EA043074B1 - CRYSTALLINE (R)-5-CARBAMOYLPYRIDIN-3-YL-2-METHYL-4-(3-(TRIFLUOROMETOXY)BENZYL)PIPERAZINE-1-CARBOXYLATE, ITS COMPOSITIONS AND METHODS OF APPLICATION - Google Patents

Description

Technical field

Provided herein are solid forms of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate. Also provided herein are pharmaceutical compositions containing such solid forms and methods for their use in the treatment, prevention, and control of various disorders.

State of the art

Many compounds can exist in various crystalline forms, or polymorphs, which are characterized by different physical, chemical, and spectroscopic properties. For example, certain polymorphs of a given compound may be more readily soluble in certain solvents, may flow more easily, or may compress more easily than others; see, for example, P. DiMartino, et al., J. Thermal Anal., 48:447-458 (1997). In the case of drugs, certain solid forms may be more bioavailable than others, while others may be more stable under certain manufacturing, storage and biological conditions.

It is known in the pharmaceutical field that polymorphic forms of a compound affect, for example, the solubility, stability, flowability, friability and compressibility of the compound, as well as the safety and efficacy of drugs containing it, see e.g. Knapman, K. Modern Drug Discoveries, 2000 , 53. Thus, the discovery of new drug polymorphs can provide many advantages.

The definition and selection of the solid form of a pharmaceutical compound is complex given that changing the solid form can affect a number of physical and chemical properties, which can provide advantages or disadvantages in processing, formulation, stability, bioavailability, storage, handling (e.g., transportation), among other important pharmaceutical characteristics. Suitable pharmaceutical solids include crystalline solids and amorphous solids, depending on the product and route of administration. Amorphous solids are characterized by a lack of structural order over long distances, while crystalline solids are characterized by structural periodicity. The class of pharmaceutical solid required depends on the particular application; amorphous solids are sometimes selected based on, for example, an improved dissolution profile, while crystalline solids may be desirable for properties such as, for example, physical or chemical stability.

The importance of the discovery of polymorphs was highlighted by the example of Ritonavir™, an HIV protease inhibitor, which was formulated as soft gelatin capsules. Approximately two years after the product was released to the market, the unexpected precipitation of a new, less soluble polymorph in the formulation necessitated the withdrawal of the product from the market until a more uniform formulation could be developed (see S. R. Chemburkar et al., Org. Process Res. Dev. , (2000) 4:413-417).

Notably, it is not possible to predict a priori whether crystalline forms of a compound exist at all, let alone how to successfully obtain them (see, for example, Braga and Grepioni, 2005, Making crystals from crystals: a green route to crystal engineering and polymorphism). , Chem. Commun.:3635-3645 (with respect to crystal engineering, if the instructions are not very precise and/or if other external factors influence the process, the result can be unpredictable); Jones et al., 2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement, MRS Bulletin 31:875879 (Currently, it is generally not possible to compute the number of observed polymorphs of even the simplest molecules by computation) Price, 2004, The computational prediction of pharmaceutical crystal structures and polymorphism, Advanced Drug Delivery Reviews 56 : 301-319 (Price); and Bernstein, 2004, Crystal Structure Prediction and Polymorphism, ACA Transactions 39:14-23 (there is still much to be learned and done before one can claim with any degree of certainty the ability to predict crystal structure , and even more so polymorphic forms)).

The multitude of possible solid forms creates a potential variety of physical and chemical properties of said pharmaceutical compound. The discovery and selection of solid forms are of great importance in the development of an effective, stable and marketable pharmaceutical product.

(L)-5-Carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is a compound that is a dual inhibitor of MAGL and FAAH and can be used to treat various disorders .

The synthesis of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is described in PCT/uS2018/022049 filed March 12, 2018.

This document describes new crystalline forms of (R)-5-carbamoylpyridin-3-yl-2methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate. New polymorphic forms of (R)-5carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate may lead to the development of compositions for the treatment of various diseases and may provide numerous advantages in formulating, manufacturing and treatment.

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The essence of the invention

Crystalline forms of ^)-5-carbamoylpyridin-3-yl-2methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate are provided herein. Also provided herein are pharmaceutical compositions containing crystalline forms of (R)-5-carbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate. In addition, provided herein are methods for treating or preventing various diseases and disorders which comprise administering to a patient a therapeutically effective amount of the crystalline form of (R)-5carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine -1-carboxylate.

This document also provides methods for preparing, isolating and characterizing crystalline (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate.

Brief description of graphic materials

In FIG. 1 is an exemplary X-ray powder diffraction (XRPD) pattern of crystalline form A of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate.

In FIG. 2 is an illustrative differential scanning calorimetry (DSC) thermogram and an illustrative thermogravimetric analysis (TGA) thermogram of the crystal form A of (R)-5-carbamoylpyridin-3 -yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1 carboxylate.

In FIG. 3 is an exemplary Dynamic Vapor Sorption (DVS) plot of crystalline form A of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1carboxylate.

In FIG. 4 shows illustrative XRPD patterns of crystalline Form A (R)-5carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate before and after the DVS experiment.

In FIG. 5 shows illustrative XRPD patterns of crystalline Form A (R)-5carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate before and after stability testing under accelerated degradation conditions.

In FIG. 6 is an exemplary nuclear magnetic resonance (NMR) spectrum of crystalline Form A of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate.

In FIG. 7 is an exemplary XRPD pattern of crystalline form B of (R)-5carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate.

In FIG. 8 shows an exemplary DSC thermogram and an exemplary TGA thermogram of crystalline form B of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate.

In FIG. 9 is an exemplary XRPD pattern of C(R)-5carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form.

In FIG. 10 shows an exemplary DSC and TGA thermogram of the C(R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1 carboxylate crystalline form.

In FIG. 11 is an exemplary XRPD pattern of the crystalline form D(R)-5carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate.

In FIG. 12 is an exemplary DSC and TGA thermogram of the crystalline form D(R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate.

In FIG. 13 is an exemplary XRPD pattern of crystalline form E(R)-5carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate.

In FIG. 14 shows an exemplary DSC thermogram and TGA thermogram of crystalline form E(R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1carboxylate.

Definitions

As used herein, unless otherwise indicated, the compound herein (R)-5-carbamoylpyridin-3 -yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate corresponds to the compound of formula (I) shown below.

(I) (R)-5-Carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate can be prepared using standard synthetic methods (see e.g. PCT/ US2018/022049).

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Unless otherwise indicated, the term crystalline and related terms as used herein, when used to describe a substance, component, product, or form, means that the substance, component, product, or form is essentially crystalline, for example, as determined by x-ray diffraction (see, for example, Remington's Pharmaceutical Sciences, ^20th ed., Lippincott Williams & Wilkins, Philadelphia PA, 173 (2000); The United States Pharmacopeia, ^37th ed., 503-509 (2014)).

As used herein, and unless otherwise indicated, the term about and approximately, when used in connection with doses, amounts, or weight percent of the ingredients of a composition or dosage form, means the dose, amount, or weight percent that is recognized by one of ordinary skill in the art, provides a pharmacological effect equivalent to that obtained from the indicated dose, amount, or weight percent. % or 5% of the indicated dose, quantity or mass percent.

As used herein, unless otherwise indicated, the term about or approximately when used in conjunction with a numerical value or range of values that is intended to characterize a particular solid form, such as a particular temperature or range of temperatures, such as, for example, describing the melting point, dehydration , desolvation or glass transition; weight change, such as, for example, weight change with temperature or humidity; solvent or water content, for example by weight or percentage; or the position of the peak, such as, for example, when analyzed, for example using IR or Raman spectroscopy or XRPD; indicates that the value or range of values may deviate to an extent that is recognized as reasonable by a person skilled in the art, while still describing a solid form. Methods for characterizing crystalline forms and amorphous forms include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), powder X-ray diffractometry (XRPD), single crystal X-ray diffractometry, vibrational spectroscopy, such as infrared (IR) and Raman spectroscopy, solid phase and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantification, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies. In certain embodiments, the terms about and approximately when used in this context indicate that a numerical value or range of values may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5 %, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the specified value or range. In the context of molar ratios, about and approximately indicate that the numerical value or range of values can vary within 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2 %, 1.5%, 1%, 0.5%, or 0.25% of the specified value or range. It should be understood that the numerical values of the peaks in an X-ray powder diffraction pattern may vary from one agent to another or from one sample to another, and therefore the values given should not be considered as absolute, but with allowance for variability, for example ±0.2 degrees two theta (°2θ) or more. For example, in some embodiments, the peak position value on the XRPD may vary up to ±0.2°2θ while still describing a particular peak on the XRPD.

As used herein, unless otherwise indicated, a solid form that is essentially physically pure contains essentially no other solid forms. In some embodiments, a crystalline form that is substantially physically pure contains less than about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05% or 0.01% of one or more other solid forms by weight. Detection of other solid forms can be performed by any method obvious to a person skilled in the art, including, but not limited to, diffraction analysis, thermal analysis, combustion elemental analysis, and/or spectroscopic analysis.

As used herein, unless otherwise indicated, a solid form that is essentially chemically pure is essentially free of other chemical species (ie, chemical impurities). In some embodiments, a solid form that is substantially chemically pure contains less than about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05% or 0.01% of one or more other chemical compounds by weight. Detection of other chemical compounds may be performed by any method obvious to one skilled in the art, including but not limited to chemical analysis methods such as, for example, mass spectrometric analysis, spectroscopic analysis, thermal analysis, combustion elemental analysis, and/or chromatographic analysis. analysis.

As used herein, unless otherwise indicated, a chemical compound, solid form, or composition that is substantially free of another chemical compound, solid form, or composition means that the compound, solid form, or composition contains, in certain embodiments, less than about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%,

7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05% or 0.01% by weight of another compound, solid form or composition.

Unless otherwise indicated, the terms anhydride and anhydrous as used herein refer to the solid form of a substance that does not contain water in its crystal lattice.

As used herein, and unless otherwise indicated, the terms treat, treat, and treat refer to the elimination or amelioration of a disease or disorder or one or more of the symptoms associated with the disease or disorder. In some embodiments, the terms refer to minimizing the spread or complication of a disease or disorder by administering one or more prophylactic or therapeutic agents to a patient with such disease or disorder. In some embodiments, the terms refer to the administration of a compound provided herein, with or without other additional active agents, after the onset of symptoms of a particular disease.

Unless otherwise indicated, the term composition, as used herein, is intended to cover a product containing the specified ingredient(s) (and in the specified amount(s), if specified), as well as any product that directly or indirectly obtained from the combination of the indicated ingredient(s) in the indicated amount(s). By pharmaceutically acceptable is meant that the diluent, excipient or carrier in the composition must be compatible with the other ingredient(s) of the composition and not harmful to their recipient.

Unless otherwise indicated, the term subject is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. .P. In specific embodiments, the subject is a human.

Unless otherwise indicated, to the extent that there is a discrepancy between the depicted chemical structure of a compound provided herein and the chemical name of a compound provided herein, the chemical structure shall prevail.

Detailed description of the invention

Provided herein are solid forms of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate. In certain embodiments, the solid form is crystalline. In certain embodiments, the implementation of the solid form is a one-component solid form. In certain embodiments, the solid form is an anhydride.

Crystalline forms of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate can be prepared by the methods described herein, including those described in the examples below , or by techniques known in the art, including heating, cooling, freeze drying, lyophilization, solvent evaporation, solvent recrystallization, addition of an anti-solvent, suspension recrystallization, rapid cooling, slow cooling, exposure to solvent and/or water, and drying. The particle size of the obtained solid forms, which may vary, for example, from sizes in nanometers to sizes in millimeters, can be controlled, for example, by changing the crystallization conditions, such as, for example, the crystallization rate and/or the crystallization solvent system, or by using techniques particle size reduction, such as crushing, grinding, micronization or sonication.

Without wishing to be bound by any particular theory, the crystalline forms of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate are characterized by physical properties such as stability, solubility and dissolution rate, suitable for pharmaceutical and therapeutic dosage forms. Moreover, without being bound by any particular theory, the crystalline forms of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate are characterized by physical properties (e.g., density, compressibility, hardness, morphology, splitting, stickiness, solubility, water absorption, electrical properties, thermal characteristics, solid state reactivity, physical stability and chemical stability) affecting specific processes (e.g. yield, filtration, washing, drying, grinding, mixing, tabletting, fluidity, dissolution, formulation and lyophilization) that make certain crystalline forms suitable for the production of a dosage form. Such properties can be determined using specific analytical chemical methods, including solid state analytical methods (eg, x-ray diffraction, microscopy, spectroscopy, and thermal analysis) as described herein and known in the art.

In certain embodiments, provided herein are compositions comprising crystalline (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate.

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In some embodiments, methods are provided for using these compositions to treat, prevent, or treat diseases and disorders, including, but not limited to, diseases and disorders associated with MAGL and/or FAAH activity.

In certain embodiments, provided herein are methods of using crystalline forms of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate to treat, prevent, or manage pain , neurological disorders, anxiety, inflammatory bowel disease, neuropathic pain, and cancer cell proliferation and migration.

In certain embodiments, provided herein is Crystal Form A of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate.

In one embodiment, the crystal form A of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate as provided herein can be prepared from methanol. In one embodiment, the crystal form A of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate as provided herein can be derived from isopropyl acetate. In one embodiment, crystal form A of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate as provided herein can be prepared from ethanol/water in 9:1 ratio. In one embodiment, the crystal form A of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate as provided herein can be derived from toluene.

In certain embodiments, the crystal form A of (R)-5-carbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate can be characterized by X-ray powder diffraction analysis.

In one embodiment, crystal form A of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, having an X-ray powder diffraction pattern showing peaks at 16.5 , 20.1 and 22.3 °2θ±0.2 °2θ.

In one embodiment, crystal form A of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having an X-ray powder diffraction pattern showing peaks at 16.4 , 20.1 and 22.3 °2θ±0.2 °2θ.

In one embodiment, crystal form A of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, having an X-ray powder diffraction pattern showing peaks at 18.1 , 20.1 and 22.3 °2θ±0.2 °2θ.

In one embodiment, crystal form A of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, wherein the X-ray powder diffraction pattern further shows peaks at 9.9 , 19.9 and 24.6 °2θ±0.2 °2θ.

In one embodiment, crystal form A of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, wherein the X-ray powder diffraction pattern further shows peaks at 9.9 , 19.9 and 24.7 °2θ±0.2 °2θ.

In certain embodiments, crystalline form A of (R)-5-carbamoylpyridin-3-yl-2methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or fourteen of the following approximate positions: 9.9, 13.3, 13.9, 14.8, 16.4, 18.0, 19.9, 20.1, 22.3, 23.0, 24.4, 24.6, 26.9 and 29.3°2θ. In certain embodiments, crystalline Form A (R)-5carbamoylpyridine-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate has an XRPD pattern having 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks matching the peaks in the illustrative XRPD pattern, proposed in this document.

In certain embodiments, crystalline form A of (R)-5-carbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or twenty in one of the following approximate positions: , 14.2, 14.9, 16.0, 16.5, 17.3, 18.1, 19.3, 19.9, 20.1, 20.6, 21.4, 22.3, 23 .1, 24.1, 24.7, 27.0, 27.2 and 29.3 °2θ. In certain embodiments, crystalline form A of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate has an XRPD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks matching peaks in illustrative XRPD pattern proposed in this document.

In one embodiment, a (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form is provided having an X-ray powder diffraction pattern corresponding to the exemplary X-ray powder diffraction pattern. shown in FIG. 1.

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In certain embodiments, the crystal form A of (R)-5-k arbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate can be characterized by thermal analysis.

In one embodiment, crystal form A of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, having a differential scanning calorimetry thermogram containing an endotherm with a maximum point of about 113°C.

In one embodiment, crystal form A of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, having a differential scanning calorimetry thermogram containing an endotherm with a maximum point of about 112°C.

In one embodiment, crystal form A of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, having a differential scanning calorimetry thermogram containing an endotherm with a starting point of about 112°C.

In one embodiment, crystal form A of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, having a differential scanning calorimetry thermogram containing an endotherm with a starting point of about 111°C.

In one embodiment, a crystalline (R)-5-carbamoylpyridin-3-yl-2methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate having a differential scanning calorimetry thermogram corresponding to the illustrative differential scanning calorimetry thermogram shown in fig. 2.

In one embodiment, crystal form A of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, which is anhydrous.

In one embodiment, a crystalline Form A of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having a thermogravimetric analysis thermogram showing a weight loss of less than about 1, 22% when heated from about 25 to about 100°C.

In one embodiment, a crystalline Form A of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having a thermogravimetric analysis thermogram showing a weight loss of less than about 1, 0% when heated from about 30°C to about 150°C.

In one embodiment, a crystalline Form A of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having a thermogravimetric analysis thermogram showing a weight loss of less than about 0, 1% when heated from about 30°C to about 150°C.

In one embodiment, a (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form is provided having a thermogravimetric analysis thermogram corresponding to the illustrative thermogravimetric analysis thermogram shown in fig. 2.

In one embodiment, crystal form A of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided which is substantially physically pure.

In one embodiment, crystal form A of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided which is substantially chemically pure.

In one embodiment, a pharmaceutical composition is provided comprising crystalline form A of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1carboxylate.

In certain embodiments, provided herein is Crystal Form B of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate.

In one embodiment, crystal form B of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate as provided herein can be prepared from acetonitrile/water in a ratio of 9:1. In one embodiment, crystal form B of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate as provided herein can be prepared from ethyl acetate/n- heptane, methyl acetate, acetone or methylene chloride.

In certain embodiments, the crystalline Form B of (R)-5-carbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate can be characterized by X-ray powder diffraction analysis.

In one embodiment, crystal form B of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, having an X-ray powder diffraction pattern showing peaks at 16.2 , 18.2 and 19.2 °2θ±0.2 °2θ.

In one embodiment, crystal form B(R)-5-carbamoylpyridine-6 043074 is provided.

3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate, wherein the X-ray powder diffraction pattern additionally shows peaks at 15.1, 18.7 and 20.1°2θ±0.2 °2θ.

In certain embodiments, crystalline form B of (R)-5-carbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate has XRPD peaks located at one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve of the following approximate positions: 15.1, 16.2, 17.9, 18.2, 18.7, 19.2, 20.1, 21, 1, 24.3, 25.0, 27.4 and 27.6°2θ. In certain embodiments, crystalline form B of (R)-5carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate has an XRPD pattern having 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks matching the peaks in the illustrative XRPD pattern, proposed in this document.

In one embodiment, crystal form B of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having an X-ray powder diffraction pattern corresponding to the exemplary X-ray powder diffraction pattern. shown in FIG. 7.

In certain embodiments, the crystal form B of (R)-5-carbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate can be characterized by thermal analysis.

In one embodiment, crystal form B of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, having a differential scanning calorimetry thermogram containing an endotherm with a maximum point of about 95°C.

In one embodiment, crystal form B of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having a differential scanning calorimetry thermogram containing an endotherm with a starting point of about 91°C.

In one embodiment, crystal form B of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having a differential scanning calorimetry thermogram corresponding to an exemplary differential scanning calorimetry thermogram shown in FIG. 8.

In one embodiment, crystal form B of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, which is anhydrous.

In one embodiment, crystal form B of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, having a thermogravimetric analysis thermogram showing a weight loss of less than about 2, 5% when heated from about 30 to about 100°C.

In one embodiment, crystal form B of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, having a thermogravimetric analysis thermogram showing a weight loss of less than about 1, 0% when heated from about 30 to about 150°C.

In one embodiment, crystal form B of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having a thermogravimetric analysis thermogram showing a weight loss of less than about 0, 1% when heated from about 30 to about 150°C.

In one embodiment, crystal form B of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having a thermogravimetric analysis thermogram corresponding to the illustrative thermogravimetric analysis thermogram shown in fig. 8.

In one embodiment, crystal form B of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided which is substantially physically pure.

In one embodiment, crystal form B of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided which is substantially chemically pure.

In one embodiment, a pharmaceutical composition is provided comprising crystalline form B of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1carboxylate.

In certain embodiments, provided herein is the C(R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1 carboxylate crystalline form.

In one embodiment, the crystal form of C(R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate as provided herein can be prepared from chloroform/hexane in a ratio of 1:3. In one embodiment, the crystalline (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate as provided herein can be prepared from an ethanol/ water in a ratio of 1:1. In one embodiment, the crystalline (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate as provided herein can be prepared from acetonitrile/water in the ratio 3:1. In one embodiment, the crystalline (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate as provided herein can be prepared from a suspension of Form B in FaSSIF. In one embodiment, the crystalline (R)-5carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate as provided herein can be prepared from a suspension of Form B in FeSSIF.

In certain embodiments, the crystalline form of C(R)-5-carbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate can be characterized by X-ray powder diffraction analysis.

In one embodiment, a C(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form is provided having an X-ray powder diffraction pattern showing peaks at 18.0 , 20.0 and 21.0 °2θ±0.2 °2θ.

In one embodiment, the crystalline form of C(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, wherein the X-ray powder diffraction pattern further shows peaks at 12.3 , 16.8 and 25.5 °2θ±0.2 °2θ.

In certain embodiments, the C(R)-5-carbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or twenty-two of the following approximate positions: 12.3, 14.1, 14.7, 14.8, 15, 5, 15.7, 16.2, 16.8, 17.1, 18.0, 18.2, 18.5, 19.5, 20.0, 20, 5, 21.0, 21.4, 22.8, 24.6, 25.5, 25.9 and 29.6°2θ. In certain embodiments, the C(R)-5carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form has an XRPD pattern having 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks matching the peaks in the illustrative XRPD pattern, proposed in this document.

In one embodiment, a C(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form is provided having an X-ray powder diffraction pattern corresponding to the exemplary X-ray powder diffraction pattern. shown in FIG. 9.

In certain embodiments, the crystalline form of C(R)-5-carbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate can be characterized by thermal analysis.

In one embodiment, a C(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form is provided having a differential scanning calorimetry thermogram containing an endotherm with a maximum point of about 99°C.

In one embodiment, a C(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form is provided having a differential scanning calorimetry thermogram containing an endotherm with a starting point of about 98°C.

In one embodiment, a C(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form is provided having a differential scanning calorimetry thermogram corresponding to an exemplary differential scanning calorimetry thermogram shown in FIG. 10.

In one embodiment, a C(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form is provided which is anhydrous.

In one embodiment, a C(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form is provided having a thermogravimetric analysis thermogram showing a weight loss of about 0.149% at heating from about 30 to about 150°C.

In one embodiment, a C(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form is provided having a thermogravimetric analysis thermogram showing a weight loss of less than about 1, 0% when heated from about 30 to about 150°C.

In one embodiment, a crystalline form of C(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having a thermogravimetric analysis thermogram showing a weight loss of about 0.15 % when heated from about 30 to about 150°C.

- 8 043074

In one embodiment, a C(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form is provided having a thermogravimetric analysis thermogram corresponding to the illustrative thermogravimetric analysis thermogram shown in fig. 10.

In one embodiment, a C(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form is provided that is substantially physically pure.

In one embodiment, a C(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form is provided that is substantially chemically pure.

In one embodiment, a pharmaceutical composition is provided comprising a crystalline form of C(R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1carboxylate.

In certain embodiments, provided herein is D(R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1 carboxylate crystalline form.

In one embodiment, the crystal form D(R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate as provided herein can be prepared from a suspension of Form B in methyl tert-butyl ether (MTBE).

In certain embodiments, the crystalline form of D(R)-5-carbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate can be characterized by X-ray powder diffraction analysis.

In one embodiment, a crystalline form of D(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having an X-ray powder diffraction pattern showing peaks at 13.4 , 21.0 and 23.8 °2θ±0.2 °2θ.

In one embodiment, the crystalline form of D(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, wherein the X-ray powder diffraction pattern further shows peaks at 18.3 , 26.7 and 29.5 °2θ±0.2 °2θ.

In certain embodiments, the D(R)-5-carbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form is characterized by XRPD peaks located at one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, or seventeen of the following approximate positions: 13.4, 14.0, 14.8, 16.1, 16.8, 18.0, 18.3, 18.6, 19.5, 19.8, 20.7, 21.0, 22.8, 23.8, 24.4, 26.7 and 29.5°2θ. In certain embodiments, crystalline form D(R)-5carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate has an XRPD pattern having 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 1 9, 20, 21, 22, 23, 24, or 25 peaks matching the peaks in the illustrative XRPD pattern proposed in this document.

In one embodiment, a crystalline form of D(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having an X-ray powder diffraction pattern corresponding to the exemplary X-ray powder diffraction pattern. shown in FIG. eleven.

In certain embodiments, the crystalline form of D(R)-5-carbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate be characterized by thermal analysis.

In one embodiment, a crystalline form of D(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having a differential scanning calorimetry thermogram containing an endotherm with a maximum point of about 101°C.

In one embodiment, a crystalline form of D(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having a differential scanning calorimetry thermogram containing an endotherm with a starting point of about 99°C.

In one embodiment, a crystalline form of D(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having a differential scanning calorimetry thermogram corresponding to an exemplary differential scanning calorimetry thermogram shown in FIG. 12.

In one embodiment, the crystalline form D(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, which is anhydrous.

In one embodiment, a crystalline form of D(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, having a thermogravimetric analysis thermogram showing a weight loss of about 0.054% at heating from about 30 to about 150°C.

- 9 043074

In one embodiment, a crystalline form of D(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having a thermogravimetric analysis thermogram showing a weight loss of less than about 0, 1% when heated from about 30 to about 150°C.

In one embodiment, a crystalline form of D(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having a thermogravimetric analysis thermogram corresponding to the illustrative thermogravimetric analysis thermogram shown in fig. 12.

In one embodiment, a crystalline form of D(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided which is substantially physically pure.

In one embodiment, a crystalline form of D(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided which is substantially chemically pure.

In one embodiment, a pharmaceutical composition is provided comprising a crystalline form of D(R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1carboxylate.

In certain embodiments, provided herein is E(R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1 carboxylate crystalline form.

In one embodiment, the crystal form E (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate as provided herein can be prepared from chloroform/hexane .

In certain embodiments, the crystal form E of (R)-5-carbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate can be characterized by X-ray powder diffraction analysis.

In one embodiment, crystal form E of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, having an X-ray powder diffraction pattern showing peaks at 17.8 , 21.3 and 22.8 °2θ±0.2 °2θ.

In one embodiment, crystal form E(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, wherein the X-ray powder diffraction pattern further shows peaks at 15.8 , 18.4 and 21.9 °2θ±0.2 °2θ.

In certain embodiments, crystalline form E(R)-5-carbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate has XRPD peaks located at one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve of the following approximate positions: 10.9, 12.7, 15.8, 17.2, 17.8, 18.4, 19.7, 21, 3, 21.9, 22.8, 24.2 and 25.6°2θ. In certain embodiments, crystalline (R)-5carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is characterized by an XRPD pattern having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 peaks matching the peaks in the illustrative XRPD pattern proposed in this document.

In one embodiment, a crystalline form of E(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having an X-ray powder diffraction pattern corresponding to the exemplary X-ray powder diffraction pattern. shown in FIG. 13.

In certain embodiments, the crystal form E of (R)-5-carbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate be characterized by thermal analysis.

In one embodiment, a crystalline form of E(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having a differential scanning calorimetry thermogram containing an endotherm with a maximum point of about 104°C.

In one embodiment, a crystalline form of E(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having a differential scanning calorimetry thermogram containing an endotherm with a starting point of about 102°C.

In one embodiment, a crystalline form of E(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided having a differential scanning calorimetry thermogram corresponding to an illustrative differential scanning calorimetry thermogram shown in FIG. 14.

In one embodiment, crystal form E of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, which is anhydrous.

In one embodiment, crystalline form E(R)-5-carbamoylpyridine-10 043074 is provided.

3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate having a thermogravimetric analysis thermogram showing a weight loss of about 0.37% when heated from about 30 to about 150°C.

In one embodiment, crystal form E of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided, having a thermogravimetric analysis thermogram showing a weight loss of less than about 1, 0% when heated from about 30 to about 150°C.

In one embodiment, E(R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate crystalline form is provided having a thermogravimetric analysis thermogram corresponding to the exemplary thermogravimetric analysis thermogram shown in fig. 14.

In one embodiment, crystal form E of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided which is substantially physically pure.

In one embodiment, crystal form E of (R)-5-carbamoylpyridin3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is provided which is substantially chemically pure.

In one embodiment, a pharmaceutical composition is provided comprising crystalline form E(R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1carboxylate.

Pharmaceutical compositions

Provided herein are pharmaceutical compositions and unit dosage forms containing crystalline forms of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate. Also provided herein are methods for preparing pharmaceutical compositions and unit dosage forms containing crystalline forms of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate. For example, in certain embodiments, individual dosage forms containing crystalline (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate as provided herein or prepared with using the crystal forms of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate provided herein may be suitable for oral, mucosal (including rectal, nasal or vaginal), parenteral (including subcutaneous, intramuscular, bolus injection, intra-arterial or intravenous), sublingual, transdermal, buccal or topical administration.

In certain embodiments, pharmaceutical compositions and dosage forms provided herein comprise crystalline forms of (R)-5-carbamoylpyridin-3yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate. In some embodiments, provided herein are pharmaceutical compositions and dosage forms comprising a crystalline form of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate, wherein the crystalline form of (R)-5carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate is essentially pure. In some embodiments, provided herein are pharmaceutical compositions and dosage forms comprising the crystalline form of (R)-5carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate as provided in herein, which is substantially free of other crystalline solid forms of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate and/or amorphous solid forms ( R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate. The pharmaceutical compositions and dosage forms provided herein generally also contain one or more pharmaceutically acceptable excipients, diluents, or carriers.

The unit dosage forms provided herein are suitable for oral or parenteral (eg, subcutaneous, intravenous, bolus injection, intramuscular, or intra-arterial) administration to a patient. Examples of dosage forms include, but are not limited to: tablets; caplets; capsules such as soft elastic gelatin capsules; powders and sterile solids which can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

The composition, external form and type of dosage forms presented herein will usually vary depending on their use. An oral dosage form may contain lesser amounts of one or more of the active ingredients it contains than an oral dosage form used to treat the same disease or disorder. These and other ways in which the specific dosage forms encompassed by the present invention will differ from each other will be apparent to those skilled in the art.

- 11 043074 in the art, see, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,

Easton Pa. (1990).

Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in the pharmaceutical arts and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for inclusion in a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the manner in which the dosage form is administered to the patient. For example, oral dosage forms such as tablets may contain excipients that are not suitable for use in oral dosage forms. The suitability of a particular excipient may also depend on the particular active ingredients in the dosage form.

Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may vary depending on factors such as, but not limited to, the manner in which they are to be administered to patients. However, typical dosage forms provided herein are in the range of about 0.1 to about 1000 mg per day administered as a single dose once a day in the morning or as divided doses throughout the day. More specifically, the daily dose may be administered two, three or four times a day in equal doses. In particular, the daily dose range may be from about 0.1 to about 500 mg per day, more specifically from about 0.1 to about 200 mg per day. The daily dose range may be 1, 2, 3, 4 or 5 mg. In the management of a patient, therapy may be initiated at a lower dose, possibly from about 1 to about 25 mg, and increased as needed to about 200-1000 mg per day in single or divided doses, depending on the patient's overall response.

Dosage forms for oral administration

Pharmaceutical compositions provided herein that are suitable for oral administration may be presented as separate dosage forms such as, but not limited to, tablets (eg chewable tablets), caplets, capsules and liquids (eg flavored syrups). Such dosage forms contain predetermined amounts of active ingredients and can be prepared by pharmaceutical methods well known to those skilled in the art, see generally Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

Typical oral dosage forms provided herein are prepared by combining the active ingredient(s) in a homogeneous mixture with at least one excipient in accordance with conventional pharmaceutical formulation techniques. Excipients can take a wide variety of forms depending on the form of preparation required for administration. For example, excipients suitable for use in liquid or aerosol oral dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavors, preservatives, and colorants. Examples of excipients suitable for use in solid oral dosage forms (eg, powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants.

If desired, the tablets may be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be obtained by any of the pharmaceutical methods. Typically, pharmaceutical compositions and dosage forms are prepared by uniformly and thoroughly mixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired form.

For example, a tablet can be obtained by compression or molding. Compressed tablets may be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be obtained by molding in a suitable device a mixture of a powdered compound moistened with an inert liquid diluent.

Examples of excipients that can be used in the oral dosage forms of the present invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as gum arabic, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (for example, ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose (for example, nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

- 12 043074

Examples of excipients suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch and mixtures thereof. The binder or excipient in the pharmaceutical compositions of the invention is typically present in an amount of from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL-PH-101™, AVICEL-PH-103™, AVICEL RC-581™, AVICEL-PH-105™ (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus-Hooke, PA), and mixtures thereof. A particular binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-58™. Suitable low moisture anhydrous excipients or additives include AVICEL-PH-103™ and 1500 LM™ starch.

Disintegrants are used in the compositions provided herein to provide tablets that disintegrate when exposed to an aqueous medium. Tablets containing too much disintegrant may disintegrate on storage, while tablets containing too little may not disintegrate at the desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant, which is neither too large nor too small to adversely alter the release of the active ingredients, should be used to form solid oral dosage forms of the present invention. The amount of disintegrant used varies depending on the type of composition and is easily determined by those skilled in the art. Typical pharmaceutical compositions contain about 0.5 to about 15 weight percent disintegrant, specifically about 1 to about 5 weight percent disintegrant.

Disintegrants that can be used in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polacrilin, sodium starch glycolate, potato or tapioca starch, pregelatinized starch, other starches, clays, other algins, other celluloses, gums and mixtures thereof.

Lubricants that can be used in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and their mixtures. Additional lubricants include, for example, siloid silica gel (AEROSIL 200™, manufactured by WR Grace Co., Baltimore, Maryland), coagulated synthetic silica aerosol (sold by Degussa Co., Plano, Texas), CAB-OSIL™ (pyrogenic silica, sold Cabot Co., Boston, Massachusetts) and mixtures thereof. If lubricants are used at all, they are typically used in an amount of less than about 1% by weight of the pharmaceutical compositions or dosage forms in which they are incorporated.

Dosage forms for parenteral use

Parenteral dosage forms can be administered to patients by a variety of routes, including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial injection. Because their administration generally bypasses the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterile or may be sterilized prior to administration to the patient. Examples of parenteral dosage forms include, but are not limited to, injectable solutions, dry products ready to be dissolved or suspended in a pharmaceutically acceptable injectable vehicle, injectable suspensions, and emulsions.

Suitable carrier media that can be used to prepare the parenteral dosage forms provided herein are well known to those skilled in the art. Examples include, but are not limited to, water for injection USP; aqueous carrier vehicles such as, but not limited to, sodium chloride injection, Ringer's solution for injection, dextrose solution for injection, dextrose and sodium chloride solution for injection, and Ringer's solution with lactate injection; water-miscible carrier media such as but not limited to ethyl alcohol, polyethylene glycol and polypropylene glycol; and non-aqueous carrier media such as but not limited to corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the active ingredients disclosed herein may also be included in the parenteral dosage forms provided herein.

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Combined treatment

Combination therapies are also provided herein, for example, the co-administration of a disclosed compound and an additional active agent as part of a particular treatment regimen designed to provide the beneficial effect of the combined action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, the pharmacokinetic or pharmacodynamic synergy resulting from the combination of therapeutic agents. The introduction of these therapeutic agents in combination is usually carried out over a certain period of time (usually within weeks, months or years, depending on the selected combination). Combination therapy involves the introduction of several therapeutic agents in a sequential manner, ie, when each therapeutic agent is administered at different times, as well as the introduction of these therapeutic agents or at least two therapeutic agents almost simultaneously.

Substantially simultaneous administration is accomplished, for example, by administering to the subject a single formulation or composition (eg, tablets or capsules with a fixed ratio of each therapeutic agent) or multiple separate formulations (eg, capsules) for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent is by any suitable route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucosal tissues. Therapeutic agents are administered by the same or different routes. For example, the first therapeutic agent of the selected combination is administered by intravenous injection, while the other therapeutic agents of the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.

Combination therapy also includes the administration of therapeutic agents as described above in additional combination with other biologically active ingredients and non-drug therapies. If the combination therapy additionally includes drug-free treatment, drug-free treatment is carried out at any appropriate time until a beneficial effect is achieved from the combined action of the combination of therapeutic agents and drug-free treatment. For example, in appropriate cases, a beneficial effect is still achieved when non-drug treatment is temporarily withdrawn due to the administration of therapeutic agents, perhaps for days or even weeks.

The components of the combination are administered to the patient simultaneously or sequentially. It should be understood that the components are present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, which are administered either simultaneously or sequentially.

For example, for the intended treatment of pain, the disclosed compound is co-administered with another pain therapeutic agent such as an opioid, a cannabinoid receptor modulator (CB-1 or CB-2), a COX-2 inhibitor, acetaminophen, and/or a non-steroidal anti-inflammatory drug. Additional therapeutic agents, for example for the treatment of pain, which are co-administered include morphine, codeine, hydromorphone, hydrocodone, oxymorphone, fentanyl, tramadol and levorphanol.

Other proposed therapeutic agents for co-administration include aspirin, naproxen, ibuprofen, salsalate, diflunisal, dexibuprofen, fenoprofen, ketoprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, celecoxib , parecoxib, rimonabant and/or etoricoxib.

Examples

Example 1 Form A of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate.

Form A was prepared with several solvents including methanol, isopropyl acetate, and a 9:1 mixture of ethanol/water. Form A was also prepared by suspending the starting material (form A/C mixture) in toluene at RT (room temperature) for 1 day. Form A NMR spectra show a trace amount of toluene on the surface. HPLC measured purity of the Form A sample was 99.87 area%. Form A has a differential scanning calorimetry thermogram showing an endotherm with an initial point of about 111-112°C and a maximum point of about 113°C (shown in Fig. 2). Form A has a thermogravimetric analysis thermogram showing a weight loss of less than about 0.1% when heated from about 30 to about 100°C, indicating an anhydrous material (shown in Fig. 2).

A Dynamic Vapor Sorption (DVS) isotherm plot of form A was obtained at 25° C. over a range of 0 to 95% RH (relative humidity) (shown in FIG. 3). Water uptake of 0.05% was observed at 25°C/80% RH. The XRPD comparison showed that no shape change was observed for Form A after the DVS test (shown in FIG. 4).

Sample Form A showed good physical and chemical stability under accelerated degradation conditions at 25°C/60% RH and 40°C/75% RH for 3 months. Powder X-ray diffractograms comparing Form A before and after accelerated degradation conditions are shown in FIG. 5.

Peaks on XRPD for Form A are shown in Table 1. 1 and 2 (various XRPD instruments and samples; peaks below a certain amplitude are omitted for clarity).

Table 1 __________ Peaks on XRPD for Form A____ No. 2-theta(deg.) d(yra.) Height (readouts)

1 4.9 17.85 445 2 9.9 8.906 7062 3 12.5 7.086 450 4 13.4 6.625 1881 5 14.0 6.324 3185 6 14.2 6.212 3613 7_____ 14.9 5.934 4377 8______ 16.0 5.545 1117 _9_____ 16.5 5.378 3668 10 16.7 5.302 461 eleven 17.3 5.131 2862 12 18.1 4.888 10138 13____ 18.8 4.721 543 14 19.3 4.589 2757 15 19.7 4.50 561 16____ 19.9 4.449 6638 17 20.1 4.405 12550 18____ 20.6 4.311 3593 19____ 21.4 4.151 2679 20 22.3 3.975 21984 21 23.1 3.851 3116 22 24.1 3.684 1875 23____ 24.7 3.605 4728 24 25.1 3.551 636 25____ 26.1 3.415 947 26____ 27.0 3.301 2208 27 27.2 3.279 2457 28 28.0 3.185 852 29____ 28.8 3.100 535 thirty 29.3 3.041 1477 31____ 31.2 2.863 536 32 32.2 2.777 594 33____ 34.3 2.615 457 34____ 36.7 2.446 592 35____ 38.2 2.352 607

table 2

Peaks on XRPD for Form A #2-theta(deg.) d(yra.) Height (readouts)

4.9 17.85 445

2_________9.9____________________8.906__________________7062____________________

J_________12.5_________________7.086________________450____________________ _4__________13.4____________________6.625___________________1881___________________________ _5__________14.0___________________6.324__________________3185_____________________ _6__________14.2___________________6.212_________________3613____________________ .7__________14.9___________________5.934________________________________4377_____________________ _8__________16.0 ___________________5.545__________________1117_____________________ _9__________16.5___________________5.378__________________3668____________________

10_______16.7___________________5.302__________________461___________________________

11_________17.3____________________5.131___________________2862_____________________

12_________18.1___________________4.888__________________10138________________________

13_________18.8____________________4.721___________________543____________________________

14________19.3___________________4.589__________________2757____________________

15_________19.7____________________4.50____________________561____________________________

16________19.9___________________4.449__________________6638____________________

17________20.1___________________4.405__________________12550________________________

18________20.6___________________4.311__________________3593__________________________

19________21.4___________________4.151__________________2679__________________________

20________22.3__________________3.975_________________21984______________________________

21_________23.1___________________3.851__________________3116__________________________

22_________24.1___________________3.684__________________1875____________________

23________24.7___________________3.605__________________4728__________________________

24________25.1___________________3.551__________________636___________________________

26.1 3.415 947

26________27.0___________________3.301__________________2208__________________________

27________27.2__________________3.279_________________2457________________________

28________28.0___________________3.185__________________852___________________________

29________28.8___________________3.100__________________535___________________________

30________29.3___________________3.041__________________1477____________________

31_______31.2___________________2.863__________________536___________________________

32________32.2___________________2.777__________________594___________________________

33_________34,3___________________2,615__________________457___________________________

36.7 2.446 592

38.2 2.352 607

Example 2 Form B of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate.

Form B was prepared using a mixture of acetonitrile/water in a ratio of 9:1. Form B was also prepared by liquid vapor diffusion from ethyl acetate/n-heptane, as well as by evaporation in pure methyl acetate, acetone or methylene chloride. Peaks on XRPD for Form B are shown in Table 1. 3. Weight loss of less than 1.0% was observed when heated from about 30 to about 100°C. The DSC result showed a sharp start endotherm at 91°C and a maximum endotherm at about 95°C. Based on the low weight loss according to TGA and the single sharp endotherm according to DSC, Form B was assumed to be anhydrous.

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Table 3

No. _______ Peaks on XRPD for Form B___________ 2-theta(deg.) a(ang.) Height (counts) 1 6.9 12.86 341____________________ 2 9.1 9.74 232___________________ 3 10.4 8.522 563____________________ 4 11.5 7.700 142____________________ 5 12.7 6.985 359___________________ 6 13.1 6.730 257___________________ 7 13.8 6.39 273____________________ 8 14.3 6.182 473____________________ 9 15.1 5.847 2206__________________ 10 16.2 5.465 8503___________________ eleven 17.3 5.114 551____________________ 12 17.9 4.950 2243__________________ 13 18.2 4.871 9600__________________ 14 18.7 4.754 4314__________________ 15 19.2 4.619 4926__________________ 16 20.1 4.421 3639__________________ 17 20.7 4.289 859____________________ 18 20.8 4.262 1649___________________ 19 21.1 4.205 2422_________________ 20 21.3 4.165 1181____________________ 21 21.6 4.120 421____________________ 22 22.7 3.922 1134___________________ 23 23.0 3.861 720___________________ 24 24.3 3.661 1424___________________ 25 25.0 3.566 2080_________________ 26 25.4 3.498 525____________________ 27 25.8 3.458 460___________________ 28 27.0 3.301 568____________________ 29 27.4 3.252 1417___________________ thirty 27.6 3.224 827____________________ 31 28.4 3.143 238___________________ 32 29.4 3.036 402___________________ 33 29.9 2.991 128_____________________ 34 30.6 2.924 715___________________ 35 31.7 2.823 129_____________________ 36 33.5 2.673 139_____________________ 37___ 34.8 2.575 198_____________________ 38 37.0 2.431 179_____________________ 39 39.5 2.282 190____________________ Example 3 Form C of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate. Form C was obtained when form B was suspended in FaSSIF-v2 or FeSSIF-v2 at 37°C for 2 h. Form C can also be obtained from a mixture of chloroform/hexane in a ratio of 1:3. DSC demonstrates endotherm with maximum point at about 99°C, and TGA shows a weight loss of less than about 0.15% when heated from about 30°C to about 150°C, which indicates that form C is co- fight anhydride. Peaks on XRPD for Form C are shown in Table 1. 4. Table 4 _______ Peaks on XRPD for Form C___________ No. 2-theta(deg.) a(ang.) Height (counts) J__ 5.1 17.18 1235___________________ _2___ 8.5 10.42 146_____________________ _3____ 10.2 8.633 661____________________ 4____ 10.4 8.463 402___________________ _5____ 10.6 8.340 697___________________ _6____ 10.8 8.179 426___________________ 7____ 12.3 7.209 4781_________________ _8____ 12.6 7.007 943____________________ _9____ 14.1 6.294 1700___________________ 10 14.7 6.021 1871____________________ eleven 14.8 5.963 2174__________________ 12 15.4 5.747 691____________________ 13___ 15.5 5.699 2577__________________ 14 15.7 5.628 1504___________________ 15 16.2 5.452 2030_________________ 16___ 16.8 5.259 5422__________________ 17 17.1 5.194 1475___________________ 18___ 17.3 5.135 611____________________ 19___ 18.0 4.928 9698__________________ 20 18.2 4.876 4834__________________ 21 18.5 4.798 6212__________________ 22 18.7 4.752 576___________________ 23___ 19.5 4.551 6357__________________ 24 20.0 4.444 11680_________________ 25___ 20.5 4.333 2281__________________ 26 21.0 4.223 15490_________________ 27__ 21.4 4.144 6065__________________ 28___ 21.8 4.070 1064___________________ 29__ 22.2 3.994 1216___________________ thirty 22.8 3.893 4382_________________ 31___ 23.3 3.808 2959__________________ 32 23.8 3.736 989___________________

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33_________24.6_____________________3.616____________________5533

34 25.5 3.490 6853 35 25.9 3.434 3080 36 26.4 3.375 372 37 26.6 3.348 605 38 27.0 3.305 1594 39 27.6 3.226 229 40 28.0 3.186 201 41 28.2 3.159 248 42 29.6 3.019 2177 43 31.2 2.868 498 44 31.3 2.852 398 45 32.0 2.797 477 46 32.8 2.728 299 47 33.3 2.692 205 48 34.2 2.621 165 49 34.5 2.598 269 50 36.0 2.490 417 51 36.5 2.462 472 52 37.2 2.418 92

Example 4 Form D of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate.

Form D can be prepared from a suspension of form B in MTBE at room temperature for 10 days. DSC shows an endotherm with a maximum point at about 101°C, and TGA shows a weight loss of less than about 0.054% when heated from about 30 to about 150°C, indicating that form D is an anhydride. Peaks on XRPD for Form D are shown in Table 1. 5.

Table 5 __________XRPD Peaks for Shape D__________ #2-theta(deg) d(yra.) Height (readouts)

5.9 15.094 2047

2___________8.4_______________________10.530___________________900_____________________ _J___________8.8______________________________10.088___________________630_____________________

A__________9.5______________________9.323_________________538____________________ _5___________11.7_____________________7.558____________________498_____________________ _6___________13.4_____________________6.625____________________8528____________________ _1___________14.0_____________________6.305____________________2653____________________ _8___________14.3_____________________6.183_____________________716________________ _9___________14.8_____________________5.985____________________2408____________________

10__________15.3______________________5.794_____________________365______________________

11__________16.1______________________________5.510_____________________4141_____________________

12__________16.8_____________________5.284____________________2986____________________

13__________17.8______________________4.981_____________________907______________________

14__________18.0_____________________4.924____________________1322____________________

15__________18.3______________________4.831_____________________6368_____________________

16__________18.6_____________________4.762____________________2087____________________

17__________18.8______________________4.707_____________________634______________________

18__________19.5_____________________4.553____________________2557____________________

19__________19.8_____________________4.488____________________2428____________________

20_________20.7_____________________4.291____________________4145____________________

21_________21.0_____________________4.218____________________11450___________________

22_________22.0_____________________4.033____________________1042____________________

23_________22.8_____________________3.893____________________1266____________________

24_________23.0_____________________3.859____________________1217____________________

25_________23.8_____________________3.734____________________23683___________________

26_________24.4_____________________3.643____________________3299____________________

27_________24.8_____________________3.588____________________1917____________________

28_________25.5_____________________3.491____________________514_____________________

29_________26.3_____________________3.389____________________1610____________________

30_________26.7_____________________3.341____________________8142____________________

31__________26.9______________________3.313_____________________1471_____________________

32_________28.0_____________________3.187____________________402_____________________

33_________29.5_____________________3.021____________________5758____________________

34_________32.5_____________________2.755____________________965_____________________

35_________33.3_____________________2.688____________________774_____________________

36_________34.1_____________________2.630____________________168_____________________

37_________34.5_____________________2.597____________________409_____________________

38_________34.8_____________________2.577____________________418_____________________

39_________35.0_____________________2.560____________________253_____________________

40_________36.2_____________________2.480____________________555_____________________

41_________36.9_____________________2.433____________________224_____________________

42_________37.2_____________________2.413____________________319_____________________

43_________37.8_____________________2.376____________________248_____________________

44_________38.6_____________________2.329____________________294_____________________

45_________39.6_____________________2.276____________________359_____________________

Example 5 Form E of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate.

Form E can be prepared from a suspension of form C in chloroform/hexane at room temperature for 9 days. DSC shows an endotherm with a maximum point at about 104° C., and TGA shows a weight loss of less than about 0.37% when heated from about 30 to about 150° C., indicating Form E is an anhydride. Peaks on XRPD for form E are shown in table. 6.

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Table 6 ___________ Peaks on XRPD for Form E___________ No. 2-theta(deg.) d(yra.) Height (counts)

7.5 11.73 333

2___________9.1_________________________9.71________________________115_____________________ _J___________10.9_____________________8.144____________________698_____________________

4___________12.7______________________________7.006____________________1164____________________ _5___________14.0_____________________6.327____________________793_____________________

6___________14.3______________________6.173_____________________1113_____________________

7___________15.8_____________________5.622____________________2425____________________ _8___________16.2_____________________5.462____________________915_____________________

9___________16.8______________________5.279_____________________274_________

10__________17.2______________________5.158_____________________1845_____________________

11__________17.8______________________4.985_____________________2556_____________________

12__________18.4______________________4.818_____________________1879_____________________

13__________19.7______________________4.502_____________________1215_____________________

14_________20.3_____________________4.371____________________778_____________________

15_________21.3_____________________4.167____________________2749____________________

16_________21.9_____________________4.054____________________2304____________________

17_________22.7_____________________3.923____________________377_____________________

18_________22.8_____________________3.892____________________5540____________________

19_________23.5_____________________3.790____________________358_____________________

20_________24.2_____________________3.681_____________________1614____________________

21_________25.4_____________________3.511____________________392_____________________

22_________25.6_____________________3.475____________________839_____________________

23_________26.2_____________________3.399____________________398_____________________

24_________27.3_____________________3.264____________________171_____________________

25_________28.3_____________________3.156____________________237_____________________

26_________29.0_____________________3.075____________________342_____________________

27_________29.7_____________________3.007____________________278_____________________

28_________30.0_____________________2.975____________________310_____________________

29_________30.7_____________________2.910____________________151_____________________

Example 6 Stability and Solubility Tests

A solution stability test for form A was performed to evaluate the significant degradation of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate in a physiologically relevant medium. A solution of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate (1 mg/mL) was prepared in acetonitrile/water (50/50 vol. /about.). The test medium (1990 µl) was added to the vial. Investigated evaluative media included pH 1-8 buffers, artificial gastric juice (SGF), fasting artificial intestinal juice (FaSSIF), and fed artificial intestinal juice (FeSSIF). The stock solution (10 μl) was added to the vial containing the medium. This mixture was agitated for proper mixing and transferred to an HPLC vial which was placed in an autosampler maintained at 37°C. Samples were taken from the vial every 4 hours for the injector for 24 hours. The results are shown in table. 7. Solubility is shown in table. 8.

Table 7

Solution Chemical Stability Data for Crystal Form A of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate at 37°C

Time (h) pH=1 pH=3 pH=5.0 pH=6.8 pH=8.0 SGF FaSSIF FeSSIF 0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 4 99.6 99.8 100.9 100.2 101.3 100.2 100.6 99.6 8 100.3 99.8 101.7 100.8 100.5 100.1 100.2 100.2 12 100.3 98.5 99.9 100.1 99.7 99.2 100.5 99.7 16 99.9 99.3 100.7 100.0 100.1 99.7 100.3 99.6 20 101.9 99.6 99.9 99.6 98.7 100.4 100.0 99.8 24 100.5 99.5 99.6 99.0 99.4 99.6 100.0 99.7

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Table 8

Solubility of crystalline form A (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate in a physiologically significant medium (37°C)

Example 7 Polymorphic Screening Under Exercise.

A polymorphic stress screening was performed using form B as the starting form. The tests were carried out at or below room temperature in various solvents. The results are shown in table. 9.

Table 9

Polymorphic stress screening using form B as base form at or below room temperature

Experiment Solvent Pace. State Result 1 ethyl acetate Room* Suspension Form A 2 Isopropyl acetate room Suspension Form A 3 Acetone 4°C Evaporation Form B 4 dichloromethane 4°C Evaporation Form B 5 Acetonitrile Room* Suspension Form A 6 2-Me THF 4°C Evaporation Form A 7 H ₂ O / MeOH 1/3 (v / v) Aw ~ 0.5 Room* Suspension Form A 8 H ₂ O/MeCN 1/3 (v/v) Aw ~0.9 4°C Evaporation Basically C shape 9 MTBE room Suspension Form D 10 EtOH Room* Suspension Form A eleven 2-Propanol Room* Suspension Form A 12 Nitromethane Room* Suspension Form A 13 H ₂ O room Suspension Form A 14 drops of DMSO dispersed in water room Suspension Form B

*A clear solution was initially observed; continued stirring at 4°C for 1 day, then at RT for 9 days.

Example 8 Polymorphic Screening

A polymorphic screening was performed at 50°C. The solution originally prepared from form B was prepared at a concentration of about 50 mg in 100 to 300 µl of the solvents listed in Table 1. 10.

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The solution was stirred at 50°C for 24 h.

Table 10

Polymorph screening at 50°C

Condition State Result H ₂ O Suspension Form A MTBE Suspension Form A SRME Clear solution Only transparent film from evaporation

Example 9 Study by lyophilization.

Attempts were made to obtain an amorphous material by freeze-drying Form B. Form B was freeze-dried using a LyoSys 3 freeze dryer in the main DPD zone at -40° C. overnight. The results are shown in table. eleven.

Table 11

Lyophilization attempts

Experiment Form/solvent Result 1 240 mg form B in H ₂ O:MeCN ~ 4:1 Form A 2 240 mg form B in H ₂ O:MeCN ~ 3:2 Form B 3 240 mg form B in H ₂ O:MeCN ~ 2:1 Form B

Example 10 Solubility Study of Form A

Solubility was evaluated after 2 h and 24 h for Form A in FaSSIF-v2 and FeSSIF-v2 at 37°C. Approximately 40 mg of Form A sample was added to 2.0 ml of the appropriate biomedium to form a suspension followed by shaking at 500 rpm at 37°C. After 2 hours and 24 hours, supernatants were isolated by centrifugation (7000 rpm for 5 minutes) followed by filtration through a 0.45 mm PTFE membrane and tested for concentration by HPLC and pH. Residual solids were characterized by XRPD. As summarized in Table. 12, the measured 24 hour solubility of form A in FaSSIF-v2 and FeSSIF-v2 was 0.063 and 1.1 mg/mL, respectively. The XRPD patterns showed that no shape changes were observed after solubility evaluation.

Table 12

Summary of Solubility Evaluation Form A at 37°C

Wednesday Moment of time (h) Solubility (mg/ml) Observation Final form final p H FaSSIF (pH 6.5) 2 0.063 muddy Form A 6.5 FaSSIF (pH 6.5) 24 0.063 muddy Form A 6.6 FeSSIF (pH 5.8) 2 1.0 muddy Form A 5.9 FeSSIF (pH 5.8) 24 1.1 muddy Form A 6.0

Example 11 Study of the stability of form A in the solid state under conditions of accelerated degradation.

Solid state stability evaluation (accelerated degradation conditions) was performed for form A at 25°C/60% RH and 40°C/75% RH. The detailed procedure used to assess stability is given below:

1) Weigh approximately 30 mg of Form A sample into each 3 ml vial;

2) cover the bottle of Parafilm® and pierce 15 holes in Parafilm® with a needle;

3) place the vial in the stabilization chamber at 25°C/60% RH or 40°C/75% RH; And

4) take samples for XRPD, TGA, DSC, HPLC purity and quantitation at 2, 4 and 6 weeks and 3 months.

The results of the evaluation of stability in the solid state are summarized in table. 13. Impurities are given in table. 14. Based on the XRPD, TGA and DSC characterization results, no significant shape change or decrease in HPLC purity was observed after 3 months under both conditions. Thus, the Form A sample showed good physical and chemical stability at 25°C/60% RH and 40°C/75% RH for 3 months.

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Table 13

Generalization of results regarding stability

Moment crystalline form Mass loss at TGA (%, up to 100 °C) Endotherm at DSC Purity by HPLC (% area) Analysis vs Control at 5°C (%) He time Condition Initial - Form A 1.2 110.9 99.86 analyzing whether 25 °С/60% OV Form A 1.1 110.1 99.84 101.2 2 weeks 40 °С/75% OV Form A 1.1 110.5 99.78 98.1 25 °С/60% OV Form A 1.7 110.9 99.86 101.4 4 weeks 40 °С/75% OV Form A 1.9 110.8 99.86 101.3 25 °С/60% Form A 0.2 110.4 99.86 99.7 6 weeks OV 40 °С/75% Form A 0.8 110.8 99.86 99.2

Analysis by

Moment time Condition crystalline form Mass loss at TGA (%, up to 100 °C) Endotherm at DSC Purity by HPLC (% area) compared to control at 5 °C (%) Chiral purity Not Not Initial analyzer Form A 1.2 110.9 99.86 analyzers 100* ali ali 3 months 25 °C/60% OV 40 °C/75% Form A Form A 0.03 0.01 112.6 112.9 99.86 99.86 97.3 96.9 100 100

OB *: Chiral purity was checked for starting material after storage at -20°C for about 3 months.

Table 14

Generalization by area % of all impurities in the solid state stability study % area

Moment time Condition Note. (OVU 0.81) 1API 1.00) (OVU Note. (OVU 1.04) 2Note 3 (OVU 1.74) Initial Not analyzed 0.09 99.86 - - 0.05 25°C/60% RH 0.07 99.84 - - 0.09 2 weeks 40°C/75% RH 0.08 99.78 0.07 0.07 25°C/60% RH 0.07 99.86 - - 0.07 4 weeks 40°C/75% RH 0.07 99.86 - - 0.07 25°C/60% RH 0.07 99.86 - - 0.07 6 weeks 40°C/75% RH 0.07 99.86 -- 0.07

- <0.05.

% area

Moment Approx. 1 (OVU Note 3 (OVU

API condition (OVU 1.00) time 0.81-1.74)

Initial Not analyzed 0.09 99.860.05 °C/60% RH 0.09 99.860.05 months °C/75% RH 0.09 99.860.05

Example 12 Form A solid state characterization.

Synthesis of initial solid state characterization of crystalline form A (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate, including pKa, measurement of partition coefficient (log D7 ,4) and 2-hour equilibrium

- 21 043074 solubility in FaSSIF and FeSSIF (version 2) are presented in this document. All results obtained are summarized in Table. 15. pKa values were first predetermined by Marvin® and then found by Sirius T3 to range from 2.0 to 12.0 (in triplicate). Log D7.4 was measured using a solvent system of phosphate buffer pH 7.4 and n-octanol using the shake flask method. Meanwhile, the measured 2-hour equilibrium solubility of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3(trifluoromethoxy)benzyl)piperazine-1-carboxylate in FaSSIF and FeSSIF (version 2) was 0. 12 and 0.080 mg/ml.

Table 15

Summary of pKa, Log D and solubility results 2-hour equilibrium pKa solubility (mg/mL) Log D ₇ .4 Estimated Measured FaSSIF FeSSIF pKa value pKa value

2.26.6.67 5.79 3.76 0.12 0.080

pKa values have been predetermined and found to range from 2.0 to 12.0 N/A: no measurements.

Example 13 Solubility of Form A

The approximate solubility of Form A was determined in 20 solvent systems at RT (room temperature). Approximately 2 mg of sample was added to a 3 ml glass vial. Solvents from the table. 16 was then added to the vials in stages (100 μl per stage) until the solids were visually dissolved or a total volume of 2 ml was reached. The results in relation to the solubility shown in table. 16 were used to select the solvent in the design of the screening experiment.

Table 16

Approximate solubility of Form A at RT

Solubility Solubility Solvent (mg/ml) Solvent (mg/ml) Meon S>23.0 1,4-dioxane S>22.0 EUN S>17.0 dhm S>19.0 IPA S>24.0 CHC1 ₃ S>19.0 Acetone S>17.0 ACN S>24.0 MIBK S>24.0 Anizol S>20.0 EtOAc S>26.0 Toluene 4.5<S<6.0 IPAc S>21.0 n-heptane S<0.9 MTBE 7.7<S<11.5 NMP S>21.0 THF S>26.0 DMSO S>20.0 2-MeTHF S>23.0 H ₂ O S>l,0

Example 14 Solubility of Form B

Solubility was evaluated after 2 hours for Form B in FaSSIF-v2 and FeSSIF-v2 at 37°C. Approximately 10 to 20 mg of Form B sample was added to 0.8 ml of the appropriate biologically significant medium to form a suspension, followed by shaking at 500 rpm at 37°C. After 2 hours, supernatants were isolated by centrifugation (7200 rpm for 5 min) followed by filtration through a 0.45 mm PTFE membrane and tested for concentration by HPLC and pH. Residual solids were characterized by XRPD. As summarized in Table. 17, form B was converted to a new form (form C) after solubility evaluation, while the measured solubility in FaSSIF-v2 and FeSSIF-v2 was 0.12 and 0.080 mg/mL, respectively.

Table 17

Summary of Form B Solubility Evaluation at 37°C

Wednesday Point in time (h) Solubility (mg/ml) Observation final form final pH FaSSIF (pH 6.5) 2 0.12 muddy Form C 6.6 FeSSIF (pH 5.8) 2 0.08 muddy Form C 5.9

Approximately 55 to 90 mg of form B was added to a 4 ml glass vial. Added solvents from the list in table. 18 in each vial. These samples were stirred for 3 min before visual solubility evaluation.

- 22 043074

Table 18

Summary of Form B Solubility Evaluation at Room Temperature _______

1 ethyl acetate >800 mg/ml 2 Isopropyl acetate <810 mg/ml 3 Acetone >430 mg/ml 4 dichloromethane >830 mg/ml 5 Acetonitrile >720 mg/ml 6 2-Me THF >810 mg/ml 7 H ₂ O / MeOH 1/3 (v / v) Aw ~ 0.5 >780 mg/ml 8 H ₂ O/MeCN 1/3 (v/v) Aw ~0.9 >730 mg/ml 10 EtOH >800 mg/ml eleven 2-Propanol >365 mg/ml 12 Nitromethane >560 mg/ml

Example 15 Antisolvent Addition Experiments

Experiments were carried out on the addition of an anti-solvent. In total, 8 experiments were carried out on the addition of an antisolvent. Approximately 15 mg of form A was dissolved in 0.5 ml of solvent to obtain a clear solution, and the solution was stirred with a magnetic stirrer, followed by the addition of anti-solvent to cause precipitation, until the total amount of anti-solvent reached 10 ml. The precipitate was isolated for XRPD analysis. Clear solutions were transferred to -20°C for 5 hours. The results summarized in table. 19 showed that only form A was obtained.

Table 19

Summary of Antisolvent Addition Experiments

Solvent Antisolvent solid form EtOH Form A* 1,4-dioxane H ₂ O Form A dmso Form A THF Form A EtOAc Form A CHCI3 n-heptane Form A* Acetone Form A* THF Form A*

*: These solids were obtained by suspending at -20°C.

Example 16 Slow Evaporation Experiments

Slow evaporation experiments were carried out under 6 conditions. Approximately 15 mg of form A was dissolved in 1.0 ml of the appropriate solvent in a 3 ml glass vial. Visually clear solutions were evaporated at RT to induce precipitation. Solids were isolated for XRPD analysis. The results summarized in table. 20 showed that form A, form B, and an amorphous substance were obtained.

Table 20

Generalization of experiments on slow evaporation

Solvent (v/v) solid form Meon Form A IPAc Form A 2-MeTHF amorphous ACN amorphous EtOH: _H2O (9:1) Form A ACN: _H2O (9:1) Form B

Example 17 Slow Cooling Experiments

Slow cooling experiments were carried out in 2 solvent systems. Approximately 50 mg Form A was suspended in 0.5-1.0 ml solvent in a 3 ml glass vial at RT. The suspension was then heated to 50° C., equilibrated for about 2 hours and filtered into a new vial. The filtrates were slowly cooled to 5° C. at a rate of 0.1° C./min. Clear solutions were transferred to -20° C. followed by evaporation to dryness at RT and then the solids were tested by XRPD. The results summarized in table. 21 showed that only form A was obtained.

- 23 043074

Table 21

Generalization of experiments on slow cooling

Solvent (v/v)

MTBE/EtOAc (9:1)

Toluene/EtOH (9:1)

solid form

Form A*

Form A* *: These solids were obtained by evaporation at RT.

Example 18 Slurry Conversion Experiments

Conducted experiments on the transformation of the suspension. Suspension conversion experiments were also carried out at RT in 7 different solvent systems. Approximately 20 mg Form A was suspended in 0.3-0.9 ml solvent in a glass HPLC vial. After stirring the suspensions for 5 days at RT, the remaining solids were isolated for XRPD analysis. After stirring, clear solutions were obtained to which the anti-solvent n-heptane was added to induce crystallization. The results summarized in table. 22 showed that only form A was obtained.

Table 22

Generalization of experiments on suspension transformation at RT

Solvent (v/v) solid form MTBE Form A Toluene Form A Acetone/n-heptane (1:2) Form A THF/n-heptane (1:2) Form A* 1,4-dioxane / H ₂ O (1: 2) Form A 1PA/N ₂ O (937/63, aw~0.5) Form A n ₂ o Form A

*: Solids were obtained after addition of the anti-solvent n-heptane.

Suspension conversion experiments were also carried out at 50° C. in 3 different solvent systems. Approximately 20 mg Form A was suspended in 0.4-1.0 ml solvent in a glass HPLC vial. After stirring the suspensions for 5 days at 50°C, the remaining solids were isolated for XRPD analysis. After stirring, clear solutions were obtained to which the anti-solvent n-heptane was added to induce crystallization. The results summarized in table. 23 showed that only form A was obtained.

Table 23

Generalization of slurry conversion experiments at 50°C

Solvent (v/v) Solid form

MTBE Form A*

Toluene Form A*

ITS Form A*: Solids were obtained after addition of the anti-solvent n-heptane.

Example 19 Liquid Vapor Diffusion Experiments.

Experiments were carried out on the diffusion of liquid vapors. Four experiments on the diffusion of liquid vapors were carried out. Approximately 15 mg of form A was dissolved in 0.5 ml of solvent to give a clear solution in a 3 ml vial. This solution was then placed into a 20 ml vial containing 4 ml of antisolvent. The 20 ml vial was sealed with a lid and kept at RT so that vapors of organic solvents interacted with the solution. The precipitates were isolated for XR PD analysis. The results summarized in table. 24 showed that Form A and Form B were obtained.

Table 24

Generalization of experiments on the diffusion of liquid vapors

Solvent Antisolvent solid form THF H ₂ O Form A EtOH Form A EtOAc n-heptane Form B SNS1 ₃ Form A

Example 20 Interconversion Study

A study of the mutual transformation of crystalline forms was carried out. In order to understand the relationship of thermodynamic stability between Form A and B, comparative suspension experiments were performed at RT and 50° C. in water and toluene. Prior to testing, Form A was used to saturate the appropriate solvent before being filtered to give an almost saturated solution. Equal quantities of Form A and Form B samples were weighed and then mixed with the prepared

- 24 043074 almost saturated solution to form a new suspension, which was stirred with a magnetic stirrer (~1000 rpm) at RT and 50°C. As summarized in Table. 25, Form A was obtained after suspending at RT and 50°C for 1~3 weeks, indicating that Form A was thermodynamically more stable than Form B from RT to 50°C.

Table 25

Thermodynamic stability study

original form Solvent (v/v) Temperature final form Form A+B _H2O /PhMe CT Form A Form A+B _H2O /PhMe 50°C Form A

Example 21 Comparative suspension study.

A comparative suspension study of all known forms from A to E was performed in water at room temperature to understand the relationship of thermodynamic stability among these forms. Form A was used to saturate the water before it was filtered to an almost saturated solution. Equal amounts of each form (from A to E) were weighed and then mixed with the prepared almost saturated solution to form a new suspension, which was stirred with a magnetic stirrer (~1000 rpm) at room temperature for 7 days. Solids were isolated and analyzed by XRPD and form A was obtained, indicating that form A is the thermodynamically most stable form at RT.

Example 22 Vapor Crystallization Experiments

A total of 9 different experiments were carried out. About 100 mg of form B was placed in a 4 ml glass vial, which was then placed in a 20 ml vial with 4 ml of the antisolvent in it. The 20 ml vial was capped and kept at RT to let the organic solvent vapor interact with the solid. After 7-10 days, wet solids were isolated and analyzed by XRPD. The results summarized in table. 26 showed that Form A and Form B were obtained.

Table 26

Generalization of experiments on crystallization under the action of vapors

Condition Result ethanol Form A DMSO Form A Isopropyl acetate Form A Methyl acetate Form B THF Transparent film after evaporation CH ₂ C1 ₂ Form B Cyclohexanone Form A Dimethylformamide Form A N-butyl acetate Form A

Methodology for characterization

Samples obtained as described by solid form screening were typically analyzed by X-ray powder diffraction (XRPD). XRPD was performed on an X-ray powder diffractometer from PANalytical Empyrean and X'Pert3 using Cu-Κα radiation at 1.54 A. In general, XRPD peak positions alone are expected to vary from measurement to measurement by about ±0.2°2θ. In general, as is understood in the art, two XRPD patterns match if the characteristic peaks of the first pattern are located at approximately the same positions as the characteristic peaks of the second pattern. As is understood in the art, determining whether two XRPD patterns match, or whether individual peaks in two XRPD patterns match, may require consideration of individual variables and parameters such as, but not limited to, preferred orientation, phase impurities, degree of crystallinity, particle size. , a change in diffractometer instrument setup, a change in XRPD data acquisition parameters, and/or a change in XRPD data processing, among other things. Determining whether two patterns match can be done by visual and/or computer analysis. An example of an XRPD pattern collected and analyzed using these methods and parameters is presented herein, for example, as in FIG. 1.

PANalytical Emptyrean

Scan Mode: Continuous

Detector: D/teX Ultra

Slit divergence: automatic

Starting angle: 3 deg.

Stop angle: 40 degrees

Step Width: 0.0200 deg.

- 25 043074

Scan time (s): 5.00 deg/min

Tilt angle: ½ deg.

Feed slot #1: 8,000 mm

Feed slot #2: 13,000 mm

Wavelength: Καί: 1.540598 A; Κα2: 1.5444426 A; intensity ratio Κα2/Κα1: 0.50; 40 kV, 44 mA.

X'Pert3

Scan Mode: Continuous

Spread gap: 1/8°

Starting angle: 3 deg.

Stop angle: 40 degrees

Step size: 0.0263 deg.

Scan Stage Time (s): 46.665

Test time: about 5 min

Wavelength: Κα1: 1.540598 A; Κα2: 1.5444426 A; intensity ratio Κα2/Κα1: 0.50

Differential scanning calorimetry (DSC) analyzes were performed on TA Q200/Q2000 instruments. Approximately 5 mg of sample was placed in a calibrated corrugated/open aluminum DSC crucible and the weight of the sample was accurately recorded. The heating rate was 10° C./min using nitrogen as the purge gas. An example of a DSC thermogram collected and analyzed using these methods and parameters is presented herein, for example, as in FIG. 2.

Thermogravimetric analyzes (TGA) were performed on TA Q500/Q5000 instruments. About 10 mg of sample was placed in an open aluminum crucible, accurately weighed, and loaded into a TGA oven. The heating rate was 10° C./min using nitrogen as the purge gas. An example of a TGA thermogram collected and analyzed using these methods and parameters is presented herein, for example, as in FIG. 2.

Dynamic Vapor Sorption (DVS) was performed on a DVS Intrinsic instrument from Surface Measurement Systems. Relative humidity at 25°C was calibrated by the melting time of LiCl, Mg(NO ₃ ) ₂ and KCl. Sample sizes were 10-20 mg. Gas and flow rate - nitrogen, 200 ml/min; dm/dt: 0.002%/min.

HPLC was performed on an Agilent 1100/1260. The analysis for form A was performed on Phenomenex Gemini C18, 150x4.6 mm, 3 μm (column). The mobile phase was 0.1% formic acid in water; flow rate 1.0 ml/min; column temperature 40°C; and UV detector 270 nm. Analysis for form B was performed on Kinetex, 5 µm, EVO C18, 150x4.6 mm, 5 µm (column). The mobile phase was 0.1% formic acid in acetonitrile; flow rate 1.0 ml/min; column temperature 40°C; and a 210 nm UV detector.

Proton NMR was collected on a Bruker 400 NMR spectrometer using DMSO-d ₆ .

The embodiments described above are intended as examples only, and those skilled in the art will recognize, or be able to ascertain using only routine experimentation, numerous equivalents of specific compounds, materials, and techniques. All such equivalents are considered to be within the scope of this invention and are covered by the appended claims.

The citation or definition of any reference in this application is not an admission that such reference is available as prior art. The full scope of the invention is best understood by reference to the appended claims.

Claims (46)

1. Crystal form A of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate, which has a powder x-ray diffraction pattern containing peaks at 18.1, 20.1 and 22.3°2θ±0.2°2θ. 2. The crystalline form A according to claim 1, wherein the X-ray powder diffraction pattern further contains peaks at 9.9, 19.9 and 24.7°2θ±0.2°2θ. 3. A crystalline form A according to claim 1 or 2, which has an X-ray powder diffraction pattern corresponding to the exemplary X-ray powder diffraction pattern shown in FIG. 1. 4. Crystal form A according to any one of claims 1 to 3, which has a differential scanning calorimetry thermogram containing an endotherm with a maximum point of about 113°C. 5. A crystalline form A according to any one of claims 1-4, which has a differential scanning calorimetry thermogram corresponding to the illustrative differential scanning calorimetry thermogram shown in FIG. 2. 6. Crystalline Form A according to any one of claims 1-5, which has a thermogravimetric analysis thermogram showing a weight loss of less than about 0.1% when heated from about 30 to about 150°C. - 26 043074 7. A crystalline form A according to any one of claims 1-6, which has a thermogravimetric analysis thermogram corresponding to the exemplary thermogravimetric analysis thermogram shown in FIG. 2. 8. Pharmaceutical composition containing crystalline form A according to any one of claims 1 to 7. 9. Crystal Form B of (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate which has a powder X-ray diffraction pattern containing peaks at 16.2, 18.2 and 19.2 °2θ±0.2 °2θ. 10. Crystal Form B according to claim 9, wherein the X-ray powder diffraction pattern further contains peaks at 15.1, 18.7 and 20.1°2θ±0.2°2θ. 11. Crystal form B according to claim 9 or 10, which has an x-ray powder diffraction pattern corresponding to the exemplary powder x-ray diffraction pattern shown in FIG. 7. 12. Crystal form B according to any one of claims 9-11, which has a differential scanning calorimetry thermogram containing an endotherm with a maximum point of about 95°C. 13. Crystal Form B according to any one of claims 9-12, which has a differential scanning calorimetry thermogram corresponding to the illustrative differential scanning calorimetry thermogram shown in FIG. 8. 14. Crystal form B according to any one of claims 9-13, which has a thermogravimetric analysis thermogram showing a weight loss of less than about 1.0% when heated from about 30 to about 150°C. 15. A crystalline Form B according to any one of claims 9-14 which has a thermogravimetric analysis thermogram corresponding to the exemplary thermogravimetric analysis thermogram shown in FIG. 8. 16. Pharmaceutical composition containing crystalline form B according to any one of claims 9-15. 17. Crystalline form of C(R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate which has a powder X-ray diffraction pattern containing peaks at 18.0, 20.0 and 21.0 °2θ±0.2 °2θ. 18. Crystal form C according to claim 17, wherein the powder X-ray diffraction pattern further contains peaks at 12.3, 16.8 and 25.5°2θ±0.2°2θ. 19. The crystalline Form C of claim 17 or 18 which has an X-ray powder diffraction pattern corresponding to the exemplary X-ray powder diffraction pattern shown in FIG. 9. 20. Crystal form C according to any one of claims 17-19, which has a differential scanning calorimetry thermogram containing an endotherm with a maximum point of about 99°C. 21. Crystalline Form C according to any one of claims 17-20, which has a differential scanning calorimetry thermogram corresponding to the exemplary differential scanning calorimetry thermogram shown in FIG. 10. 22. Crystalline Form C according to any one of claims 17-21, which has a thermogravimetric analysis thermogram showing a weight loss of less than about 1.0% when heated from about 30 to about 150°C. 23. A crystalline Form C according to any one of claims 17-22 which has a thermogravimetric analysis thermogram corresponding to the exemplary thermogravimetric analysis thermogram shown in FIG. 10. 24. Pharmaceutical composition containing crystalline form C according to any one of claims 17-23. 25. Crystal form D(R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate which has a powder X-ray diffraction pattern containing peaks at 13.4, 21.0 and 23.8°2θ±0.2°2θ. 26. The crystalline Form D of claim 25, wherein the X-ray powder diffraction pattern further contains peaks at 18.3, 26.7, and 29.5°2θ±0.2°2θ. 27. The D crystalline form of claim 24 or 25 which has a powder x-ray pattern corresponding to the exemplary powder x-ray diffraction pattern shown in FIG. eleven. 28. Crystal form D according to any one of claims 24-27, which has a differential scanning calorimetry thermogram containing an endotherm with a maximum point of about 101°C. 29. A crystalline form D according to any one of claims 24-28, which has a differential scanning calorimetry thermogram corresponding to the exemplary differential scanning calorimetry thermogram shown in FIG. 12. 30. A crystalline form D according to any one of claims 24-29, which has a thermogravimetric analysis thermogram showing a weight loss of less than about 1.0% when heated from about 30 to about 150°C. 31. A crystalline form D according to any one of claims 24-30 which has a thermogravimetric analysis thermogram corresponding to the exemplary thermogravimetric analysis thermogram shown in FIG. 12. - 27 043074 32. Pharmaceutical composition containing crystalline form D according to any one of claims 24-31. 33. Crystalline Form E (R)-5-carbamoylpyridin-3-yl-2-methyl-4-(3-(trifluoromethoxy)benzyl)piperazine-1-carboxylate which has a powder X-ray diffraction pattern containing peaks at 17.8, 21.3 and 22.8°2θ±0.2°2θ. 34. The crystalline Form E of claim 33, wherein the X-ray powder diffraction pattern further contains peaks at 15.8, 18.4, and 21.9°2θ±0.2°2θ. 35. A crystalline form E according to claim 33 or 34 which has an X-ray powder diffraction pattern corresponding to the exemplary X-ray powder diffraction pattern shown in FIG. 13. 36. Crystal form E according to any one of claims 33-35, which has a differential scanning calorimetry thermogram containing an endotherm with a maximum point of about 104°C. 37. A crystalline form E according to any one of claims 33-36 which has a differential scanning calorimetry thermogram corresponding to the illustrative differential scanning calorimetry thermogram shown in FIG. 14. 38. A crystalline form E according to any one of claims 33-37, which has a thermogravimetric analysis thermogram showing a weight loss of less than about 1.0% when heated from about 30 to about 150°C. 39. A crystalline form E according to any one of claims 33-38, which has a thermogravimetric analysis thermogram corresponding to the exemplary thermogravimetric analysis thermogram shown in FIG. 14. 40. Pharmaceutical composition containing crystalline Form E according to any one of claims 33-39. 41. A method of treating pain, comprising administering to a subject a composition containing a crystalline form according to any one of claims 1-40. 42. A method of treating neurological disorders, comprising administering to a subject a composition containing a crystalline form according to any one of claims 1-40. 43. A method of treating anxiety, comprising administering to a subject a composition containing a crystalline form according to any one of claims 1-40. 44. A method of treating inflammatory bowel disease, comprising administering to a subject a composition comprising a crystalline form according to any one of claims 1-40. 45. A method of treating neuropathic pain, comprising administering to a subject a composition containing a crystalline form according to any one of claims 1-40. 46. A method of treating cancer cell proliferation and migration, comprising administering to a subject a composition containing a crystalline form according to any one of claims 1-40.