
  • 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 %
  • 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. [0279] 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.
  • 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
  • the pharmaceutical composition comprises about 2 wt/wt% of one or more flavoring agents.
  • 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.
  • at least one of the flavoring agents is grape flavoring.
  • the pharmaceutical composition comprises 0 wt/wt% to about 5.0 wt/wt% grape flavoring.
  • 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%
  • the pharmaceutical composition comprises about 2 wt/wt% grape flavoring. [0281] 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.
  • 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%,
  • the pharmaceutical composition comprises about 1 wt/wt% of one or more sweeteners.
  • at least one of the sweeteners is selected from the group consisting of sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, and aspartame.
  • at least one of the sweeteners is sucralose.
  • the sweetener is sucralose.
  • the pharmaceutical composition comprises 0 wt/wt% to about 5 wt/wt% sucralose.
  • the pharmaceutical composition comprises 0 wt/wt% to about 2 wt/wt% sucralose.
  • 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%, 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
  • the pharmaceutical composition comprises about 1 wt/wt% sucralose.
  • the pharmaceutical composition is a capsule.
  • 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
  • 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 lub
  • 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 lubric
  • 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 lub
  • 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 0.1 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;
  • 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 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
  • 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
  • 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 lub
  • 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).
  • 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).
  • the pharmaceutical composition is a tablet (e.g., dispersible tablet).
  • the tablet is a dispersible tablet.
  • 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 diluent
  • the 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% 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
  • the 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)
  • the 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)- 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)
  • the 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
  • the 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)
  • the 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)
  • the 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)
  • the 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
  • the 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 disintegrants; (d)
  • the 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)
  • the 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)
  • the tablet e.g., dispersible tablet
  • the 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)
  • the tablet e.g., dispersible tablet
  • the 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
  • the tablet e.g., dispersible tablet
  • the potable liquid is water, milk or a juice (e.g., orange juice or apple juice).
  • the potable liquid is water.
  • the potable liquid is a juice.
  • the tablet is orodispersible in a subject’s saliva.
  • the pharmaceutical composition is a powder (e.g., dispersible powder).
  • the powder e.g., dispersible powder
  • a capsule or sachet comprises the dispersible powder.
  • the 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 w
  • the 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
  • the 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)
  • the 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 0.5 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)
  • the 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
  • the 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)
  • the 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)-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)
  • the 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)
  • the 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
  • the 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/wt% of one or more disintegrants; (d)
  • the 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)
  • the 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)
  • 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)
  • 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
  • the powder e.g., dispersible powder
  • the potable liquid is water, milk or a juice (e.g., orange juice or apple juice).
  • the potable liquid is water.
  • the potable liquid is a juice.
  • the powder is orodispersible in a subject’s saliva.
  • the pharmaceutical composition is in the form of granules (e.g., dispersible granules).
  • the granules e.g., dispersible granules
  • a capsule or sachet comprises the dispersible granules.
  • the granules e.g., dispersible granules
  • the 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 dil
  • the 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
  • the 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 0.1 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
  • the 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 w
  • the 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/
  • the 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
  • the 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
  • the 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 w
  • the 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/
  • the 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
  • the 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
  • the 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 w
  • the 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
  • the 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
  • the granules are dissolved in a potable liquid before administration.
  • the potable liquid is water, milk or a juice (e.g., orange juice or apple juice).
  • the potable liquid is water.
  • the potable liquid is a juice.
  • the granules are orodispersible in a subject’s saliva.
  • the pharmaceutical composition is in the form of minitablets (e.g., dispersible minitablets). In some aspects, the minitablets are dispersible minitablets.
  • the 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 dis
  • the 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/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
  • the 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/wt% of one or more diluents; (c) about 1 wt/wt% to about 10 wt/wt% of
  • the 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%
  • the 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 0.1 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
  • the 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%
  • the 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
  • the 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 0.5 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%
  • the 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
  • the 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
  • the 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
  • the 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%
  • the 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 dis
  • the 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 0.5 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
  • the minitablets are dissolved in a potable liquid before administration.
  • the potable liquid is water, milk or a juice (e.g., orange juice or apple juice).
  • the potable liquid is water.
  • the potable liquid is a juice.
  • the minitablets are orodispersible in a subject’s saliva.
  • the pharmaceutical composition is in the form of pellets (e.g., dispersible pellet). In some aspects, the pellets are dispersible pellets.
  • the 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)
  • the 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 disintegr
  • the 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;
  • the 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
  • the 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; (a) about 0.1 wt/wt% to about 7 wt
  • the 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 0.5 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;
  • the 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 disintegrants;
  • the 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
  • the 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; (a) about 0.1 wt/wt% to about 7 wt/
  • the 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;
  • the 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;
  • the 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/wt% of one or more disintegrants
  • the 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; (a) about 0.1 wt/wt% to about 7 wt/
  • the 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;
  • the pellets are dissolved in a potable liquid before administration.
  • the potable liquid is water, milk or a juice (e.g., orange juice or apple juice).
  • the potable liquid is water.
  • the potable liquid is a juice.
  • the pellets are orodispersible in a subject’s saliva.
  • the tumor is a neurofibroma associated with Neurofibromatosis Type 1.
  • 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.
  • the tumor is plexiform neurofibroma.
  • 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.
  • 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.
  • the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia.
  • 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.
  • 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.
  • 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.
  • 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.
  • tablet e.g., dispersible tablet
  • dose of powder e.g, dispersible powder
  • dose of granules e.g., dispersible granules
  • minitablets e.g., dispersible minitablets
  • pellets e.g., dispersible pellets
  • 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.
  • 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.
  • 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.
  • 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.
  • 0.5 mg e.g., as one 0.5 mg tablet (e.g., dispersible tablet)
  • 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.
  • 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.
  • 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 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 per dose.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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 8 mg each.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the 28-day dosing cycle is repeated up to a total of 24 consecutive 28-day dosing cycles.
  • 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.
  • a potable liquid e.g., water or a juice (e.g., orange juice or apple juice)
  • 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.
  • the subject experiences dysphagia.
  • the subject has been diagnosed with an autism spectrum disorder.
  • the subject has been diagnosed with a craniofacial disorder.
  • the subject has been diagnosed with myasthenia gravis.
  • the subject has been diagnosed with tardive dyskinesia.
  • the subject is a pediatric subject.
  • 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.
  • 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.
  • 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.
  • 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. [0388] In some aspects, the subject is a geriatric subject.
  • 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.
  • the subject is more than 50 years old.
  • the subject is more than 60 years old.
  • the subject is more than 70 years old.
  • the subject is more than 80 years old.
  • the subject is more than 90 years old.
  • the subject is more than 100 years old.
  • 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 [0390] Novel methods of producing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide of Formula (I) (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.
  • the T3P is in solution. In some aspects, T3P is provided as a solution in ethyl acetate.
  • 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.
  • 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.
  • the essentially pure Form IV crystalline composition contains ⁇ 0.2% of dimeric impurity PF-00191189 .
  • 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. [0398] 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.
  • HPLC High Performance Liquid Chromatography
  • Example 1 Production of Seed Crystals of Form IV Step 1: Preparation of “Side Chain”, PD-0337792 [0400] 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.
  • Step 2 Preparation of PD-0315209 [0401] The process yielded 21.4 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.).
  • Step 3 Preparation of PD-0325901 [0402] 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).
  • 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.
  • Chromatographic Conditions Agilent Zorbax SB C18, 5 ⁇ 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.
  • Example 3 Improved Process for Preparation of Form IV [0410] 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.
  • the route is a convergent four step synthesis with six chemical steps overall, using the proposed starting materials (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol (SGA), 2,3,4-trifluorobenzoic acid (TFBA), 2-fluoro-4-idodoaniline (FIA), and N- hydroxyphthalimide (NHP).
  • SGA 2,3,4-trifluorobenzoic acid
  • FIA 2-fluoro-4-idodoaniline
  • NHS N- hydroxyphthalimide
  • 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-Dimethyl-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.
  • anhydrous toluene 99.8 kg, 5.75 volumes
  • 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.
  • 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).
  • 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 NMT 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 10 ⁇ 5 °C for NLT 3 hours.
  • Step 4 (Preparation of Essentially Pure Form IV 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-0325901 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).
  • FIG.1A 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 [0419] 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
  • Example 5 Comprehensive Crystal-Form Screening [0420] 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 [0421] 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
  • Example 6 Amorphous Material Preparation and Experiments
  • Amorphous mirdametinib was prepared on a 100 mg scale by rapid evaporation u nder reduced pressure (Genevac ® vacuum centrifuge) of 100 mg/mL solutions of the mirdametinib in methanol and THF (A-1 and A-2, respectfully).
  • Solutions of mirdametinib (100 mg/mL) were prepared in methanol and THF, and each solution was divided into three equal parts to be used for 1) open at RT stability evaluation, 2) closed at RT stability evaluation, and 3) closed at -20 ⁇ C stability evaluation.
  • 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 Characterization of Amorphous Material (A-1)
  • 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 [0429] The crystal-form screen consisted of about 450 crystallization experiments covering crystalline and amorphous input materials, and various crystallization modes, solvents, and temperatures. [0430] 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.
  • Example 8 Description of the Obtained Crystal Forms of Mirdametinib [0433] The following sections descrig117be and summarize the physical properties of each of the crystal forms observed for mirdametinib.
  • Transient Non-Solvated Form XIV [0434] 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.
  • 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).
  • 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 ⁇ m PTFE filter. The solution was rapidly evaporated under reduced pressure (GeneVac®) overnight to yield amorphous material.
  • 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.
  • 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.
  • Form VI (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 ⁇ m PTFE filter and rapidly evaporated under reduced pressure (GeneVac®) overnight. Water (1.0 mL) and a stir disc were added to the dry solids, followed by seeds ( ⁇ 0.1 mg).
  • Form IX (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 [0442] 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.
  • 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.
  • Example 9 Water Activity Studies of Hydrates at 23 °C
  • 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
  • Form V Toluene Solvate
  • Form VI Partially converted to Form A
  • Form XIII Hydrate
  • Form XIII/Form IV mixture converted to Form IV
  • Form XIX Hydrate
  • Example 14: Dispersible Tablets a Based on theoretical potency of 1.000. Quantity may be adjusted based on the actual potency.
  • E2 The crystalline form of E1, 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.
  • 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.
  • 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.
  • 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-E8, 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.
  • 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.
  • E11 The crystalline form of E1, 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.
  • E11-E18 The crystalline form of E11-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.
  • E20 The crystalline form of any one of E11-E19, wherein the crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide is Form VI.
  • E21 The crystalline form of E1, 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.
  • 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.
  • 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 °C and a second endotherm onset at about 110 °C. [0483] E27.
  • 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.
  • E30 The crystalline form of E1, 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.
  • E31 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-iodo-phenylamino)-benzamide is Form VII.
  • E30 The crystalline form of E1, wherein the crystalline form of N-((R)-2,3- dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is characterized by an XRP
  • 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 E39-E46, 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. [0504] E48.
  • 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.
  • 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 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.
  • E65 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)- benzamide is Form XI.
  • E65 The crystalline form of E1, 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.
  • E66 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)
  • 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.
  • E74 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)- benzamide is Form XII.
  • E74 The crystalline form of E1, 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.
  • 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 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. [0538] E82.
  • 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.
  • 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 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.
  • 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 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.
  • E107 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.
  • E107 The crystalline form of E1, 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.
  • E108 E108.
  • the crystalline form of any one of E107-E110, 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.
  • 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.
  • E114 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.
  • E114 The crystalline form of E1, 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.
  • 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 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.
  • 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.
  • E121 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.
  • E121 The crystalline form of E1, 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.
  • 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 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.
  • E131 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.
  • E131 The crystalline form of E1, 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.
  • 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 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.
  • E141 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.
  • E141 The crystalline form of E1, 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.
  • E142 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)
  • E141 The crystalline form of E141, 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. [0599] E143.
  • 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.
  • E150 The crystalline form of E1, 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.
  • E151 The crystalline form of E150, 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.
  • E152 The crystalline form of E150, 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.
  • 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.
  • E160 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.
  • E160 The crystalline form of E1, 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.
  • 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 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.
  • E169 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.
  • E169 The crystalline form of E1, 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.
  • 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 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 XRPD pattern substantially as shown in FIG.21A.
  • 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 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.
  • E179. 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • E186 The pharmaceutical composition of any one of E179-E185, wherein the pharmaceutical composition is for oral administration.
  • E187 E187.
  • E179-E186 The pharmaceutical composition of any one of E179-E186, wherein the pharmaceutical composition is a solid dosage form.
  • E188 The pharmaceutical composition of any one of E179-E187, wherein the pharmaceutical composition is a capsule, tablet, powder, granules, minitablet, or pellet.
  • E189 The pharmaceutical composition of E188, wherein the pharmaceutical composition is a capsule.
  • 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 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 lub
  • 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)-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
  • 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.
  • 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.
  • E196 The pharmaceutical composition of E195, wherein at least one of the disintegrants is croscarmellose sodium.
  • E200 The pharmaceutical composition of E199, wherein the tablet is a dispersible tablet.
  • E201 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.
  • E202 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.
  • E202 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.
  • 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.
  • E204 The pharmaceutical composition of E203, wherein at least one of the diluents is microcrystalline cellulose.
  • E205 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.
  • E201-E204 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.
  • E206 The pharmaceutical composition of E205, wherein at least one of the disintegrants is croscarmellose sodium.
  • E207 E207.
  • E208. The pharmaceutical composition of E207, wherein at least one of the flavoring agents is grape flavoring.
  • 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.
  • E210 The pharmaceutical composition of E209, wherein the sweetener is sucralose.
  • E211 E211.
  • E213. The pharmaceutical composition of any one of E199-E212, wherein the tablet is an orodispersible tablet.
  • E214 The pharmaceutical composition of E188, wherein the pharmaceutical composition is a powder.
  • E215. The pharmaceutical composition of E214, wherein the powder is a dispersible powder.
  • 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.
  • 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.
  • 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.
  • E220 The pharmaceutical composition of any one of E216-E219, 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.
  • E221. The pharmaceutical composition of E220, wherein at least one of the disintegrants is croscarmellose sodium.
  • E222 The pharmaceutical composition of E220, wherein at least one of the disintegrants is croscarmellose sodium.
  • 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.
  • 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
  • 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.
  • E225 The pharmaceutical composition of E224, wherein the sweetener is sucralose.
  • E227 The pharmaceutical composition of E226, wherein at least one of the lubricants is magnesium stearate.
  • E228 The pharmaceutical composition of any one of E215-E227, wherein the powder is an orodispersible powder.
  • E230 The pharmaceutical composition of E229, wherein the granules are dispersible granules.
  • 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.
  • 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.
  • 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.
  • E233 The pharmaceutical composition of E233, wherein at least one of the diluents is microcrystalline cellulose.
  • 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.
  • E236 The pharmaceutical composition of E235, wherein at least one of the disintegrants is croscarmellose sodium.
  • E237 The pharmaceutical composition of E235, wherein at least one of the disintegrants is croscarmellose sodium.
  • 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.
  • 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.
  • 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.
  • 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.
  • E242 The pharmaceutical composition of E241, wherein at least one of the lubricants is magnesium stearate.
  • E243 The pharmaceutical composition of any one of E229-E242, wherein the granules are orodispersible granules. [0700] E244.
  • E245. The pharmaceutical composition of E244, wherein the minitablets are dispersible minitablets.
  • 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.
  • 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.
  • 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.
  • E248, wherein at least one of the diluents is microcrystalline cellulose.
  • 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.
  • E251 The pharmaceutical composition of E250, wherein at least one of the disintegrants is croscarmellose sodium.
  • the pharmaceutical composition of E252, wherein at least one of the flavoring agents is grape flavoring.
  • 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.
  • the sweetener is sucralose.
  • E257 The pharmaceutical composition of E256, wherein at least one of the lubricants is magnesium stearate.
  • E258. The pharmaceutical composition of any one of E244-E257, wherein the minitablets are orodispersible minitablets. [0715] E259.
  • E260. The pharmaceutical composition of E259, wherein the pellets are dispersible pellets.
  • 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.
  • 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.
  • 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.
  • E264 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.
  • E263 wherein at least one of the diluents is microcrystalline cellulose.
  • E265. The pharmaceutical composition of any one of E261-E264, 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.
  • E266 The pharmaceutical composition of E265, wherein at least one of the disintegrants is croscarmellose sodium.
  • 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.
  • 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.
  • 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.
  • 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.
  • E272 The pharmaceutical composition of E271, wherein at least one of the lubricants is magnesium stearate.
  • 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.
  • E275 The method of E274, wherein the tumor is a neurofibroma.
  • E276 The method of E274 or E275, wherein the tumor is a neurofibroma associated with Neurofibromatosis Type 1.
  • 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.
  • E278 The method of E277, wherein the tumor is plexiform neurofibroma.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • E283. 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 macro
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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-4-iodo-phenylamino)-benzamide is administered two times daily.
  • 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.
  • 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.
  • E301 The method of E301.
  • 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.
  • 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.
  • E305 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.
  • E308 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.
  • 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.
  • E309 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,
  • E307 or E308, wherein the subject is a pediatric subject.
  • 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 N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered.
  • E311 The method of E307 or E308, wherein the subject is a pediatric subject.
  • 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-iodo-phenylamino)-benzamide is administered.
  • 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.
  • 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.
  • E316. The use of E315, wherein the tumor is a neurofibroma.
  • E317. The use of E315 or E316, wherein the tumor is a neurofibroma associated with Neurofibromatosis Type 1.
  • 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.
  • E319. The use of E318, wherein the tumor is plexiform neurofibroma.
  • 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.
  • 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.
  • 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.
  • 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, colore
  • 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.
  • 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 macroglobulinemia.
  • 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.
  • 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, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1, or NF2. [0782] E326.
  • 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.
  • 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.
  • 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.
  • 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.
  • E330 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.
  • E315-E329 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.
  • E331. The use of E330, 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.
  • 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.
  • E333 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 1 mg.
  • 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.
  • 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.
  • E336 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.
  • 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.
  • 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.
  • E338 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.
  • 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.
  • 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.
  • E340 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.
  • 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.
  • 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.
  • E342 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.
  • 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 1 mg each.
  • E343 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.
  • E344 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.
  • 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.
  • 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.
  • E346 E346.
  • 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.
  • E349. 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.
  • 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- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered. [0808] E352.
  • 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.
  • 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.
  • 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.
  • 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.
  • E356. A method of producing N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benzamide of Formula (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 .
  • E357 The method of E356, wherein the 1-propylphosphonic anhydride is in solution.
  • E358 The method of E356 or E357, wherein the 1-propylphosphonic anhydride is provided as a solution in ethyl acetate.
  • 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), 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:

Abstract

La présente divulgation concerne : a) des formes cristallines de N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phénylamino))-benzamide ; b) des compositions pharmaceutiques comprenant une ou plusieurs formes cristallines de N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phénylamino)-benzamide et, éventuellement, un ou plusieurs supports pharmaceutiquement acceptables ; c) des méthodes de traitement d'une tumeur, d'un cancer ou d'un dérèglement concernant les RASopathies par l'administration d'une ou de plusieurs formes cristallines de N-((R) -2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phénylamino)-benzamide à un patient en ayant besoin ; et des procédés de production de la forme IV essentiellement pure de N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide.
PCT/US2021/018381 2021-02-17 2021-02-17 Solides cristallins d'inhibiteur de mek n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide et utilisations associées WO2022177557A1 (fr)

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PCT/US2021/018381 WO2022177557A1 (fr) 2021-02-17 2021-02-17 Solides cristallins d'inhibiteur de mek n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide et utilisations associées
CN202180095459.2A CN117083264A (zh) 2021-02-17 2021-02-17 Mek抑制剂n-((r)-2，3-二羟基丙氧基)-3，4-二氟-2-(2-氟-4-碘-苯基氨基)-苯甲酰胺的结晶固体及其用途
AU2021428512A AU2021428512A1 (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
JP2023549993A JP2024509759A (ja) 2021-02-17 2021-02-17 Ｍｅｋ阻害剤ｎ－（（ｒ）－２，３－ジヒドロキシプロポキシ）－３，４－ジフルオロ－２－（２－フルオロ－４－ヨード－フェニルアミノ）－ベンズアミドの結晶性固体及びその使用
EP21710829.9A EP4294526A1 (fr) 2021-02-17 2021-02-17 Solides cristallins d'inhibiteur de mek n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophénylamino)-benzamide et utilisations associées
CA3207513A CA3207513A1 (fr) 2021-02-17 2021-02-17 Solides cristallins d'inhibiteur de mek n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide et utilisations associees
IL305078A IL305078A (en) 2021-02-17 2021-02-17 Crystalline solids of the MEK inhibitor N-((R)-3,2-dihydroxypropoxy)-4,3-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide and their uses
KR1020237031522A KR20230147139A (ko) 2021-02-17 2021-02-17 Mek 저해제인 n-((r)-2,3-다이하이드록시프로폭시)-3,4-다이플루오로-2-(2-플루오로-4-아이오도페닐아미노)-벤즈아마이드의 결정질 고체 및 이의 용도
TW111105779A TW202302526A (zh) 2021-02-17 2022-02-17 Ｍｅｋ抑制劑ｎ－（（ｒ）－２，３－二羥基丙氧基）－３，４－二氟－２－（２－氟－４－碘－苯基胺基）－苯甲醯胺之結晶固體及其用途
ARP220100336A AR124911A1 (es) 2021-02-17 2022-02-17 Sólidos cristalinos del inhibidor mek n-((r)-2,3-dihidroxipropoxi)-3,4-difluoro-2-(2-fluoro-4-yodo-fenilamino)-benzamida y usos de los mismos

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KR20230147139A (ko) 2023-10-20
AR124911A1 (es) 2023-05-17
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