WO2008013823A2

WO2008013823A2 - Co-crystals of (2r-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-1-piperazinyl]carbonyl]-n,n,1-trimethyl-alpha-oxo-1h-indole-3-acetamide

Info

Publication number: WO2008013823A2
Application number: PCT/US2007/016668
Authority: WO
Inventors: Renato Andres Chiarella
Original assignee: Scios Inc.
Priority date: 2006-07-26
Filing date: 2007-07-25
Publication date: 2008-01-31
Also published as: WO2008013823A3

Abstract

The present invention relates to novel co-crystals of the Active Pharmaceutical Ingredient (API) (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 - piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide, methods for their preparation, and pharmaceutical compositions comprising the novel co-crystals.

Description

CO-CRYSTALS OF (2R-TRANS)-6-CHLORO-5-[[4-[(4-

FLUOROPHENYL)METHYL]-I₅S-DIMETHYL-I-PIPERAZINYL]CARBONYL]- N₅N₅ I-TRIMETHYL-ALPHA-OXO-IH-INDOLE-S-ACETAMIDE

TECHNICAL FIELD

[001] The present invention relates to novel co-crystals of the Active Pharmaceutical Ingredient (API) (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl-l-piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide, methods for their preparation, and pharmaceutical compositions comprising these co- crystals.

BACKGROUND OF THE INVENTION

[002] The compound (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl-1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo-lH-indole-3-acetamide is an agent that can be used to treat a variety of disorders such as multiple myeloma, metastic cancers and bone disease, psoriasis, rheumatoid arthritis and other inflammatory related disorders. Its structure, properties, utility and preparation are described in United States Patent No. 6,867,209, issued March 15, 2005, which is hereby incorporated by reference in its entirety.

[003] Delivering an API to a patient requires more than just identifying a molecule and its use. An API must be formulated for delivery to a patient and this formulation (in addition to the API activity) is evaluated by regulatory agencies such as the US Food and Drug Administration (FDA). The FDA evaluates the formulation for, among other properties, delivery properties, stability, consistency, and manufacturing controls. An important factor in determining the properties of a particular formulation is the form of the API. APIs have been known to exist as amorphous forms, crystalline forms, polymorphs, hydrates and solvates. The forms for every API are different. While one particular API may be known to exist as a polymorph or a solvate, another API may be known to only exist in amorphous form. This form diversity is important because each different polymorph, solvate, hydrate or amorphous form may have different properties such as stability, solubility, and hygroscopicity. [004] Some forms of an API can be formulated into an FDA approvable formulation, while other forms lack the required properties to meet the high regulatory standards of the FDA. Even if a particular API can exist in more than one form suitable for formulation, different properties of an API form can affect the manufacturing process, shelf stability, route of administration, bioavailability and other important product characteristics. For example, the ability to improve or modulate stability or hygroscopicity can decrease manufacturing costs by reducing the need for humidity controlled chambers or reducing the need to package an API in humidity resistant packaging. In addition these same changes can increase product shelf stability thereby improving product distribution possibilities and affecting cost. In another example, one form of an API may have greater bioavailability than another form. Choosing the higher bioavailability form allows for a lower drug dose to be administered to a patient.

[005] Thus, increasing the form diversity of a particular API increases opportunities to identify the ideal form for formulation. In addition, increasing form diversity increases the possibility of finding improved forms which can reduce manufacturing costs, increase shelf stability, offer new routes of administration, and offer new formulation options.

[006] While APIs in general have been recognized to form crystalline polymorphs, solvates, hydrates and amorphous forms for a number of years, there is little knowledge about which APIs will form co-crystals. Co-crystals are a specific type of crystalline form which provide a new avenue to modulate the API form and thus to modulate API properties. Co-crystals contain an API and at least one other component which crystallize together. Selection of the other component helps determine whether a co-crystal will form and what properties the co-crystal will have. Just as a polymorph, solvate, hydrate or amorphous form of an API can modulate stability, solubility, and hygroscopicity, a co-crystal can modulate those same properties.

[007] Applicants have discovered that (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- lH-indole-3-acetamide can form co-crystals which modulate the properties of this API. This discovery increases opportunities for the identification of an improved formulation suitable for FDA approval and for the ability of affect manufacturing process, shelf stability, route of administration, bioavailability and other product characteristics through co-crystal and crystal form selection. SUMMARY OF THE INVENTION

[008] It has now been found that novel co-crystals of (2R-trans)-6-chloro-5-[[4- [(4-fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha- oxo-lH-indole-3-acetamide can be obtained.

[009] In one embodiment, the invention provides a co-crystal of (2R-trans)-6- chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1- trimethyl-alpha-oxo-lH-indole-3-acetamide and a co-crystal former.

[0010] In another embodiment, the invention provides a co-crystal of (2R-trans)- 6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 - trimethyl-alpha-oxo-lH-indole-3-acetamide hydrochloride and a co-crystal former.

[0011] In a further embodiment, the invention provides a co-crystal of (2R- trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]- N₅N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide hydrochloride and urea.

[0012] In a still further embodiment, the invention provides a co-crystal of (2R- trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]- N,N, l-trirnethyl-alpha-oxo-lH-indole-3-acetamide hydrochloride and arginine.

[0013] In one embodiment, the invention provides a co-crystal of (2R-trans)-6- chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 - trimethyl-alpha-oxo-lH-indole-3-acetamide free base and a co-crystal former.

[0014] In another embodiment, the invention provides a co-crystal of (2R-trans)- 6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1- trimethyl-alpha-oxo-lH-mdole-3-acetamide free base and salicylic acid.

[0015] In further embodiment, the invention provides a co-crystal of (2R-trans)- 6-chloro-5-[[4-[(4-fiuorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 - trimethyl-alpha-oxo-lH-indole-3-acetamide free base and 4-aminosalicylic acid.

[0016] In still further embodiment, the invention provides a co-crystal of (2R- trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 -piperazinyl]carbonyl] - N₅N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base and benzoic acid.

[0017] The invention also provides for methods of making the novel co-crystals of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo-1 H-indole-3-acetamide. [0018] The invention also provides pharmaceutical compositions comprising these novel co-crystals of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)rnethyl]-2,5- dimethyl-l-piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo-1 H-indole-3-acetamide.

[0019] Compositions and methods of the invention are useful in the treatment or prevention of a variety of diseases including, among others, multiple myeloma, metastic cancers and bone disease, psoriasis, rheumatoid arthritis and other inflammatory related disorders.

DESCRIPTION OF THE FIGURES

[0020] FIG. 1 illustrates powder X-ray diffraction (PXRD) measurements of a (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo-1 H-indole-3-acetamide hydrochloride: urea co-crystal.

[0021] FIG. 2 illustrates differential scanning calorimetry (DSC) measurements of a (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l - piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide hydrochloride: urea co-crystal.

[0022] FIG. 3 illustrates therrnogravirnetric analysis (TGA) measurements of a (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide hydrochloride: urea co-crystal.

[0023] FIG. 4 illustrates powder X-ray diffraction (PXRD) measurements of a (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo-1 H-indole-3-acetamide hydrochloride: arginine co-crystal.

[0024] FIG. 5 illustrates differential scanning calorimetry (DSC) measurements of a (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2_>5-dimethyl-l - piperazinyI]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide hydrochloride: arginine co-crystal.

[0025] FIG. 6 illustrates thermogravimetric analysis (TGA) measurements of a (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo-1 H-indole-3-acetamide hydrochloride: arginine co-crystal. [0026] FIG. 7 illustrates powder X-ray diffraction (PXRD) measurements of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base (top pattern), a (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide: salicylic acid co-crystal (middle pattern), and salicylic acid (bottom pattern).

[0027] FIG. 8 illustrates powder X-ray diffraction (PXRD) measurements of a (2R-rrans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide: salicylic acid co-crystal.

[0028] FIG. 9 illustrates differential scanning calorimetry (DSC) measurements of a (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 - piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide: salicylic acid co-crystal.

[0029] FIG. 10 illustrates thermogravimetric analysis (TGA) measurements of a (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide: salicylic acid co-crystal.

[0030] FIG. 11 illustrates powder X-ray diffraction (PXRD) measurements of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base (top pattern), a (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo-1 H-indole-3-acetamide: 4- aminosalicylic acid co-crystal (middle pattern), and 4-aminosalicylic acid (bottom pattern).

[0031 ] FIG. 12 illustrates powder X-ray diffraction (PXRD) measurements of a (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide: 4- aminosalicylic co-crystal.

[0032] FIG. 13 illustrates differential scanning calorimetry (DSC) measurements of a (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l - piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo-1 H-indole-3-acetamide: 4- aminosalicylic acid co-crystal. [0033] FIG. 14 illustrates thermogravimetric analysis (TGA) measurements of a (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-S-acetamide: 4- aminosalicylic acid co-crystal.

[0034] FIG. 15 illustrates powder X-ray diffraction (PXRD) measurements of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base (top pattern), a (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l - piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide: benzoic acid co-crystal (middle pattern), and benzoic acid (bottom pattern).

[0035] FIG. 16 illustrates powder X-ray diffraction (PXRD) measurements of a (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide: benzoic co- crystal.

[0036] FIG. 17 is the molecular structure of the compound (2R-trans)-6-chloro- 5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1-trimethyl- alpha-oxo- 1 H-indole-3-acetamide.

DETAILED DESCRIPTION OF THE INVENTION Definitions:

[0037] The term "co-crystal" as used herein means a crystalline material comprised of two or more unique solids at room temperature (22 degrees C), at least one of which is a co-crystal former. Solvates of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide that do not further comprise a co-crystal former are not co- crystals according to the present invention. The co-crystals may however, include one or more solvate molecules in the crystalline lattice. An API bound to an acid or base in the form of a salt can be one unique solid, but it cannot be two unique solids by itself.

[0038] The term "co-crystal former" as use herein means a small molecule with a melting point above room temperature (22 degrees C).

[0039] "Substantially pure" for the purposes of this invention means a pharmaceutical composition containing greater than or equal to 95% of one particular crystalline form and less than 5% of any other crystalline or non-crystalline form of 2R- trans)-6-chloro-5-[[4-[(4-fluorophenyl) methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]- N,N, 1 -trimethyl-alpha-oxo-lH-indole-S-acetamide.

[0040] In one embodiment, the invention provides a co-crystal of (2R-trans)-6- chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 - trimethyl-alpha-oxo-lH-indole-3-acetamide and a co-crystal former. In another embodiment, the invention provides a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- lH-indole-3-acetamide hydrochloride and a co-crystal former.

[0041] In another embodiment, the invention provides a co-crystal of (2R-trans)- 6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 - trimethyl-alpha-oxo-lH-indole-3-acetamide hydrochloride and urea. In one aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3 -acetamide hydrochloride and urea is characterized by a powder X-ray diffraction pattern comprising one peak at about 6.7 degrees 2-theta. In another aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3 -acetamide hydrochloride and urea is characterized by a powder X-ray diffraction pattern comprising one powder X-ray diffraction peak at about 6.7 degrees 2-theta and one or more powder X-ray diffraction peaks at about 9.1, 10.5, or 11.2 degrees 2-theta. In a further aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl- 1 -piperazinyl] carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide hydrochloride and urea is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks at about 6.7, 9.1, 10.5, and 11.2 degrees 2-theta. In a still further aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl3-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1-trimethyl-alpha-oxo- 1 H-indole-3-acetamide hydrochloride and urea is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks at about 6.7, 9.1, 10.5, 11.2, 14.1, 15.2, and 16.2 degrees 2-theta. In a still further aspect of this invention, a co- crystal of (2R-trans)-6-chloro-5- [[4-[(4-fluorophenyl)methyl] -2,5-dimethyl- 1 - piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3 -acetamide hydrochloride and urea is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks at about 6.7, 9.1, 10.5, 11.2, 12.1, 12.7, 14.1, 15.2, 16.2, 19.1, and 20.2 degrees 2-theta. In another aspect of this invention, a co-crystal of (2R-trans)-6-chloro- 5-[[4-[(4-fluorophehyl)methyl3-2,5-dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl- alpha-oxo-lH-indole-3-acetamide hydrochloride and urea is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks substantially similar to the powder X-ray diffraction peaks in Figure 1. In one aspect of this invention, a co- crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l - piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide hydrochloride and urea is characterized by a TGA thermogram comprising about a 8 percent weight loss between about 25 degrees C and about 150 degrees C. In another aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl-l-piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide hydrochloride and urea is characterized by a TGA thermogram substantially similar to the TGA thermogram in Figure 3. In still another aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide hydrochloride and urea is characterized by an endothermic transition at about 178 degrees C. In a further aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- lH-indole-3-acetamide hydrochloride and urea is characterized by a differential scanning calorimetry (DSC) measurement substantially similar to the DSC in Figure 2. In one aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- lH-indole-3-acetamide hydrochloride and urea is substantially pure. In another embodiment, the invention provides a crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- lH-indole-3-acetamide hydrochloride and urea and said crystal is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks at about 6.7, 9.1, 10.5, 11.2, 12.1, 12.7, 14.1, 15.2, 16.2, 19.1, and 20.2 degrees 2-theta.

[0042] In another embodiment, the invention provides a co-crystal of (2R-trans)- 6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 - trimethyl-alpha-oxo-lH-indole-3-acetamide hydrochloride and arginine. In one aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyi- 1 -piρerazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3 -acetamide hydrochloride and arginine is characterized by a powder X-ray diffraction pattern comprising one powder X-ray diffraction peak at about 7.6 degrees 2-theta. In another aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- lH-indole-3-acetamide hydrochloride and arginine is characterized by a powder X-ray diffraction pattern comprising one powder X-ray diffraction peak at about 7.6 or 9.4 degrees 2-theta and one or more powder X-ray diffraction peaks at about 13.2 and 16.5 degrees 2-theta. In a further aspect of this invention, a co-crystal of (2R-trans)-6-chloro- 5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1-trimethyl- alpha-oxo-lH-indole-3-acetamide hydrochloride and arginine is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks at about 7.6, 9.4, 13.2, and 16.5 degrees 2-theta. In a still further aspect of this invention, a co- crystal of(2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide hydrochloride and arginine is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks at about 7.6, 9.4, 13.2, 16.5, 18.8, 21.2, and 23.4 degrees 2-theta. In another aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1-trimethyl-alpha-oxo- lH-indole-3-acetamide hydrochloride and arginine is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks substantially similar to the powder X-ray diffraction peaks in Figure 4. In one aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 - piperazinyl]carbonyl]-N,N, l-trirnethyl-alpha-oxo-lH-indole-3-acetamide hydrochloride and arginine is characterized by a TGA thermogram comprising about a 10 percent weight loss between about 25 degrees C and about 160 degrees C. In another aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl-l-piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide hydrochloride and arginine is characterized by a TGA thermogram substantially similar to the TGA thermogram in Figure 6. In still another aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 - piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide hydrochloride and arginine is characterized by an endothermic transition at about 193 degrees C. In a further aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1-trimethyl-alpha-oxo- lH-indole-3-acetamide hydrochloride and arginine is characterized by a differential scanning calorimetry (DSC) measurement substantially similar to the DSC in Figure 5. In one aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl- 1 -piperazinyl]carbonyl]-N,N., 1 -trimethyl-alpha-oxo- lH-indole-3-acetamide hydrochloride and arginine is substantially pure. In another embodiment, the invention provides a crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1-trimethyl-alpha-oxo- lH-indole-3-acetamide hydrochloride and arginine and said crystal is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks at about 7.6, 9.4, 13.2, 16.5, 18.8, 21.2, and 23.4 degrees 2-theta. ^•

[0043] In one embodiment, the invention provides a co-crystal of (2R-trans)-6- chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 - trimethyl-alpha-oxo-lH-indole-3-acetamide free base and a co-crystal former. In another embodiment, the invention provides a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- lH-indole-3-acetamide free base and salicylic acid. In one aspect of this invention, a co- crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 - piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base and salicylic acid is characterized by a powder X-ray diffraction pattern comprising one powder X-ray diffraction peak at about 10.1 degrees 2-theta. In another aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo-1 H-indole-3-acetamide free base and salicylic acid is characterized by a powder X-ray diffraction pattern comprising one powder X-ray diffraction peak at about 10.1 degrees 2-theta and one or more powder X-ray diffraction peaks at about 5.0, 5.7, or 6.8 degrees 2-theta. In a further aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide free base and salicylic acid is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks at about 5.0, 5.7, 6.8, and 10.1 degrees 2-theta. In a still further aspect of this invention, a co-crystal of (2R-trans)- 6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piρerazinyl]carbonyl]-N,N, 1- trimethyl-alpha-oxo-1 H-indole-3-acetamide free base and salicylic acid is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks at about 5.0, 5.7, 6.8, 10.1, 13.6, and 16.8 degrees 2-theta. In another aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl- 1 -piperazinyl] carbonyl] -N₅N, 1 -trimethyl-alpha-oxo- 1 H-indole-3 -acetamide free base and salicylic acid is characterized by.a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks substantially similar to the powder X-ray diffraction peaks in Figure 8. In one aspect of this invention, a co-crystal of (2R-trans)- 6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl] carbonyl] -N₅N, 1 - trimethyl-alpha-oxo- lH-indole-3-acetamide free base and salicylic acid is characterized by a TGA thermogram comprising about a 16 percent weight loss between about 25 degrees C and about 191 degrees C. In another aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3 -acetamide free base and salicylic acid is characterized by a TGA thermogram substantially similar to the TGA thermogram in Figure 10. In still another aspect of this invention, a co-crystal of (2R- trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]- N₅N, 1 -trimethyl-alpha-oxo- 1 H-indole-3 -acetamide free base and salicylic acid is characterized by an endothermic transition at about 191 degrees C. In a further aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dirnethyl-l-piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base and salicylic acid is characterized by a differential scanning calorimetry (DSC) measurement substantially similar to the DSC in Figure 9. In one aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl-1 -piperazinyI]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide free base and salicylic acid is substantially pure. In another embodiment, the invention provides a crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base and salicylic acid and said crystal is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks at about 5.0, 5.7, 6.8, 10.1, 13.6, and 16.8 degrees 2-theta.

[0044] In a further embodiment, the invention provides a co-crystal of (2R- trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 -piperazinyl] carbonyl]- N₅N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide free base and 4-aminosalicylic acid. In one aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- lH-indole-3-acetamide free base and 4-aminosalicylic acid is characterized by a powder X-ray diffraction pattern comprising one powder X-ray diffraction peak at about 10.2 degrees 2-theta. In another aspect of this invention, a co-crystal of (2R-trans)-6-chloro- 5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl- alpha-oxo-lH-indole-3-acetamide free base and 4-aminosalicylic acid is characterized by a powder X-ray diffraction pattern comprising one powder X-ray diffraction peak at about 10.2 degrees 2-theta and one or more powder X-ray diffraction peaks at about 8.4, 9.2, and 13.4 degrees 2-theta. In a farther aspect of this invention, a co-crystal of (2R- trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]- N₅N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base and 4-aminosalicylic acid is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks at about 8.4, 9.2, 10.2 and 13.4 degrees 2-theta. In a still further aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl-l-piperazinylJcarbonylJ-N.N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base and 4-aminosalicylic acid is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks at about 5.0, 5.8, 6.7, 8.4, 9.2, 10.2 and 13.4 degrees 2-theta. In another aspect of this invention, a co-crystal of (2R-trans)- 6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 - trimethyl-alpha-oxo-lH-indole-3-acetamide free base and 4-aminosalicylic acid is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks substantially similar to the powder X-ray diffraction peaks in Figure 12. In one aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- lH-indole-3-acetamide free base and 4-aminosalicylic acid is characterized by a TGA thermogram comprising about a 15 percent weight loss between about 50 degrees C and about 165 degrees C. In another aspect of this invention, a co-crystal of (2R-trans)-6- chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 - trimethyl-alpha-oxo-lH-indole-3-acetamide free base and 4-aminosalicylic acid is characterized by a TGA thermogram substantially similar to the TGA thermogram in Figure 14. In still another aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5- [[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl- alpha-oxo-lH-indole-3-acetamide free base and 4-aminosalicylic acid is characterized by an endothermic transition at about 165 degrees C. In a further aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l - piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base and 4-aminosalicylic acid is characterized by a having a differential scanning calorimetry (DSC) measurement substantially similar to the DSC in Figure 13. In one aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl-1 -piperazinyl]carbonyl]-N₅N, 1 -trimethyl-alpha-oxo-lH-indole-S-acetamide free base and 4-aminosalicylic acid is substantially pure. In another embodiment, the invention provides a crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl-l-piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base and 4-aminosalicylic acid and said crystal is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks at about 5.0, 5.8, 6.7, 8.4, 9.2, 10.2 and 13.4 degrees 2-theta.

[0045] In still further embodiment, the invention provides a co-crystal of (2R- trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]- N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base and benzoic acid. In one aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1-trimethyl-alpha-oxo- lH-indole-3-acetamide free base and benzoic acid is characterized by a powder X-ray diffraction pattern comprising one powder X-ray diffraction peak at about 9.8 degrees 2- theta. In another aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1-trimethyl-alpha-oxo- lH-indole-3-acetamide free base and benzoic acid is characterized by a powder X-ray diffraction pattern comprising one powder X-ray diffraction peak at about 9.8 degrees 2- theta and one or more powder X-ray diffraction peaks at about 4.9, 5.7, and 6.8 degrees 2-theta. In a further aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4- [(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha- oxo-lH-indole-3-acetamide free base and benzoic acid is characterized by a powder X- ray diffraction pattern comprising powder X-ray diffraction peaks at about 4.9, 5.7, 6.8, and 9.8 degrees 2-theta. In a still further aspect of this invention, a co-crystal of (2R- trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]- N₅N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base and benzoic acid is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks at about 4.9, 5.7, 6.8, 9.8, 13.6, 15.1, and 16.7 degrees 2-theta. In a still further aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- lH-indole-3-acetamide free base and benzoic acid is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks at about 4.9, 5.7, 6.8, 9.8, 13.6, 15.1 , 16.7, 18.8, and 20.0 degrees 2-theta. In another aspect of this invention, a co- crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 - piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base and benzoic acid is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks substantially similar to the powder X-ray diffraction peaks in Figure 16. In one aspect of this invention, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyI)methyl]-2,5-dimethyl-l-piperazinyl3carbonyl]-N,N, 1-trimethyl-alpha-oxo- lH-indole-3-acetamide free base and benzoic acid is substantially pure. In another embodiment, the invention provides a crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1-trimethyl-alpha-oxo- lH-indole-3-acetamide free base and benzoic acid and said crystal is characterized by a powder X-ray diffraction pattern comprising powder X-ray diffraction peaks at about 4.9, 5.7, 6.8, 9.8, 13.6, 15.1, 16.7, 18.8, and 20.0 degrees 2-theta.

[0046] The ratio of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl-1 -piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide to co-crystal former may be stoichiometric or non-stoichiometric according to the present invention. Non-limiting examples such as, 1:1, 1:1.5, 1.5:1, 1 :2, and 2:1 ratios of (2R- trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]- N₅N, l-trimethyl-alpha-oxo-lH-indole-S-acetamidexo-crystal former are acceptable. In addition, co-crystals with vacancies within the crystalline lattice are included in the present invention. For example, a co-crystal with less than or about 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 percent vacancies within the crystalline lattice are included in the present invention. The vacancies can be due to missing (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 - piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide molecules or missing co-crystal former molecules from the crystalline lattice, or both. [0047] It has been found that when (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo- lH-indole-3-acetamide and a selected co-crystal former are allowed to form co-crystals, the resulting co-crystals may give rise to improved or different properties of (2R-trans)- 6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 - . trimethyl-alpha-oxo-lH-indole-3-acetamide, as compared to (2R-trans)-6-chloro-5-[[4- [(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1-trimethyl-alpha- oxo-lH-indole-3-acetamide in the free base or hydrochloride salt, particularly with respect to: solubility, dissolution, bioavailability, stability, C_max, T_max, processability (including compressibility), longer lasting therapeutic plasma concentration, etc.

[0048] Accordingly, in a first aspect, the present invention provides a pharmaceutical composition (or medicament) comprising a co-crystal of (2R-trans)-6- chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 - trimethyl-alpha-oxo-lH-indole-3-acetamide and a co-crystal former, such that the (2R- trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]- N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide and the co-crystal former are capable of co-crystallizing from a solution phase under crystallization conditions or from the solid-state, for example, through grinding or heating.

[0049] In another embodiment, the use of an excess (more than 1 molar equivalent for a 1 : 1 co-crystal) of a co-crystal former can be used to drive the formation of stoichiometric co-crystals. For example, co-crystals with stoichiometrics of 1 : 1 , 2: 1 , or 1 :2 can be produced by adding co-crystal former in an amount that is 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100 times or more than the stoichiometric amount for a given co-crystal. Such an excessive use of a co-crystal former to form a co-crystal can be employed in solution or when grinding (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- lH-indole-3-acetamide and a co-crystal former to cause co-crystal formation. Examples of co-crystal formers include urea, arginine, salicylic acid, 4-aminosalicylic acid, benzoic acid, citric acid, succinic acid, and malonic acid. Other examples of co-crystal formers are described in WO2004/078163. The co-crystal formers described in WO2004/078163 are hereby incorporated in by reference.

[0050] In another embodiment, the co-crystal comprises more than one co- crystal former. For example, two, three, four, five, or more co-crystal formers can be incorporated in a co-crystal with (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl-1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo-lH-indole-S-acetamide. Co-crystals which comprise two or more co-crystal formers and an API are bound together via hydrogen bonds. In one embodiment, incorporated co-crystal formers are hydrogen bonded to (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide molecules. In another embodiment, co-crystal formers are hydrogen bonded to either the (2R-trans)-6- chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1- trimethyl-alpha-oxo-lH-indole-3-acetamide molecules or the incorporated co-crystal formers.

[0051] The invention also provides pharmaceutical compositions comprising these novel co-crystals of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl-l-piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide. In one embodiment, a pharmaceutical composition comprises a co-crystal of (2R-trans)- 6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 - trimethyl-alpha-oxo-lH-indole-3-acetamide and a co-crystal former and one or more excipients. In another embodiment, a pharmaceutical composition comprises a co- crystal of(2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo-1 H-indole-3-acetamide hydrochloride and a co-crystal former and one or more excipients. In another embodiment, a pharmaceutical composition comprises a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl- 1 -piperazinyl] carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide free base and a co-crystal former and one or more excipients. In another embodiment, a pharmaceutical composition comprises a co-crystal or crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, 1 -trimethyl-alρha-oxo-1 H-indole-3-acetamide hydrochloride and urea and one or more excipients. Ln another embodiment, a pharmaceutical composition comprises a co-crystal or crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide hydrochloride and arginine and one or more excipients. In another embodiment, a pharmaceutical composition comprises a co-crystal of (2R-trans)- 6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1- trimethyl-alpha-oxo-1 H-indole-3-acetamide free base and salicylic acid and one or more excipients. In another embodiment, a pharmaceutical composition comprises a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 - piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base and 4-aminosalicylic acid and one or more excipients. hi another embodiment, a pharmaceutical composition comprises a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1-trimethyl-alpha-oxo- lH-indole-3-acetamide free base and benzoic acid and one or more excipients.

[0052] Compositions and methods of the invention are useful in the treatment or prevention of a variety of diseases including, among others, multiple myeloma, metastic cancers and bone disease, psoriasis, rheumatoid arthritis and other inflammatory related disorders.

[0053] In order to form the co-crystals of this invention, there is a need to contact (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide with the co- crystal former. This may involve grinding the two solids together or melting one or both components and allowing them to recrystallize. This may also involve either solubilizing (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piρerazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide and adding the co-crystal former, or solubilizing the co-crystal former and adding (2R-trans)-6-chloro-5- [[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl- alpha-oxo-lH-indole-3-acetamide. Crystallization conditions are applied to (2R-trans)- 6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 - trimethyl-alpha-oxo-lH-indole-3-acetamide and the co-crystal former. This may entail altering a property of the solution, such as pH or temperature and may require concentration of the solute, usually by removal of the solvent, typically by drying the solution. Solvent removal results in the concentration of both (2R-trans)-6-chloro-5-[[4- [(4-fluorophenyl)methyl]-2,5-dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha- oxo-lH-indole-3-acetamide and the co-crystal former increasing over time so as to facilitate crystallization. For example, evaporation, cooling, or the addition of an antisolvent may be used to crystallize co-crystals. In another embodiment, a slurry comprising (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide and a co- crystal former is used to form co-crystals. [0054] Assaying the solid phase for the presence of co-crystals of (2R-trans)-6- chloro5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl] carbonyl]-N,N, 1 - trimethyl-alpha-oxo-lH-indole-3-acetamide and the co-crystal former may be carried out by conventional methods known in the art. For example, X-ray diffraction techniques can be used to assess the presence of co-crystals. Other techniques, used in an analogous fashion, include differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared spectroscopy (IR), single crystal X-ray diffraction and Raman spectroscopy.

[0055] The co-crystals obtained as a result of such process steps may be readily incorporated into a pharmaceutical composition (or medicament) by conventional means. Pharmaceutical compositions and medicaments may further comprise a pharmaceutically-acceptable diluent, excipient or carrier.

[0056] In one embodiment, the compositions of the present invention, including (2R-trans)-6-chloro-5-[[4-[(4-fiuorophenyl)methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide co-crystals and formulations comprising (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl-l-piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide, are suitably stable for pharmaceutical use.

[0057] For preparing pharmaceutical compositions from the co-crystals described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets maybe comprised of from about 0.1 to about 95 percent active ingredient. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), The Science and Practice of Pharmacy, 20.sup.th Edition, Lippincott Williams & Wilkins, Baltimore, Md., (2000).

[0058] Liquid form preparations include solutions, suspensions and emulsions. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. 2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 - piperazinyl]carbonyl]-N,N, l-triinethyl-alpha-oxo-lH-indole-3-acetamide compositions of this invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

[0059] Specific dosage and treatment regimens for any particular patient may be varied and will depend upon a variety of factors, including the activity of the specific co- crystal or crystal employed, the age, body weight, general health status, sex and diet of the patient, the time of administration, the rate of excretion, the specific drug combination, the severity and course of the symptoms being treated, the patient's disposition to the condition being treated and the judgment of the treating physician. Determination of the proper dosage regimen for a particular situation is within the skill of the art. The amount and frequency of the administration of the compositions of this invention, or the pharmaceutical compositions thereof, may be regulated according to the judgment of the attending clinician, based on the factors recited above. As a skilled artisan will appreciate, lower or higher doses than those recited above may be required.

General Methods for the Preparation of Co-Crystals

[0060] a) Crystallization from solution

Co-crystals may be obtained by dissolving the separate components in a solvent and adding one to the other. The co-crystal may then precipitate or crystallize as the solvent mixture is evaporated slowly. The co-crystal may also be obtained by dissolving the two components in the same solvent or a mixture of solvents. The co-crystal may also be obtained by seeding a saturated solution of the two components and seeding with a ground mixture of the co-crystal. In one example, a co-crystal of (2R-trans)-6-chloro-5- [[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1-trimethyl- alpha-oxo-lH-indole-3-acetamide hydrochloride and urea is prepared by combining (2R- trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 -piperazinyl] carbonyl]- N₅N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide hydrochloride, urea and isopropyl acetate to make a slurry or solution and subsequently crystallizing a co-crystal. In another example, a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]- . 2,5-dimethyl-l -piperazinyl]caτbonyl]-N,N, 1 -trimethyl-alpha-oxo-lH-indole-S- acetamide free base and salicylic acid is prepared by combining (2R-trans)-6-chloro-5- [[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl- alpha-oxo-lH-indole-3-acetamide free base, salicylic acid and acetonitrile to make a slurry or solution and subsequently crystallizing a co-crystal. In a further example, a co- crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl3-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-iτimethyl-alpha-oxo-lH-indole-3-acetamide free base and 4-aminosalicylic acid is prepared by combining (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1-trimethyl-alpha-oxo- lH-indole-3-acetamide free base, 4-aminosalicylic acid and acetonitrile to make a slurry or solution and subsequently crystallizing a co-crystal. In a still further examples, a co- crystal of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l - piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base and benzoic acid is prepared by combining (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)methyl] -2,5-dimethyl- 1 -piperazinyl] carbonyl]-N,N, 1 -trimethyl-alpha-oxo- lH-indole-3-acetamide free base, benzoic acid and acetonitrile to make a slurry or solution and subsequently crystallizing a co-crystal.

[0061] b) Crystallization from the melt (Co-melting)

A co-crystal may be obtained by melting the two components together (i.e., co-melting) and allowing recrystallization to occur. In some cases, an anti-solvent or solvent may be added to facilitate crystallization.

[0062] c) Thermal microscopy

A co-crystal may be obtained by melting the higher melting component on a glass slide and allowing it to recrystallize. The second component is then melted and is also allowed to recrystallize. The co-crystal may form as a separated phase/band in between the eutectic bands of the two original components.

[0063] d) Mixing and/or grinding

A co-crystal may be obtained by mixing or grinding two components together in the solid state. For example, Example 2 describes the synthesis of a (2R-trans)-6-chloro-5- [[4-[(4-fluorophenyl) methyl]-2,5-dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl- alpha-oxo-iH-indole-3-acetamide hydrochloride and arginine co-crystal obtained by milling with and without the addition of a small amount of an appropriate solvent (wet grinding). In one embodiment, a co-crystal is prepared via milling or grinding (2R- trans)-6-chloro- 5 -[ [4-[(4-fhxorophenyl)methyl] -2 , 5-dimethyl- 1 -piperazinyl] carbonyl] - N₅N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide with a co-crystal former (dry grinding). In another embodiment, a co-crystal is prepared via milling or grinding (2R- trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]- N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide, a co-crystal former, and a small amount of solvent (wet grinding). In one example, a co-crystal^' of (2R-trans)-6-chloro- 5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl- alpha-oxo-lH-indole-3-acetamide hydrochloride and arginine is prepared by combining (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)memyl]-2,5-dimethyl- 1 - piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo-lH-indole-3-acetamide hydrochloride and arginine and then grinding the compounds to prepare a co-crystal.

[0064] In another embodiment, a co-crystal is prepared with the addition of solvent, without the addition of solvent, or both. Solvents used in such a co- crystallization process can be, for example, but not limited to, acetone, methanol, ethanol, isopropyl alcohol, ethyl acetate, isopropyl acetate, nitromethane, dichloromethane, chloroform, toluene, propylene glycol, dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), diethyl ether (ether), ethyl formate, hexane, acetonitrile, benzyl alcohol, water, or another organic solvent including alcohols.

[0065] e) Co-sublimation

A co-crystal may be obtained by co-subliming a mixture of 2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl) methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1-trimethyl-alpha- oxo-lH-indole-3-acetamide and a co-crystal former in the same sample cell as an intimate mixture either by heating, mixing or placing the mixture under vacuum. A co- crystal may also be obtained by co-sublimation using a Kneudsen apparatus where the API and the co-crystal former are contained in separate sample cells, connected to a single cold finger, each of the sample cells is maintained at the same or different temperatures under a vaccum atmosphere in order to co-sublime the two components onto the cold-finger forming the desired co-crystal. The Co-crystals of the present invention were analyzed using the following methods.

[0066] Differential scanning calorimetric (DSC) analysis of the samples was performed using a QlOOO Differential Scanning Calorimeter (TA Instruments, New Castle, DE, U.S.A.), which uses Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release 2.0 (2001 TA Instruments- Water LLC). In addition, the analysis software used was Universal Analysis 2000 for Windows 95/98/2000/NT, version 3.1E;Build 3.1.0.40 (2001 TA Instruments-Water LLC).

[0067] For the DSC analysis, the purge gas used was dry nitrogen, the reference material was an empty aluminum pan that was crimped, and the sample purge was 50 mL/minute.

[0068] DSC analysis of the sample was performed by placing the (2R-trans)-6- chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1- trimethyl-alpha-oxo-lH-indole-3-acetamide sample in an aluminum pan with a crimped pan closure. The starting temperature was typically 20 degrees C with a heating rate of 10 degrees C/minute, and the ending temperature was 200 degrees C. All reported DSC transitions represent the temperature of endothermic or exothermic transition at their respective peaks with an error of +/- 2 degrees C, unless otherwise indicated.

[0069] Thermogravimetric analysis (TGA) of samples was performed using a Q500 Thermogravimetric Analyzer (TA Instruments, New Castle, DE, U.S.A.), which uses Advantage for QW-Series, version 1.0.0.78, Thermal Advantage Release 2.0 (2001 TA Instruments- Water LLC). In addition, the analysis software used was Universal Analysis 2000 for Windows 95/98/2000/NT, version 3.1E;Build 3.1.0.40 (2001 TA Instruments- Water LLC).

[0070] For the TGA experiments, the purge gas used was dry nitrogen, the balance purge was 40 mL/minute N₂, and the sample purge was 60 mL/minute N₂.

[0071 ] TGA can be performed on the sample by placing the (2R-trans)-6-chloro- 5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1-trimethyl- alpha-oxo-lH-indole-3-acetamide sample in a platinum pan. The starting temperature was typically 20 degrees C with a heating rate of 10 degrees C/minute, and the ending temperature was 300 degrees C.

[0072] PXRD diffractograms can be acquired via the Bruker AXS D8 Discover X-ray Diffractometer. This instrument was equipped with GADDS™ (General Area Diffraction Detection System), a Bruker AXS HI-STAR Area Detector at a distance of 15.05 cm as per system calibration, a copper source (Cu/K_α 1.54056 angstroms), automated x-y-z stage, and 0.5mm collimator. The sample was compacted into pellet form and mounted on the x-y-z stage. A diffractogram was acquired under ambient conditions (25 degrees C) at a powder setting of 4OkV and 4OmA in reflection mode while the sample remained stationary. The exposure time was varied and specified for each sample. The diffractogram obtained underwent a spatial remapping procedure to account for the geometrical pincushion distortion of the area detector then integrated along chi from -118.8 to -61.8 degrees and 2-theta 2.1-37 degrees at a step size of 0.02 degrees with normalization set to bin normalize.

[0073] The relative intensity of peaks in a diffractogram is not necessarily a limitation of the PXRD pattern because peak intensity can vary from sample to sample, e.g., due to crystalline impurities. Further, the angles of each peak can vary by about +/- 0.1 degrees, preferably +/- 0.05. The entire pattern or most of the pattern peaks may also shift by about +/- 0.1 degrees to about +/- 0.2 degrees due to differences in calibration, settings, and other variations from instrument to instrument and from operator to operator. All reported PXRD peaks in the Figures, Examples, and elsewhere herein are reported with an error of about ± 0.1 degrees 2-theta.

[0074] For PXRD data herein, including Tables and Figures, each composition of the present invention may be characterized by any one, any two, any three, any four, any five, any six, any seven, or any eight or more of the 2 theta angle peaks. Any one, two, three, four, five, or six DSC transitions can also be used to characterize the compositions of the present invention. The different combinations of the PXRD peaks and the DSC transitions can also be used to characterize the compositions.

[0075] Thermal (hotstage) microscopy was completed on a Zeiss Axioplan 2 microscope equipped with a Mettler Toledo FP90 controller. The hotstage used was a Mettler Toledo FP82HT. All melting point determinations were completed by placing the sample on a microscope slide and covered with a coverslip. The initial temperature was set at 30 degrees C and the temperature was increased at a rate of 10 degrees C/minute. Melting was observed through a 5x microscope objective.

[0076] Data from some of these methods are included in Figures 1 -16. [0077] The following specific examples illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner.

EXAMPLES

[0078] Example 1 : Preparation of a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl) methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha- oxo-lH-indole-3-acetamide hydrochloride and urea.

[0079] 20 mg of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide hydrochloride dihydrate and ~11 mg of urea (1 :5.4 molar ratio) were added to 300 ml of isopropyl acetate in a 1 ml glass vial to make a slurry. The slurry was magnetically stirred at room temperature for 1 day using a PTFE coated magnetic stir bar. The solids were then filtered using a centrifuge 0.2 μm nylon filter tube, and left to dry at room temperature for one day. Powder XRD was used to confirm the solid form. Representative PXRD measurements, DSC measurements, and TGA measurements of this crystal are found in Figures 1 , 2, and 3 respectively.

[0080] Example 2: Preparation of a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl) methyl]-2,5-dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha- oxo- 1 H-indole-3-acetamide hydrochloride and arginine.

[0081 ] A 1 : 1 mol ratio mixture of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl)rnethyl]-2,5-dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide hydrochloride dihydrate (20 mg) and dl-arginine (~2 mg) were ground in a ball impact mill both without solvent and with a drop of hexane (5 ml) for 10 min. PXRD was used to confirm the solid form. Representative PXRD measurements, DSC measurements, and TGA measurements of this crystal are found in Figures 4, 5, and 6 respectively. [0082] Example 3: Preparation of a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl) methyl] -2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha- oxo-lH-indole-3-acetamide free base and salicylic acid.

[0083] 95 mg of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5- dimethyl-l-piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide along with 1 molar equivalent of salicylic acid was dissolved in 700 ml of acetonitrile in a 4 ml glass vial. The sample was then incubated at 5 ⁰C for 72 hours. The solids were then filtered using a centrifuge 0.2 μm nylon filter tube, and left to dry at room temperature for one day. PXRD was used to confirm the solid form. Representative PXRD measurements, DSC measurements, and TGA measurements of this co-crystal are found in Figures 8, 9, and 10 respectively. Figure 7 compares the PXRD measurements of(2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl) methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base, the co-crystal, and salicylic acid.

[0084] Example 4: Preparation of a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl) methyl]-2,5-dimethyl-l -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha- oxo-lH-indole-3-acetamide free base and 4-aminosalicylic acid.

[0085] 95 mg of (2R-trans)-6-chloro-5-[[4-[(4-fiuorophenyl)methyl]-2,5- dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3 -acetamide along with 1 molar equivalent of 4-aminosalicylic acid was dissolved in 700 ml of acetonitrile in a 4 ml glass vial. The sample was then incubated at 5 ⁰C for 1 week. The solids were then filtered using a centrifuge 0.2 μm nylon filter tube, and left to dry at room temperature for one day. PXRD was used to confirm the solid form. Representative PXRD measurements, DSC measurements, and TGA measurements of this co-crystal are found in Figures 12, 13, and 14 respectively. Figure 11 compares the PXRD measurements of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl) methyl]-2,5- dimethyl-1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3 -acetamide free base, the co-crystal, and 4-aminosalicylic acid.

[0086] Example 5: Preparation of a co-crystal of (2R-trans)-6-chloro-5-[[4-[(4- fluorophenyl) methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha- oxo- 1 H-indole-3 -acetamide free base and benzoic acid. [0087] 89 mg of (2R-tτans)-6-chloro-5-[[4-[(4-fluorophenyl)rnethyl]-2,5- dimethyl- 1 -piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide along with 1 molar equivalent of benzoic acid was dissolved in 1.0 ml of acetonitrile in a 4 ml glass vial. The sample was then incubated at 5 ⁰C for 1 week. The solids were then filtered using a centrifuge 0.2 μm nylon filter tube, and left to dry at room temperature for one day. PXRD was used to confirm the solid form. Representative PXRD measurements of this co-crystal are found in Figures 16. Figure 15 compares the PXRD measurements of (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl) methyl]-2,5-dimethyl- 1 - piperazinyl]carbonyl]-N,N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide free base, the co-crystal, and benzoic acid.

Claims

Claims:

1. A co-crystal comprising (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl) methyl]-2,5- dimethyl-l-piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide and a co-crystal former.

2. The co-crystal of claim 1 , wherein said (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl) methyl]-2,5 -dimethyl- 1 -piperazinyl] carbonyl] -N₅N, 1 -trimethyl-alpha-oxo- 1 H-indole-3 - acetamide is (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl) methyl]-2,5-dimethyl-l- piperazinyl] carbonyl] -N₅N, 1 -trimethyl-alpha-oxo- 1 H-indole-3-acetamide hydrochloride.

3. The co-crystal of claim 2, wherein said co-crystal former is urea.

4. The co-crystal of claim 3, wherein said crystal is characterized by a powder X-ray diffraction pattern having one powder X-ray diffraction peak at about 6.7 degrees 2- theta.

5. The co-crystal of claim 3, wherein said crystal is characterized by a powder X-ray diffraction pattern having one powder X-ray diffraction peak at about 6.7 degrees 2-theta and at least one powder X-ray diffraction peak selected from the group consisting of about 9.1, 10.5, and 1 1.2 degrees 2-theta.

6. The co-crystal of claim 3, wherein said crystal is characterized by a powder X-ray diffraction pattern having powder X-ray diffraction peaks at about 6.7, 9.1, 10.5, and 11.2 degrees 2-theta.

7. The co-crystal of claim 3, wherein said crystal is characterized by a powder X-ray diffraction pattern having powder X-ray diffraction peaks at about 6.7, 9.1, 10.5, 1 1.2, 14.1, 15.2, and 16.2 degrees 2-theta.

8. The co-crystal of claim 3, having a powder X-ray diffraction pattern that is substantially similar to the powder X-ray diffraction pattern of Figure 1.

9. The co-crystal of claim 3, wherein said crystal is characterized by a TGA thermogram comprising about a 8 percent weight loss between about 25 degrees C and about 150 degrees C.

10. The co-crystal of claim 3, wherein said crystal is characterized by having an endothermic transition at about 178 ⁰C.

11. A pharmaceutical composition comprising said co-crystal of claim 3 and one or more excipients.

12. The co-crystal of claim 2, wherein said co-crystal former is arginine.

13. The co-crystal of claim 12, wherein said crystal is characterized by a powder X-ray diffraction pattern having one powder X-ray diffraction peak at about 7.6 degrees 2- theta.

14. The co-crystal of claim 12, wherein said crystal is characterized by a powder X-ray diffraction pattern having powder X-ray diffraction peaks at about 7.6 and 9.4 degrees 2- theta and at least one powder X-ray diffraction peak selected from the group consisting of 13.2 and 16.5 degrees 2-theta.

15. The co-crystal of claim 12, wherein said crystal is characterized by a powder X-ray diffraction pattern having powder X-ray diffraction peaks at about 7.6, 9.4, 13.2, and 16.5 degrees 2-theta.

16. The co-crystal of claim 12, having a powder X-ray diffraction pattern that is substantially similar to the powder X-ray diffraction pattern of Figure 4.

17. The co-crystal of claim 12, wherein said crystal is characterized by a TGA thermogram comprising about a 10 percent weight loss between about 25 degrees C and about 160 degrees C.

18. The co-crystal of claim 12, wherein said crystal is characterized by having an endothermic transition at about 193 ⁰C.

19. A pharmaceutical composition comprising said co-crystal of claim 12 and one or more excipients.

20. The co-crystal of claim 1, wherein said (2R-trans)-6-chloro-5-[[4-[(4-fluorophenyl) methyl]-2,5-dimethyl-l-piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3- acetamide is (2R-trans)-6-chloro-5-[[4-[(4-fiuorophenyl) methyl]-2,5-dimethyl-l- piperazinyl]carbonyl]-N,N, l-trimethyl-alpha-oxo-lH-indole-3-acetamide free base.

21. The co-crystal of claim 20, wherein said co-crystal former is salicylic acid.

22. The co-crystal of claim 21, wherein said co-crystal is characterized by a powder X- ray diffraction pattern having one powder X-ray diffraction peak at about 10.1 degrees 2- theta.

23. The co-crystal of claim 21 , wherein said co-crystal is characterized by a powder X- ray diffraction pattern having one powder X-ray diffraction peak at about 10.1 degrees 2- theta and at least one powder X-ray diffraction peak selected from the group consisting of about 5.0, 5.7, and 6.8 degrees 2-theta.

24. The co-crystal of claim 21, wherein said co-crystal is characterized by a powder X- ray diffraction pattern having powder X-ray diffraction peaks at about 5.0, 5.7, 6.8 and 10.1 degrees 2-theta.

25. The co-crystal of claim 21, having a powder X-ray diffraction pattern that is substantially similar to the powder X-ray diffraction pattern of Figure 8.

26. The co-crystal of claim 21 , wherein said co-crystal is characterized by a TGA thermogram comprising about a 16 percent weight loss between about 25 degrees C and about 191 degrees C.

27. The co-crystal of claim 21, wherein said co-crystal is characterized by having an endothermic transition at about 191 ⁰C.

28. A pharmaceutical composition comprising said co-crystal of claim 21 and one or more excipients.

29. The co-crystal of claim 20, wherein said co-crystal former is 4-aminosalicylic acid.

30. The co-crystal of claim 29, wherein said co-crystal is characterized by a powder X- ray diffraction pattern having one powder X-ray diffraction peak at about 10.2 degrees 2- theta.

31. The co-crystal of claim 29, wherein said co-crystal is characterized by a powder X- ray diffraction pattern having one powder X-ray diffraction peak at about 10.2 degrees 2- theta and at least one powder X-ray diffraction peak selected from the group consisting of about 8.4, 9.2, and 13.4 degrees 2-theta.

32. The co-crystal of claim 29, wherein said co-crystal is characterized by a powder X- ray diffraction pattern having powder X-ray diffraction peaks at about 8.4, 9.2, 10.2 and 13.4 degrees 2-theta.

33. The co-crystal of claim 29, wherein said co-crystal is characterized by a powder X- ray diffraction pattern having powder X-ray diffraction peaks at about 5.0 5.8, 6.7, 8.4, 9.2, 10.2 and 13.4 degrees 2-theta.

34. The co-crystal of claim 29, having a powder X-ray diffraction pattern that is substantially similar to the powder X-ray diffraction pattern of Figure 12.

35. The co-crystal of claim 29, wherein said co-crystal is characterized by a TGA thermogram comprising about a 15 percent weight loss between about 50 degrees C and about 165 degrees C.

36. The co-crystal of claim 29, wherein said co-crystal is characterized by having an endothermic transition at about 165 ⁰C.

37. A pharmaceutical composition comprising said co-crystal of claim 29 and one or more excipients.

38. The co-crystal of claim 20, wherein said co-crystal former is benzoic acid.

39. The co-crystal of claim 38, wherein said co-crystal is characterized by a powder X- ray diffraction pattern having one powder X-ray diffraction peak at about 9.8 degrees 2- theta.

40. The co-crystal of claim 38, wherein said co-crystal is characterized by a powder X- ray diffraction pattern having one powder X-ray diffraction peak at about 9.8 degrees 2- theta and at least one powder X-ray diffraction peak selected from the group consisting of about 4.9, 5.7, and 6.8 degrees 2-theta.

41. The co-crystal of claim 38, wherein said co-crystal is characterized by a powder X- ray diffraction pattern having powder X-ray diffraction peaks at about 4.9, 5.7, 6.8, and 9.8 degrees 2-theta.

42. The co-crystal of claim 38, wherein said co-crystal is characterized by a powder X- ray diffraction pattern having powder X-ray diffraction peaks at about 4.9, 5.7, 6.8, 9.8, 13.6, 15.1, and 16.7 degrees 2-theta.

43. The co-crystal of claim 38, having a powder X-ray diffraction pattern that is substantially similar to the powder X-ray diffraction pattern of Figure 16.