A solid form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide used to treat kidney disease

Abstract

The present disclosure is directed, in part, to crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide and pharmaceutical compositions thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 243,813, filed September 14, 2021, and Chinese Application No. 202111049581.4, filed September 8, 2021, the entire contents of each of which are incorporated by reference as if each were a part of this specification. [Background technology]

[0002] Chronic kidney disease is characterized by a gradual decline in kidney function over months to years. Chronic kidney disease affected 753 million people worldwide in 2016 and caused 1.2 million deaths in 2015. The most common causes of death are diabetes, hypertension, and glomerulonephritis. Early treatments include, for example, medications to lower blood pressure, blood sugar, and cholesterol, and dietary modifications, but in severe cases, hemodialysis, peritoneal dialysis, and kidney transplants are required for survival. Therefore, there is a continuing need for the development of therapeutic agents, e.g., small molecule drugs, for the treatment of kidney disease.

[0003] Polymorphism is the ability of a substance to crystallize in more than one crystal lattice arrangement. Crystallization, or polymorphism, can affect many aspects of a drug's solid-state properties. A crystalline substance can be significantly different from its amorphous form, and different crystalline modifications of a substance can differ significantly from each other in many ways, including solubility, dissolution rate, and / or bioavailability. In general, it is difficult to predict whether a compound will form crystalline solid forms. It is even more difficult to predict the physical and pharmaceutical properties of these crystalline solid forms. Therefore, in certain formulations and / or manufacturing processes, it is advantageous to have a crystalline form of a therapeutic agent. Summary of the Invention [Means for solving the problem]

[0004] The present disclosure is directed, at least in part, to crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide and its stereoisomers, as well as crystalline anhydrates, hydrates and solvates thereof.

[0005] For example, disclosed herein is a powder X-ray diffraction pattern having characteristic peaks at about 10.3 degrees 2θ, e.g., a powder X-ray diffraction pattern having characteristic peaks at about 10.3, 15.9, and 20.6 degrees 2θ, e.g., a powder X-ray diffraction pattern having characteristic peaks at about 10.3, 15.9, 17.7, 20.6, 21.4, and 26.1 degrees 2θ. For example, a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 10.3, 14.9, 15.9, 17.7, 18.9, 20.6, 21.4, 21.8, 26.1, 29.7, 33.0 and 39.3 degrees 2θ.

[0006] 5-(3,4-Dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, for example, is an ATP-binding cassette transporter A1 protein (ABCA1) inducer (e.g., stabilizes the expression level and / or activity of ABCA1 in the cell membrane) and has the following formula: JPEG2024533420000002.jpg2853

[0007] Further contemplated herein are pharmaceutical compositions comprising the disclosed crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide and a pharma- ceutically acceptable excipient, e.g., a composition formulated for oral administration. Further contemplated herein are drugs that contain at least a detectable amount of the disclosed forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide. For example, disclosed herein are drugs that contain a substantially pure crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide.

[0008] Also provided herein is a method of treating kidney disease in a patient in need thereof comprising administering to the patient an effective amount of the disclosed crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide. For example, provided herein is a method of treating kidney disease in a patient in need thereof comprising administering to the patient an effective amount of a pharmaceutical composition comprising the disclosed crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide. [Brief description of the drawings]

[0009] [Figure 1] Figure 2 shows the powder X-ray diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous (Form E). [Figure 1A] Figure 2 shows the powder X-ray diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous (Form E). [Diagram 2] 1 shows characterization of Form E by differential scanning calorimetry (DSC). [Diagram 3] 1 shows the thermogravimetric analysis (TGA) profile of Form E. [Figure 4] 1 shows the dynamic vapor sorption (DVS) profile of Form E. [Diagram 5] FIG. 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous (Form A). [Figure 5A] FIG. 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous (Form A). [Figure 6] 1 shows characterization of Form A by differential scanning calorimetry (DSC). [Figure 7] 1 shows a thermogravimetric analysis (TGA) profile of Form A. [Figure 8] 1 shows the dynamic vapor sorption (DVS) profile of Form A. [Figure 9] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, monohydrate (Form B). [Figure 9A] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, monohydrate (Form B). [Figure 10] 1 shows characterization of Form B by differential scanning calorimetry (DSC). [Figure 11] 1 shows a thermogravimetric analysis (TGA) profile of Form B. [Figure 12] Figure 2 shows the powder X-ray diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous (Form C). [Figure 13] 1 shows characterization of Form C by differential scanning calorimetry (DSC). [Figure 14] 1 shows a thermogravimetric analysis (TGA) profile of Form C. [Figure 15] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous (Form D). [Figure 16] 1 shows characterization of Form D by differential scanning calorimetry (DSC). [Figure 17] 1 shows the thermogravimetric analysis (TGA) profile of Form D. [Figure 18] 1 shows the dynamic vapor sorption (DVS) profile of Form D. [Figure 19] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (Form F). [Figure 19A] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (Form F). [Figure 20] 1 shows characterization of Form F by differential scanning calorimetry (DSC). [Figure 21] 1 shows the thermogravimetric analysis (TGA) profile of Form F. [Figure 22] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, diisopropylamine monosolvate (Form G). [Figure 22A] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, diisopropylamine monosolvate (Form G). [Figure 23]1 shows the characterization of Form G by Differential Scanning Calorimetry (DSC). [Figure 24] 1 shows the thermogravimetric analysis (TGA) profile of Form G. [Diagram 25] Figure 2 shows the powder X-ray diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous (Form H). [Figure 26] 1 shows characterization of Form H by differential scanning calorimetry (DSC). [Figure 27] 1 shows the thermogravimetric analysis (TGA) profile of Form H. [Figure 28] 1 shows the dynamic vapor sorption (DVS) profile of Form H. [Figure 29] FIG. 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous (Form I). [Figure 29A] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous (Form I). [Diagram 30] 1 shows characterization of Form I by differential scanning calorimetry (DSC). [Diagram 31] 1 shows the thermogravimetric analysis (TGA) profile of Form I. [Diagram 32] 1 shows the dynamic vapor sorption (DVS) profile of Form I. [Diagram 33] Figure 2 shows the powder X-ray diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, ethanol solvate (Form J). [Diagram 34]Figure 2 shows the powder X-ray diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, methanol solvate (Form K). [Diagram 35] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (form L). [Diagram 36] 1 shows characterization of Form L by differential scanning calorimetry (DSC). [Figure 37] 1 shows the thermogravimetric analysis (TGA) profile of Form L. [Figure 38] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (Form M). [Figure 39] 1 shows characterization of Form M by differential scanning calorimetry (DSC). [Diagram 40] 1 shows the thermogravimetric analysis (TGA) profile of Form M. [Diagram 41] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (form N). [Diagram 42] 1 shows characterization of Form N by differential scanning calorimetry (DSC). [Diagram 43] 1 shows the thermogravimetric analysis (TGA) profile of Form N. [Diagram 44] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (form O). [Diagram 45] 1 shows characterization of form O by differential scanning calorimetry (DSC). [Figure 46] 1 shows the thermogravimetric analysis (TGA) profile of Form O. [Figure 47] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, methanol solvate (Form P). [Figure 48] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, acetonitrile solvate (Form Q). [Figure 49] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, 1,4-dioxane solvate (Form R). [Figure 50] Figure 2 shows the powder X-ray diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, trifluoroethanol solvate (Form S). [Figure 51] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (form T). [Figure 52] 1 shows characterization of Form T by differential scanning calorimetry (DSC). [Diagram 53] 1 shows the thermogravimetric analysis (TGA) profile of Form T. [Figure 54] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (form U). [Figure 55] 1 shows characterization of form U by differential scanning calorimetry (DSC). [Figure 56] 1 shows the thermogravimetric analysis (TGA) profile of Form U. [Figure 57] FIG. 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (Form V). [Figure 58] 1 shows characterization of Form V by differential scanning calorimetry (DSC). [Figure 59] 1 shows the thermogravimetric analysis (TGA) profile of Form V. [Figure 60] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (form W). [Figure 61] 1 shows characterization of Form W by differential scanning calorimetry (DSC). [Figure 62] 1 shows the thermogravimetric analysis (TGA) profile of Form W. [Figure 63] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, dioxane solvate (Form X). [Figure 64] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, ethanol solvate (Form Y). [Figure 65] Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, isopropanol solvate (Form Z). [Figure 66]Figure 2 shows the X-ray powder diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, tetrahydrofuran solvate (Form AA). [Figure 67] Figure 2 shows the powder X-ray diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous (Form 2). [Figure 68] 1 shows characterization of Form 2 by differential scanning calorimetry (DSC). [Figure 69] 1 shows a thermogravimetric analysis (TGA) profile of Form 2. [Figure 70] 1 shows the dynamic vapor sorption (DVS) profile of Form 2. [Figure 71] FIG. 1 shows the powder X-ray diffraction (XRPD) pattern of amorphous 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide. [Figure 72] FIG. 1 shows the powder X-ray diffraction (XRPD) pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide / sorbic acid co-crystal (4:1 molar ratio). [Figure 73] FIG. 1 shows the differential scanning calorimetry (DSC) profile of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide / sorbic acid co-crystal (4:1 molar ratio). [Figure 74] FIG. 1 shows the thermogravimetric analysis (TGA) profile of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide / sorbic acid co-crystal (4:1 molar ratio). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The features and other details of the present disclosure will now be described in more detail.Before further description of the present disclosure, certain terms employed in the present specification, examples and appended claims are collected here.These definitions should be read in light of the remaining parts of the present disclosure as understood by those skilled in the art.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0011] definition The term "crystalline form" refers to a crystalline form or modification that can be characterized by analytical methods such as, for example, X-ray powder diffraction (XRPD) and / or differential scanning calorimetry (DSC). The crystalline compounds disclosed herein can exist in unsolvated forms as well as solvated forms with solvents such as water, ethanol, etc. Unless otherwise indicated or inferred, the crystalline compounds disclosed are intended to include both solvated and unsolvated forms.

[0012] "Treating" includes any effect that results in the improvement of a condition, disease, disorder, or the like, for example, alleviating, reducing, modulating, or eliminating.

[0013] The term "disorder" refers to, and is used interchangeably with, the terms "disease," "condition," or "illness," unless otherwise indicated.

[0014] "Pharmaceutically or pharmacologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to animals or humans. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by the Office of Biologics of the FDA.

[0015] As used herein, the term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to any solvent, dispersion medium, coating, isotonicity agent, absorption delaying agent, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

[0016] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one compound disclosed herein formulated together with one or more pharma- ceutically acceptable excipients.

[0017] "Individual", "patient", or "subject" are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans. The compounds of the present disclosure may be administered to mammals, such as humans, but also to other mammals, such as animals in need of veterinary treatment, for example, livestock animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). The mammal treated in the methods of the present disclosure is desirably a mammal in which treatment of, for example, kidney disease, cancer, or blood disease is desired. "Modulation" includes antagonism (e.g., inhibition), agonism, partial antagonism, and / or partial agonism.

[0018] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a subject compound that elicits a biological or medical response in a tissue, system, or animal (e.g., a mammal or human) that is desired by a researcher, veterinarian, medical doctor, or other clinician. The compounds of the present disclosure are administered in a therapeutically effective amount to treat a disease. Alternatively, a therapeutically effective amount of a compound is the amount necessary to achieve a desired therapeutic and / or prophylactic effect.

[0019] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts of basic groups that may be present in the compounds used in the compositions. Compounds contained in the compositions that are basic can form a wide variety of salts with various inorganic and organic acids.

[0020] In this disclosure, the term "and / or" means either "and" or "or," unless otherwise stated.

[0021] As used herein, the terms "a" and "an" are meant to include one or more, unless otherwise specified. For example, the term "an agent" includes both a single agent and a combination of two or more agents.

[0022] When the term "about" is used before a quantitative value, the disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" means ±10% variation from the nominal value, unless otherwise indicated or inferred. The term "about" in the context of a peak at 2θ degrees means that there is an uncertainty in the measurement of 2θ of ±0.5 (expressed in 2θ) or that there is an uncertainty in the measurement of 2θ of ±0.2 (expressed in 2θ). In general, DSC thermograms can vary in a range of ±3°C. Thus, temperature values ​​should be understood to include values ​​in a range of about ±3°C.

[0023] Generally, provided herein are crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide substantially free of other crystalline forms, unless otherwise indicated. As used herein, "substantially free" or "substantially free of other crystalline forms" means that the disclosed crystalline forms contain no more than about 20%, no more than about 10%, no more than about 5%, no more than about 2%, no more than about 1% of other crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, e.g., as measured by XRPD, or contain less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1% of other crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, e.g., as measured by XRPD. Thus, the disclosed crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, which are described herein as being substantially free of other crystalline forms, will be understood to contain greater than 80% (w / w), greater than 90% (w / w), greater than 95% (w / w), greater than 98% (w / w) or greater than 99% (w / w) of said crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide. Thus, in some embodiments, the disclosed crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide may contain 1% to 20% (w / w), 5% to 20% (w / w), or 5% to 10% (w / w) of one or more other crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide.

[0024] Crystal morphology The present disclosure is directed, at least in part, to a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide.

[0025] For example, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.3 degrees 2θ (referred to herein as “Form E”).

[0026] In one embodiment, the crystalline form E of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 10.3 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 14.9 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 15.9 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 17.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.9 degrees 2θ. In another embodiment, crystalline form E is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 10.3, 15.9, and 20.6 degrees 2θ, ... In a further embodiment, crystalline form E is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 10.3, 15.9, 17.7, 20.6, 21.4, and 26.1 degrees 2θ. In yet another embodiment, crystalline form E is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 10.3, 14.9, 15.9, 17.7, 18.9, 20.6, 21.4, 21.8, 26.1, 29.7, 33.0, and 39.3 degrees 2θ.In another embodiment, crystalline form E is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 10.3, 14.9, 15.9, 17.7, 18.9, 20.6, 21.4, 21.8, 23.3, 25.2, 26.1, 26.7, 29.7, 28.0, 33.0, 36.1, 37.2, and 39.3 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 1. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0027] In one embodiment, crystalline form E of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous is characterized by a powder X-ray diffraction pattern having a characteristic peak at about 10.2 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 17.6 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 18.3 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 19.0 degrees 2θ; characterized by a powder X-ray diffraction pattern having a characteristic peak at about 19.3 degrees 2θ. In another embodiment, crystalline form E is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 19.3, 21.6, and 21.9 degrees 2θ. In a further embodiment, crystalline form E is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at degrees 2θ at about 19.3, 21.0, 21.6, 21.9, 23.4, and 24.0. In yet another embodiment, crystalline form E is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at degrees 2θ at about 10.2, 17.6, 18.3, 19.0, 19.3, 21.0, 21.6, 21.9, 23.4, 23.6, 24.0, and 26.1.In another embodiment, crystalline form E is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.1, 10.2, 15.8, 17.6, 18.3, 19.0, 19.3, 20.7, 21.0, 21.6, 21.9, 23.4, 23.6, 24.0, 26.1, 27.8, 29.5, and 32.3 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 1A. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0028] The postulated crystalline form E of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 168° C. and a peak at about 169° C. For example, form E can be characterized by the differential scanning calorimetry profile shown in FIG.

[0029] The assumed crystalline form E of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous can be characterized by a thermogravimetric analysis (TGA) profile that exhibits a mass loss of about 0.6% by weight up to about 150° C. ( FIG. 3 ). In some embodiments, crystalline form E can be characterized by a dynamic vapor sorption (DVS) profile that exhibits a reversible total mass change of about 0.3% by weight between about 0 and about 90% relative humidity (RH) at 25° C. ( FIG. 4 ).

[0030] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.4 degrees 2θ (herein referred to as “Form A”).

[0031] In one embodiment, crystalline Form A of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.5 degrees 2θ. and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.4 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.1 degrees 2θ. In another embodiment, crystalline form A is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 8.4, 11.7, 14.9, 15.8, 17.5, 18.4, 19.1, 20.4, 21.6, 22.2, 23.4, and 25.1 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 5. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0032] In one embodiment, crystalline Form A of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.3 degrees 2θ. In another embodiment, crystalline Form A is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 8.4, 9.5, 17.5, 18.1, 18.3, 19.1, 20.0, 20.4, 20.6, 21.0, 21.7, and / or 22.2 degrees 2θ. For example, a contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 5 A. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0033] The postulated crystalline form A of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset and peak at about 164° C. and a characteristic endotherm with an onset at about 168° C. and a peak at about 169° C. For example, form A can be characterized by the differential scanning calorimetry profile shown in FIG.

[0034] The assumed crystalline form A of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous can be characterized by a thermogravimetric analysis (TGA) profile that exhibits a mass loss of about 0.33% by weight up to about 180° C. ( FIG. 7 ). In some embodiments, crystalline form A can be characterized by a dynamic vapor sorption (DVS) profile that exhibits a reversible total mass change of about 1.8% by weight between about 0 and about 90% relative humidity (RH) at 25° C. ( FIG. 8 ).

[0035] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, monohydrate, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.0 degrees 2θ (herein referred to as “Form B”).

[0036] In one embodiment, crystalline form B of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, monohydrate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.4 degrees 2θ. and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 29.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 32.7 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 34.0 degrees 2θ. In another embodiment, crystalline form B is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.5, 11.2, 13.0, 17.2, 19.4, 22.5, 23.4, 26.0, 28.2, 29.8, 32.7, and 34.0 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 9. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0037] In one embodiment, crystalline form B of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, monohydrate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.3 degrees 2θ. and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.0 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.1 degrees 2θ. In another embodiment, crystalline form B is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.4, 12.9, 17.0, 19.1, 19.3, 20.2, 21.6, 23.6, 24.8, 25.7, 27.0, and 28.1 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 9A. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0038] The assumed crystalline form B of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, monohydrate can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 74° C. and a peak at about 87° C., a characteristic endotherm with an onset of about 163° C. and a peak at about 164° C., a characteristic exotherm with an onset and peak at about 165° C., and a characteristic endotherm with an onset of about 168° C. and a peak at about 169° C. Form B can be characterized, for example, by the differential scanning calorimetry profile shown in FIG. 10.

[0039] The assumed crystalline form B of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, monohydrate can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.5% by weight up to about 120° C. ( FIG. 11 ). In some embodiments, crystalline form B can be characterized by a Karl Fischer (KF) analysis showing 3.8% water by weight (1.02 equivalents by molar ratio).

[0040] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.9 degrees 2θ (herein referred to as “Form C”).

[0041] In one embodiment, crystalline Form C of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.0 degrees 2θ; In another embodiment, crystalline form C is characterized by an X-ray powder diffraction pattern having one or more characteristic peaks at about 5.1, 5.3, 6.9, 9.0, 18.0, 18.8, 19.7, 20.3, 20.9, 22.2, 23.5, and / or 24.4 degrees 2θ. For example, the contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 12. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0042] The assumed crystalline form C of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 144° C., a characteristic endotherm with an onset of about 164° C., and a characteristic endotherm with an onset of about 168° C. For example, form C can be characterized by the differential scanning calorimetry profile shown in FIG. 13. In some embodiments, form C can be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 0.1 wt % up to about 130° C. (FIG. 14).

[0043] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.1 degrees 2θ (herein referred to as “Form D”).

[0044] In one embodiment, the crystalline form D of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.1 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 11.8 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 19.1 degrees 2θ, and an X-ray powder diffraction pattern having a characteristic peak at about 19.4 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.0 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.1 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.8 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.1 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.9 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.4 2θ degrees, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.6 2θ degrees, and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.6 2θ degrees. In another embodiment, crystalline form D is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.1, 11.8, 19.1, 19.4, 21.0, 22.1, 22.8, 23.1, 24.9, 26.4, 26.6, and 27.6 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 15. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0045] The postulated crystalline form D of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 152° C., a characteristic endotherm with an onset of about 165° C., and a characteristic endotherm with an onset of about 168° C. For example, form D can be characterized by the differential scanning calorimetry profile shown in FIG.

[0046] The assumed crystalline form D of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.16% by weight up to about 150° C. ( FIG. 17 ). In some embodiments, crystalline form D can be characterized by a dynamic vapor sorption (DVS) profile showing a reversible total mass change of about 20% by weight between about 0 and about 90% relative humidity (RH) at 25° C. ( FIG. 18 ).

[0047] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.2 degrees 2θ (herein referred to as “Form F”).

[0048] In one embodiment, crystalline form F of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.3 degrees 2θ. , an X-ray powder diffraction pattern having a characteristic peak at about 16.7 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 18.0 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 21.1 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 21.4 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 24.0 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 25.3 degrees 2θ, and / or an X-ray powder diffraction pattern having a characteristic peak at about 26.2 degrees 2θ. In another embodiment, crystalline form F is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.0, 8.3, 11.6, 12.0, 13.3, 16.7, 18.0, 21.1, 21.4, 24.0, 25.3, and 26.2 degrees 2θ. For example, the contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 19. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0049] In one embodiment, crystalline form F of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.8 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 29.7 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 31.7 degrees 2θ. In another embodiment, crystalline form F is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.0, 13.2, 17.0, 18.1, 19.8, 21.1, 23.2, 23.9, 25.2, 26.1, 29.7, and 31.7 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 19A. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0050] The postulated crystalline form F of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate is characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 87° C. and a peak at about 100° C., a characteristic endotherm with an onset of about 164° C. and a peak at about 165° C., and a characteristic endotherm with an onset of about 168° C. and a peak at about 169° C. For example, form F can be characterized by the differential scanning calorimetry profile shown in FIG. 20.

[0051] The assumed crystalline form F of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 4.1% by weight up to about 150° C. ( FIG. 21 ). In some embodiments, crystalline form F can be characterized by a Karl Fischer (KF) analysis showing 5.0% water by weight (1.35 equivalents by molar ratio).

[0052] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, diisopropylamine monosolvate, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 18.2 degrees 2θ (herein referred to as “Form G”).

[0053] In one embodiment, crystalline form G of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, diisopropylamine monosolvate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.5 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.4 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.2 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.8 degrees 2θ. In another embodiment, crystalline form G is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.3, 9.0, 13.4, 15.5, 16.4, 18.2, 18.5, 19.1, 20.3, 20.8, 22.2, and 27.8 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 22. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0054] In one embodiment, the crystalline form G of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, diisopropylamine monosolvate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.8 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.0 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.0 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 31.7 degrees 2θ. In another embodiment, crystalline form G is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.3, 16.4, 18.2, 19.8, 20.0, 20.8, 21.7, 22.2, 22.4, 25.4, 27.0, and 31.7 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 22A. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0055] The postulated crystalline form G of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, diisopropylamine monosolvate can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 88° C. and a peak at about 93° C., and a characteristic endotherm with an onset and peak at about 164° C. For example, form G can be characterized by the differential scanning calorimetry profile shown in FIG. 23. In some embodiments, form G can be characterized by a thermogravimetric analysis (TGA) profile exhibiting a mass loss of about 3.9% by weight up to about 150° C. (FIG. 24).

[0056] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.5 degrees 2θ (herein referred to as “Form H”).

[0057] In one embodiment, the crystalline form H of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.9 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.0 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 31.7 degrees 2θ. In another embodiment, crystalline form H is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 9.2, 12.1, 18.8, 19.1, 19.9, 20.5, 21.9, 22.5, 22.8, 24.5, 26.0, and 31.7 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 25. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0058] The postulated crystalline form H of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic exotherm with an onset of about 120° C., a characteristic endotherm with an onset of about 136° C., a characteristic endotherm with an onset of about 164° C., and a characteristic endotherm with an onset of about 169° C. For example, form H can be characterized by the differential scanning calorimetry profile shown in FIG. 26.

[0059] The assumed crystalline form H of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.11% by weight up to about 120° C. (FIG. 27). In some embodiments, crystalline form H can be characterized by a dynamic vapor sorption (DVS) profile showing a total mass change of about 2.5% by weight between about 0 and about 70% relative humidity (RH) at 25° C., and a total mass change of about 25% by weight between about 70 and about 90% relative humidity (RH) at 25° C. (FIG. 28).

[0060] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.7 degrees 2θ (herein referred to as “Form I”).

[0061] In one embodiment, crystalline Form I of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.7 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.1 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.5 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 36.9 degrees 2θ. In another embodiment, crystalline Form I is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 9.2, 12.1, 18.8, 19.1, 19.9, 20.5, 21.9, 22.5, 22.8, 24.5, 26.0, and 31.7 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 29. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0062] In one embodiment, crystalline Form I of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.0 degrees 2θ. and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.1 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.5 degrees 2θ. In another embodiment, crystalline form I is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.5, 12.7, 17.6, 19.2, 20.0, 21.3, 22.8, 23.4, 24.3, 24.8, 26.1, and 28.5 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 29A. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0063] The postulated crystalline Form I of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 154° C., a characteristic exotherm with an onset of about 156° C., a characteristic endotherm with an onset of about 164° C., and a characteristic endotherm with an onset of about 168° C. For example, Form I can be characterized by the differential scanning calorimetry profile shown in FIG.

[0064] The assumed crystalline form I of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.1% by weight up to about 120° C. (FIG. 31). In some embodiments, crystalline form I can be characterized by a dynamic vapor sorption (DVS) profile showing a total mass change of about 10% by weight between about 0 and about 90% relative humidity (RH) at 25° C. (FIG. 32).

[0065] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, ethanol solvate, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 19.6 degrees 2θ (herein referred to as “Form J”).

[0066] In one embodiment, crystalline form J of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, ethanol solvate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.6 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.9 degrees 2θ. and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.4 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 40.5 degrees 2θ. In another embodiment, the crystalline form J is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 11.5, 16.9, 19.2, 19.6, 19.9, 23.7, 24.1, 24.4, 24.6, 25.0, 26.4, and 40.5 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 33. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0067] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, methanol solvate, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.2 degrees 2θ (herein referred to as “Form K”).

[0068] In one embodiment, the crystalline form K of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, methanol solvate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.0 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.7 degrees 2θ. and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.6 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.2 degrees 2θ. In another embodiment, the crystalline form K is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.2, 12.0, 12.8, 17.0, 18.7, 19.5, 20.2, 24.5, 24.9, 25.8, 26.6, and 27.2 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 34. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0069] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.5 degrees 2θ (herein referred to as “Form L”).

[0070] In one embodiment, crystalline form L of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.0 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.1 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 38.2 degrees 2θ. In another embodiment, crystalline form L is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.3, 12.5, 18.1, 18.8, 20.0, 23.1, 25.1, 25.5, 26.1, 27.7, 28.1, and 38.2 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 35. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0071] The assumed crystalline form L of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 35° C. and a peak at about 56° C., a characteristic endotherm with an onset of about 90° C. and a peak at about 95° C., a characteristic exotherm with an onset of about 97° C. and a peak at about 100° C., a characteristic endotherm with an onset and peak at about 164° C., and a characteristic endotherm with an onset of about 168° C. and a peak at about 169° C. For example, form L can be characterized by the differential scanning calorimetry profile shown in FIG. 36.

[0072] The postulated crystalline form L of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 2.2% by weight up to about 120° C. ( FIG. 37 ). In some embodiments, crystalline form L can be characterized by a Karl Fischer (KF) analysis showing 4.4% water by weight (1.18 equivalents by molar ratio).

[0073] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.7 degrees 2θ (herein referred to as “Form M”).

[0074] In one embodiment, the crystalline form M of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.2 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.2 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 34.3 degrees 2θ. In another embodiment, crystalline form M is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 8.5, 14.5, 17.7, 20.9, 21.2, 21.6, 22.7, 23.8, 24.3, 24.5, 25.2, and 34.3 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 38. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0075] The assumed crystalline form M of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 61° C. and a peak at about 77° C., a characteristic exotherm with an onset of about 83° C. and a peak at about 90° C., a characteristic endotherm with an onset of about 147° C. and a peak at about 153° C., a characteristic endotherm with an onset of about 164° C. and a peak at about 165° C., and a characteristic endotherm with an onset and peak at about 169° C. For example, form M can be characterized by the differential scanning calorimetry profile shown in FIG. 39.

[0076] The assumed crystalline form M of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.4% by weight up to about 120° C. ( FIG. 40 ). In some embodiments, crystalline form M can be characterized by a Karl Fischer (KF) analysis showing 3.5% water by weight (0.93 equivalents by molar ratio).

[0077] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.9 degrees 2θ (herein referred to as “Form N”).

[0078] In one embodiment, the crystalline form N of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.9 degrees 2θ. and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 29.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 34.6 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 35.6 degrees 2θ. In another embodiment, the crystalline form N is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 8.2, 12.4, 17.4, 17.6, 17.9, 20.4, 22.4, 23.3, 28.9, 29.0, 34.6, and 35.6 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 41. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0079] The postulated crystalline form N of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 50° C. and a peak at about 98° C., a characteristic endotherm with an onset of about 163° C. and a peak at about 164° C., and a characteristic endotherm with an onset of about 168° C. and a peak at about 169° C. For example, form N can be characterized by the differential scanning calorimetry profile shown in FIG.

[0080] The assumed crystalline form N of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.9% by weight up to about 120° C. ( FIG. 43 ). In some embodiments, the crystalline form N can be characterized by a Karl Fischer (KF) analysis showing 4.2% water by weight (1.13 equivalents by molar ratio).

[0081] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.6 degrees 2θ (herein referred to as “Form O”).

[0082] In one embodiment, crystalline form O of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 15.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.7 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 29.8 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 39.0 degrees 2θ. In another embodiment, crystalline form O is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.6, 11.9, 12.7, 15.1, 17.7, 19.2, 22.0, 22.7, 24.4, 25.2, 29.8, and 39.0 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 44. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0083] The postulated crystalline form O of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 83° C. and a peak at about 88° C., a characteristic exotherm with an onset of about 91° C. and a peak at about 95° C., a characteristic endotherm with an onset of about 164° C. and a peak at about 165° C., and a characteristic endotherm with an onset of about 169° C. and a peak at about 170° C. For example, crystalline form O can be characterized by the differential scanning calorimetry profile shown in FIG. 45.

[0084] The assumed crystalline form O of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 1.5% by weight up to about 160° C. ( FIG. 46 ). In some embodiments, crystalline form O can be characterized by a Karl Fischer (KF) analysis showing 3.2% water by weight (0.85 equivalents by molar ratio).

[0085] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, methanol solvate, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 6.3 degrees 2θ (herein referred to as “Form P”).

[0086] In one embodiment, crystalline form P of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, methanol solvate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.7 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.9 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.7 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 38.8 degrees 2θ. In another embodiment, crystalline form P is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.3, 12.1, 12.5, 12.7, 18.9, 19.6, 19.7, 25.0, 25.5, 27.3, 27.7, and 38.8 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 47. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0087] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, acetonitrile solvate, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 23.8 degrees 2θ (herein referred to as “Form Q”).

[0088] In one embodiment, the crystalline form Q of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, acetonitrile solvate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 14.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.6 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.9 degrees 2θ. and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.5 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.4 degrees 2θ. In another embodiment, crystalline form Q is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.6, 8.4, 14.4, 18.6, 19.9, 20.9, 21.1, 22.7, 23.6, 23.8, 24.5, and 26.4 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 48. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0089] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, 1,4-dioxane solvate, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 22.4 degrees 2θ (herein referred to as “Form R”).

[0090] In one embodiment, the crystalline form R of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, 1,4-dioxane solvate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 11.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.9 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.2 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 29.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 33.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 34.5 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 39.7 degrees 2θ. In another embodiment, crystalline form R is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 11.1, 17.3, 17.5, 17.9, 18.2, 22.4, 23.3, 28.4, 29.1, 33.8, 34.5, and 39.7 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 49. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0091] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, trifluoroethanol solvate, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 22.8 degrees 2θ (herein referred to as “Form S”).

[0092] In one embodiment, the crystalline form S of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, trifluoroethanol solvate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.5 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 12.0 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 17.7 degrees 2θ; an X-ray powder diffraction pattern having a characteristic peak at about 19.2 degrees 2θ; and an X-ray powder diffraction pattern having a characteristic peak at about 21.6 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 30.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 31.6 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 34.3 degrees 2θ. In another embodiment, crystalline form S is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 7.5, 12.0, 17.7, 19.2, 21.6, 22.8, 23.5, 24.4, 25.3, 30.0, 31.6, and 34.3 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 50. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0093] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.2 degrees 2θ (herein referred to as “Form T”).

[0094] In one embodiment, crystalline form T of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 5.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 7.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 9.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 10.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.2 degrees 2θ. , characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.0 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.1 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.4 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.7 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.9 degrees 2θ, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.5 degrees 2θ, and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.3 degrees 2θ. In another embodiment, crystalline form T is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 5.4, 7.0, 9.0, 10.8, 12.2, 13.0, 16.1, 19.4, 19.7, 20.9, 22.5, and 28.3 degrees 2θ. For example, the contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 51. In one embodiment, the X-ray powder diffraction pattern for the crystalline form was obtained using Cu Kα radiation.

[0095] The postulated crystalline form T of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 55° C., a characteristic endotherm with an onset of about 89° C. and a peak at about 98° C., a characteristic endotherm with an onset of about 163° C. and a peak at about 164° C., and a characteristic endotherm with an onset and peak at about 169° C. Form T can be characterized, for example, by the differential scanning calorimetry profile shown in FIG.

[0096] The assumed crystalline form T of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.9% by weight up to about 150° C. ( FIG. 53 ). In some embodiments, the crystalline form T can be characterized by a Karl Fischer (KF) analysis showing 6.7% water by weight (1.85 equivalents by molar ratio).

[0097] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.0 degrees 2θ (herein referred to as “Form U”).

[0098] In one embodiment, crystalline form U of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.9 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.9 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 32.3 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 36.3 degrees 2θ. In another embodiment, crystalline form U is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.0, 12.0, 13.3, 17.9, 18.9, 21.4, 22.0, 24.0, 24.3, 26.3, 32.3, and 36.3 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 54. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0099] The postulated crystalline form U of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 33° C., a characteristic endotherm with an onset of about 92° C. and a peak at about 99° C., a characteristic endotherm with an onset of about 164° C. and a peak at about 165° C., and a characteristic endotherm with an onset and peak at about 169° C. For example, form U can be characterized by the differential scanning calorimetry profile shown in FIG. 55.

[0100] The assumed crystalline form U of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.9% by weight up to about 150° C. ( FIG. 56 ). In some embodiments, crystalline form U can be characterized by a Karl Fischer (KF) analysis showing 5.1% water by weight (1.38 equivalents by molar ratio).

[0101] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.4 degrees 2θ (herein referred to as “Form V”).

[0102] In one embodiment, crystalline Form V of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.4 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 29.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 32.7 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 34.4 degrees 2θ. In another embodiment, crystalline form V is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.5, 13.0, 17.1, 17.4, 19.4, 23.4, 23.7, 26.0, 28.3, 29.2, 32.7, and 34.4 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 57. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0103] The postulated crystalline form V of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 48° C., a characteristic endotherm with a peak at about 90° C. and a peak at about 96° C., a characteristic endotherm with an onset of about 163° C. and a peak at about 165° C., and a characteristic endotherm with an onset and peak at about 169° C. For example, form V can be characterized by the differential scanning calorimetry profile shown in FIG. 58.

[0104] The postulated crystalline form V of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.9% by weight up to about 150° C. ( FIG. 59 ). In some embodiments, crystalline form V can be characterized by a Karl Fischer (KF) analysis showing 7.1% water by weight (1.97 equivalents by molar ratio).

[0105] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.5 degrees 2θ (herein referred to as “Form W”).

[0106] In one embodiment, crystalline form W of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.9 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.5 degrees 2θ. , characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 21.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.7 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.1 degrees 2θ. In another embodiment, crystalline form W is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.2, 12.4, 13.8, 18.9, 19.5, 20.6, 21.8, 24.8, 25.5, 26.4, 27.7, and 28.1 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 60. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0107] The postulated crystalline form W of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 50° C., a characteristic endotherm with an onset of about 98° C. and a peak at about 99° C., a characteristic endotherm with an onset and peak at about 164° C., and a characteristic endotherm with an onset and peak at about 169° C. For example, form W can be characterized by the differential scanning calorimetry profile shown in FIG.

[0108] The postulated crystalline form W of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate can be characterized by a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.9% by weight up to about 150° C. (FIG. 62). In some embodiments, crystalline form W can be characterized by a Karl Fischer (KF) analysis showing 4.5% water by weight (1.21 equivalents by molar ratio).

[0109] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, 1,4-dioxane solvate, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 20.5 degrees 2θ (herein referred to as “Form X”).

[0110] In one embodiment, crystalline form X of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, 1,4-dioxane solvate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 8.1 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 17.3 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 17.5 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 18.3 degrees 2θ, and an X-ray powder diffraction pattern having a characteristic peak at about 18.8 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.6 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.9 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 31.7 degrees 2θ. In another embodiment, crystalline form X is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 8.1, 17.3, 17.5, 18.3, 18.8, 20.5, 22.0, 23.3, 23.7, 24.6, 24.9, and 31.7 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 63. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0111] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, ethanol solvate, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 6.2 degrees 2θ (herein referred to as “Form Y”).

[0112] In one embodiment, crystalline form Y of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, ethanol solvate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.2 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.8 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.4 degrees 2θ. and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 20.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 24.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 25.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 27.7 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.0 degrees 2θ. In another embodiment, crystalline form Y is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.2, 12.3, 18.0, 18.8, 19.4, 20.5, 24.1, 24.8, 25.5, 26.3, 27.7, and 28.0 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 64. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0113] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, isopropanol solvate, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 19.4 degrees 2θ (herein referred to as “Form Z”).

[0114] In one embodiment, crystalline form Z of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, isopropanol solvate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.4 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.5 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 29.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 29.8 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 32.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 34.0 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 34.4 degrees 2θ. In another embodiment, crystalline form Z is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.5, 12.9, 17.1, 19.4, 22.5, 23.4, 26.0, 29.7, 29.8, 32.7, 34.0, and 34.4 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 65. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0115] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, tetrahydrofuran solvate, characterized by an X-ray powder diffraction pattern with a characteristic peak at about 13.0 degrees 2θ (herein referred to as “Form AA”).

[0116] In one embodiment, the crystalline form AA of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, tetrahydrofuran solvate is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 17.1 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 19.4 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 22.5 degrees 2θ. characterized by an X-ray powder diffraction pattern having a characteristic peak at about 23.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 26.0 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 28.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 29.9 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 32.7 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 34.0 degrees 2θ; and / or characterized by an X-ray powder diffraction pattern having a characteristic peak at about 34.6 degrees 2θ. In another embodiment, crystalline form AA is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.5, 13.0, 17.1, 19.4, 22.5, 23.4, 26.0, 28.3, 29.9, 32.7, 34.0, and 34.6 degrees 2θ. For example, a contemplated crystalline form has the X-ray powder diffraction pattern shown in Figure 66. In one embodiment, the X-ray powder diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0117] In another embodiment, disclosed herein is a crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, characterized by an X-ray powder diffraction pattern having a characteristic peak at about 18.7 degrees 2θ (herein referred to as “Form 2”).

[0118] In one embodiment, crystalline Form 2 of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous is characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.3 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 6.5 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 12.4 degrees 2θ; characterized by an X-ray powder diffraction pattern having a characteristic peak at about 13.0 degrees 2θ; and characterized by an X-ray powder diffraction pattern having a characteristic peak at about 16.0 degrees 2θ. , an X-ray powder diffraction pattern having a characteristic peak at about 16.6 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 18.1 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 18.7 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 19.4 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 19.9 degrees 2θ, an X-ray powder diffraction pattern having a characteristic peak at about 25.0 degrees 2θ, and / or an X-ray powder diffraction pattern having a characteristic peak at about 26.0 degrees 2θ. In another embodiment, crystalline Form 2 is characterized by an X-ray powder diffraction pattern having at least one or more characteristic peaks at about 6.3, 6.5, 12.4, 13.0, 16.0, 16.6, 18.1, 18.7, 19.4, 19.9, 25.0, and 26.0 degrees 2θ. For example, the contemplated crystalline form has the powder X-ray diffraction pattern shown in Figure 67. In one embodiment, the powder X-ray diffraction pattern of the crystalline form was obtained using Cu Kα radiation.

[0119] The postulated crystalline Form 2 of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous can be characterized by a differential scanning calorimetry (DSC) profile exhibiting a characteristic endotherm with an onset of about 94° C., a characteristic exotherm with an onset of about 98° C., a characteristic endotherm with an onset of about 165° C., and a characteristic endotherm with an onset and peak at about 169° C. For example, Form 2 can be characterized by the differential scanning calorimetry profile shown in FIG.

[0120] The assumed crystalline Form 2 of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous can be characterized by a thermogravimetric analysis (TGA) profile that exhibits a mass loss of about 0.9% by weight up to about 120° C. (FIG. 69). In some embodiments, crystalline Form 2 can be characterized by a dynamic vapor sorption (DVS) profile that exhibits a reversible total mass change of about 2.1% by weight between about 0 and about 90% relative humidity (RH) at 25° C. (FIG. 70).

[0121] In another embodiment, disclosed herein is a substantially amorphous form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide.

[0122] In further embodiments, disclosed herein are pharmaceutical compositions comprising the disclosed crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, and a pharma- ceutically acceptable excipient. For example, disclosed herein are pharmaceutical compositions comprising 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline form E, and a pharma- ceutically acceptable excipient. In another embodiment, disclosed herein are pharmaceutical compositions formed from the disclosed crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide. For example, disclosed herein is a pharmaceutical composition formed from crystalline form E of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous. In some embodiments, the disclosed pharmaceutical compositions can be formulated for oral administration.

[0123] In yet another embodiment, disclosed herein is a pharmaceutical composition comprising the disclosed amorphous form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide and a pharma- ceutically acceptable excipient.

[0124] In one embodiment, disclosed herein is a drug comprising at least a detectable amount of the disclosed crystalline forms of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide. In another embodiment, disclosed herein is a drug comprising a substantially pure crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide. For example, disclosed herein is a drug consisting of substantially pure crystalline form E of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous.

[0125] composition Another aspect of the present disclosure provides pharmaceutical compositions comprising crystalline compounds as disclosed herein, formulated with a pharmaceutically acceptable excipient. In particular, the present disclosure provides pharmaceutical compositions comprising crystalline compounds as disclosed herein, formulated with one or more pharmaceutically acceptable excipients. These formulations include those suitable for oral, topical (e.g., transdermal), buccal, ocular, parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous), rectal, vaginal or aerosol administration, although the most suitable administration form in any given case will depend on the extent and severity of the condition being treated and the nature of the particular compound being used. For example, the disclosed compositions can be formulated as a unit dose and / or can be formulated for oral, subcutaneous or intravenous administration.

[0126] Exemplary pharmaceutical compositions of the present disclosure can be used in the form of pharmaceutical preparations, for example, in solid, semi-solid or liquid form, which contain, as an active ingredient, one or more of the compounds of the present disclosure mixed with organic or inorganic excipients or vehicles suitable for external, enteral or parenteral use. The active ingredient can be compounded with conventional non-toxic pharmaceutically acceptable excipients for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use. The active subject compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect on the disease process or condition.

[0127] To prepare solid compositions such as tablets, the primary active ingredient can be mixed with pharmaceutical excipients, such as conventional tableting ingredients, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogenous mixture of the compound of the present disclosure or a non-toxic pharma-ceutically acceptable salt thereof. When these preformulation compositions are referred to as homogenous, it is meant that the active ingredient is evenly dispersed throughout the composition, such that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0128] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are mixed with one or more pharma- ceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid, (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia, (3) humectants, such as glycerol, (4) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, (5) solution retardants such as paraffin, (6) absorption accelerators, such as quaternary ammonium compounds, (7) wetting agents, such as acetyl alcohol and glycerol monostearate, (8) adsorbents, such as kaolin and bentonite clay, (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, and (10) coloring agents. In the case of capsules, tablets, and pills, the compositions can also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar or high molecular weight polyethylene glycols or the like.

[0129] Tablets can be produced by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be produced with binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents or dispersants. Molded tablets can be produced by molding a mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as dragees, capsules, pills and granules, can be optionally scored or produced with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art.

[0130] Compositions for inhalation or insufflation include pharmaceutically acceptable solutions and suspensions in aqueous or organic solvents, or mixtures thereof, as well as powders.Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, nanosuspensions, syrups and elixirs.In addition to the subject composition, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0131] Suspensions may contain, in addition to the subject compositions, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0132] Formulations for rectal or vaginal administration can be presented as suppositories, which can be prepared by mixing the subject compositions with one or more suitable non-irritating excipients or vehicles consisting of, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which are solid at room temperature but liquid at body temperature and thus melt within the body cavity to release the active agent.

[0133] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharma- ceutically acceptable excipient, and any required preservatives, buffers, or propellants.

[0134] The ointments, pastes, creams and gels may contain, in addition to the subject compositions, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0135] Powders and sprays can contain, in addition to the subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0136] The compositions and compounds of the present disclosure can alternatively be administered by aerosol. This is accomplished by producing an aqueous aerosol, liposomal formulation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension can be used. Sonic nebulizers can be used to minimize exposure of the drug to shear that may result in degradation of the compounds contained in the subject composition. Typically, aqueous aerosols are produced by formulating an aqueous solution or suspension of the subject composition with conventional pharma- ceutically acceptable excipients and stabilizers. Excipients and stabilizers vary depending on the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycols), innocuous proteins such as serum albumin, sorbitan esters, amino acids such as oleic acid, lecithin, glycine, buffers, salts, sugars or sugar alcohols. Aerosols are generally produced from isotonic solutions.

[0137] Pharmaceutical compositions of the present disclosure suitable for parenteral administration consist of the subject compositions in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately prior to use; these compositions can contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0138] Examples of suitable aqueous and non-aqueous excipients that can be employed in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin.Proper fluidity can be maintained, for example, by using coating materials such as lecithin, maintaining the required particle size in the case of dispersion, and using surfactants.For example, the crystalline forms provided herein can be milled to obtain a specific particle size, and in at least some embodiments, such crystalline forms can remain substantially stable when milled.

[0139] The amount of the crystalline compound described herein in the formulation can vary depending on factors such as the disease state, age, sex, and weight of the individual. The dosage regimen can be adjusted to provide the optimal therapeutic response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. For ease of administration and uniformity of dosage, it is particularly advantageous to formulate parenteral compositions in dosage unit form. As used herein, dosage unit form refers to physically discrete units suitable as a unitary dosage for the mammalian subject to be treated, each unit containing a predetermined amount of the active crystalline compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0140] The specifications for the dosage unit forms of the present disclosure are dictated by and directly dependent upon (a) the inherent properties of the crystalline compound selected and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the technology of compounding such active crystalline compounds for the treatment of an individual's hypersensitivity.

[0141] The disclosed compositions can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable for high drug concentration. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, etc.), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In many cases, it is preferable to include an isotonic agent, for example, sugar, polyalcohol such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of an injectable composition can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts or gelatin.

[0142] The disclosed crystalline compounds can be administered in time-release formulations, such as compositions containing slow-release polymers. The crystalline compounds can be prepared with carriers that protect the compounds against rapid release, such as controlled release formulations, such as implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, polylactic acid-polyglycolic acid copolymers (PLG), and the like. Many methods for preparing such formulations are generally known to those skilled in the art.

[0143] In accordance with an alternative embodiment of the present disclosure, the disclosed crystalline compounds can be formulated with one or more additional compounds that enhance the solubility of the compound.

[0144] method In some embodiments, the disclosure provides a method of treating kidney disease, cancer, blood disease, or other disease in a patient in need thereof comprising administering to the patient an effective amount of a disclosed crystalline compound, e.g., a disclosed crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide. In other embodiments, the disclosure provides a method of treating kidney disease in a patient in need thereof comprising administering to the patient an effective amount of a pharmaceutical composition comprising a disclosed crystalline compound, e.g., a disclosed crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide.

[0145] In some embodiments, the kidney disease or disorder may be a chronic kidney disease, a glomerular disease, or a proteinuric kidney disease. In certain embodiments, the present disclosure provides a method of treating a chronic kidney disease, a glomerular disease, or a proteinuric kidney disease in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed crystalline compound, such as a disclosed crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide. In other embodiments, the disclosure provides a method of treating chronic kidney disease, glomerular disease, or proteinuric kidney disease in a patient in need thereof comprising administering to the patient an effective amount of a pharmaceutical composition comprising a disclosed crystalline compound, e.g., a disclosed crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide.

[0146] In certain embodiments, the kidney disease may be selected from the group consisting of, for example, Alport syndrome, focal segmental glomerulosclerosis, and diabetic kidney disease. In certain embodiments, the present disclosure provides a method of treating Alport syndrome, focal segmental glomerulosclerosis, or diabetic kidney disease in a patient in need thereof, comprising administering to the patient an effective amount of a disclosed crystalline compound, for example, a disclosed crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide. In other embodiments, the disclosure provides a method of treating Alport syndrome, focal segmental glomerulosclerosis, or diabetic nephropathy in a patient in need thereof, comprising administering to the patient an effective amount of a pharmaceutical composition comprising a disclosed crystalline compound, e.g., a disclosed crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide.

[0147] In particular, in certain embodiments, the present disclosure provides a method of treating the above medical indications comprising administering to a patient in need thereof an effective amount of a crystalline compound disclosed herein, hi certain other embodiments, the present disclosure provides a method of treating the above medical indications in a patient in need thereof comprising administering orally, subcutaneously, or intravenously to the patient a composition comprising a disclosed crystalline form.

[0148] The crystalline compounds disclosed herein can be used as medicines or pharma- ceutically acceptable compositions, for example, in the form of pharmaceutical preparations for oral, enteral, parenteral, or topical administration, and the contemplated methods disclosed herein can include administering the disclosed crystalline compounds or compositions comprising or formed from such disclosed crystalline compounds orally, enterally, parenterally, or topically. For example, the disclosed crystalline forms can control one or more pharmacokinetic properties (e.g., longer or shorter release profile) when administered by a particular route (e.g., oral) or in a particular formulation, compared to a different route (e.g., subcutaneous) or other formulation, for example, a formulation having an amorphous form. In one embodiment, the disclosed crystalline forms can provide substantial reproducibility from one formulation to another.

[0149] Working Example The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. The following non-limiting examples illustrate the disclosure.

[0150] Powder X-ray diffraction was performed using a Bruker D8 Advance according to the parameters shown in Table 1. [Table 1]

[0151] Differential scanning calorimetry (DSC) was performed according to the parameters shown in Table 2. [Table 2]

[0152] Thermogravimetric analysis (TGA) was performed according to the parameters shown in Table 3. [Table 3]

[0153] Dynamic vapor sorption (DVS) analysis was performed according to the parameters shown in Table 4. Karl Fischer analysis was performed using a Mettler Toledo Coulometric KF Titrator C30. [Table 4]

[0154] Example 1 The XRPD pattern of crystalline form E is shown in Figure 1. Characteristic peaks include one or more of the peaks shown in Table 5. [Table 5]

[0155] The XRPD pattern of crystalline form E is shown in Figure 1A. Characteristic peaks include one or more of the peaks shown in Table 6. [Table 6] JPEG2024533420000009.jpg67146

[0156] Figure 2 shows the differential scanning calorimetry (DSC) profile of crystalline form E. As shown in Figure 2, crystalline form E exhibits a characteristic endotherm with an onset of about 168°C and a peak at about 169°C.

[0157] Crystalline form E of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, exhibited a thermogravimetric analysis (TGA) profile indicating a mass loss of about 0.6 wt% up to about 150 °C. Crystalline form E exhibited a dynamic vapor sorption (DVS) profile indicating a reversible total mass change of about 0.3 wt% between about 0 and about 90% relative humidity (RH) at 25 °C. Crystalline form E exhibited a needle-like morphology under polarized light microscopy.

[0158] Approximately 5 mg of crystalline form E was weighed into a 2 mL glass vial. A 20 μL aliquot of each solvent was added and the compound was dissolved at 25 °C. Vortexing and sonication were performed to aid in dissolution. The maximum amount of each solvent added was 1 mL. Approximate solubility was determined by visual observation and is shown in Table 7. [Table 7]

[0159] Example 2 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline, Form A material was prepared as follows. A sample of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, crystalline, Form N material was further dried by heating at 150° C. XRPD analysis showed the dried material to be crystalline with a pattern consistent with Form A.

[0160] The XRPD pattern of crystalline form A is shown in Figure 5. Characteristic peaks include one or more of the peaks shown in Table 8. [Table 8]

[0161] The XRPD pattern of crystalline form A is shown in Figure 5A. Characteristic peaks include one or more of the peaks shown in Table 9. [Table 9] JPEG2024533420000013.jpg88146

[0162] Figure 6 shows a differential scanning calorimetry (DSC) profile of crystalline form A. As shown in Figure 6, crystalline form A exhibits a characteristic endotherm with an onset and peak at about 164°C, and a characteristic endotherm with an onset at about 168°C and a peak at about 169°C. Crystalline form A exhibited a thermogravimetric analysis (TGA) profile that showed a mass loss of about 0.33 wt% up to about 180°C. Crystalline form A exhibited a dynamic vapor sorption (DVS) profile that showed a reversible total mass change of about 1.8 wt% between about 0 and about 90% relative humidity (RH) at 25°C.

[0163] Example 3 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, monohydrate, crystalline, Form B material was prepared as follows. Approximately 50 mg of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline Form E material was equilibrated in water at 50° C. for one week with stirring at 400 rpm. The resulting suspension was filtered through a 0.45 μm nylon membrane filter and centrifuged at 14,000 rpm. XRPD analysis of the material was crystalline with a pattern consistent with Form B.

[0164] The XRPD pattern of crystalline form B is shown in Figure 9. Characteristic peaks include one or more of the peaks shown in Table 10. [Table 10]

[0165] The XRPD pattern of crystalline form B is shown in Figure 9A. Characteristic peaks include one or more of the peaks shown in Table 11. [Table 11]

[0166] FIG. 10 shows a differential scanning calorimetry (DSC) profile of crystalline form B. As shown in FIG. 10, crystalline form B exhibits a characteristic endotherm with an onset of about 74° C. and a peak at about 87° C., a characteristic endotherm with an onset of about 163° C. and a peak at about 164° C., a characteristic exotherm with an onset of about 165° C. and a peak, and a characteristic endotherm with an onset of about 168° C. and a peak at about 169° C. Crystalline form B exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.5% by weight up to about 120° C. Crystalline form B exhibited a dynamic vapor sorption (DVS) profile showing a reversible total mass change of about 0.3% by weight between about 0 and about 90% relative humidity (RH) at 25° C. Karl Fischer (KF) analysis showed 3.8% by weight water (1.02 equivalents by molar ratio).

[0167] Example 4 The XRPD pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline form C material is shown in Figure 12. Characteristic peaks include one or more of the peaks shown in Table 12. [Table 12] JPEG2024533420000017.jpg187151

[0168] Figure 3 shows a differential scanning calorimetry (DSC) profile of crystalline form C. As shown in Figure 3, crystalline form C exhibits a characteristic endotherm with an onset of about 144° C., a characteristic endotherm with an onset of about 164° C., and a characteristic endotherm with an onset of about 168° C. Crystalline form C exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.1 wt % up to about 130° C.

[0169] Example 5 The XRPD pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline form D material is shown in Figure 15. Characteristic peaks include one or more of the peaks shown in Table 13. [Table 13] JPEG2024533420000019.jpg135153

[0170] Figure 16 shows a differential scanning calorimetry (DSC) profile of crystalline form D. As shown in Figure 16, crystalline form D exhibits a characteristic endotherm with an onset of about 152°C, a characteristic endotherm with an onset of about 165°C, and a characteristic endotherm with an onset of about 168°C. Crystalline form D exhibited a thermogravimetric analysis (TGA) profile that showed a mass loss of about 0.6 wt% up to about 150°C. Crystalline form D exhibited a dynamic vapor sorption (DVS) profile that showed a reversible total mass change of about 20 wt% between about 0 and about 90% relative humidity (RH) at 25°C.

[0171] Example 6 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, crystalline, Form F material was prepared as follows: Approximately 50 mg of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline, Form E material was equilibrated in isopropanol with stirring at 400 rpm under temperature cycling from 5° C. to 50° C. at a heating / cooling rate of 0.2° C. / min for 10 cycles. XRPD analysis of the wet cake showed the material to be crystalline in a pattern consistent with Form Z. XRPD analysis of the dried material showed the material to be crystalline in a pattern consistent with Form F.

[0172] The XRPD pattern of crystalline form F is shown in Figure 19. Characteristic peaks include one or more of the peaks shown in Table 14. [Table 14] JPEG2024533420000021.jpg135153

[0173] The XRPD pattern of crystalline form F is shown in Figure 19A. Characteristic peaks include one or more of the peaks shown in Table 15. [Table 15] JPEG2024533420000023.jpg229154

[0174] Figure 20 shows a differential scanning calorimetry (DSC) profile of crystalline form F. As shown in Figure 20, crystalline form F exhibits a characteristic endotherm with an onset of about 87°C and a peak at about 100°C, a characteristic endotherm with an onset of about 164°C and a peak at about 165°C, and a characteristic endotherm with an onset of about 168°C and a peak at about 169°C. Crystalline form F exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 4.1% by weight up to about 150°C. Karl Fischer (KF) analysis showed 5.0% water by weight (1.35 equivalents by molar ratio).

[0175] Example 7 Crystalline, Form G material of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, diisopropylamine monosolvate was prepared as follows. Approximately 50 mg of crystalline Form E material of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous was equilibrated in diisopropylamine at 25° C. with stirring at 400 rpm for 2 weeks. The resulting suspension was filtered through a 0.45 μm nylon membrane filter and centrifuged at 14,000 rpm. XRPD analysis showed the material to be crystalline with a pattern consistent with Form G.

[0176] The XRPD pattern of crystalline form G is shown in Figure 22. Characteristic peaks include one or more of the peaks shown in Table 16. [Table 16] JPEG2024533420000025.jpg208151

[0177] The XRPD pattern of crystalline form G is shown in Figure 22A. Characteristic peaks include one or more of the peaks shown in Table 17. [Table 17] JPEG2024533420000027.jpg114154

[0178] Figure 23 shows a differential scanning calorimetry (DSC) profile of crystalline form G. As shown in Figure 23, crystalline form G exhibits a characteristic endotherm with an onset at about 88° C. and a peak at about 93° C., as well as a characteristic endotherm with an onset and peak at about 164° C. Crystalline form G exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.9% by weight up to about 150° C.

[0179] Example 8 The XRPD pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline form H material is shown in Figure 25. Characteristic peaks include one or more of the peaks shown in Table 18. [Table 18] JPEG2024533420000029.jpg244157 JPEG2024533420000030.jpg62146

[0180] FIG. 26 shows a differential scanning calorimetry (DSC) profile of crystalline form H. As shown in FIG. 26, crystalline form H exhibits a characteristic exotherm with an onset of about 120° C., a characteristic endotherm with an onset of about 136° C., a characteristic endotherm with an onset of about 164° C., and a characteristic endotherm showing an onset of about 169° C. Crystalline form H exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 0.11% by weight up to about 152° C. Crystalline form H exhibited a dynamic vapor sorption (DVS) profile showing a total mass change of about 2.5% by weight between about 0 and about 70% relative humidity (RH) at 25° C. and a total mass change of about 25% by weight between about 70 and about 90% relative humidity (RH) at 25° C.

[0181] Example 9 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline, Form I material was prepared as follows: Approximately 50 mg of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline Form E material was equilibrated in toluene at 50° C. with stirring at 400 rpm for one week. The resulting suspension was filtered through a 0.45 μm nylon membrane filter and centrifuged at 14,000 rpm. XRPD analysis showed the material to be crystalline with a pattern consistent with Form I.

[0182] The XRPD pattern of crystalline Form I is shown in Figure 29. Characteristic peaks include one or more of the peaks shown in Table 19. [Table 19] JPEG2024533420000032.jpg244157 JPEG2024533420000033.jpg62146

[0183] The XRPD pattern of crystalline Form I is shown in Figure 29A. Characteristic peaks include one or more of the peaks shown in Table 20. [Table 20] JPEG2024533420000035.jpg125153

[0184] Figure 30 shows a differential scanning calorimetry (DSC) profile of crystalline form I. As shown in Figure 30, crystalline form I exhibits a characteristic endotherm with an onset of about 154°C, a characteristic exotherm with an onset of about 156°C, a characteristic endotherm with an onset of about 164°C, and a characteristic endotherm with an onset of about 168°C. Crystalline form I exhibited a thermogravimetric analysis (TGA) profile that showed a mass loss of about 0.1% by weight up to about 120°C. Crystalline form I exhibited a dynamic vapor sorption (DVS) profile that showed a total mass change of about 10% by weight between about 0 and about 90% relative humidity (RH) at 25°C.

[0185] Example 10 The XRPD pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, ethanol solvate, crystalline form J material is shown in Figure 33. Characteristic peaks include one or more of the peaks shown in Table 21. [Table 21] JPEG2024533420000037.jpg239157 JPEG2024533420000038.jpg93146

[0186] Example 11 The XRPD pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, methanol solvate, crystalline form K material is shown in Figure 34. Characteristic peaks include one or more of the peaks shown in Table 22. [Table 22] JPEG2024533420000040.jpg249157

[0187] Example 12 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, crystalline, Form L material was prepared as follows. Approximately 50 mg of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline, Form E material was equilibrated in methanol at 50° C. with stirring at 400 rpm for one week. The resulting suspension was filtered through a 0.45 μm nylon membrane filter and centrifuged at 14,000 rpm. XRPD analysis of the wet cake indicated the material was crystalline with a pattern consistent with Form P. XRPD analysis of the dried material indicated the material was crystalline with a pattern consistent with Form L.

[0188] The XRPD pattern of crystalline form L is shown in Figure 35. Characteristic peaks include one or more of the peaks shown in Table 23. [Table 23] JPEG2024533420000042.jpg197151

[0189] Figure 36 shows a differential scanning calorimetry (DSC) profile of crystalline form L. As shown in Figure 36, crystalline form L exhibits a characteristic endotherm with an onset of about 35°C and a peak at about 56°C, a characteristic endotherm with an onset of about 90°C and a peak at about 95°C, a characteristic exotherm with an onset of about 97°C and a peak at about 100°C, a characteristic endotherm with an onset and peak at about 164°C, and a characteristic endotherm with an onset of about 168°C and a peak at about 169°C. Crystalline form L exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 2.2 wt% up to about 120°C. Karl Fischer (KF) analysis showed 4.4 wt% water (1.18 equivalents by molar ratio).

[0190] Example 13 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, crystalline form M material was prepared as follows: Approximately 50 mg of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline form E material was dissolved in a minimum amount of acetonitrile at 50° C., and the solution was centrifuged at 14,000 rpm and filtered through a 0.45 μm nylon membrane filter. The clear solution was cooled to 5° C. at 0.1° C. / min and centrifuged at 14,000 rpm through a 0.45 μm nylon membrane filter to collect the precipitate. XRPD analysis of the wet cake indicated that the material was crystalline with a pattern consistent with form Q. XRPD analysis of the dried material showed that the material was crystalline with a pattern consistent with Form M.

[0191] The XRPD pattern of crystalline form M is shown in Figure 38. Characteristic peaks include one or more of the peaks shown in Table 24. [Table 24] JPEG2024533420000044.jpg197151

[0192] Figure 39 shows a differential scanning calorimetry (DSC) profile of crystalline form M. As shown in Figure 39, crystalline form M shows a characteristic endotherm with an onset of about 61 ° C and a peak at about 77 ° C, a characteristic exotherm with an onset of about 83 ° C and a peak at about 90 ° C, a characteristic endotherm with an onset of about 147 ° C and a peak at about 153 ° C, a characteristic endotherm with an onset of about 164 ° C and a peak at about 165 ° C, and a characteristic endotherm with an onset and peak at about 169 ° C. Crystalline form M showed a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.4 wt% up to about 120 ° C. Karl Fischer (KF) analysis showed 3.5 wt% water (0.93 equivalents by molar ratio).

[0193] Example 14 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, crystalline, Form N material was prepared as follows. Approximately 50 mg of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline Form E material was equilibrated in 1,4-dioxane at 50° C. with stirring at 400 rpm for one week. The resulting suspension was filtered through a 0.45 μm nylon membrane filter and centrifuged at 14,000 rpm. XRPD analysis of the wet cake showed the material to be crystalline with a pattern consistent with Form R. XRPD analysis of the dried material showed the material to be crystalline with a pattern consistent with Form N.

[0194] The XRPD pattern of crystalline form N is shown in Figure 41. Characteristic peaks include one or more of the peaks shown in Table 25. [Table 25] JPEG2024533420000046.jpg192151

[0195] Figure 42 shows the differential scanning calorimetry (DSC) profile of crystalline form N. As shown in Figure 42, crystalline form N shows a characteristic endotherm with an onset of about 50°C and a peak at about 98°C, a characteristic endotherm with an onset of about 163°C and a peak at about 164°C, and a characteristic endotherm with an onset of about 168°C and a peak at about 169°C. The thermogravimetric analysis (TGA) profile of crystalline form N showed a mass loss of about 3.9 wt% up to about 120°C. Karl Fischer (KF) analysis showed 4.2 wt% water (1.13 equivalents by molar ratio).

[0196] Example 15 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, crystalline, form O material was prepared as follows. Approximately 50 mg of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline form E material was equilibrated in trifluoroethanol at 50° C. with stirring at 400 rpm for one week. The resulting suspension was filtered through a 0.45 μm nylon membrane filter and centrifuged at 14,000 rpm. XRPD analysis of the wet cake indicated that the material was crystalline in a pattern consistent with form S. XRPD analysis of the dried material indicated that the material was crystalline in a pattern consistent with form O.

[0197] The XRPD pattern of crystalline form O is shown in Figure 44. Characteristic peaks include one or more of the peaks shown in Table 26. [Table 26] JPEG2024533420000048.jpg177151

[0198] Figure 44 shows a differential scanning calorimetry (DSC) profile of crystalline form O. As shown in Figure 44, crystalline form O exhibits a characteristic endotherm with an onset of about 83°C and a peak at about 88°C, a characteristic exotherm with an onset of about 91°C and a peak at about 95°C, a characteristic endotherm with an onset of about 164°C and a peak at about 165°C, and a characteristic endotherm with an onset of about 169°C and a peak at about 170°C. Crystalline form O exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 1.5 wt% up to about 160°C. Karl Fischer (KF) analysis showed 3.2 wt% water (0.85 equivalents by molar ratio).

[0199] Example 16 The XRPD pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, methanol solvate, crystalline form P material prepared according to the procedure of Example 12 is shown in Figure 47. Characteristic peaks include one or more of the peaks shown in Table 27. [Table 27] JPEG2024533420000050.jpg130153

[0200] Example 17 The XRPD pattern of crystalline form Q material of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, acetonitrile solvate prepared according to the procedure of Example 13 is shown in Figure 48. Characteristic peaks include one or more of the peaks shown in Table 28. [Table 28] JPEG2024533420000052.jpg249157 JPEG2024533420000053.jpg41145

[0201] Example 18 An XRPD pattern for 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, 1,4-dioxane solvate, crystalline form R material, prepared according to the procedure of Example 14, is shown in Figure 49. Characteristic peaks include one or more of the peaks shown in Table 29. [Table 29] JPEG2024533420000055.jpg197151

[0202] Example 19 The XRPD pattern of crystalline form S material of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, trifluoroethanol solvate prepared according to the procedure of Example 15 is shown in Figure 50. Characteristic peaks include one or more of the peaks shown in Table 30. [Table 30] JPEG2024533420000057.jpg135153

[0203] Example 20 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, crystalline, Form T material was prepared as follows: Approximately 50 mg of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline Form E material was equilibrated in acetone at 25° C. with stirring at 400 rpm for 2 weeks. The resulting suspension was filtered through a 0.45 μm nylon membrane filter and centrifuged at 14,000 rpm. XRPD analysis of this material indicated that the material was crystalline with a pattern consistent with Form T.

[0204] The XRPD pattern of crystalline form T is shown in Figure 51. Characteristic peaks include one or more of the peaks shown in Table 31. [Table 31] JPEG2024533420000059.jpg249157 JPEG2024533420000060.jpg88146

[0205] Figure 52 shows a differential scanning calorimetry (DSC) profile of crystalline form T. As shown in Figure 52, crystalline form T shows a characteristic endotherm with an onset of about 55°C, a characteristic endotherm with an onset of about 89°C and a peak at about 98°C, a characteristic endotherm with an onset of about 163°C and a peak at about 164°C, and a characteristic endotherm with an onset and peak at about 169°C. Crystalline form T showed a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.9% by weight up to about 150°C. Karl Fischer (KF) analysis showed 6.7% water by weight (1.85 equivalents by molar ratio).

[0206] Example 21 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, crystalline, Form U material was prepared as follows: Approximately 50 mg of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline Form E material was dissolved in a minimum amount of isopropanol at 50° C. and the solution was centrifuged at 14,000 rpm and filtered through a 0.45 μm nylon membrane filter. The clear solution was cooled to 5° C. at 0.1° C. / min and the precipitate was collected by centrifugation at 14,000 rpm through a 0.45 μm nylon membrane filter. XRPD analysis of the material indicated that the material was crystalline with a pattern consistent with Form U.

[0207] The XRPD pattern of crystalline form U is shown in Figure 54. Characteristic peaks include one or more of the peaks shown in Table 32. [Table 32] JPEG2024533420000062.jpg135153

[0208] Figure 55 shows a differential scanning calorimetry (DSC) profile of crystalline form U. As shown in Figure 55, crystalline form U exhibits a characteristic endotherm with an onset of about 33°C, a characteristic endotherm with an onset of about 92°C and a peak at about 99°C, a characteristic endotherm with an onset of about 164°C and a peak at about 165°C, and a characteristic endotherm with an onset and peak at about 169°C. Crystalline form U exhibited a thermogravimetric analysis (TGA) profile showing a mass loss of about 3.9% by weight up to about 150°C. Karl Fischer (KF) analysis showed 5.1% water by weight (1.38 equivalents by molar ratio).

[0209] Example 22 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, crystalline, Form V material was prepared as follows: Approximately 50 mg of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline Form E material was dissolved in a minimal amount of tetrahydrofuran at 50° C. The solution was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm and placed in an ice bath at 0° C. with stirring. The precipitate was collected by centrifugation at 14,000 rpm through a 0.45 μm nylon membrane filter. XRPD analysis of the wet cake indicated the material was crystalline with a pattern consistent with Form AA. XRPD analysis of the dried material showed it to be crystalline with a pattern consistent with Form V.

[0210] The XRPD pattern of crystalline form V is shown in Figure 57. Characteristic peaks include one or more of the peaks shown in Table 33. [Table 33] JPEG2024533420000064.jpg130153

[0211] Figure 58 shows the differential scanning calorimetry (DSC) profile of crystalline form V. As shown in Figure 58, crystalline form V exhibits a characteristic endotherm with an onset of about 48°C, a characteristic endotherm with a peak at about 90°C and a peak at about 96°C, a characteristic endotherm with an onset of about 163°C and a peak at about 165°C, and a characteristic endotherm with an onset and peak at about 169°C. Crystalline form V exhibited a thermogravimetric analysis (TGA) profile of about 3.9% weight loss up to about 150°C. Karl Fischer (KF) analysis showed 7.1% weight water (1.97 equivalents by molar ratio).

[0212] Example 23 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate, crystalline, Form W material was prepared as follows: Approximately 50 mg of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline Form E material was dissolved in a minimum amount of ethanol at 50° C. The solution was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm and placed in an ice bath at 0° C. with stirring. The precipitate was collected by centrifugation at 14,000 rpm through a 0.45 μm nylon membrane filter. XRPD analysis of the wet cake material indicated the material was crystalline with a pattern consistent with Form Y. XRPD analysis of the dried material showed the material to be crystalline with a pattern consistent with Form W.

[0213] The XRPD pattern of crystalline form W is shown in Figure 60. Characteristic peaks include one or more of the peaks shown in Table 34. [Table 34] JPEG2024533420000066.jpg130153

[0214] Figure 61 shows the differential scanning calorimetry (DSC) profile of crystalline form W. As shown in Figure 61, crystalline form W exhibits a characteristic endotherm with an onset of about 50°C, a characteristic endotherm with an onset of about 98°C and a peak at about 99°C, a characteristic endotherm with an onset and peak at about 164°C, and a characteristic endotherm with an onset and peak at about 169°C. The thermogravimetric analysis (TGA) profile of crystalline form W showed a mass loss of about 3.9 wt% up to about 150°C. Karl Fischer (KF) analysis showed 4.5 wt% water (1.21 equivalents by molar ratio).

[0215] Example 24 The XRPD pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, 1,4-dioxane solvate crystalline form X material is shown in Figure 63. Characteristic peaks include one or more of the peaks shown in Table 35. [Table 35] JPEG2024533420000068.jpg135153

[0216] Example 25 The XRPD pattern of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, ethanol solvate crystalline form Y material prepared according to the procedure of Example 23 is shown in Figure 64. Characteristic peaks include one or more of the peaks shown in Table 36. [Table 36] JPEG2024533420000070.jpg249157 JPEG2024533420000071.jpg47145

[0217] Example 26 The XRPD pattern of crystalline form Z material of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, isopropanol solvate, prepared according to the procedure of Example 6, is shown in Figure 65. Characteristic peaks include one or more of the peaks shown in Table 37. [Table 37] JPEG2024533420000073.jpg197151

[0218] Example 27 The XRPD pattern of crystalline form AA material of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, tetrahydrofuran solvate prepared according to the procedure of Example 22 is shown in Figure 66. Characteristic peaks include one or more of the peaks shown in Table 38. [Table 38] JPEG2024533420000075.jpg135153

[0219] Example 28 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline, Form 2 material was prepared as follows: 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, ethanol solvate, crystalline Form J material was dried under vacuum (<5 mbar) at 25° C. XRPD analysis showed the dried material to be crystalline with a pattern consistent with Form 2.

[0220] The XRPD pattern of Form 2 is shown in Figure 67. Characteristic peaks include one or more of the peaks shown in Table 39. [Table 39] JPEG2024533420000077.jpg135153

[0221] Figure 68 shows a differential scanning calorimetry (DSC) profile of crystalline form 2. As shown in Figure 68, crystalline form 2 exhibits a characteristic endotherm with an onset of about 94°C; a characteristic exotherm with an onset of about 98°C; a characteristic exotherm with an onset of about 165°C; and a characteristic endotherm with an onset and peak of about 169°C. Crystalline form 2 exhibited a thermogravimetric analysis (TGA) profile that showed a mass loss of about 0.9 wt% up to about 120°C. Crystalline form 2 exhibited a dynamic vapor sorption (DVS) profile that showed a reversible total mass change of about 2.1 wt% between about 0 and about 90% relative humidity (RH) at 25°C.

[0222] Example 29 Amorphous material of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide was prepared as follows: A sample of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous, crystalline form E material was heated to 164° C. XRPD analysis showed the material to be amorphous, as shown in FIG. 71.

[0223] Example 29 Co-crystals of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide and sorbic acid (4:1 molar ratio) were prepared as follows: 150 mg of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide were equilibrated in 2000 ul of saturated sorbic acid solution in acetonitrile for 24 hours at room temperature by head-over-head rotation in a 4 ml screw-cap glass vial using a magnetic stir bar (5x10 mm). After equilibration, the solid phase was separated from the liquid phase by centrifugal filtration. The remaining solid was dried in a vacuum tray dryer at 40°C and 40 mbar for 4 hours. XRPD analysis showed that the dried material was crystalline. NMR, IR and LC-MS analyses showed this material to be a co-crystal of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide and sorbic acid (4:1 molar ratio). The XRPD pattern of Form 2 is shown in Figure 72.

[0224] Figure 73 shows a differential scanning calorimetry (DSC) profile of the co-crystal. As shown in Figure 73, the co-crystal exhibits a characteristic endotherm with an onset of about 153° C. and a peak at about 154° C. As shown in Figure 74, thermogravimetric analysis (TGA) of the co-crystal (sample weight 1.8860 mg) did not show a substantial weight loss step (about 0.05 mg) upon heating.

[0225] Incorporation by Reference All publications and patents mentioned in this specification, including those listed below, are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including definitions herein, will control. Equivalent Although specific embodiments of the present disclosure have been described, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the present disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. Unless otherwise indicated, all numerical values ​​expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are understood to be modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

Claims

1. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous (Form E), characterized by a powder X-ray diffraction pattern with a characteristic peak at about 10.3 degrees 2θ.

2. 10. The crystalline form of claim 1, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 10.3, 15.9, and 20.6 degrees 2θ.

3. 10. The crystalline form of claim 1, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 10.3, 15.9, 17.7, 20.6, 21.4, and 26.1 degrees 2θ.

4. 10. The crystalline form of claim 1, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 10.3, 14.9, 15.9, 17.7, 18.9, 20.6, 21.4, 21.8, 26.1, 29.7, 33.0, and 39.3 degrees 2θ.

5. 10. The crystalline form of claim 1, characterized by a powder X-ray diffraction pattern having characteristic peaks in degrees 2θ at about 10.3, 14.9, 15.9, 17.7, 18.9, 20.6, 21.4, 21.8, 23.3, 25.2, 26.1, 26.7, 29.7, 28.0, 33.0, 36.1, 37.2, and 39.

3.

6. 2. The crystalline form of claim 1, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

7. 10. The crystalline form of claim 1, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 168°C and a peak at about 169°C.

8. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous (Form A), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 8.4, 11.7, 14.9, 15.8, 17.5, 18.4, 19.1, 20.4, 21.6, 22.2, 23.4, and 25.1 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

9. 9. The crystalline form of claim 8, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset and peak at about 164°C and a characteristic endotherm with an onset at about 168°C and a peak at about 169°C.

10. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, monohydrate (Form B), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.5, 11.2, 13.0, 17.2, 19.4, 22.5, 23.4, 26.0, 28.2, 29.8, 32.7, and 34.0 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

11. 11. The crystalline form of claim 10, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 74°C and a peak at about 87°C, a characteristic endotherm with an onset of about 163°C and a peak at about 164°C, a characteristic exotherm with an onset and peak at about 165°C, and a characteristic endotherm with an onset of about 168°C and a peak at about 169°C.

12. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous (Form C), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 5.1, 5.3, 6.9, 9.0, 18.0, 18.8, 19.7, 20.3, 20.9, 22.2, 23.5 and 24.4 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

13. 13. The crystalline form of claim 12, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 144°C, a characteristic endotherm with an onset of about 164°C, and a characteristic endotherm with an onset of about 168°C.

14. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous (Form D), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 7.1, 11.8, 19.1, 19.4, 21.0, 22.1, 22.8, 23.1, 24.9, 26.4, 26.6, and 27.6 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

15. 15. The crystalline form of claim 14, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 152°C, a characteristic endotherm with an onset of about 165°C, and a characteristic endotherm with an onset of about 168°C.

16. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (Form F), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.0, 8.3, 11.6, 12.0, 13.3, 16.7, 18.0, 21.1, 21.4, 24.0, 25.3 and 26.2 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

17. 17. The crystalline form of claim 16, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 87°C and a peak at about 100°C, a characteristic endotherm with an onset of about 164°C and a peak at about 165°C, and a characteristic endotherm with an onset of about 168°C and a peak at about 169°C.

18. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, diisopropylamine monosolvate (Form G), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.3, 9.0, 13.4, 15.5, 16.4, 18.2, 18.5, 19.1, 20.3, 20.8, 22.2 and 27.8 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

19. 20. The crystalline form of claim 18, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 88°C and a peak at about 93°C and a characteristic endotherm with an onset and peak at about 164°C.

20. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous (Form H), characterized by a powder X-ray diffraction pattern having characteristic peaks at about 9.2, 12.1, 18.8, 19.1, 19.9, 20.5, 21.9, 22.5, 22.8, 24.5, 26.0, and 31.7 degrees 2θ, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

21. 21. The crystalline form of claim 20, characterized by a differential scanning calorimetry (DSC) profile having a characteristic exotherm with an onset of about 120°C, a characteristic endotherm with an onset of about 136°C, a characteristic endotherm with an onset of about 164°C, and a characteristic endotherm with an onset of about 169°C.

22. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, anhydrous (Form I), characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.6, 12.2, 12.7, 17.7, 20.1, 22.7, 22.9, 23.4, 24.4, 25.2, 28.5, and 36.9 degrees 2θ, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

23. 23. The crystalline form of claim 22, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 154°C, a characteristic exotherm with an onset of about 156°C, a characteristic endotherm with an onset of about 164°C, and a characteristic endotherm with an onset of about 168°C.

24. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, ethanol solvate (Form J), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 11.5, 16.9, 19.2, 19.6, 19.9, 23.7, 24.1, 24.4, 24.6, 25.0, 26.4, and 40.5 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

25. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, methanol solvate (Form K), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.2, 12.0, 12.8, 17.0, 18.7, 19.5, 20.2, 24.5, 24.9, 25.8, 26.6, and 27.2 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

26. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (Form L), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.3, 12.5, 18.1, 18.8, 20.0, 23.1, 25.1, 25.5, 26.1, 27.7, 28.1, and 38.2 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

27. 27. The crystalline form of claim 26, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 35°C and a peak at about 56°C, a characteristic endotherm with an onset of about 90°C and a peak at about 95°C, a characteristic exotherm with an onset of about 97°C and a peak at about 100°C, a characteristic endotherm with an onset and peak at about 164°C, and a characteristic endotherm with an onset of about 168°C and a peak at about 169°C.

28. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (Form M), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 8.5, 14.5, 17.7, 20.9, 21.2, 21.6, 22.7, 23.8, 24.3, 24.5, 25.2 and 34.3 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

29. 29. The crystalline form of claim 28, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 61°C and a peak at about 77°C, a characteristic exotherm with an onset of about 83°C and a peak at about 90°C, a characteristic endotherm with an onset of about 147°C and a peak at about 153°C, a characteristic endotherm with an onset of about 164°C and a peak at about 165°C, and a characteristic endotherm with an onset and peak at about 169°C.

30. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (Form N), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 8.2, 12.4, 17.4, 17.6, 17.9, 20.4, 22.4, 23.3, 28.9, 29.0, 34.6, and 35.6 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

31. 31. The crystalline form of claim 30, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 50°C and a peak at about 98°C, a characteristic endotherm with an onset of about 163°C and a peak at about 164°C, and a characteristic endotherm with an onset of about 168°C and a peak at about 169°C.

32. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (Form O), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 7.6, 11.9, 12.7, 15.1, 17.7, 19.2, 22.0, 22.7, 24.4, 25.2, 29.8, and 39.0 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

33. 33. The crystalline form of claim 32, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 83°C and a peak at about 88°C, a characteristic exotherm with an onset of about 91°C and a peak at about 95°C, a characteristic endotherm with an onset of about 164°C and a peak at about 165°C, and a characteristic endotherm with an onset of about 169°C and a peak at about 170°C.

34. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, methanol solvate (Form P), characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.3, 12.1, 12.5, 12.7, 18.9, 19.6, 19.7, 25.0, 25.5, 27.3, 27.7, and 38.8 degrees 2θ, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

35. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, acetonitrile solvate (Form Q), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.6, 8.4, 14.4, 18.6, 19.9, 20.9, 21.1, 22.7, 23.6, 23.8, 24.5, and 26.4 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

36. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, 1,4-dioxane solvate (Form R), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 11.1, 17.3, 17.5, 17.9, 18.2, 22.4, 23.3, 28.4, 29.1, 33.8, 34.5, and 39.7 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

37. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, trifluoroethanol solvate (Form S), characterized by a powder X-ray diffraction pattern having characteristic peaks at about 7.5, 12.0, 17.7, 19.2, 21.6, 22.8, 23.5, 24.4, 25.3, 30.0, 31.6, and 34.3 degrees 2θ, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

38. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (Form T), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 5.4, 7.0, 9.0, 10.8, 12.2, 13.0, 16.1, 19.4, 19.7, 20.9, 22.5, and 28.3 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

39. 39. The crystalline form of claim 38, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 55°C, a characteristic endotherm with an onset of about 89°C and a peak at about 98°C, a characteristic endotherm with an onset of about 163°C and a peak at about 164°C, and a characteristic endotherm with an onset and peak at about 169°C.

40. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (Form U), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.0, 12.0, 13.3, 17.9, 18.9, 21.4, 22.0, 24.0, 24.3, 26.3, 32.3 and 36.3 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

41. 41. The crystalline form of claim 40, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 33°C, a characteristic endotherm with an onset of about 92°C and a peak at about 99°C, a characteristic endotherm with an onset of about 164°C and a peak at about 165°C, and a characteristic endotherm with an onset and peak at about 169°C.

42. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (Form V), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.5, 13.0, 17.1, 17.4, 19.4, 23.4, 23.7, 26.0, 28.3, 29.2, 32.7, and 34.4 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

43. 43. The crystalline form of claim 42, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 48°C, a characteristic endotherm with a peak at about 90°C and a peak at about 96°C, a characteristic endotherm with an onset of about 163°C and a peak at about 165°C, and a characteristic endotherm with an onset and peak at about 169°C.

44. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, hydrate (Form W), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.2, 12.4, 13.8, 18.9, 19.5, 20.6, 21.8, 24.8, 25.5, 26.4, 27.7, and 28.1 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

45. 45. The crystalline form of claim 44, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 50°C, a characteristic endotherm with an onset of about 98°C and a peak at about 99°C, a characteristic endotherm with an onset and peak at about 164°C, and a characteristic endotherm with an onset and peak at about 169°C.

46. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, 1,4-dioxane solvate (Form X), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 8.1, 17.3, 17.5, 18.3, 18.8, 20.5, 22.0, 23.3, 23.7, 24.6, 24.9, and 31.7 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

47. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, (Form Y), ethanol solvate, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.2, 12.3, 18.0, 18.8, 19.4, 20.5, 24.1, 24.8, 25.5, 26.3, 27.7, and 28.0 degrees 2θ, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

48. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, (Form Z), isopropanol solvate, characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.5, 12.9, 17.1, 19.4, 22.5, 23.4, 26.0, 29.7, 29.8, 32.7, 34.0 and 34.4 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

49. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, (Form AA), tetrahydrofuran solvate, characterized by a powder X-ray diffraction pattern having characteristic peaks at about 6.5, 13.0, 17.1, 19.4, 22.5, 23.4, 26.0, 28.3, 29.9, 32.7, 34.0, and 34.6 degrees 2θ, wherein the powder X-ray diffraction pattern was obtained using Cu Kα radiation.

50. A crystalline form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide, Anhydrous (Form 2), characterized by an X-ray powder diffraction pattern having characteristic peaks at about 6.3, 6.5, 12.4, 13.0, 16.0, 16.6, 18.1, 18.7, 19.4, 19.9, 25.0 and 26.0 degrees 2θ, wherein the X-ray powder diffraction pattern was obtained using Cu Kα radiation.

51. 51. The crystalline form of claim 50, characterized by a differential scanning calorimetry (DSC) profile having a characteristic endotherm with an onset of about 94°C, a characteristic exotherm with an onset of about 98°C, a characteristic endotherm with an onset of about 166°C, and a characteristic endotherm with an onset of about 169°C.

52. A substantially amorphous form of 5-(3,4-dichlorophenyl)-N-((1R,2R)-2-hydroxycyclohexyl)-6-(2,2,2-trifluoroethoxy)nicotinamide.

53. 52. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 51 and a pharmaceutically acceptable excipient.

54. A pharmaceutical composition comprising crystalline form E according to any one of claims 1 to 7 and a pharmaceutically acceptable excipient.

55. 52. A pharmaceutical composition formed from the crystalline form of any one of claims 1 to 51.

56. A pharmaceutical composition formed from crystalline form E of any one of claims 1 to 7.

57. 54. The pharmaceutical composition of claim 53, wherein the composition is formulated for oral administration.

58. 55. The pharmaceutical composition of claim 54, wherein the composition is formulated for oral administration.

59. A drug comprising at least a detectable amount of the crystalline form of any one of claims 1 to 51.

60. A drug comprising the substantially pure crystalline form of any one of claims 1 to 51.

61. A drug comprising the substantially pure crystalline form E of any one of claims 1 to 7.

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