Solid form of GPR119 agonist and process for its preparation

Abstract

This invention relates to the solid form of the GPR119 agonist of formula I and a process for preparing the same. In particular, this invention relates to the crystalline form of the compound of formula I and the preparation thereof. JPEG2026528934000006.jpg31170

Description

[Technical Field]

[0001] This application claims the interests of Indian Patent Application No. 202311054016, filed on 11 August 2023, the entire contents of which are incorporated herein by reference.

[0002] This invention relates to the solid form of the GPR119 agonist of formula I and a process for preparing the same. In particular, this invention relates to the crystalline form of the compound of formula I and its preparation. [ka] [Background technology]

[0003] Many drugs are useful in treating diabetes, including insulin, metformin, sulfonylurea, acarbose, thiazolidinediones, GLP-1 analogs, and DPP-IV inhibitors. While humans have numerous receptor classes, the overwhelmingly abundant and therapeutically relevant ones are represented by the G protein-coupled receptor (GPCR) class. GPR119 is a cell surface GPCR highly expressed in human (and rodent) pancreatic islets and insulin-secreting cell lines. Activation of GPR119 has been demonstrated to stimulate intracellular cAMP, leading to glucose-dependent GLP-1 and insulin secretion (see, e.g., Soga et al., Biochem. Biophys. Res.Commun., 2005, 326).

[0004] U.S. Patent No. 10,208,030 describes a GPR119 agonist and a process for preparing the same. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] U.S. Patent No. 10,208,030 [Non-patent literature]

[0006] [Non-Patent Document 1] Soga et al.,Biochem. Biophys. Res.Commun.,2005,326 [Overview of the project] [Means for solving the problem]

[0007] In one embodiment, the present invention relates to the solid form of the compound of formula I. [ka] Or, with respect to a pharmaceutically acceptable salt thereof, the solid form is, X-ray powder diffraction (XRPD) spectrum showing characteristic peaks at Ai)6.0±0.2, 8.1±0.2, and 17.3±0.2°2θ. ii) XRPD, substantially shown in Figure 1, iii) A differential scanning calorimetry (DSC) plot showing endothermic peaks at approximately 111°C and approximately 141.7°C, or iv) Crystal morphology M-1 characterized by any combination of the above; XRPD shows characteristic peaks at Bi)6.9±0.2, 10.6±0.2, 16.6±0.2, 19.2±0.2, 20.4±0.2, 25.8±0.2 and 26.4±0.2°2θ. ii) XRPD, substantially shown in Figure 2, iii) A DSC plot showing an endothermic peak at approximately 144°C, or iv) Crystal morphology M-2 characterized by any combination of the above; XRPD shows characteristic peaks at 7.1±0.2°, 13.3±0.2°, 17.6±0.2°, and 21.8±0.2°²θ. ii) XRPD, substantially shown in Figure 3, iii) A DSC plot showing an endothermic peak at approximately 113°C, or iv) Crystal morphology M-3 characterized by any combination of the above; XRPD shows characteristic peaks at Di)8.8±0.2, 11.3±0.2, 17.8±0.2, 19.0±0.2, 23.1±0.2 and 25.8±0.2°2θ. ii) XRPD showing characteristic peaks at 4.4±0.2, 7.2±0.2, 8.8±0.2, 11.3±0.2, 13.3±0.2, 14.7±0.2, 15.6±0.2, 16.0±0.2, 17.8±0.2, 19.0±0.2, 20.4±0.2, 23.7±0.2 and 27.3±0.2°2θ. iii) XRPD, substantially shown in Figure 4, iv) DSC plot substantially shown in Figure 5, v) A DSC plot showing an endothermic peak at approximately 107°C, or vi) Crystal morphology M-4 characterized by any combination of the above; Ei) XRPD shows characteristic peaks at 4.3±0.2, 7.8±0.2, 10.2±0.2, 16.3±0.2 and 16.8±0.2°2θ. ii) XRPD, substantially shown in Figure 6, iii) A DSC plot showing an endothermic peak at approximately 148°C, or iv) Crystal morphology M-5 characterized by any combination of the above; XRPD shows characteristic peaks at Fi)5.6±0.2, 9.7±0.2, and 19.8±0.2°2θ. ii) XRPD, substantially shown in Figure 7, iii) A DSC plot showing endothermic peaks at approximately 87°C, 112°C, and 142°C, or iv) Crystal morphology M-6 characterized by any combination of the above; XRPD shows characteristic peaks at Gi)4.3±0.2, 8.7±0.2, 10.6±0.2, 16.4±0.2 and 18.5±0.2°2θ. ii) XRPD showing peaks characteristic of 4.3 ± 0.2, 8.7 ± 0.2, 10.6 ± 0.2, 16.4 ± 0.2, 18.5 ± 0.2, 19.5 ± 0.2 and 21.9 ± 0.2° 2θ, iii) XRPD substantially shown in Figure 8, iv) a DSC plot including an endothermic peak at about 100 °C, or, v) the crystalline form M-7 characterized by any arbitrary combination of any of the above; H.i) XRPD showing peaks characteristic of 4.6 ± 0.2, 9.3 ± 0.2, 12.3 ± 0.2, 15.5 ± 0.2 and 17.0 ± 0.2° 2θ, ii) XRPD showing peaks characteristic of 4.6 ± 0.2, 6.4 ± 0.2, 9.3 ± 0.2, 12.3 ± 0.2, 15.5 ± 0.2, 17.0 ± 0.2 and 17.7 ± 0.2° 2θ, iii) XRPD substantially shown in Figure 9, iv) a DSC plot showing a start at about 127 °C and an endothermic peak at about 11 °C, or, v) the crystalline form M-8 characterized by any arbitrary combination of any of the above; I.i) XRPD showing peaks characteristic of 11.5 ± 0.2, 13.3 ± 0.2, 17.9 ± 0.2, 19.0 ± 0.2, 23.2 ± 0.2 and 25.8 ± 0.2° 2θ, ii) XRPD showing peaks characteristic of 7.2 ± 0.2, 8.8 ± 0.2, 11.5 ± 0.2, 12.3 ± 0.2, 13.3 ± 0.2, 15.6 ± ɼ.2, 16.0 ± 0.2, 17.9 ± 0.2, 19.0 ± 0.2, 22.3 ± 0.2, 23.2 ± 0.2, 25.8 ± 0ɼ2, 27.3 ± 0.2 and 29.4 ± 0.2° 2θ, iii) XRPD substantially shown in Figure 10, iv) a DSC plot showing endothermic peaks at about 108 °C and about 142 °C, or, v) the crystalline form M-9 characterized by any arbitrary combination of any of the above; J. selected from the amorphous form;

[0008] In one embodiment, the present invention relates to form M-2 of a compound of formula I according to any embodiment described herein.

[0009] In one embodiment, the present invention relates to form M-4 of a compound of formula I according to any embodiment described herein.

[0010] In one embodiment of the compound of formula I in any crystalline or amorphous form, the compound has d particles of about 60 μm to about 100 μm. 90 It holds.

[0011] In one embodiment of the solid form described above, a) Morphology M-1 further includes one or more characteristic XRPD peaks at 4.5±0.2, 7.0±0.2, 10.5±0.2, 12.5±0.2, 14.9±0.2, 15.1±0.2, 15.4±0.2, 16.6±0.2, 18.6±0.2, 19.3±0.2, 20.4±0.2, 25.8±0.2 and 26.4±0.2°2θ, b) Morphology M-2 further includes one or more characteristic XRPD peaks at 4.5±0.2, 12.5±0.2, 14.1±0.2, 14.9±0.2, 15.4±0.2, 17.9±0.2 and 20.8±0.2°2θ, c) Morphology M-3 further includes one or more characteristic XRPD peaks at 4.3±0.2, 11.1±0.2, 15.2±0.2, 15.7±0.2, 16.0±0.2, 17.5±0.2, 18.8±0.2, 20.2±0.2, 21.7±0.2, 23.2±0.2 and 25.7±0.2°2θ, d) Morphology M-4 further includes one or more characteristic XRPD peaks at 11.5±0.2, 12.3±0.2, 19.4±0.2, 22.0±0.2, 23.1±0.2, 24.5±0.2 and 25.9±0.2°2θ, e) Morphology M-5 further includes one or more characteristic XRPD peaks at 7.6±0.2, 12.3±0.2, 17.8±0.2, 19.4±0.2 and 20.6±0.2°2θ, f) Morphology M-6 further includes one or more characteristic XRPD peaks at 15.9±0.2, 17.3±0.2, 18.6±0.2, and 20.3±0.2°2θ.

[0012] In another embodiment, the present invention relates to a process for preparing a crystalline form M-1 of a compound of formula I or a pharmaceutically acceptable salt thereof, according to any embodiment described herein, wherein the process is: a) Dissolving the compound of formula I in one or more solvents (for example, one or more polar aprotic solvents, e.g., acetonitrile), b) Heating the reaction mixture (for example, refluxing from a suitable temperature, e.g., heating to about 50°C to about 70°C for about 20 to about 30 minutes or until completely solubilized), c) Cooling the heated mixture obtained in step b) to room temperature (for example, to room temperature (approximately 25°C to approximately 30°C)), d) Optionally, seed the reaction mixture with the crystalline form M-1 of the compound of formula I, e) optionally includes isolating the crystalline form M-1 of the compound of formula I.

[0013] In another embodiment, the present invention relates to a process for preparing a crystalline form M-2 of a compound of formula I according to any embodiment described herein, wherein the process is: a) Mixing the racemic compound of formula I in one or more solvents (for example, one or more polar protic solvents, e.g., methanol), b) Stirring the reaction mixture (for example, at an appropriate temperature for an appropriate time), c) Isolating the obtained solid (for example, by filtering the reaction mixture), d) Obtaining the desired isomer of the crystalline form M-2 of the compound of formula I (for example, by performing chiral resolution using chiral chromatography), e) optionally includes isolating the crystalline form M-2 of the compound of formula I.

[0014] In another embodiment, the present invention relates to a process for preparing a crystalline form M-2 of a compound of formula I according to any embodiment described herein, the process comprising heating the compound of formula I (for example, at a suitable temperature for a suitable time, e.g., about 100-120°C for about 2-4 hours) to obtain a crystalline form M-2 of the compound of formula I. In one embodiment, the process comprises heating an amorphous or crystalline form M1 of the compound of formula I.

[0015] In another aspect, the present invention relates to a process for preparing the crystalline form M-3 of a compound of formula I according to any of the embodiments described herein, wherein the process is: a) Dissolving the compound of formula I in one or more solvents (for example, one or more polar protic solvents, e.g., ethanol), b) Heating the reaction mixture (for example, heating to approximately 50°C to 70°C for approximately 20 to 30 minutes or until completely solubilized), c) optionally includes isolating the crystalline form M-3 of the compound of formula I.

[0016] In another aspect, the present invention relates to a process for preparing crystalline form M-4 of a compound of formula I according to any of the embodiments described herein, wherein the process is: a) Dissolving the compound of formula I in a mixture of solvents (for example, a combination of ethanol and heptane), b) Heating the reaction mixture (for example, at an appropriate temperature for an appropriate amount of time), c) The reaction reaction crystallizes (for example, by cooling to ambient temperature), d) optionally includes isolating the crystalline form M-4 of the compound of formula I.

[0017] In another aspect, the present invention relates to a process for preparing crystalline form M-4 of a compound of formula I according to any of the embodiments described herein, wherein the process is: a) Mixing the compound of formula I with one or more solvents (for example, one or more polar aprotic solvents, e.g., acetonitrile), b) Stirring the reaction mixture (for example, stirring at approximately 25°C to 30°C for approximately 60 to 120 minutes), c) Optionally, isolate the product from step b), d) Drying the product of step b) or step c) (for example, in a vacuum at approximately 50°C to 70°C), e) Stirring the dried product from step d) in a polar protic solvent (e.g., methanol), f) Drying the product of step e), g) optionally includes isolating the crystalline form M-4 of the compound of formula I.

[0018] In another aspect, the present invention relates to a process for preparing a crystalline form M-4 of a compound of formula I according to any embodiment described herein, the process comprising heating a crystalline form M-3 of a compound of formula I (for example, at about 50-70°C for about 60-70 hours) to obtain a crystalline form M-4 of a compound of formula I.

[0019] In another aspect, the present invention relates to a process for preparing crystalline form M-5 of a compound of formula I according to any of the embodiments described herein, wherein the process is: a) Mixing the compound of formula I with one or more solvents (for example, polar aprotic solvents, such as acetonitrile), b) Stirring the reaction mixture at ambient temperature (for example, for an appropriate amount of time), c) optionally includes isolating the crystalline form M-5 of the compound of formula I.

[0020] In another aspect, the present invention relates to a process for preparing crystalline form M-6 of a compound of formula I according to any embodiment described herein, wherein the process is: a) Dissolving a compound of formula I (e.g., form M-2) in one or more solvents (e.g., xylene, heptane, nitromethane, or any combination thereof) under liquid nitrogen conditions (e.g., crush cooling to approximately -190°C) to obtain a solid mass, b) Maintaining the solid mass at room temperature to obtain a clear solution (e.g., a solution without visible particles), c) optionally includes isolating the crystalline form M-6 of the compound of formula I.

[0021] In another aspect, the present invention relates to a process for preparing the crystalline form M-7 of a compound of formula I according to any of the embodiments described herein, wherein the process is: a) Dissolving the compound of formula I in one or more solvents (for example, one or more nonpolar aliphatic and / or aromatic hydrocarbons, e.g., a mixture of xylene and heptane), b) Heating the reaction mixture obtained in step a), c) Evaporate the solvent (for example, by maintaining it at ambient temperature for about 24 to 48 hours) to obtain crystal form M-7, d) optionally includes isolating the crystalline form M-7 of the compound of formula I.

[0022] In another aspect, the present invention relates to a process for preparing crystalline form M-8 of a compound of formula I according to any of the embodiments described herein, wherein the process is: a) Mixing the compound of formula I with a mixture of solvents (for example, propanol and heptane), b) Heating the reaction mixture from step a), c) Cooling the reaction mixture obtained from step b), d) optionally includes isolating the crystalline form M-8 of the compound of formula I.

[0023] In another aspect, the present invention relates to a process for preparing the crystalline form M-9 of a compound of formula I according to any of the embodiments described herein, wherein the process is: a) Dissolving a compound of formula I (e.g., form M-2, etc.) in one or more solvents (e.g., one or more polar protic solvents) under liquid nitrogen conditions (e.g., crush cooling to approximately -190°C) to obtain a solid mass, b) Maintaining the solid mass at room temperature to obtain a clear solution (e.g., a solution without visible particles), c) optionally includes isolating the crystalline form M-9 of the compound of formula I.

[0024] In another aspect, the present invention relates to a process for preparing an amorphous form of a compound of formula I according to any of the embodiments described herein, wherein the process is: a) To provide a solution of the compound of formula I in one or more solvents (e.g., acetone, acetonitrile, water, or any combination thereof), b) Freeze-dry the solution obtained in step a), c) optionally includes isolating the amorphous form of the compound of formula I.

[0025] In another aspect, the present invention relates to a process for preparing an amorphous form of a compound of formula I according to any of the embodiments described herein, wherein the process is: a) To provide a solution of a compound of formula I in one or more solvents, b) Removing the solvent (for example, by evaporation or distillation), c) optionally includes isolating the amorphous form of the compound of formula I.

[0026] In another aspect, the present invention relates to a process for preparing a premix of a compound of formula I, wherein the process is: a) Mixing one or more pharmaceutically acceptable excipients (e.g., hydroxypropyl methylcellulose), a compound of formula I according to any of the embodiments described herein, and one or more solvents (e.g., dichloromethane), b) Removing the solvent (for example, by evaporation), c) optionally includes isolating a premix of the compound of formula I.

[0027] In certain embodiments, in any of the processes described herein, the compound of formula I provided in step a) is selected from amorphous form, crystalline form, or a mixture thereof.

[0028] In another aspect, the present invention relates to a pharmaceutical composition comprising a solid form of a compound of formula I according to any embodiment described herein and a pharmaceutically acceptable excipient.

[0029] In another aspect, the present invention relates to a solid form of a compound of formula I according to any embodiment herein, wherein the solid form substantially does not include other solid forms of the compound of formula I described herein. [Brief explanation of the drawing]

[0030] [Figure 1] The X-ray powder diffraction (XRPD) pattern of the crystalline form M-1 of the compound of formula I of the present invention is shown. [Figure 2] The X-ray powder diffraction (XRPD) pattern of the crystalline form M-2 of the compound of formula I of the present invention is shown. [Figure 3] The X-ray powder diffraction (XRPD) pattern of the crystalline form M-3 of the compound of formula I of the present invention is shown. [Figure 4] The X-ray powder diffraction (XRPD) pattern of the crystalline form M-4 of the compound of formula I of the present invention is shown. [Figure 5] The differential scanning calorimetry (DSC) of the crystalline form M-4 of the compound of formula I of the present invention is shown. [Figure 6] The X-ray powder diffraction (XRPD) pattern of the crystalline form M-5 of the compound of formula I of the present invention is shown. [Figure 7] The X-ray powder diffraction (XRPD) pattern of the crystalline form M-6 of the compound of formula I of the present invention is shown. [Figure 8] The X-ray powder diffraction (XRPD) pattern of the crystalline form M-7 of the compound of formula I of the present invention is shown. [Figure 9] The X-ray powder diffraction (XRPD) pattern of the crystalline form M-8 of the compound of formula I of the present invention is shown. [Figure 10] The X-ray powder diffraction (XRPD) pattern of the crystalline form M-9 of the compound of formula I of the present invention is shown. [Figure 11] This shows the X-ray powder diffraction (XRPD) pattern of the stable amorphous form of the compound of formula I of the present invention. [Modes for carrying out the invention]

[0031] As used herein, the term “pharmaceutically acceptable salt” means salts of inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphates, etc.; salts of organic acids, e.g., succinic acid, formic acid, acetic acid, diphenylacetic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene- 2-carboxylic acids, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethanesulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, etc.; salts of pharmaceutically acceptable bases, such as alkali metal salts or alkaline earth metal salts including sodium salts, potassium salts, magnesium salts, calcium salts, and zinc salts, ammonium salts, etc.; and any combination of any of the above.

[0032] As used herein, the term “premix” generally refers to a combination of a compound of formula I according to any of the embodiments described herein and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable polymer such as hydroxypropyl methylcellulose). In one embodiment, individual particles of the components are indistinguishable in the premix by using techniques such as optical microscopy.

[0033] As used herein, the terms “excipient” or “pharmaceutically acceptable excipient” mean a component of a pharmaceutical product that is not an active ingredient, and include, but are not limited to, fillers, diluents, disintegrants, flow enhancers, stabilizers, surfactants, polymers, and carriers. Excipients useful for preparing the premixes or pharmaceutical compositions described herein are generally safe, non-toxic, not biologically or otherwise undesirable, and are acceptable for veterinary and human pharmaceutical applications. One excipient may perform two or more functions.

[0034] In one embodiment, at least one pharmaceutically acceptable excipient is selected from the group consisting of polyvinylpyrrolidone, povidone K-30, povidone K-60, povidone K-90, methylcellulose, methacrylate copolymer, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate acetate (HPMC-AS), hydroxypropyl methylcellulose, hydroxypropylcellulose SSL (HPC-SSL), hydroxypropylcellulose SL (HPC-SL), hydroxypropylcellulose L (HPC-L), hydroxyethylcellulose, Soluplus® (polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), Gelucire 44 / 14, ethylcellulose, D-α-tocopheryl polyethylene glycol 1000 succinate, cellulose phthalate acetate, carboxymethyl ethylcellulose, sodium starch glycolate, or any combination of any of the above.

[0035] As used herein, the term “substantially free” means that each impurity is present in a compound of formula I (or a pharmaceutically acceptable salt thereof) at a concentration of less than approximately 0.2% by HPLC area percentage, for example, less than approximately 0.15% by HPLC area percentage. In one embodiment, the compound of formula I (or a pharmaceutically acceptable salt thereof) is free of impurities (for example, certain impurities are not present in detectable amounts by HPLC area percentage).

[0036] As used herein, in one embodiment, the term “substantially pure” refers to the chemical purity of a compound that is at least about 85%, for example, at least about 90%, at least about 95%, at least about 98%, at least about 99%, at least about 99.5%, or at least about 99.9%, as measured by HPLC.

[0037] As used herein, the terms “amorphous” or “stable amorphous” form of a compound of formula I are interchangeable, and “amorphous” compound of formula I indicates that the compound of formula I exists in a substantially amorphous state. “Substantially pure amorphous” means that at least about 90%, e.g., at least about 95%, at least about 98%, at least about 99%, or at least about 99.5%, of the compound of formula I is essentially amorphous.

[0038] As used herein, in some embodiments, the terms “preferred solvent” or “solvent” can be used to prepare compounds of formula I or pharmaceutically acceptable salts thereof (and intermediates thereof), and may include, but are not limited to, solvents selected from C1-C6 alcohols, C1-C8 hydrocarbons, halogenated hydrocarbons, ethers, C3-C8 ketones, esters, nitriles, sulfonamides, acetamides, pyrrolidines, formamides, water, and mixtures of any of the foregoing. Examples include, but are not limited to, methanol, ethanol, butanol, t-butanol, isopropyl alcohol, n-propyl alcohol, iso-butanol, pentanol, glycol, toluene, chlorobenzene, acetonitrile, dimethylacetamide (DMA), dimethylformamide (DMF), N-methylpyrrolidine (NMP), dimethyl sulfoxide (DMSO), hexamethylphosphoramide (HMPA), tetrahydrofuran (THF), methyltetrahydrofuran, dioxane, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl t-butyl ketone, dichloromethane, dichloroethane, chloroform, tetrachloromethane, chlorobenzene, ethyl acetate, propyl acetate, propenyl acetate, t-butyl acetate, hexane, n-heptane, cyclohexane, petroleum benzine, water, and any combination of any of the above.

[0039] The present invention will now be described in more detail. While the present invention accepts various modifications and alternative forms, specific embodiments will be described in detail below herein. However, it should be understood that the present invention is not intended to be limited to any particular form disclosed, but rather encompasses all modifications, equivalents, and alternatives that fall within the scope of the present invention.

[0040] Crystal form M-1 In one embodiment, the present invention relates to a crystalline form M-1 of a compound of formula I, characterized by an XRPD pattern showing one or more (e.g., two or three) characteristic peaks at 6.0±0.2, 8.1±0.2, and 17.3±0.2°2θ. In one embodiment, form M-1 further shows characteristic XRPD peaks at 4.5±0.2, 7.0±0.2, 10.5±0.2, 12.5±0.2, 14.9±0.2, 15.1±0.2, 15.4±0.2, 16.6±0.2, 18.6±0.2, 19.3±0.2, 20.4±0.2, 25.8±0.2, and 26.4±0.2°2θ.

[0041] In one embodiment, the present invention relates to a crystalline form M-1 of a compound of formula I, characterized by an XRPD pattern exhibiting one or more characteristic peaks (e.g., 2, 3, 4, 5, 6, 7, or 8) at 4.5±0.2, 6.0±0.2, 8.1±0.2, 14.9±0.2, 15.1±0.2, 15.4±0.2, 17.3±0.2, and 18.6±0.2°2θ, and optionally one or more additional peaks at 7.0±0.2, 10.5±0.2, 12.5±0.2, 16.6±0.2, 19.3±0.2, 20.4±0.2, 25.8±0.2, and 26.4±0.2°2θ.

[0042] In another embodiment, the present invention relates to a crystalline form M-1 of a compound of formula I, characterized by the XRPD pattern substantially shown in Figure 1.

[0043] In another embodiment, the present invention relates to a crystalline form M-1 of the compound of formula I, characterized by a DSC plot showing endothermic peaks at approximately 111°C and approximately 141.7°C.

[0044] In another embodiment, the present invention relates to a crystalline form M-1 of the compound of formula I, characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 0.01 to about 0.20 ± 1% when heated to about 110°C.

[0045] In another embodiment, the present invention relates to a process for preparing form M-1 of a compound of formula I, wherein the process is a) Mixing the compound of formula I with one or more solvents (e.g., acetonitrile), b) Heating the reaction mixture (for example, from approximately 40°C to reflux temperature), c) Cooling the reaction mixture (for example, to room temperature), d) Optionally, seed the reaction mixture with the crystalline form M-1 of the compound of formula I, e) optionally includes isolating the crystalline form M-1 of the compound of formula I.

[0046] In one embodiment, one or more solvents used in step a) are selected from methanol, ethanol, 1-propanol, 2-propanol, n-butanol, isobutanol, nitromethane, chloroform, acetonitrile, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), toluene, heptane, ethyl acetate, propyl acetate, n-pentyl acetate, isopropyl acetate, butyl acetate, propionitrile, diethyl ether, dimethyl ether, diisopropyl ether, diphenyl ether, methyl tert-butyl ether (MTBE), tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane, o-xylene, m-xylene, p-xylene, n-pentane, cyclopentane, n-hexane, cyclohexane, benzene, dichloromethane, dichloroethane, tetrachloromethane, chlorobenzene, dimethylacetamide (DMA), dimethylformamide (DMF), water, and any mixture of any of the above.

[0047] In one embodiment, the solvent used in step a) is selected from acetonitrile, methanol, and mixtures thereof.

[0048] In one embodiment, the present invention relates to a process for preparing the crystalline form M-1 of a compound of formula I, wherein the process is: a) Mixing the compound of formula I with acetonitrile, b) Heating the reaction mixture from approximately 60°C to reflux temperature (e.g., approximately 179°C), c) Cool the reaction mixture to room temperature, d) Optionally, sow crystalline form M-1 into the reaction mixture at a temperature of approximately 30°C to 40°C. e) optionally includes isolating the crystalline form M-1 of the compound of formula I.

[0049] In another embodiment, the present invention relates to d of about 60 μm to about 100 μm 90 This relates to the crystalline form M-1 of the compound of formula I, having a particle size distribution characterized by the following.

[0050] Crystal form M-2 In another embodiment, the present invention relates to a crystalline form M-2 of a compound of formula I, characterized by an XRPD pattern exhibiting one or more characteristic peaks (e.g., 2, 3, 4, 5, 6, 7, or 8) at 6.9±0.2, 10.6±0.2, 16.6±0.2, 19.2±0.2, and 20.4±0.2°2θ.

[0051] In another embodiment, form M-2 further exhibits one or more characteristic XRPD peaks at 4.5±0.2, 12.5±0.2, 14.1±0.2, 14.9±0.2, 15.4±0.2, 17.9±0.2 and 20.8±0.2°2θ.

[0052] In another embodiment, the present invention relates to a crystalline form M-2 of a compound of formula I, characterized by the XRPD pattern substantially shown in Figure 2.

[0053] In another embodiment, the present invention relates to a crystalline form M-2 of a compound of formula I, characterized by a DSC showing an endothermic peak at approximately 144°C.

[0054] In another embodiment, the present invention relates to a crystalline form M-2 of a compound of formula I, characterized by a DSC showing an onset at approximately 140°C and an endothermic peak at approximately 144°C.

[0055] In another embodiment, the present invention relates to a crystalline form M-2 of a compound of formula I, characterized by dynamic vapor adsorption analysis showing a weight increase of 0.1% or less, for example, 0.05% or less or 0.01% or less, when the crystalline form M-2 is equilibrated at 25°C ± 1°C and 80% ± 2% RH for 24 hours.

[0056] In another embodiment, the present invention relates to a crystalline form M-2 of the compound of formula I, characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 0.01 to about 0.10 ± 1% when heated to about 110°C.

[0057] In another embodiment, the present invention relates to d of about 60 μm to about 100 μm 90 This relates to the crystalline form M-2 of the compound of formula I, having a particle size distribution characterized by the following.

[0058] In another embodiment, the present invention relates to a crystalline form M-2 of a compound of formula I that is nonhygroscopic.

[0059] In another embodiment, the present invention relates to a process for preparing the crystalline form M-2 of a compound of formula I, wherein the process is: a) Mixing a racemic compound of formula I with one or more solvents, b) Stirring the reaction mixture (for example, at approximately 20-40°C for about 1-2 hours), c) Isolating the obtained solid (for example, by filtering the reaction mixture), d) Obtaining the desired isomer of the crystalline form M-2 of the compound of formula I (for example, by performing chiral resolution using chiral chromatography), e) optionally includes isolating the crystalline form M-2 of the compound of formula I.

[0060] In another embodiment, the present invention provides a process for preparing form M-2 of the compound of formula I, the process being: a) Mixing a racemic compound of formula I with one or more solvents, b) Stirring the reaction mixture (for example, at approximately 20-40°C for about 1-2 hours), c) Isolating the obtained solid (for example, by filtering the reaction mixture), d) Obtain the desired isomer of the compound of formula I in crystalline form M-2 by chiral chromatography using a dichloromethane / methanol mixture (1:1), e) optionally includes isolating the crystalline form M-2 of the compound of formula I.

[0061] In another embodiment, the present invention provides a process for preparing the crystalline form M-2 of a compound of formula I, the process being: a) Mixing the racemic compound of formula I with methanol, b) Stirring the reaction mixture (for example, at approximately 20-40°C for about 1-2 hours), c) Isolating the obtained solid (for example, by filtering the reaction mixture), d) Obtain the desired isomer of the compound of formula I in crystalline form M-2 by chiral chromatography using a dichloromethane / methanol mixture (1:1), e) optionally includes isolating the crystalline form M-2 of the compound of formula I.

[0062] In one embodiment, one or more solvents used in step a) are selected from methanol, ethanol, 1-propanol, 2-propanol, n-butanol, isobutanol, nitromethane, chloroform, acetonitrile, acetone, MIBK, MEK, toluene, heptane, ethyl acetate, propyl acetate, n-pentyl acetate, isopropyl acetate, butyl acetate, propionitrile, diethyl ether, dimethyl ether, diisopropyl ether, diphenyl ether, MTBE, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane, o-xylene, m-xylene, p-xylene, n-pentane, cyclopentane, n-hexane, cyclohexane, benzene, dichloromethane, dichloroethane, tetrachloromethane, chlorobenzene, dimethylacetamide (DMA), dimethylformamide (DMF), water, and any mixture of any of the above.

[0063] In one embodiment, the solvent used in step a) is methanol.

[0064] In another embodiment, the present invention provides a process for preparing a crystalline form M-2 of a compound of formula I, the process comprising heating a compound of formula I (e.g., amorphous or crystalline form M-1) to obtain a crystalline form M-2. In one embodiment, a compound of formula I (e.g., amorphous or crystalline form M-1) is heated, for example, to a temperature of about 100 to 130°C for about 1 to 4 hours to obtain a crystalline form M-2.

[0065] Crystal form M-3 In another embodiment, the present invention relates to a crystalline form M-3 of a compound of formula I, characterized by an XRPD pattern exhibiting one or more (e.g., two, three, or four) characteristic peaks at approximately 7.1±0.2, 13.3±0.2, 17.6±0.2, and 21.8±0.2°2θ.

[0066] In another embodiment, form M-3 further includes one or more characteristic XRPD patterns at 4.3±0.2, 11.1±0.2, 15.2±0.2, 15.7±0.2, 16.0±0.2, 17.5±0.2, 18.8±0.2, 20.2±0.2, 21.7±0.2, 23.2±0.2 and 25.7±0.2°2θ.

[0067] In another embodiment, the present invention relates to a crystalline form M-3 of a compound of formula I, characterized by the XRPD pattern substantially shown in Figure 3.

[0068] In another embodiment, the present invention relates to a crystalline form M-3 of a compound of formula I, characterized by a DSC showing an endothermic peak at approximately 113°C.

[0069] In another embodiment, the present invention relates to a crystalline form M-3 of a compound of formula I, characterized by a DSC showing an onset at approximately 109°C and an endothermic peak at approximately 113°C.

[0070] In another embodiment, the present invention relates to a crystalline form M-3 of the compound of formula I, characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 4.7 to about 5.7 ± 1% when heated to about 140°C.

[0071] In another embodiment, the present invention relates to d of about 60 μm to about 100 μm 90 This relates to the crystalline form M-3 of the compound of formula I, having a particle size distribution characterized by the following.

[0072] In another embodiment, the present invention provides a process for preparing the crystalline form M-3 of the compound of formula I, the process being: a) Dissolve the compound of formula I in one or more solvents, b) Heating the reaction mixture, c) Isolating the crystalline form M-3 of the compound of formula I, and

[0073] In another embodiment, the present invention relates to a process for preparing the crystalline form M-3 of a compound of formula I, wherein the process is: a) Mixing the compound of formula I with one or more solvents, b) Stir the reaction mixture at ambient temperature for approximately 10-15 hours. c) Isolating the crystalline form M-3 of the compound of formula I, and

[0074] In one embodiment, the compound of formula I used in step a) is selected from amorphous, one or more crystalline forms, or any mixture of the above. In one embodiment, the compound of formula I used in step a) is crystalline form M-1.

[0075] In another embodiment, one or more solvents used in step a) are selected from ethanol, methanol, 1-propanol, 2-propanol, n-butanol, isobutanol, nitromethane, chloroform, acetonitrile, acetone, MIBK, MEK, toluene, heptane, ethyl acetate, propyl acetate, n-pentyl acetate, isopropyl acetate, butyl acetate, propionitrile, diethyl ether, dimethyl ether, diisopropyl ether, diphenyl ether, MTBE, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane, o-xylene, m-xylene, p-xylene, n-pentane, cyclopentane, n-hexane, cyclohexane, heptane, benzene, dichloromethane, dichloroethane, tetrachloromethane, chlorobenzene, dimethylacetamide (DMA), dimethylformamide (DMF), water, and any mixture of any of the above.

[0076] In a preferred embodiment, one or more solvents used in step a) are selected from ethanol, heptane, and mixtures thereof.

[0077] Crystal form M-4 In another embodiment, the present invention relates to a crystalline form M-4 of a compound of formula I, characterized by an XRPD pattern exhibiting characteristic peaks at 8.8±0.2, 11.3±0.2, 17.8±0.2, 19.0±0.2, 23.1±0.2, and 25.8±0.2°2θ.

[0078] In another embodiment, the present invention relates to a crystalline form M-4 of a compound of formula I, characterized by an XRPD pattern exhibiting characteristic peaks at 7.2±0.2, 8.8±0.2, 13.3±0.2, 14.7±0.2, 19.4±0.2, 24.5±0.2, 25.9±0.2 and 27.3±0.2°2θ, and one or more additional characteristic peaks (e.g., 2, 3, 4, 5, 6, 7, or 8) at 11.5±0.2, 12.3±0.2, 15.6±0.2, 16.0±0.2, 17.8±0.2, 19.0±0.2, 22.0±0.2 and 23.1±0.2°2θ.

[0079] In another embodiment, the present invention relates to a crystalline form M-4 of a compound of formula I, characterized by the XRPD pattern substantially shown in Figure 4.

[0080] In another embodiment, the present invention provides a crystalline form M-4 of the compound of formula I, characterized by a DSC showing an endothermic peak at approximately 107°C.

[0081] In another embodiment, the present invention provides a crystalline form M-4 of the compound of formula I, characterized by the DSC substantially shown in Figure 5.

[0082] In another embodiment, the present invention relates to a crystalline form M-4 of the compound of formula I, characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 0.1 to about 0.8 ± 1% when heated to about 110°C.

[0083] In another embodiment, the present invention relates to d of about 60 μm to about 100 μm 90 This relates to the crystalline form M-4 of the compound of formula I, having a particle size distribution characterized by the following.

[0084] In another embodiment, the present invention relates to a process for preparing the crystalline form M-4 of a compound of formula I, wherein the process is: a) Mixing the compound of formula I with one or more solvents (for example, a combination of ethanol and heptane), b) Heating the reaction mixture (for example, at an appropriate temperature for an appropriate amount of time), c) Crystallization of the polymerization compound, d) optionally includes isolating the crystalline form M-4 of the compound of formula I.

[0085] In another embodiment, the present invention relates to a process for preparing the crystalline form M-4 of a compound of formula I, wherein the process is: a) Adding one or more compounds of formula I to a solvent, b) Stir the reaction mixture (for example, for about 20-60 minutes), c) optionally includes isolating the crystalline form M-4 of the compound of formula I.

[0086] In one embodiment, the compound of formula I used in step a) of the process for preparing form M-4 is selected from amorphous, one or more crystalline forms, and any mixture thereof. In one embodiment, the compound of formula I used in step a) of the process for preparing form M-4 is crystalline form M-1.

[0087] In another embodiment, the present invention relates to a process for preparing a crystalline form M-4 of a compound of formula I, the process comprising heating a crystalline form M-1 of a compound of formula I (for example, at a suitable temperature for a suitable time) to obtain a crystalline form M-4 of a compound of formula I.

[0088] In another embodiment, the present invention relates to a process for preparing a crystalline form M-4 of a compound of formula I, the process comprising heating a crystalline form M-1 of a compound of formula I at about 50 to about 70°C for about 70 to about 75 hours to obtain a crystalline form M-4 of a compound of formula I.

[0089] In another embodiment, the present invention relates to a process for preparing a crystalline form M-3 of a compound of formula I, the process comprising heating a crystalline form M-1 of a compound of formula I (for example, at a suitable temperature for a suitable time) to obtain a crystalline form M-4 of a compound of formula I.

[0090] In another embodiment, the present invention relates to a process for preparing a crystalline form M-4 of a compound of formula I, the process comprising heating a crystalline form M-3 of a compound of formula I at about 50 to about 70°C for about 70 to about 75 hours to obtain a crystalline form M-4 of a compound of formula I.

[0091] In certain embodiments, one or more solvents used in step a) of the process for preparing form M-4 are selected from ethanol, methanol, 1-propanol, 2-propanol, n-butanol, isobutanol, nitromethane, heptane, chloroform, acetonitrile, acetone, MIBK, MEK, toluene, ethyl acetate, propyl acetate, n-pentyl acetate, isopropyl acetate, butyl acetate, propionitrile, diethyl ether, dimethyl ether, diisopropyl ether, diphenyl ether, MTBE, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane, o-xylene, m-xylene, p-xylene, n-pentane, cyclopentane, n-hexane, cyclohexane, heptane, benzene, dichloromethane, dichloroethane, tetrachloromethane, chlorobenzene, dimethylacetamide (DMA), dimethylformamide (DMF), water, and mixtures thereof.

[0092] In one embodiment, one or more solvents used in step a) are selected from methanol, ethanol, acetonitrile, heptane, and mixtures thereof.

[0093] Crystal form M-5 In another embodiment, the present invention relates to a crystalline form M-5 of a compound of formula I, characterized by an XRPD pattern exhibiting characteristic peaks at approximately 4.3±0.2, 7.8±0.2, 10.2±0.2, 16.3±0.2, and 16.8±0.2°2θ.

[0094] In another embodiment, the present invention relates to a crystalline form M-5 of a compound of formula I, characterized by an XRPD pattern showing characteristic peaks at approximately 4.3±0.2, 7.6±0.2, 16.3±0.2 and 16.8±0.2°2θ, and one or more (e.g., two, three, or four) additional peaks at 12.3±0.2, 17.8±0.2, 19.4±0.2 and 20.6±0.2°2θ.

[0095] In another embodiment, the present invention relates to the crystalline form M-5 of the compound of formula I, characterized by the XRPD pattern substantially shown in Figure 6.

[0096] In another embodiment, the present invention relates to a crystalline form M-5 of a compound of formula I, characterized by a DSC showing an onset at approximately 146°C and an endothermic peak at approximately 148°C.

[0097] In another embodiment, the present invention relates to a crystalline form M-5 of a compound of formula I, characterized by a DSC showing an endothermic peak at approximately 148°C.

[0098] In another embodiment, the present invention relates to a crystalline form M-5 of the compound of formula I, characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 0.03 to about 0.1 ± 1% when heated to about 110°C.

[0099] In another embodiment, the present invention relates to d of about 60 μm to about 100 μm 90 This relates to the crystalline form M-5 of the compound of formula I, having a particle size distribution characterized by the following.

[0100] In another embodiment, the present invention relates to a process for preparing the crystalline form M-5 of a compound of formula I, wherein the process is: a) Mixing the compound of formula I in one or more solvents, b) Stirring the reaction mixture (for example, at ambient temperature for about 10-15 hours), c) optionally includes isolating the crystalline form M-5 of the compound of formula I.

[0101] In another embodiment, the present invention relates to a process for preparing the crystalline form M-5 of a compound of formula I, wherein the process is: a) Mixing the compound of formula I with acetonitrile, b) Stir the reaction mixture at ambient temperature for approximately 10-15 hours. c) optionally includes isolating the crystalline form M-5 of the compound of formula I.

[0102] In another embodiment, the compound of formula I used in step a) of the process for preparing crystalline form M-5 of the compound of formula I is selected from amorphous, one or more crystalline forms, and any mixture of any of the aforementioned. In one embodiment, the compound of formula I used in step a) of the process for preparing crystalline form M-5 of the compound of formula I is crystalline form M-2.

[0103] In another embodiment, one or more solvents used in step a) of the process for preparing crystalline forms M-5 of the compound of formula I are selected from acetonitrile, methanol, ethanol, 1-propanol, 2-propanol, n-butanol, isobutanol, nitromethane, chloroform, acetone, MIBK, MEK, toluene, heptane, ethyl acetate, propyl acetate, n-pentyl acetate, isopropyl acetate, butyl acetate, propionitrile, diethyl ether, dimethyl ether, diisopropyl ether, diphenyl ether, MTBE, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane, o-xylene, m-xylene, p-xylene, n-pentane, cyclopentane, n-hexane, cyclohexane, heptane, benzene, dichloromethane, dichloroethane, tetrachloromethane, chlorobenzene, dimethylacetamide (DMA), dimethylformamide (DMF), water, and mixtures thereof.

[0104] In one embodiment, one or more solvents used in step a) of the process for preparing crystalline forms M-5 of the compound of formula I are selected from nitromethane, acetonitrile, and mixtures thereof.

[0105] Crystal form M-6 In another embodiment, the present invention relates to a crystalline form M-6 of a compound of formula I, characterized by an XRPD pattern exhibiting characteristic peaks at 5.6±0.2, 9.7±0.2, and 19.8±0.2°2θ.

[0106] In another embodiment, the present invention relates to a crystalline form M-6 of a compound of formula I, characterized by an XRPD pattern showing characteristic peaks at 5.6±0.2, 9.7±0.2, and 19.8±0.2°2θ, and one or more additional peaks selected from 15.9±0.2, 17.3±0.2, 18.6±0.2, and 20.3±0.2°2θ.

[0107] In another embodiment, the present invention provides a crystalline form M-6 of the compound of formula I, characterized by the XRPD pattern substantially shown in Figure 7.

[0108] In another embodiment, the present invention provides crystalline forms M-6 of the compound of formula I, characterized by DSCs showing onset and endothermic peaks at approximately 80°C and 87°C, approximately 103°C and 112°C, and 139°C and 142°C, respectively.

[0109] In another embodiment, the present invention provides a crystalline form M-6 of the compound of formula I, characterized by DSCs showing endothermic peaks at approximately 87°C, approximately 112°C, and approximately 142°C.

[0110] In another embodiment, the present invention relates to a crystalline form M-6 of the compound of formula I, characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 0.3 to about 1.5 ± 1% when heated to about 120°C.

[0111] In another embodiment, the present invention relates to d of about 60 μm to about 100 μm 90 This relates to the crystalline form M-6 of the compound of formula I, having a particle size distribution characterized by the following.

[0112] In another embodiment, the present invention relates to a process for preparing forms M-6 of the compound of formula I, wherein the process is a) Adding the compound of formula I to one or more solvents under liquid nitrogen to obtain a solid mass, b) Maintaining the solid mass at room temperature to obtain a clear solution, c) optionally includes isolating the crystalline form M-6 of the compound of formula I.

[0113] In another embodiment, the compound of formula I used in step a) of the process for preparing crystalline form M-6 of the compound of formula I is selected from amorphous, one or more crystalline forms, and a mixture thereof. In another embodiment, the compound of formula I used in step a) of the process for preparing crystalline form M-6 of the compound of formula I is crystalline form M-2.

[0114] In another embodiment, one or more solvents used in step a) of the process for preparing crystalline forms M-6 of the compound of formula I are selected from nitromethane, methanol, ethanol, 1-propanol, 2-propanol, n-butanol, isobutanol, chloroform, acetonitrile, acetone, MIBK, MEK, toluene, heptane, ethyl acetate, propyl acetate, n-pentyl acetate, isopropyl acetate, butyl acetate, propionitrile, diethyl ether, dimethyl ether, diisopropyl ether, diphenyl ether, MTBE, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane, o-xylene, m-xylene, p-xylene, n-pentane, cyclopentane, n-hexane, cyclohexane, heptane, benzene, dichloromethane, dichloroethane, tetrachloromethane, chlorobenzene, dimethylacetamide (DMA), dimethylformamide (DMF), water, and mixtures thereof.

[0115] In one embodiment, one or more solvents used in step a) of the process for preparing crystalline forms M-6 of the compound of formula I are selected from o-xylene, heptane, nitromethane, and mixtures thereof.

[0116] Crystal form M-7 In another embodiment, the present invention relates to a crystalline form M-7 of a compound of formula I, characterized by an XRPD pattern exhibiting characteristic peaks at 4.3±0.2, 8.7±0.2, 10.6±0.2, 16.4±0.2, 18.5±0.2, 19.5±0.2 and 21.9±0.2°2θ.

[0117] In another embodiment, the present invention relates to a crystalline form M-7 of a compound of formula I, characterized by the XRPD pattern substantially shown in Figure 8.

[0118] In another embodiment, the present invention relates to a crystalline form M-7 of a compound of formula I, characterized by a DSC showing an onset peak at about 97°C and an endothermic peak at about 100°C.

[0119] In another embodiment, the present invention relates to a crystalline form M-7 of a compound of formula I, characterized by a DSC showing an endothermic peak at about 100°C.

[0120] In another embodiment, the present invention relates to a crystalline form M-7 of the compound of formula I, characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 5.0 to about 6.0 ± 1% when heated to about 150°C.

[0121] In another embodiment, the present invention relates to d of about 60 μm to about 100 μm 90 This relates to the crystalline form M-7 of the compound of formula I, having a particle size distribution characterized by the following.

[0122] In another embodiment, the present invention relates to a process for preparing forms M-7 of the compound of formula I, wherein the process is a) Mixing the compound of formula I in one or more solvents, b) Heating the reaction mixture obtained in step a), c) Evaporating the solvent, d) optionally includes isolating the crystalline form M-7 of the compound of formula I.

[0123] In another embodiment, the compound of formula I used in step a) of the process for preparing crystalline form M-7 of the compound of formula I is selected from amorphous, one or more crystalline forms, and a mixture thereof. In another embodiment, the compound of formula I used in step a) of the process for preparing crystalline form M-7 of the compound of formula I is crystalline form M-2.

[0124] In another embodiment, one or more solvents used in step a) of the process for preparing crystalline forms M-7 of the compound of formula I are selected from o-xylene, m-xylene, p-xylene, heptane, methanol, ethanol, 1-propanol, 2-propanol, n-butanol, isobutanol, nitromethane, chloroform, acetonitrile, acetone, MIBK, MEK, toluene, ethyl acetate, propyl acetate, n-pentyl acetate, isopropyl acetate, butyl acetate, propionitrile, diethyl ether, dimethyl ether, diisopropyl ether, diphenyl ether, MTBE, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane, n-pentane, cyclopentane, n-hexane, cyclohexane, heptane, benzene, dichloromethane, dichloroethane, tetrachloromethane, chlorobenzene, dimethylacetamide (DMA), dimethylformamide (DMF), water, and mixtures thereof.

[0125] In one embodiment, one or more solvents used in step a) of the process for preparing the crystalline form M-7 of the compound of formula I are selected from 2-propanol, hexane, o-xylene, heptane, and mixtures thereof.

[0126] Crystal form M-8 In another embodiment, the present invention provides a crystalline form M-8 of the compound of formula I, characterized by an XRPD pattern exhibiting characteristic peaks at 4.6±0.2, 6.4±0.2, 9.3±0.2, 12.3±0.2, 15.5±0.2, 17.0±0.2 and 17.7±0.2°2θ.

[0127] In another embodiment, the present invention relates to a crystalline form M-8 of a compound of formula I, characterized by the XRPD pattern substantially shown in Figure 9.

[0128] In another embodiment, the present invention provides a crystalline form M-8 of the compound of formula I, characterized by a DSC showing an onset at approximately 127°C and an endothermic peak at approximately 133°C.

[0129] In another embodiment, the present invention provides crystalline form M-8 of a compound of formula I, which is characterized by DSC showing an endothermic peak at about 133°C.

[0130] In another embodiment, the present invention relates to crystalline form M-8 of a compound of formula I, which is characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 0.05 to about 0.5 ± 1% when heated to about 110°C.

[0131] In another embodiment, the present invention relates to crystalline form M-8 of a compound of formula I having a particle size distribution characterized by a d 90 from about 60 μm to about 100 μm.

[0132] In another embodiment, the present invention relates to a process for the preparation of crystalline form M-8 of a compound of formula I, the process comprising a) mixing a compound of formula I with one or more solvents, b) heating the reaction mixture of step a), c) cooling the reaction mixture obtained from step b), d) optionally isolating crystalline form M-8 of the compound of formula I.

[0133] In another embodiment, the compound of formula I used in step a) of the process for the preparation of crystalline form M-8 of the compound of formula I is selected from amorphous, one or more crystalline forms, and mixtures of any of these. In another embodiment, the compound of formula I used in step a) of the process for the preparation of crystalline form M-8 of the compound of formula I is crystalline form M-1.

[0134] In another embodiment, one or more solvents used in step a) of the process for preparing crystalline forms M-8 of the compound of formula I are selected from isopropanol, hexane, heptane, methanol, ethanol, 2-propanol, n-butanol, isobutanol, nitromethane, chloroform, acetonitrile, acetone, MIBK, MEK, toluene, ethyl acetate, propyl acetate, n-pentyl acetate, isopropyl acetate, butyl acetate, propionitrile, diethyl ether, dimethyl ether, diisopropyl ether, diphenyl ether, MTBE, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane, o-xylene, m-xylene, p-xylene, n-pentane, cyclopentane, cyclohexane, heptane, benzene, dichloromethane, dichloroethane, tetrachloromethane, chlorobenzene, dimethylacetamide (DMA), dimethylformamide (DMF), water, and mixtures thereof.

[0135] In one embodiment, one or more solvents used in step a) of the process for preparing the crystalline form M-8 of the compound of formula I are selected from methanol, isopropanol, hexane, and mixtures thereof.

[0136] Crystal form M-9 In another embodiment, the present invention relates to a crystalline form M-9 of the compound of formula I, characterized by an XRPD pattern exhibiting characteristic peaks at 7.2±0.2, 8.8±0.2, 11.5±0.2, 12.3±0.2, 13.3±0.2, 15.6±0.2, 16.0±0.2, 17.9±0.2, 19.0±0.2, 22.3±0.2, 23.2±0.2, 25.8±0.2, 27.3±0.2 and 29.4±0.2°2θ.

[0137] In another embodiment, the present invention features characteristic peaks at 4.3±0.2, 8.8±0.2, 11.5±0.2, 12.3±0.2, 13.2±0.2, 15.5±0.2, 16.0±0.2, 17.9±0.2, 19.0±0.2, 22.3±0.2, 23.2±0.2, 25.8±0.2, 27.3±0.2 and 29.4±0.2°2θ, as well as 11.7±0 This relates to the crystalline form M-9 of the compound of formula I, characterized by an XRPD pattern showing one or more additional peaks (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) selected from 0.2, 11.9±0.2, 14.7±0.2, 16.5±0.2, 20.5±0.2, 21.3±0.2, 24.5±0.2, 26.3±0.2, and 28.4±0.2°2θ.

[0138] In another embodiment, the present invention relates to a crystalline form M-9 of a compound of formula I, characterized by the XRPD pattern substantially shown in Figure 10.

[0139] In another embodiment, the present invention provides a crystalline form M-9 of the compound of formula I, characterized by DSCs showing two onsets and endothermic peaks at approximately 98°C and 108°C, and 138°C and 142°C, respectively.

[0140] In another embodiment, the present invention relates to a crystalline form M-9 of a compound of formula I, characterized by DSCs showing endothermic peaks at approximately 108°C and approximately 142°C.

[0141] In another embodiment, the present invention relates to a crystalline form M-9 of the compound of formula I, characterized by a thermogravimetric analysis (TGA) thermogram showing a mass loss of about 0.07 to about 0.5 ± 1% when heated to about 110°C.

[0142] In another embodiment, the present invention relates to d of about 60 μm to about 100 μm 90 This relates to the crystalline form M-9 of the compound of formula I, having a particle size distribution characterized by the following.

[0143] In another embodiment, the present invention relates to a process for preparing the crystalline form M-9 of a compound of formula I, wherein the process is: a) To obtain a solid mass by mixing the compound of formula I with one or more solvents under liquid nitrogen, b) Maintaining the solid mass at room temperature to obtain a clear solution, c) optionally includes isolating the crystalline form M-9 of the compound of formula I.

[0144] In another embodiment, the compound of formula I used in step a) of the process for preparing crystalline form M-9 of the compound of formula I is selected from amorphous, one or more crystalline forms, and a mixture thereof. In another embodiment, the compound of formula I used in step a) of the process for preparing crystalline form M-9 of the compound of formula I is crystalline form M-2.

[0145] In another embodiment, one or more solvents used in step a) of the process for preparing crystalline forms M-9 of the compound of formula I are selected from methanol, ethanol, isopropanol, 2-propanol, n-butanol, isobutanol, nitromethane, chloroform, acetonitrile, acetone, MIBK, MEK, toluene, heptane, ethyl acetate, propyl acetate, n-pentyl acetate, isopropyl acetate, butyl acetate, propionitrile, diethyl ether, dimethyl ether, diisopropyl ether, diphenyl ether, MTBE, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane, o-xylene, m-xylene, p-xylene, n-pentane, cyclopentane, n-hexane, cyclohexane, heptane, benzene, dichloromethane, dichloroethane, tetrachloromethane, chlorobenzene, dimethylacetamide (DMA), dimethylformamide (DMF), water, and mixtures thereof.

[0146] In another embodiment, one or more solvents used in step a) of the process for preparing crystalline forms M-9 of the compound of formula I are selected from acetonitrile, water, methanol, and mixtures thereof.

[0147] Amorphous form In another embodiment, the present invention relates to amorphous forms of compounds of formula I and processes for preparing them.

[0148] In another embodiment, the present invention relates to a stable amorphous form of the compound of formula I and a process for preparing the same.

[0149] In another embodiment, the present invention relates to a stable amorphous form of the compound of formula I, characterized by the XRPD pattern substantially shown in Figure 11.

[0150] In another embodiment, the present invention relates to a process for preparing an amorphous form of a compound of formula I, wherein the process is: a) To provide a solution of a compound of formula I in one or more solvents, b) Freeze-dry the solution obtained in step a), c) optionally includes isolating the amorphous form of the compound of formula I.

[0151] In another embodiment, the present invention relates to a process for preparing an amorphous form of a compound of formula I, wherein the process is: a) Milling / grinding the compound of formula I (for example, under suitable milling / grinding conditions), b) optionally includes isolating the amorphous form of the compound of formula I.

[0152] In another embodiment, the present invention provides a process for preparing an amorphous form of a compound of formula I, the process being: a) To provide a solution of a compound of formula I in one or more solvents, b) Removing the solvent (for example, by evaporation or distillation), c) optionally includes isolating the amorphous form of the compound of formula I.

[0153] In another embodiment, the present invention relates to a stable amorphous form of the compound of formula I containing less than 0.5% by weight of total impurities after exposure to 40°C / 75%RH for about 6 months or to 25°C / 60%RH for at least 12 months. In one embodiment, the stable amorphous form does not change into any other solid form after exposure to 40°C / 75%RH for about 6 months or to 25°C / 60%RH for at least 12 months.

[0154] Premix of the compound of formula I In another embodiment, the present invention relates to a premix containing a compound of formula I and a process for preparing the same.

[0155] In another embodiment, the present invention relates to a premix comprising a compound of formula I and one or more pharmaceutically acceptable excipients.

[0156] In another embodiment, the present invention relates to a process for preparing a premix containing a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the process is: a) Forming a reaction mixture comprising a compound of formula I or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable excipients, and one or more solvents. b) Removing the solvent (for example, by evaporation), c) optionally includes isolating a premix of the compound of formula I or a pharmaceutically acceptable salt thereof.

[0157] In certain embodiments, one or more pharmaceutically acceptable excipients are selected from, but are not limited to, the group consisting of polyvinylpyrrolidone, povidone K-30, povidone K-60, povidone K-90, methylcellulose, methacrylate copolymer, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate acetate (HPMC-AS), hydroxypropyl methylcellulose, hydroxypropylcellulose SSL (HPC-SSL), hydroxypropylcellulose SL (HPC-SL), hydroxypropylcellulose L (HPC-L), hydroxyethylcellulose, Soluplus® (polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), Gelucire 44 / 14, ethylcellulose, D-α-tocopheryl polyethylene glycol 1000 succinate, cellulose phthalate acetate, carboxymethyl ethylcellulose, sodium starch glycolate, or any combination of any of the above.

[0158] In certain embodiments, the removal of the solvent at any stage in the preparation of any crystalline, amorphous, or premix of the compounds of Formula I described herein may include, but are not limited to, centrifugal separation, crystallization, filtration, extraction, solvent evaporation, solvent evaporation under atmospheric pressure or reduced pressure / vacuum, such as rotary distillation using Buchi® Rotavapor®, flash evaporation, rotary drying, stirred Nucche filter drying, spray drying, freeze-drying, thin-film drying, stirred thin-film drying, rotary vacuum paddle dryer (RVPD), freeze-drying, etc. In certain embodiments, the solvent may be removed under reduced pressure at temperatures below about 100°C, for example, below about 60°C, below about 40°C, below about 20°C, below about 0°C, below about -20°C, below about -40°C, below about -60°C, or below about -80°C.

[0159] In additional embodiments, the compound of formula I used as input (starting material) for preparing any of the solid forms described herein may be a crude mass, a reaction mixture, an amorphous form, one or more crystalline forms, or any mixture of any of the aforementioned in any proportion.

[0160] In additional embodiments, the chemical purity (measured by high-pressure liquid chromatography) of any of the crystalline forms of the compounds of formula I described herein is greater than about 90%, for example, about 90.5%, about 91.0%, about 91.5%, about 92.0%, about 92.5%, about 93.0%, about 93.5%, about 94.0%, about 94.5%, about 95.0%, about 95.5%, about 96.0%, about 96.5%, about 97.0%, about 97.5%, about 98.0%, about 98.5%, about 99.0%, about 99.5%, or about 99.9%.

[0161] In additional embodiments, the chemical purity (measured by high-pressure liquid chromatography) of any of the crystalline forms of the compounds of Formula I described herein is greater than about 90%, for example, greater than about 90.5%, greater than about 91.0%, greater than about 91.5%, greater than about 92.0%, greater than about 92.5%, greater than about 93.0%, greater than about 93.5%, greater than about 94.0%, greater than about 94.5%, greater than about 95.0%, greater than about 95.5%, greater than about 96.0%, greater than about 96.5%, greater than about 97.0%, greater than about 97.5%, greater than about 98.0%, greater than about 98.5%, greater than about 99.0%, greater than about 99.5%, or greater than about 99.9%.

[0162] In additional embodiments, the crystalline forms of the compounds of Formula I described herein are all approximately 99.9% chemically pure (as measured by high-pressure liquid chromatography).

[0163] In further embodiments, any crystalline form of any compound of formula I described herein contains any one impurity introduced, obtained, or produced as a result of chemosynthesis or decomposition, as measured by high-pressure liquid chromatography, in amounts less than 2.0%, for example, about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, or about 0.009%.

[0164] In further embodiments, the crystalline form of any compound of formula I described herein is less than about 2.0%, for example, less than about 1.9%, less than about 1.8%, less than about 1.7%, less than about 1.6%, less than about 1.5%, less than about 1.4%, less than about 1.3%, less than about 1.2%, less than about 1.1%, less than about 1.0%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than 0.2%, It includes any one impurity measured by high-pressure liquid chromatography (e.g., any impurity introduced, obtained, or generated as a result of the chemical synthesis or decomposition of the compound of formula I) in amounts of less than approximately 0.1%, less than approximately 0.09%, less than approximately 0.08%, less than approximately 0.07%, less than approximately 0.06%, less than approximately 0.05%, less than approximately 0.04%, less than approximately 0.03%, less than approximately 0.02%, less than approximately 0.01%, or less than approximately 0.009%.

[0165] In further embodiments, any of the crystalline forms (M-1 to M-9) of the compound of formula I described herein are substantially pure.

[0166] In additional embodiments, a substantially pure crystalline form of the compound of formula I means that the crystalline form substantially does not contain any other polymorphic forms of the compound of formula I. For example, the compound of formula I has a polymorphic purity of at least about 90% w / w, e.g., about 95% w / w, about 98% w / w, or about 99% w / w, as characterized by XRPD.

[0167] In additional embodiments, any of the crystalline forms of the compounds of formula I described herein includes one or more other crystalline forms of the compounds of formula I, or an amorphous form of the compounds of formula I, in amounts of about 20% or less, for example, about 10% or less, about 5% or less, about 2% or less, about 1% or less, about 0.5% or less, about 0.1% or less, or about 0.05% based on the total volume or weight of the crystalline forms. In additional embodiments, any of the crystalline forms of the compounds of formula I described herein includes one or more other crystalline forms, or an amorphous form, in amounts undetectable (for example, by XRPD) based on the total volume or weight of the crystalline forms.

[0168] In further embodiments, any of the crystalline forms of the compounds of formula I described herein may include one or more other crystalline forms of the compounds of formula I in amounts less than about 15%, for example less than about 10%, less than about 5%, or less than about 2%, based on the total volume or weight of the crystalline forms.

[0169] In further embodiments, any of the crystalline forms of the compounds of formula I described herein contains one or more other crystalline forms of the compounds of formula I in an amount less than about 5%, for example less than about 1%, or less than about 0.5%, based on the total volume or weight of the crystalline forms. In further embodiments, any of the crystalline forms of the compounds of formula I described herein contains one or more other crystalline forms of the compounds of formula I in an undetectable amount, based on the total volume or weight of the crystalline forms.

[0170] In another embodiment, the amorphous form of the compound of formula I described herein is substantially free of any other impurities.

[0171] In another embodiment, the amorphous form of the compound of formula I described herein is substantially pure.

[0172] In another embodiment, the amorphous form of the compound of formula I described herein includes about 10% or less of one or more crystalline forms of the compound of formula I described herein, for example, about 7% or less, about 5% or less, about 3% or less, about 1% or less, or 0.5% or less.

[0173] In further embodiments, either the crystalline or amorphous form of the compound of formula I described herein is d 90 It is characterized by a particle size distribution ranging from approximately 0.1 μm to approximately 200 μm.

[0174] In further embodiments, either the crystalline or amorphous form of the compound of formula I described herein is d 90 It is characterized by a particle size distribution ranging from approximately 2.0 μm to approximately 150 μm.

[0175] In further embodiments, one or more solvents used to prepare either the crystalline or amorphous form of the compound of Formula I described herein are: ketones, e.g., methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl t-butyl ketone, acetone, etc.; alcohols, e.g., ethanol, methanol, n-propanol, 2-propanol (isopropanol), n-butanol, isobutanol, tert-butanol, etc.; esters, e.g., ethyl acetate, propyl acetate, n-pentyl acetate, isopropyl acetate, butyl acetate, etc.; ethers, e.g., dimethyl ether, diethyl ether, ethyl methyl ether, 1,4-dioxane, tetrahydrofuran (THF), methyltetrahydro The solvent is selected from the group consisting of furan, for example; hydrocarbons, such as n-heptane, cyclohexane, n-hexane, benzene, toluene, o-, m- or p-xylene; nitriles, such as acetonitrile, propanenitrile; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, tetrachloromethane, chlorobenzene; amides, such as dimethylacetamide (DMA), dimethylformamide (DMF); nitromethane; and water or mixtures thereof, preferably one or more solvents selected from methanol, ethanol, 2-propanol, hexane, heptane, acetonitrile, nitromethane, xylene, acetone, water, and any mixture of any of the above.

[0176] In another embodiment, the present invention relates to a pharmaceutical composition comprising a substantially pure solid form of a compound of formula I according to any embodiment described herein, and one or more pharmaceutically acceptable excipients.

[0177] Certain aspects and embodiments of this application will be described in further detail with reference to the following examples, which are provided for illustrative purposes only and should not be construed as limiting the scope of this application in any way. As will be apparent to those skilled in the art, variations of the procedures described are also intended to be within the scope of this application. [Examples]

[0178] Analysis method Differential scanning calorimetry (DSC) was performed using a Perkin Elmer instrument, model DSC8000. Samples were placed in their respective sample positions on the DSC instrument, and an empty pan was placed in the reference position. Scans were performed using the specified instrument parameters within a scan temperature range of 30°C to 250°C (10°C / min), and data were collected. Thermograms were recorded by integrating the endothermic peaks.

[0179] Powder X-ray diffraction was recorded using a PANalytical X'Pert3 powder diffractometer; K-alpha 1 [Å] (l=1.54060 Å); X'Celerator detector. Before analysis, a sufficient amount of powder sample was gently ground using a mortar and pestle. The ground sample was uniformly packed into the grooves of the sample holder, and the XRPD graph was recorded in the range of 3–40°²θ.

[0180] Thermogravimetric analysis was performed using a Perkin Elmer Pyris1 TGA. The platinum sample pan was placed on a hangdown wire and allowed to stabilize. TGA curves were recorded with an airflow of 50 mL / min over a temperature range of 30°C to 400°C (100°C / min).

[0181] Particle size analysis was performed using a Malvern particle size analyzer (Mastersizer3000, Malvern Instrument Ltd).

[0182] Sample preparation Accurately weigh 100 mg of the sample into a 100 mL beaker. Add 3 drops of Tween-80 and 1 mL of water, and mix with a glass rod to make a paste. Next, add 10 mL of water and sonicate externally for 10 seconds while continuing to shake.

[0183] Equipment parameters [Table 1]

[0184] Chemical purity was determined by high-pressure liquid chromatography (HPLC).

[0185] Example 1: Preparation of crystalline form M-1 of compound of formula I Compound I (200 gm) and acetonitrile (1.2 L, 6V) were placed in a round-bottom flask (500 mL) at approximately 25-30°C. The reaction mixture was heated at approximately 70°C for 20-25 minutes to completely dissolve the solid. The resulting solution was maintained at room temperature for 40 minutes and then gradually cooled. After 1.5 hours, the formed crystals were isolated by filtration, washed with acetonitrile (0.3 L, 1.5V), and dried in a vacuum tray dryer at approximately 45-50°C to obtain crystalline form M-1 of compound I (yield: 70%, 140 gm). Purity: 99.89% PSD(d90): 84.9μm

[0186] Example 2: Preparation of crystalline form M-1 of compound of formula I Compound I (200 gm) and acetonitrile (1.2 L, 6V) were placed in a round-bottom flask (500 mL) at approximately 20-25°C. The reaction mixture was heated at approximately 60°C for 20-25 minutes to completely dissolve the solid. The resulting solution was maintained at room temperature for 30 minutes and then gradually cooled. After 1.5 hours, the formed crystals were isolated by filtration, washed with acetonitrile (0.3 L, 1.5V), and dried in a vacuum tray dryer at approximately 45-50°C to obtain crystalline form M-1 of compound I (yield: 70%, 140 gm). Purity: 99.89% PSD(d90): 62.4μm

[0187] Example 3: Preparation of the crystalline form M-1 of the compound of formula I Compound I (200 gm) and acetonitrile (1.2 L, 6V) were placed in a round-bottom flask (500 mL) at approximately 25-30°C. The reaction mixture was heated at approximately 70°C for 20-25 minutes to completely dissolve the solid. The resulting solution was maintained at room temperature for 40 minutes, then the crystalline form M-1 of compound I was seeded (at approximately 35-40°C), and then gradually cooled. After 1.5 hours, the formed crystals were filtered, washed with acetonitrile (0.3 L, 1.5V), and dried in a vacuum tray dryer at approximately 45-50°C to obtain the crystalline form M-1 of compound I (yield: 70%, 140 gm). Purity: 99.89% PSD(d90): 106μm

[0188] Example 4: Preparation of crystalline form M-2 of the compound of formula I 200 gm of the racemic compound of formula I and methanol (2 L, 10V) were placed in a round-bottom flask at approximately 25-30°C. The reaction mixture was stirred at approximately 25-30°C for 1 hour. The solid was then isolated by filtration, washed with methanol (0.3 L, 1.5V), and dried in a vacuum tray dryer at approximately 45-50°C. The resulting product was further purified by chiral chromatography (dichloromethane / methanol 50 / 50) to obtain the chiral pure crystalline form M-2 of the compound of formula I. This was freeze-dried in acetonitrile (5V), the slurry was washed with MeOH (5V), and the solid was then isolated by filtration and dried in a vacuum tray dryer at approximately 45-50°C to obtain the crystalline form M-2 of the compound of formula I (yield: 35%, 70 gm). Purity: 99.8% PSD(d90): 99.8μm

[0189] Example 5: Preparation of crystalline form M-2 of compound I Crystalline form M-1 (200g) of the compound of formula I was dried at approximately 100-120°C for 2-4 hours to obtain crystalline form M-2 of the compound of formula I (yield: 95%, 190gm).

[0190] Example 6: Preparation of crystalline form M-3 of the compound of formula I (evaporation method) 300 gm of the compound of formula I and 25 mL of ethanol were placed in a 50 mL round-bottom flask at 25-30°C. The reaction mixture was heated to 60-70°C to dissolve the solid. The solvent was evaporated to obtain crystalline form M-3 of the compound of formula I (yield: 90%, 270 mg). Purity: 99.85%

[0191] Example 7: Preparation of crystalline form M-3 of the compound of formula I (slurry method) 500 gm of the compound of formula I and 5 mL of ethanol were placed in a 25 mL round-bottom flask at approximately 25-30°C. This reaction mixture (slurry) was stirred at ambient temperature for 10-12 hours (RPM 500-600). The slurry was filtered, and the resulting solid was dried at room temperature to obtain crystalline form M-3 of the compound of formula I (yield: 80%, 400 mg).

[0192] Example 8: Preparation of crystalline form M-4 of the compound of formula I (slow evaporation method) Crystallized form M-1 (500 gm) of the compound of formula I and 40 mL of ethanol-heptane (1:1) were placed in a round-bottom flask (100 mL) at approximately 25-30°C. The reaction mixture was heated and then maintained at ambient temperature for crystallization. The solvent was evaporated to obtain crystallized form M-4 of the compound of formula I (yield: 90%, 450 mg). Purity:99.88%

[0193] Example 9: Preparation of crystalline form M-4 of compound of formula I The compound of formula I (95 gm) and 570 mL of acetonitrile were placed in a round-bottom flask (1 L) at approximately 25-30°C. The reaction mixture was stirred for 30-45 minutes. The resulting solid was isolated by filtration, washed with 150 mL of acetonitrile, and dried under vacuum in a tray dryer at approximately 50-70°C. The dried solid was placed in 475 mL of methanol at approximately 25-30°C for 1-2 hours. The reaction mixture was isolated by filtration, washed with methanol, and dried under vacuum in a tray dryer at approximately 50-70°C to obtain the crystalline form M-4 of the compound of formula I (yield: 80%, 76 gm). Purity: 99.9% PSD(d90): 30-60 μm

[0194] Example 10: Preparation of crystalline form M-4 of the compound of formula I. Crystalline form M-3 (200g) of the compound of formula I was dried at approximately 60°C for 72 hours to obtain crystalline form M-4 of the compound of formula I (yield: 95%, 190gm).

[0195] Example 11: Preparation of crystalline form M-5 of the compound of formula I (slurry method) Crystallized form M-2 of the compound of formula I (200 gm) and acetonitrile (3 mL) were placed in a round-bottom flask (25 mL) at approximately 25-30°C. The slurry was stirred overnight at ambient temperature. The slurry was filtered, and the resulting solid was dried at room temperature to obtain crystalline form M-5 of the compound of formula I (yield: 80%, 160 mg). Purity:99.93%

[0196] Example 12: Preparation of crystalline form M-6 of the compound of formula I (crush cooling method) Crystallized form M-2 (200 mg) of the compound of formula I and nitromethane (3 mL) were added under liquid nitrogen. The reaction mixture solidified at a low temperature and was then maintained at room temperature to obtain a clear solution. The clear solution was further evaporated at room temperature to obtain crystallized form M-6 of the compound of formula I (yield: 40%, 80 mg). Purity: 99.81%

[0197] Example 13: Preparation of crystalline form M-7 of the compound of formula I 50 gm of the compound of formula I and 2 mL of o-xylene-heptane (1:1) were placed in a 25 mL round-bottom flask at 25-30°C. The reaction mixture was heated and then maintained at ambient temperature. The solvent was evaporated to obtain the crystalline form M-7 of the compound of formula I (yield: 80%, 40 mg). Purity: 99.50%

[0198] Example 14: Preparation of the crystalline form M-8 of the compound of formula I The compound of formula I (50 g) and 4 mL of 2-propanol-hexane (1:1) were placed in a round-bottom flask (25 mL) at about 25 - 30 °C. The reaction mass was heated and then crystallized in a temperature-controlled oven at about 40 °C. The solvent was evaporated to obtain the crystalline form M-8 of the compound of formula I (yield 90%, 45 mg). Purity: 99.83%

[0199] Example 15: Preparation of crystalline form M-9 of the compound of formula I (crash cooling method) The crystalline form M-2 (200 mg) of the compound of formula I and methanol (3 mL) were placed under liquid nitrogen. The reaction mass was solidified at low temperature and then maintained at room temperature to obtain a clear solution. The clear solution was further maintained at room temperature and evaporated to obtain the crystalline form M-9 of the compound of formula I (yield: 80%, 160 mg). Purity: 99.82%

[0200] Example - 16: Preparation of the amorphous form of the compound of formula I The compound of formula I (0.4 g) was dissolved in methanol (20 mL) at about 25 °C, and the mixture was filtered to make it particle-free. The solvent was evaporated at about 50 °C under reduced pressure using a rotavapor. The resulting product was redissolved in methanol (20 mL) at about 25 °C, and the solvent was evaporated at about 50 °C for 20 minutes under reduced pressure using a Rotavapor to obtain the amorphous form of the compound of formula I (yield 90%, 0.36 g).

[0201] Example - 17: Preparation of the amorphous form of the compound of formula I The crystalline form (10 gm) of the compound of formula I was dissolved in water (150 mL), and the resulting mixture was stirred at room temperature for 15 minutes. Then, the solution was filtered on a high flow bed, and the obtained solid was washed with water. Water was removed by distillation under vacuum at about 55 - 60 °C to obtain a solid mass. Heptane (100 mL) was added to this solid mass, and then it was removed by distillation. The obtained solid was recovered. Heptane (100 mL) was added, and the mixture was stirred at room temperature for 2 hours. The obtained solid was isolated by filtration, then washed with heptane, and dried at about 90 - 100 °C for 5 hours to obtain an amorphous form of the compound of the formula (yield 30%, 3 gm).

[0202] Example - 18: Preparation of the amorphous form of the compound of formula I The compound of formula I (1.0 gm) was dissolved in acetone (50 mL) at about 25 °C, and the resulting mixture was stirred at about 60 °C for 4 - 6 hours. Then, the obtained solution was lyophilized to obtain an amorphous form of the compound of the formula (yield: 95%, 0.95 gm).

[0203] Example - 19: Preparation of the amorphous form of the compound of formula I The compound of formula I (1.0 gm) was dissolved in acetonitrile / water (8 ml / 2 mL) at about 25 °C, and the resulting mixture was stirred at about 60 °C. Then, the obtained solution was lyophilized to obtain an amorphous form of the compound of formula I (yield: 95%, 0.95 gm). Purity: 99.8%; PSD (d90): 50 - 80 μm

[0204] Example - 2​​​​​All references and patent publications cited herein are incorporated herein by reference.

Claims

1. The solid form of the compound of formula I, 【Chemistry 1】 The aforementioned solid form is A. i) X-ray powder diffraction (XRPD) spectrum showing characteristic peaks at 6.0±0.2, 8.1±0.2 and 17.3±0.2°2θ. ii) The X-ray powder diffraction spectrum (XRPD) substantially shown in Figure 1, iii) A differential scanning calorimetry (DSC) plot showing endothermic peaks at approximately 111°C and approximately 141.7°C, or iv) Crystal morphology M-1 characterized by any combination of the above; B. v) X-ray powder diffraction spectrum (XRPD) showing characteristic peaks at 6.9±0.2, 10.6±0.2, 16.6±0.2, 19.2±0.2 and 20.4±0.2°2θ. vi) The X-ray powder diffraction spectrum (XRPD) substantially shown in Figure 2, vii) A differential scanning calorimetry (DSC) plot showing an endothermic peak at approximately 144°C, or viiii) Crystal morphology M-2 characterized by any combination of the above; C. v) X-ray powder diffraction spectrum (XRPD) showing characteristic peaks at 7.1±0.2, 13.3±0.2, 17.6±0.2 and 21.8±0.2°2θ. vi) The X-ray powder diffraction spectrum (XRPD) substantially shown in Figure 3, vii) A differential scanning calorimetry (DSC) plot showing an endothermic peak at approximately 113°C, or viiii) Crystal morphology M-3 characterized by any combination of the above; D. vii) X-ray powder diffraction (XRPD) spectrum showing characteristic peaks at 8.8±0.2, 11.3±0.2, 17.8±0.2, 19.0±0.2, 23.1±0.2 and 25.8±0.2°2θ. viiii) The X-ray powder diffraction spectrum (XRPD) substantially shown in Figure 4, ix) Differential scanning calorimetry (DSC) plots substantially shown in Figure 5, x) A differential scanning calorimetry (DSC) plot showing an endothermic peak at approximately 107°C, or xi) Crystal morphology M-4 characterized by any combination of the above; E. v) X-ray powder diffraction spectrum (XRPD) showing characteristic peaks at 4.3±0.2, 7.8±0.2, 10.2±0.2, 16.3±0.2 and 16.8±0.2°2θ. vi) The X-ray powder diffraction spectrum (XRPD) substantially shown in Figure 6, vii) A differential scanning calorimetry (DSC) plot showing an endothermic peak at approximately 148°C, or viiii) Crystal morphology M-5 characterized by any combination of the above; F. v) X-ray powder diffraction spectrum (XRPD) showing characteristic peaks at 5.6±0.2, 9.7±0.2 and 19.8±0.2°2θ. vi) The X-ray powder diffraction spectrum (XRPD) substantially shown in Figure 7, vii) A differential scanning calorimetry (DSC) plot showing endothermic peaks at approximately 87°C, 112°C, and 142°C, or viiii) Crystal morphology M-6 characterized by any combination of the above; G. vi) X-ray powder diffraction (XRPD) spectrum showing characteristic peaks at 4.3±0.2, 8.7±0.2, 10.6±0.2, 16.4±0.2 and 18.5±0.2°2θ. vii) The X-ray powder diffraction spectrum (XRPD) substantially shown in Figure 8, viiii) A differential scanning calorimetry (DSC) plot containing an endothermic peak at approximately 100°C, or ix) Crystal morphology M-7 characterized by any combination of the above; H. vi) X-ray powder diffraction spectrum (XRPD) showing characteristic peaks at 4.6±0.2, 9.3±0.2, 12.3±0.2, 15.5±0.2 and 17.0±0.2°2θ. vii) The X-ray powder diffraction spectrum (XRPD) substantially shown in Figure 9, viiii) A differential scanning calorimetry (DSC) plot showing an onset at approximately 127°C and an endothermic peak at approximately 133°C, or ix) Crystal morphology M-8 characterized by any combination of the above; I. vi) X-ray powder diffraction (XRPD) spectra showing characteristic peaks at 11.5±0.2, 13.3±0.2, 15.6±0.2, 17.9±0.2, 19.0±0.2, 23.2±0.2 and 25.8±0.2°2θ. vii) The X-ray powder diffraction spectrum (XRPD) substantially shown in Figure 10, viiii) A differential scanning calorimetry (DSC) plot showing an onset at approximately 108°C and an endothermic peak at approximately 142°C, or ix) Crystal morphology M-9 characterized by any combination of the above; J. The solid form, selected from; an amorphous form characterized by the X-ray powder diffraction spectrum (XRPD) substantially shown in Figure 11.

2. g) Morphology M-1 further includes characteristic XRPD peaks at 4.5±0.2, 7.0±0.2, 10.5±0.2, 12.5±0.2, 14.9±0.2, 15.1±0.2, 15.4±0.2, 16.6±0.2, 18.6±0.2, 19.3±0.2, 20.4±0.2, 25.8±0.2 and 26.4±0.2°2θ, h) Morphology M-2 further includes characteristic XRPD peaks at 4.5±0.2, 12.5±0.2, 14.1±0.2, 14.9±0.2, 15.4±0.2, 17.9±0.2 and 20.8±0.2°2θ, i) Morphology M-3 further includes characteristic XRPD peaks at 4.3±0.2, 11.1±0.2, 15.2±0.2, 15.7±0.2, 16.0±0.2, 17.5±0.2, 18.8±0.2, 20.2±0.2, 21.7±0.2, 23.2±0.2 and 25.7±0.2°2θ, j) Morphology M-4 further includes characteristic XRPD peaks at 11.5±0.2, 12.3±0.2, 19.4±0.2, 22.0±0.2, 23.1±0.2, 24.5±0.2 and 25.9±0.2°2θ, k) Morphology M-5 further includes characteristic XRPD peaks at 7.6±0.2, 12.3±0.2, 17.8±0.2, 19.4±0.2 and 20.6±0.2°2θ, l) The solid morphology according to claim 1, wherein morphology M-6 further includes characteristic XRPD peaks at 15.9±0.2, 17.3±0.2, 18.6±0.2 and 20.3±0.2°2θ.

3. A process for preparing a crystalline form M-1 of the compound of formula I according to claim 1 or claim 2, wherein the process is: a) Dissolving the compound of formula I in one or more solvents, b) Heating the reaction mixture, c) Cooling the heated mixture obtained in step b), d) Optionally, seed the reaction mixture with the crystalline form M-1 of the compound of formula I, e) A process comprising, optionally, isolating the crystalline form M-1 of the compound of formula I.

4. A process for preparing a crystalline form M-2 of the compound of formula I according to claim 1 or claim 2, wherein the process is: a) Mixing a racemic compound of formula I in one or more solvents, b) Stirring the reaction mixture, c) Isolating the obtained solid, d) To obtain the desired isomer of the crystalline form M-2 of the compound of formula I, e) A process comprising, optionally, isolating the crystalline form M-2 of the compound of formula I.

5. A process for preparing a crystalline form M-2 of the compound of formula I according to claim 1 or claim 2, the process comprising heating the compound of formula I to obtain a crystalline form M-2 of the compound of formula I.

6. A process for preparing a crystalline form M-3 of the compound of formula I according to claim 1 or claim 2, wherein the process is: a) Dissolving the compound of formula I in one or more solvents, b) Heating the reaction mixture, c) A process comprising, optionally, isolating the crystalline form M-3 of the compound of formula I.

7. A process for preparing a crystalline form M-4 of the compound of formula I according to claim 1 or claim 2, wherein the process is: a) Dissolving the compound of formula I in a mixture of solvents, b) Heating the reaction mixture, c) Crystallizing the reaction mixture, d) A process comprising, optionally, isolating the crystalline form M-4 of the compound of formula I.

8. A process for preparing a crystalline form M-4 of the compound of formula I according to claim 1 or claim 2, wherein the process is: a) Dissolving the compound of formula I in one or more solvents, b) Stirring the reaction mixture, c) A process comprising, optionally, isolating the crystalline form M-4 of the compound of formula I.

9. A process for preparing a crystalline form M-4 of the compound of formula I according to claim 1 or claim 2, the process comprising heating a crystalline form M-3 of the compound of formula I to obtain a crystalline form M-4 of the compound of formula I.

10. A process for preparing a crystalline form M-5 of the compound of formula I according to claim 1 or claim 2, wherein the process is: a) Dissolving the compound of formula I in one or more solvents, b) Stirring the reaction mixture at ambient temperature, c) A process comprising, optionally, isolating the crystalline form M-5 of the compound of formula I.

11. A process for preparing a crystalline form M-6 of the compound of formula I according to claim 1 or claim 2, wherein the process is: a) Dissolving the compound of formula I in one or more solvents under liquid nitrogen conditions to obtain a solid mass, b) Maintaining the solid mass at room temperature to obtain a clear solution, c) A process comprising, optionally, isolating the crystalline form M-6 of the compound of formula I.

12. A process for preparing the crystalline form M-7 of the compound of formula I described in claim 1, wherein the process is: e) Dissolving the compound of formula I in one or more solvents, f) Heating the reaction mixture obtained in step a), g) Evaporate the solvent to obtain crystalline form M-7, h) A process comprising, optionally, isolating the crystalline form M-7 of the compound of formula I.

13. A process for preparing the crystalline form M-8 of the compound of formula I described in claim 1, wherein the process is: a) Dissolving the compound of formula I in a mixture of solvents, b) Heating the reaction mixture from step a), c) Cooling the reaction mixture obtained from step b), d) A process comprising, optionally, isolating the crystalline form M-8 of the compound of formula I.

14. A process for preparing the crystalline form M-9 of the compound of formula I described in claim 1, wherein the process is: a) Dissolving the compound of formula I in one or more solvents under liquid nitrogen conditions to obtain a solid mass, b) Maintaining the solid mass at room temperature to obtain a clear solution, c) A process comprising isolating the crystalline form M-9 of the compound of formula I.

15. A process for preparing an amorphous form of the compound of formula I described in claim 1, wherein the process is: a) To provide a solution of the compound of formula I in one or more solvents, b) Freeze-dry the solution obtained in step a), c) A process comprising, optionally, isolating the amorphous form of the compound of formula I.

16. A process for preparing an amorphous form of the compound of formula I described in claim 1, wherein the process is: d) To provide a solution of the compound of formula I in one or more solvents, e) Removing the solvent, f) A process comprising, optionally, isolating the amorphous form of the compound of formula I.

17. The process according to any one of claims 3 to 16, wherein the compound of formula I provided in step a) is selected from amorphous form, crystalline form, or a mixture thereof.

18. A process for preparing a premix of a compound of formula I, wherein the process is: d) Mixing one or more pharmaceutically acceptable excipients, a compound of formula I according to claim 1 or claim 2, and one or more solvents, e) Removing the solvent, f) A process comprising, optionally, isolating a premix of the compound of formula I.

19. A pharmaceutical composition comprising the solid form of the compound according to claim 1 or claim 2, and a pharmaceutically acceptable excipient.

20. The solid form of the compound of formula I according to claim 1 or claim 2, wherein the solid form substantially does not include any other solid form of the compound of formula I.

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