Polymorphic forms of soluble epoxide hydrolase inhibitors and formulations thereof

Abstract

In aspects, the present invention encompasses crystalline forms of soluble epoxide hydrolase inhibitors having a range of characteristics that facilitate formulation and administration. In one aspect, the disclosure provides a method of treating a soluble epoxide hydrolase (sEH) mediated disorder or disease in a subject by administering to the subject a composition of the invention.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Application Nos. 63 / 421,961, filed November 2, 2022, and 63 / 457,722, filed April 6, 2023. The disclosures of the prior applications are considered part of the disclosure of the present application and are incorporated herein by reference in their entirety into the disclosure of the present application.

[0003] Government Rights Statement

[0004] This disclosure was made in part by the National Institute of Neurological Disorders and Stroke (NINDS) Blueprint Neurotherapeutics Network UC3 / UH3NS094258. The government has certain rights in this invention. Background Art

[0005] Soluble epoxide hydrolase (sEH, EC 3.3.2.10) is a bifunctional enzyme present in the cytosol and cytosolic peroxisomal fractions in mammals. sEH has a dual function (hydrolyzing bioepoxides and lipid phosphoryl groups) and thus plays a central role in numerous lipid anabolism, catabolism, and signaling pathways. Therefore, sEH disorders may exacerbate or manifest as metabolic disorders, inflammatory disorders, systemic disorders, and cardiovascular disorders. Of particular clinical significance is that changes in sEH expression appear to be associated with a variety of diseases, including certain cancers, neurodegenerative diseases, and various types of diabetes. Therefore, controlling sEH activity in patients with and at-risk patients may provide a means to control the pathogenesis of a variety of diseases.

[0006] Despite this, targeted sEH inhibition remains a major challenge. sEH inhibitor design faces the challenge of simultaneously meeting the following requirements: water solubility, which is necessary for sEH delivery, and an extended hydrophobic structure, which is important for sEH binding affinity. The sEH active site, which is configured to bind to a variety of fatty acid substrates, contains two deep hydrophobic pockets on either side of the hydrophilic epoxide binding core. Due to these limitations, drug delivery in sEH is generally limited. Summary of the Invention

[0007] The present disclosure provides a crystalline form of formula (I) having high purity, stability and compliance suitable for drug delivery platforms, and thus provides an improved approach for selectively targeting sEH. Although formula (I) is an effective sEH inhibitor, its amorphous form has limited solvent compatibility, may have a relatively slow dissolution rate and is difficult to prepare in a homogeneous, uniform manner in a pharmaceutical formulation. The properties of the crystalline form of formula (I) disclosed herein are different from those of the amorphous form of formula (I), and thus expand the options for formulating formula (I) beyond previously available options.

[0008] Aspects of the present disclosure provide a composition comprising an anhydrous crystalline form of formula (I):

[0009]

[0010] or a pharmaceutically acceptable salt thereof. In some embodiments, the anhydrous crystalline form of formula (I) comprises less than 2.9% water content. In some embodiments, the anhydrous crystalline form of formula (I) comprises less than 1.0% water content. In some embodiments, the anhydrous crystalline form of formula (I) has a purity of at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% by weight. In some embodiments, the composition comprises less than 5% by weight of degradation products of formula (I), less than 3% by weight of degradation products of formula (I), less than 2% by weight of degradation products of formula (I) or less than 1% by weight of degradation products of formula (I). In some embodiments, the anhydrous crystalline form of formula (I) is prepared by substantially as follows Figure 1 Characterized by an X-ray powder diffraction pattern shown in any one of panels A to L of .

[0011] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0012]

[0013] or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form D, such as by substantially Figure 1 In some embodiments, at least 80% of the composition of Formula (I) is in Form D, at least 85% of the composition of Formula (I) is in Form D, at least 90% of the composition of Formula (I) is in Form D, at least 95% of the composition of Formula (I) is in Form D, at least 98% of the composition of Formula (I) is in Form D, or at least 99% of the composition of Formula (I) is in Form D.

[0014] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0015]

[0016] or a pharmaceutically acceptable salt thereof, wherein the crystalline form of formula (I) comprises Form A, such as by substantially Figure 1 In some embodiments, at least 80% of the composition of Formula (I) is in Form A, at least 85% of the composition of Formula (I) is in Form A, at least 90% of the composition of Formula (I) is in Form A, at least 95% of the composition of Formula (I) is in Form A, at least 98% of the composition of Formula (I) is in Form A, or at least 99% of the composition of Formula (I) is in Form A.

[0017] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0018]

[0019] or a pharmaceutically acceptable salt thereof, wherein the crystalline form of formula (I) comprises Form B, such as by substantially Figure 1 In some embodiments, at least 80% of the composition of Formula (I) is in Form B, at least 85% of the composition of Formula (I) is in Form B, at least 90% of the composition of Formula (I) is in Form B, at least 95% of the composition of Formula (I) is in Form B, at least 98% of the composition of Formula (I) is in Form B, or at least 99% of the composition of Formula (I) is in Form B.

[0020] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0021]

[0022] or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form C, such as by substantially Figure 1 Small Figure C In some embodiments, at least 80% of the composition of Formula (I) is in Form C, at least 85% of the composition of Formula (I) is in Form C, at least 90% of the composition of Formula (I) is in Form C, at least 95% of the composition of Formula (I) is in Form C, at least 98% of the composition of Formula (I) is in Form C, or at least 99% of the composition of Formula (I) is in Form C.

[0023] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0024]

[0025] or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form E, such as by substantially Figure 1 In some embodiments, at least 80% of the composition of Formula (I) is in Form E, at least 85% of the composition of Formula (I) is in Form E, at least 90% of the composition of Formula (I) is in Form E, at least 95% of the composition of Formula (I) is in Form E, at least 98% of the composition of Formula (I) is in Form E, or at least 99% of the composition of Formula (I) is in Form E.

[0026] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0027]

[0028] or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form F, such as by substantially Figure 1 In some embodiments, at least 80% of the composition of Formula (I) is in Form F, at least 85% of the composition of Formula (I) is in Form F, at least 90% of the composition of Formula (I) is in Form F, at least 95% of the composition of Formula (I) is in Form F, at least 98% of the composition of Formula (I) is in Form F, or at least 99% of the composition of Formula (I) is in Form F.

[0029] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0030]

[0031] or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form G, such as by substantially Figure 1 In some embodiments, at least 80% of the composition of Formula (I) is in Form G, at least 85% of the composition of Formula (I) is in Form G, at least 90% of the composition of Formula (I) is in Form G, at least 95% of the composition of Formula (I) is in Form G, at least 98% of the composition of Formula (I) is in Form G, or at least 99% of the composition of Formula (I) is in Form G.

[0032] A composition comprising a crystalline form of formula (I):

[0033]

[0034] or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form H, such as by substantially Figure 1 In some embodiments, at least 80% of the composition of Formula (I) is in Form H, at least 85% of the composition of Formula (I) is in Form H, at least 90% of the composition of Formula (I) is in Form H, at least 95% of the composition of Formula (I) is in Form H, at least 98% of the composition of Formula (I) is in Form H, or at least 99% of the composition of Formula (I) is in Form H.

[0035] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0036]

[0037] or a pharmaceutically acceptable salt thereof, wherein the crystalline form of formula (I) comprises Form I, such as by substantially Figure 1 In some embodiments, at least 80% of the composition of Formula (I) is in Form I, at least 85% of the composition of Formula (I) is in Form I, at least 90% of the composition of Formula (I) is in Form I, at least 95% of the composition of Formula (I) is in Form I, at least 98% of the composition of Formula (I) is in Form I, or at least 99% of the composition of Formula (I) is in Form I.

[0038] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0039]

[0040] or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) includes Form J, such as by substantially Figure 1 In some embodiments, at least 80% of the composition of Formula (I) is in Form J, at least 85% of the composition of Formula (I) is in Form J, at least 90% of the composition of Formula (I) is in Form J, at least 95% of the composition of Formula (I) is in Form J, at least 98% of the composition of Formula (I) is in Form J, or at least 99% of the composition of Formula (I) is in Form J.

[0041] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0042]

[0043] or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form K, such as by substantially Figure 1In some embodiments, at least 80% of the composition of Formula (I) is in Form K, at least 85% of the composition of Formula (I) is in Form K, at least 90% of the composition of Formula (I) is in Form K, at least 95% of the composition of Formula (I) is in Form K, at least 98% of the composition of Formula (I) is in Form K, or at least 99% of the composition of Formula (I) is in Form K.

[0044] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0045]

[0046] or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form L, such as by substantially Figure 1 Small Figure L In some embodiments, at least 80% of the composition of Formula (I) is in Form L, at least 85% of the composition of Formula (I) is in Form L, at least 90% of the composition of Formula (I) is in Form L, at least 95% of the composition of Formula (I) is in Form L, at least 98% of the composition of Formula (I) is in Form L, or at least 99% of the composition of Formula (I) is in Form L.

[0047] In some embodiments, the crystalline form of formula (I) comprises at least 98% of formula (I) by weight. In some embodiments, the crystalline form of formula (I) comprises at least 99% of formula (I) by weight. In some embodiments, the crystalline form of formula (I) has an average particle size between about 10 microns and about 100 microns. In some embodiments, the crystalline form of formula (I) has an average particle size between about 2 microns and about 12 microns. In some embodiments, the crystalline form of formula (I) has a melting temperature between 140°C and 145°C. In some embodiments, the crystalline form of formula (I), wherein the crystalline form of formula (I) has a melting temperature between 145°C and 150°C. In some embodiments, the crystalline form of formula (I) has a heat of fusion of at least 25J / g. In some embodiments, the crystalline form of formula (I) has a heat of fusion of at least 50J / g. In some embodiments, the crystalline form of formula (I) has a heat of fusion of at least 55J / g. In some embodiments, the crystalline form of formula (I) has less than 10% solvent by weight. In some embodiments, the crystalline form of formula (I) has less than 5% solvent by weight. In some embodiments, the crystalline form of formula (I) is stable for at least 28 days at 25° C. and 0% humidity. In some embodiments, the crystalline form of formula (I) is stable for at least 180 days at 25° C. and 0% humidity.

[0048] Aspects of the present disclosure provide a method for producing a crystalline form of formula (I), the method comprising: dissolving formula (I) in a solvent system comprising acetone, acetonitrile, dichloromethane, dioxane, isopropanol, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ether, n-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or a combination thereof at a temperature between 35°C and 80°C, and cooling the solvent system to a temperature between 0°C and 30°C. In some embodiments, the dissolution is carried out at a temperature between 50°C and 75°C. In some embodiments, the cooling brings the solvent to a temperature between 27°C and -20°C. In some embodiments, the cooling brings the solvent system to a temperature between 10°C and -20°C. In some embodiments, the cooling is at a rate between 0.1°C / hour and 600°C / hour. In some embodiments, the solvent system comprises a secondary solvent in which formula (I) has a solubility of up to 5 mg / mL. In some embodiments, the secondary solvent is water or a C5-C 12 In some embodiments, the secondary solvent is hexane or heptane. In some embodiments, the secondary solvent is cyclohexane or n-heptane. In some embodiments, the method further comprises seeding the solid formula (I) into the solvent system after the dissolution. In some embodiments, the solid formula (I) is any one of Forms A to L. In some embodiments, the method further comprises adding an additional volume of the secondary solvent during or after the cooling period.

[0049] Aspects of the present disclosure provide a method for producing a crystalline form of Formula (I), comprising: (i) dissolving Formula (I) in a solvent system comprising at least 90% methanol or at least 90% toluene, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 60°C / hour and 600°C / hour; (ii) dissolving Formula (I) in a solvent system comprising water and a solvent selected from the group consisting of acetonitrile and acetone, and cooling the solvent system to a temperature between 0°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (iii) dissolving Formula (I) in a solvent system comprising water and acetonitrile to a concentration of at least about 0.4 mg / ml, and cooling the solvent system to a temperature between 0°C and 30°C at a rate between 60°C / hour and 600°C / hour; (iv) incubating Form C of Formula (I) at a temperature between 40°C and 90°C for at least 1 hour; or (v) a combination thereof. In some embodiments, (i) and (iii) comprise cooling the solvent system to a temperature between -20°C and 30°C at a rate between 60°C / hour and 150°C / hour. In some embodiments, (ii) comprises cooling the solvent system to a temperature between 0°C and 30°C at a rate between 1°C / hour and 30°C / hour. In some embodiments, the solvent system of (ii) comprises water at a ratio between 5:1 and 1:5 and a solvent selected from the group consisting of acetonitrile and acetone. In some embodiments, the solvent system of (ii) comprises water at a ratio between 2:1 and 1:2 and a solvent selected from the group consisting of acetonitrile and acetone. In some embodiments, the crystalline form is at least 80% Form A, at least 85% Form A, at least 90% Form A, at least 95% Form A, at least 98% Form A, or at least 99% Form A.

[0050] Aspects of the present disclosure provide a method for producing a crystalline form of formula (I), comprising: (i) dissolving formula (I) in a solvent system comprising at least 90% methanol, at least 90% ethanol, at least 90% isopropanol, or at least 90% n-butanol, and cooling the solvent system at a rate between 0.1°C / hour and 40°C / hour to a temperature between -20°C and 30°C; (ii) dissolving formula (I) in a solvent system comprising at least 90% ethanol, at least 90% isopropanol, or at least 90% n-butanol, and cooling the solvent system at a rate between 60°C / hour and 600°C / hour to a temperature between -20°C and 30°C; ii) dissolving formula (I) in a solvent system comprising water and n-propanol and cooling the solvent system to a temperature between 0°C and 30°C at a rate between 60°C / hour and 600°C / hour; (iv) dissolving formula (I) in a solvent system comprising hexane and dioxane and cooling the solvent system to a temperature between 12°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (v) dissolving formula (I) in a solvent system comprising hexane and acetonitrile to a concentration of up to 0.1 mg / ml and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; or a combination thereof. In some embodiments, (i) and (v) comprise cooling the solvent system to a temperature between 0°C and 30°C at a rate between 1°C / hour and 30°C / hour. In some embodiments, (ii) and (iii) comprise cooling the solvent system to a temperature between 4° C. and 30° C. at a rate between 60° C. / hour and 150° C. / hour. In some embodiments, the solvent system of (iii) comprises water and n-propanol in a volume to volume ratio of 5:1 to 1:5. In some embodiments, the solvent system of (iv) comprises hexane and dioxane in a volume to volume ratio of 5:1 to 1:5. In some embodiments, the solvent system of (v) comprises hexane and acetonitrile in a volume to volume ratio of 10:1 to 150:1. In some embodiments, the crystalline form is at least 80% Form B, at least 85% Form B, at least 90% Form B, at least 95% Form B, at least 98% Form B, or at least 99% Form B.

[0051] Aspects of the present disclosure provide a method for producing a crystalline form of formula (I), the method comprising: (i) dissolving formula (I) in a solvent system comprising water and methanol, and cooling the solvent system to a temperature between 0°C and 30°C at a rate between 60°C / hour and 600°C / hour; (ii) incubating formula (I) in water for at least one hour; (iii) incubating formula (I) in a polyethylene glycol (PEG) water mixture comprising at least 50% water by volume for at least one hour; or (iv) a combination thereof. In some embodiments, (i) comprises cooling the solvent system to a temperature between 0°C and 15°C at a rate between 60°C / hour and 150°C / hour. In some embodiments, (ii) comprises incubating formula (I) in water for at least one day. In some embodiments, (iii) comprises incubating formula (I) in a polyethylene glycol (PEG) water mixture comprising at least 50% water by volume for at least one day. In some embodiments, (ii) and (iii) comprise incubating solid formula (I). In some embodiments, the crystalline form is at least 80% Form C, at least 85% Form C, at least 90% Form C, at least 95% Form C, at least 98% Form C, or at least 99% Form C.

[0052] Aspects of the present disclosure provide a method for producing a crystalline form of formula (I), the method comprising: (i) dissolving formula (I) in a solvent system comprising heptane and a solvent selected from the group consisting of dimethyl sulfoxide and n-methyl-2-pyrrolidone, and cooling the formula (I) to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 600°C / hour; (ii) dissolving formula (I) in a solvent system comprising water and dimethylformamide to a concentration of up to 0.25 mg / ml, and cooling the solvent system to a temperature between 0°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (iii) dissolving formula (I) in a solvent system comprising heptane and a solvent selected from the group consisting of ethanol, isopropanol and ethyl acetate, and cooling the formula (I) to a concentration between -20°C and 30°C at a rate between 0.1°C / hour and 600°C / hour. (iv) dissolving Formula (I) in a solvent system comprising hexane and dimethyl sulfoxide and cooling at a rate between 0.1°C / hour and 40°C / hour to a temperature between -20°C and 30°C; (v) dissolving Formula (I) in a solvent system comprising hexane and isopropanol to a concentration of at least 0.4 mg / ml and cooling the solvent system at a rate between 0.1°C / hour and 40°C / hour to a temperature between -20°C and 30°C; (vi) incubating Formula (I) in heptane for at least 1 day; (vii) incubating Formula (I) in a polyethylene glycol:water mixture comprising greater than 50% polyethylene glycol by volume for at least 1 hour; or (viii) combinations thereof. In some embodiments, (i) comprises cooling the solvent system to a temperature between -10°C and 15°C at a rate between 60°C / hour and 150°C / hour. In some embodiments, (ii) to (v) comprise cooling the solvent system to a temperature between 10°C and 30°C at a rate between 1°C / hour and 30°C / hour. In some embodiments, the solvent system of (i) comprises heptane at a ratio between 10:1 and 200:1 to the solvent selected from the group consisting of dimethyl sulfoxide and n-methyl-2-pyrrolidone. In some embodiments, the solvent system of (ii) comprises water and dimethylformamide at a ratio between 5:1 and 1:5. In some embodiments, the solvent system of (iii) comprises heptane at a ratio between 5:1 and 1:5 to the solvent selected from the group consisting of ethanol, isopropanol, and ethyl acetate. In some embodiments, the solvent system of (iv) comprises hexane and dimethyl sulfoxide at a ratio between 10:1 and 200:1. In some embodiments, the solvent system of (v) comprises heptane and isopropanol in a ratio of between 3:1 and 40:1.In some embodiments, the crystalline form is at least 80% Form E, at least 85% Form D, at least 90% Form D, at least 95% Form D, at least 98% Form D, or at least 99% Form D.

[0053] Aspects of the present disclosure provide a method for producing a crystalline form of formula (I), the method comprising: (i) dissolving formula (I) in a solvent system comprising heptane and a solvent selected from the group consisting of methanol, ethanol, acetonitrile, isopropanol, acetone and n-propanol, and cooling the solvent system at a rate between 60°C / hour and 600°C / hour to a temperature between -20°C and 30°C; (ii) dissolving formula (I) in a solvent system comprising heptane and a solvent selected from the group consisting of methanol, ethanol, acetonitrile and n-propanol, and cooling the solvent system at a rate between 0.1°C / hour and 40°C / hour to a temperature between -20°C and 30°C; (iii) dissolving formula (I) in a solvent system comprising heptane and methyl alcohol (iv) dissolving Formula (I) in a solvent system comprising heptane and isopropanol to a concentration of up to 0.25 mg / ml, the solvent system comprising heptane and isopropanol, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (v) dissolving Formula (I) in a solvent system comprising hexane and methanol, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (vi) incubating Formula (I) in heptane for less than one day; or (vii) a combination thereof. In some embodiments, (i) comprises cooling the solvent system to a temperature between -10°C and 15°C at a rate between 60°C / hour and 150°C / hour. In some embodiments, (ii) to (v) include cooling the solvent system to a temperature between 10°C and 30°C at a rate between 1°C / hour and 30°C / hour. In some embodiments, the solvent system of (i) comprises heptane and methanol, ethanol, acetonitrile, isopropanol or n-propanol in a ratio between 5:1 and 200:1. In some embodiments, the solvent system of (i) comprises heptane and acetone in a ratio between 1:1 and 15:1. In some embodiments, the solvent system of (ii) comprises heptane and methanol, ethanol, acetonitrile or n-propanol in a ratio between 5:1 and 200:1. In some embodiments, the solvent system of (iii) comprises heptane and methyl ethyl ketone in a ratio between 1:1 and 15:1. In some embodiments, the solvent system of (iv) comprises heptane and isopropanol in a ratio between 5:1 and 100:1. In some embodiments, the solvent system of (v) comprises hexane and methanol in a ratio between 10:1 and 200:1. In some embodiments, (vi) comprises incubating solid Formula (I) in heptane for less than one day.In some embodiments, the crystalline form is at least 80% Form E, at least 85% Form E, at least 90% Form E, at least 95% Form E, at least 98% Form E, or at least 99% Form E.

[0054] Aspects of the present disclosure provide a method for producing a crystalline form of formula (I), the method comprising: (i) dissolving formula (I) in a solvent system comprising water and a solvent selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dimethyl sulfoxide, dimethylformamide, N-methyl-2-pyrrolidone (NMP), and cooling the solvent system to a temperature between 0°C and 30°C at a rate between 60°C / hour and 600°C / hour; (ii) dissolving formula (I) in the solvent system to a concentration of up to 0.25 mg / ml, the solvent system comprising (iii) dissolving the compound of formula (I) in a solvent system comprising heptane and dimethylformamide, and cooling the solvent system at a rate between 60°C / hour and 600°C / hour to a temperature between -20°C and 30°C; (iv) dissolving the compound of formula (I) in a solvent system comprising hexane and a solvent selected from the group consisting of ethanol, NMP and n-propanol, and cooling the solvent system at a rate between 60°C / hour and 600°C / hour to a temperature between -20°C and 30°C. (v) dissolving the compound of formula (I) in a solvent system comprising hexane and dioxane, and cooling the solvent system at a rate between 60°C / hour and 600°C / hour to a temperature between 4°C and 30°C; (vi) dissolving the compound of formula (I) in a solvent system comprising water and a solvent selected from the group consisting of ethanol, tetrahydrofuran, dimethylformamide and n-propanol, and cooling the solvent system at a rate between 0.1°C / hour and 40°C / hour to a temperature between 0°C and 30°C. (vii) dissolving formula (I) in a solvent system comprising heptane and dimethyl sulfoxide, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (viii) dissolving formula (I) in a solvent system comprising hexane and a solvent selected from the group consisting of methanol, isopropanol, dimethylformamide, and n-propanol, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; or (ix) a combination thereof. In some embodiments, (i) to (iv) comprise cooling the solvent system to a temperature between 0°C and 15°C at a rate between 60°C / hour and 150°C / hour. In some embodiments, (v) comprises cooling the solvent system to a temperature between 4°C and 15°C at a rate between 60°C / hour and 150°C / hour.In some embodiments, (vi) to (viii) include cooling the solvent system to a temperature between 10°C and 30°C at a rate between 1°C / hour and 30°C / hour. In some embodiments, the solvent system of (i) comprises water and methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dimethyl sulfoxide, dimethylformamide, or NMP in a ratio between 5:1 and 1:5. In some embodiments, the solvent system of (ii) comprises water and acetonitrile in a ratio between 5:1 and 1:5. In some embodiments, the solvent system of (iii) comprises heptane and dimethylformamide in a ratio between 10:1 and 200:1. In some embodiments, the solvent system of (iv) comprises hexane and ethanol, NMP, or n-propanol in a ratio between 5:1 and 100:1. In some embodiments, the solvent system of (v) comprises hexane and dioxane in a ratio between 5:1 and 1:5. In some embodiments, the solvent system of (vi) comprises water and ethanol, tetrahydrofuran, dimethylformamide, or n-propanol in a ratio between 5:1 and 1:5. In some embodiments, the solvent system of (vii) comprises heptane and dimethyl sulfoxide in a ratio between 10:1 and 200:1. In some embodiments, the solvent system of (viii) comprises hexane and methanol, isopropanol, dimethylformamide, or n-propanol in a ratio between 10:1 and 200:1. In some embodiments, the crystalline form is at least 80% Form F, at least 85% Form F, at least 90% Form F, at least 95% Form F, at least 98% Form F, or at least 99% Form F.

[0055] Aspects of the present disclosure provide a process for producing a crystalline form of formula (I), comprising: (i) dissolving formula (I) in a solvent system comprising at least 90% tetrahydrofuran or at least 90% methyl ethyl ketone, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (ii) dissolving formula (I) in a solvent system comprising at least 90% dioxane, and cooling the solvent system to a temperature between 12°C and 30°C at a rate between 0.1°C / hour and 600°C / hour. ℃; (iii) dissolving formula (I) in a solvent system comprising at least 90% tetrahydrofuran and cooling the solvent system at a rate between 60 ℃ / hour and 600 ℃ / hour to a temperature between -20 ℃ and 30 ℃; (iv) dissolving formula (I) in a solvent system comprising water and dioxane and cooling the solvent system at a rate between 0.1 ℃ / hour and 600 ℃ / hour to a temperature between 12 ℃ and 30 ℃; (v) dissolving formula (I) in a solvent system comprising heptane and dioxane, and The solvent system is cooled at a rate between 0.1°C / hour and 600°C / hour to a temperature between 4°C and 30°C; (vi) formula (I) is dissolved in a solvent system comprising heptane and tetrahydrofuran, and the solvent system is cooled at a rate between 60°C / hour and 600°C / hour to a temperature between -20°C and 30°C; (vii) formula (I) is dissolved in a solvent system comprising hexane and acetone to a concentration of up to 0.25 mg / ml, and the solvent system is cooled at a rate between 60°C / hour and 600°C / hour to a temperature between -20°C and 30°C. (viii) dissolving Formula (I) in a solvent system comprising hexane and tetrahydrofuran and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (ix) dissolving Formula (I) in a solvent system comprising hexane and dioxane to a concentration of at least 0.4 mg / ml and cooling the solvent system to a temperature between 12°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; or (x) a combination thereof. In some embodiments, (i) comprises cooling the solvent system to a temperature between 0°C and 30°C at a rate between 1°C / hour and 30°C / hour. In some embodiments, (iv) comprises water to dioxane in a ratio between 5:1 and 1:5. In some embodiments, (v) comprises heptane to dioxane in a ratio between 3:1 and 60:1. In some embodiments, (vi) comprises heptane and tetrahydrofuran in a ratio of between 5:1 and 1:5.In some embodiments, (viii) comprises hexane to tetrahydrofuran in a ratio between 5:1 and 1:5. In some embodiments, (ix) comprises hexane to dioxane in a ratio between 5:1 and 1:5. In some embodiments, the crystalline form is at least 80% Form G, at least 85% Form G, at least 90% Form G, at least 95% Form G, at least 98% Form G, or at least 99% Form G.

[0056] Aspects of the present disclosure provide a process for producing a crystalline form of formula (I), comprising: (i) dissolving formula (I) in a solvent system comprising at least 90% 2-methyltetrahydrofuran or at least 90% isopropyl acetate, and cooling the solvent system at a rate between 0.1°C / hour and 600°C / hour to a temperature between -20°C and 30°C; (ii) dissolving formula (I) in a solvent system comprising at least 90% methyl isobutyl ketone, and cooling the solvent system at a rate between 0.1°C / hour and 40°C / hour to a temperature between -20°C and 30°C; (iii) dissolving formula (I) in a solvent system comprising hexane and a solvent selected from the group consisting of acetonitrile and tetrahydrofuran, and cooling the solvent system at a rate between 60°C / hour and 600°C / hour to a temperature between -20°C and 30°C. (iv) dissolving formula (I) in a solvent system comprising hexane and acetone to a concentration of at least 0.4 mg / ml, the solvent system comprising hexane and acetone, and cooling the solvent system at a rate of between 60°C / hour and 600°C / hour to a temperature between -20°C and 30°C; (v) dissolving formula (I) in a solvent system comprising hexane and acetone, and cooling the solvent system at a rate of between 0.1°C / hour and 40°C / hour to a temperature between -20°C and 30°C; (vi) dissolving formula (I) in a solvent system comprising hexane and acetonitrile to a concentration of at least 0.5 mg / ml, the solvent system comprising hexane and acetonitrile, and cooling the solvent system at a rate of between 0.1°C / hour and 40°C / hour to a temperature between -20°C and 30°C; or (vii) a combination thereof. In some embodiments, (i), (ii), (v) and (vi) comprise cooling the solvent system to a temperature between 0°C and 30°C at a rate between 1°C / hour and 30°C / hour. In some embodiments, (i), (iii) and (iv) comprise cooling the solvent system to a temperature between 0°C and 30°C at a rate between 60°C / hour and 150°C / hour. In some embodiments, (iii) or (vi) comprises hexane and acetonitrile in a ratio between 5:1 and 100:1. In some embodiments, (iii) comprises hexane and tetrahydrofuran in a ratio between 5:1 and 1:5. In some embodiments, (iv) or (v) comprises hexane and acetone in a ratio between 5:1 and 1:5. In some embodiments, the crystalline form is at least 80% Form H, at least 85% Form H, at least 90% Form H, at least 95% Form H, at least 98% Form H or at least 99% Form H.

[0057] Aspects of the present disclosure provide a method for producing a crystalline form of formula (I), the method comprising: (i) dissolving formula (I) in a solvent system comprising at least 90% dichloromethane and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 600°C / hour; (ii) dissolving formula (I) in a solvent system to a concentration of up to 0.25 mg / ml, the solvent system comprising at least 90% acetonitrile and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 60°C / hour and 600°C / hour; or (iii) a combination thereof. In some embodiments, (i) and (ii) comprise cooling to a temperature between 0°C and 30°C at a rate between 60°C / hour and 150°C / hour. In some embodiments, the crystalline form is at least 80% Form I, at least 85% Form I, at least 90% Form I, at least 95% Form I, at least 98% Form I, or at least 99% Form I.

[0058] Aspects of the present disclosure provide a method for producing a crystalline form of Formula (I), comprising dissolving Formula (I) in a solvent system comprising at least 90% toluene, and cooling the solvent system at a rate between 0.1° C. / hour and 40° C. / hour to a temperature between −20° C. and 30° C. In some embodiments, the method comprises cooling the solvent system at a rate between 1° C. / hour and 30° C. / hour to a temperature between 0° C. and 30° C. In some embodiments, the crystalline form is at least 80% Form J, at least 85% Form J, at least 90% Form J, at least 95% Form J, at least 98% Form J, or at least 99% Form J.

[0059] Aspects of the present disclosure provide a method for producing a crystalline form of Formula (I), comprising: (i) dissolving Formula (I) in a solvent system comprising at least 90% methyl tert-butyl ether and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 600°C / hour; (ii) incubating Formula (I) in methyl tert-butyl ether for at least one hour; or (iii) a combination thereof. In some embodiments, the method comprises cooling the solvent system to a temperature between 0°C and 30°C at a rate between 1°C / hour and 150°C / hour. In some embodiments, the crystalline form is at least 80% Form K, at least 85% Form K, at least 90% Form K, at least 95% Form K, at least 98% Form K, or at least 99% Form K.

[0060] Aspects of the present disclosure provide a method for producing a crystalline form of formula (I), the method comprising: (i) dissolving formula (I) in a solvent system comprising water and isopropanol to a concentration of at least 0.4 mg / ml, the solvent system comprising water and isopropanol, and cooling the solvent system to a temperature between 0°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (ii) dissolving formula (I) in a solvent system comprising hexane and acetonitrile to a concentration of at least about 0.2 mg / ml, the solvent system comprising hexane and acetonitrile, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (iii) dissolving formula (I) in a solvent system comprising heptane and tetrahydrofuran, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 60°C / hour and 600°C / hour; or (iv) a combination thereof. In some embodiments, (i) and (ii) comprise cooling the solvent system at a rate between 1°C / hour and 40°C / hour to a temperature between 10°C and 30°C. In some embodiments, (iii) comprises cooling the solvent system at a rate between 60°C / hour and 150°C / hour to a temperature between 0°C and 30°C. In some embodiments, (i) comprises water to isopropanol in a ratio between 5:1 and 1:5. In some embodiments, (ii) comprises hexane to acetonitrile in a ratio between 5:1 and 1:5. In some embodiments, the crystalline form is at least 80% Form L, at least 85% Form L, at least 90% Form L, at least 95% Form L, at least 98% Form L, or at least 99% Form L.

[0061] Aspects of the present disclosure provide a method for treating a soluble epoxide hydrolase (sEH)-mediated disorder or disease in a subject, comprising administering the composition to the subject, thereby treating the disorder or disease in the subject. In some embodiments, the sEH-mediated disorder or disease is selected from the group consisting of: pain, epileptic disorder, epilepsy, Parkinson's disease, Alzheimer's disease, depression, spinal cord injury, peripheral nerve injury, stroke, multiple sclerosis, cognitive dysfunction, nephropathy, cardiomyopathy, wound healing, and inflammation. In some embodiments, the sEH-mediated disorder or disease is selected from the group consisting of: pain, epileptic disorder, nephropathy, cardiomyopathy, wound healing, and inflammation. In some embodiments, the pain is neuropathic pain. In some embodiments, the neuropathic pain is associated with nerve damage. In some embodiments, the nerve damage is caused by diabetes or other diseases. In some embodiments, the pain is diabetic neuropathic pain. In some embodiments, the pain is inflammatory pain. In some embodiments, the epileptic disorder is epilepsy.

[0062] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0063]

[0064] Or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) includes Form A, as characterized by an X-ray powder diffraction pattern comprising peaks at 3.3±0.3°2θ, 30.3±0.3°2θ, and 20.0±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 12.1±0.3°2θ, 15.6±0.3°2θ, and 6.0±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 21.7±0.3°2θ, 10.6±0.3°2θ, and 21.6±0.3°2θ.

[0065] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0066]

[0067] Or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) includes Form B, as characterized by an X-ray powder diffraction pattern comprising peaks at 12.2 ± 0.3 ° 2θ, 3.5 ± 0.3 ° 2θ, and 17.2 ± 0.3 ° 2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 19.6 ± 0.3 ° 2θ, 13.1 ± 0.3 ° 2θ, and 18.0 ± 0.3 ° 2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, at least three, or at least four peaks selected from the group consisting of 20.2 ± 0.3 ° 2θ, 14.1 ± 0.3 ° 2θ, 17.6 ± 0.3 ° 2θ, and 14.8 ± 0.3 ° 2θ.

[0068] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0069]

[0070] Or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) includes Form C, as characterized by an X-ray powder diffraction pattern comprising peaks at 16.3 ± 0.3 ° 2θ, 16.1 ± 0.3 ° 2θ, and 3.2 ± 0.3 ° 2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 21.6 ± 0.3 ° 2θ, 23.2 ± 0.3 ° 2θ, and 21.7 ± 0.3 ° 2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 16.5 ± 0.3 ° 2θ, 21.4 ± 0.3 ° 2θ, and 10.7 ± 0.3 ° 2θ.

[0071] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0072]

[0073] Or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) includes Form D, as characterized by an X-ray powder diffraction pattern comprising peaks at 20.1±0.3°2θ, 18.3±0.3°2θ, and 18.1±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one or at least two peaks selected from 20.3±0.3°2θ and 17.1±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, at least three, or at least four peaks selected from 3.4±0.3°2θ, 19.6±0.3°2θ, 23.4±0.3°2θ, and 25.1±0.3°2θ.

[0074] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0075]

[0076] Or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) includes Form E, as characterized by an X-ray powder diffraction pattern comprising peaks at 13.4 ± 0.3 ° 2θ, 11.2 ± 0.3 ° 2θ, and 3.1 ± 0.3 ° 2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 9.0 ± 0.3 ° 2θ, 22.2 ± 0.3 ° 2θ, and 14.3 ± 0.3 ° 2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 14.9 ± 0.3 ° 2θ, 18.4 ± 0.3 ° 2θ, and 16.8 ± 0.3 ° 2θ.

[0077] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0078]

[0079] Or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) includes Form F, as characterized by an X-ray powder diffraction pattern comprising peaks at 14.6 ± 0.3 ° 2θ, 3.4 ± 0.3 ° 2θ, and 9.7 ± 0.3 ° 2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 18.1 ± 0.3 ° 2θ, 20.2 ± 0.3 ° 2θ, and 16.7 ± 0.3 ° 2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 17.6 ± 0.3 ° 2θ, 19.2 ± 0.3 ° 2θ, and 17.3 ± 0.3 ° 2θ.

[0080] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0081]

[0082] Or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) includes Form G, as characterized by an X-ray powder diffraction pattern comprising peaks at 18.2±0.3°2θ, 3.2±0.3°2θ, and 18.0±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 10.8±0.3°2θ, 19.2±0.3°2θ, and 5.4±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 10.6±0.3°2θ and 21.7±0.3°2θ.

[0083] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0084]

[0085] Or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) includes Form H, as characterized by an X-ray powder diffraction pattern comprising peaks at 8.8±0.3°2θ, 3.4±0.3°2θ, and 21.4±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, at least three, or at least four peaks selected from the group consisting of 17.9±0.3°2θ, 14.5±0.3°2θ, 12.7±0.3°2θ, and 8.7±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 14.8±0.3°2θ, 12.8±0.3°2θ, and 21.2±0.3°2θ.

[0086] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0087]

[0088] Or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) includes Form I, as characterized by an X-ray powder diffraction pattern comprising peaks at 12.0 ± 0.3 ° 2θ, 12.3 ± 0.3 ° 2θ, and 3.2 ± 0.3 ° 2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 14.5 ± 0.3 ° 2θ, 18.1 ± 0.3 ° 2θ, and 13.4 ± 0.3 ° 2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 18.6 ± 0.3 ° 2θ, 24.8 ± 0.3 ° 2θ, and 19.1 ± 0.3 ° 2θ.

[0089] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0090]

[0091] Or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) includes Form J, as characterized by an X-ray powder diffraction pattern comprising peaks at 15.5 ± 0.3 ° 2θ, 15.7 ± 0.3 ° 2θ, and 17.6 ± 0.3 ° 2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from 15.1 ± 0.3 ° 2θ, 11.4 ± 0.3 ° 2θ, and 15.0 ± 0.3 ° 2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from 3.4 ± 0.3 ° 2θ, 20.2 ± 0.3 ° 2θ, and 21.0 ± 0.3 ° 2θ.

[0092] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0093]

[0094] Or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) includes Form K, as characterized by an X-ray powder diffraction pattern comprising peaks at 5.3±0.3°2θ, 14.5±0.3°2θ, and 7.3±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, at least three, at least four, or at least five peaks selected from the group consisting of 20.9±0.3°2θ, 3.4±0.3°2θ, 21.1±0.3°2θ, 7.4±0.3°2θ, and 14.8±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises a peak at 17.4±0.3°2θ.

[0095] Aspects of the present disclosure provide a composition comprising a crystalline form of formula (I):

[0096]

[0097] or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) includes Form L, as characterized by an X-ray powder diffraction pattern comprising peaks at 8.9±0.3°2θ, 3.4±0.3°2θ, and 18.3±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from 14.4±0.3°2θ, 21.9±0.3°2θ, and 18.0±0.3°2θ. In some embodiments, the X-ray powder diffraction pattern further comprises at least one, at least two, at least three, at least four, or at least five peaks selected from 14.3±0.3°2θ, 13.2±0.3°2θ, 20.0±0.3°2θ, 19.3±0.3°2θ, and 14.9±0.3°2θ.

[0098] Aspects of the present disclosure provide a composition comprising an amorphous form of formula (I):

[0099]

[0100] or a pharmaceutically acceptable salt thereof.

[0101] Aspects of the present disclosure provide a method of producing an amorphous form of formula (I):

[0102]

[0103] It includes converting the non-amorphous form of formula (I) into an amorphous form of the formula (I). In some embodiments, the conversion includes an amorphous solid dispersion method. In some embodiments, the amorphous solid dispersion method includes hot melt extrusion or spray drying. In some embodiments, the non-amorphous form of formula (I) includes a crystalline form of formula (I). In some embodiments, the crystalline form of formula (I) is any one of Forms A to L. In some embodiments, the crystalline form of formula (I) is Form D.

[0104] In some embodiments, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% of Formula (I) is amorphous. In some embodiments, at most about 50%, at most about 45%, at most about 40%, at most about 35%, at most about 30%, at most about 25%, at most about 20%, at most about 15%, at most about 10%, at most about 5%, at most about 4%, at most about 3%, at most about 2%, at most about 1%, or at most about 0.5% of Formula (I) is amorphous.

[0105] Incorporated by Reference

[0106] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0107] The novel features of the present invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description which sets forth illustrative embodiments in which the principles of the invention are utilized, and in the accompanying drawings which illustrate:

[0108] Figure 1 Panel A provides a representative X-ray powder diffraction spectrum (XRD) of Form A of Formula (I). Figure 1 Panel B provides a representative XRD of Form B of Formula (I). Figure 1 Small Figure C A representative XRD of Form C of Formula (I) is provided. Figure 1 Panel D provides a representative XRD of Form D of Formula (I). Figure 1 Panel E provides a representative XRD of Form E of Formula (I). Figure 1 Panel F provides a representative XRD of Form F of Formula (I). Figure 1 Panel G provides a representative XRD of Form G of Formula (I). Figure 1 Panel H provides a representative XRD of Form H of Formula (I). Figure 1 Panel I provides a representative XRD of Form I of Formula (I). Figure 1 Panel J provides a representative XRD of Form J of Formula (I). Figure 1 Panel K provides a representative XRD of Form K of Formula (I). Figure 1 Small Figure L A representative XRD of Form L of Formula (I) is provided.

[0109] Figure 2 A representative differential scanning calorimetry (DSC) thermogram of Form A of Formula (I) is provided.

[0110] Figure 3 A representative DSC thermogram of Form B of Formula (I) is provided.

[0111] Figure 4 A representative DSC thermogram of Form C of Formula (I) is provided.

[0112] Figure 5 A representative DSC thermogram of Form D of Formula (I) is provided.

[0113] Figure 6 A representative DSC thermogram of Form E of Formula (I) is provided.

[0114] Figure 7 A representative DSC thermogram of Form F of Formula (I) is provided.

[0115] Figure 8 A representative DSC thermogram of Form G of Formula (I) is provided.

[0116] Figure 9 A representative DSC thermogram of Form H of Formula (I) is provided.

[0117] Figure 10 A representative DSC thermogram of Form I of Formula (I) is provided.

[0118] F Figure 11 A representative DSC thermogram of Form J of Formula (I) is provided.

[0119] Figure 12 A representative DSC thermogram of Form K of Formula (I) is provided.

[0120] Figure 13 A representative DSC thermogram of Form L of Formula (I) is provided.

[0121] Figure 14 A representative thermogravimetric analysis (TGA) thermogram of Form A of Formula (I) is provided.

[0122] Figure 15A representative TGA thermogram of Form B of Formula (I) is provided.

[0123] Figure 16 A representative TGA thermogram of Form C of Formula (I) is provided.

[0124] Figure 17 A representative TGA thermogram of Form D of Formula (I) is provided.

[0125] Figure 18 A representative TGA thermogram of Form E of Formula (I) is provided.

[0126] Figure 19 A representative TGA thermogram of Form F of Formula (I) is provided.

[0127] Figure 20 A representative TGA thermogram of Form G of Formula (I) is provided.

[0128] Figure 21 A representative TGA thermogram of Form H of Formula (I) is provided.

[0129] Figure 22 A representative TGA thermogram of Form I of Formula (I) is provided.

[0130] Figure 23 A representative TGA thermogram of Form J of Formula (I) is provided.

[0131] Figure 24 A representative TGA thermogram of Form K of Formula (I) is provided.

[0132] Figure 25 A representative TGA thermogram of Form L of Formula (I) is provided.

[0133] Figure 26 A representative nuclear magnetic resonance (NMR) spectrum of Form A of Formula (I) is provided.

[0134] Figure 27 A representative NMR spectrum of Form B of Formula (I) is provided.

[0135] Figure 28 A representative NMR spectrum of Form C of Formula (I) is provided.

[0136] Figure 29 A representative NMR spectrum of Form D of Formula (I) is provided.

[0137] Figure 30 A representative NMR spectrum of Form E of Formula (I) is provided.

[0138] Figure 31 A representative NMR spectrum of Form F of Formula (I) is provided.

[0139] Figure 32 A representative NMR spectrum of Form G of Formula (I) is provided.

[0140] Figure 33 A representative NMR spectrum of Form H of Formula (I) is provided.

[0141] Figure 34 A representative NMR spectrum of Form I of Formula (I) is provided.

[0142] Figure 35 A representative NMR spectrum of Form J of Formula (I) is provided.

[0143] Figure 36 A representative NMR spectrum of Form K of Formula (I) is provided.

[0144] Figure 37 A representative NMR spectrum of Form L of Formula (I) is provided.

[0145] Figure 38 A calibration curve for polarized optical microscopy analysis at 254 nm is provided.

[0146] Figure 39 XRD spectra of Form B of Formula (I) at the ten milligram scale (top) and the hundred milligram scale (bottom) are shown.

[0147] Figure 40 XRD spectra of Form A of Formula (I) at the ten milligram scale (top) and the hundred milligram scale (bottom) are shown.

[0148] Figure 41 XRD spectra of Form L of Formula (I) at the ten milligram scale (top) and the hundred milligram scale (bottom) are shown.

[0149] Figure 42 XRD spectra of Form A of Formula (I) at the ten milligram scale (top) and the hundred milligram scale (bottom) are shown.

[0150] Figure 43 XRD spectra of Form D of Formula (I) at the ten milligram scale (top) and the hundred milligram scale (bottom) are shown.

[0151] Figure 44 XRD spectra of Form H of Formula (I) at the ten milligram scale (top) and the hundred milligram scale (bottom) are shown.

[0152] Figure 45 XRD spectra of Form L of Formula (I) at the ten milligram scale (top) and the hundred milligram scale (bottom) are shown.

[0153] Figure 46A DSC thermogram of Form B of Formula (I) is provided.

[0154] Figure 47 A DSC thermogram of Form A of Formula (I) is provided.

[0155] Figure 48 A DSC thermogram of Form L of Formula (I) is provided.

[0156] Figure 49 A DSC thermogram of Form A of Formula (I) is provided.

[0157] Figure 50 A DSC thermogram of Form D of Formula (I) is provided.

[0158] Figure 51 A DSC thermogram of Form H of Formula (I) is provided.

[0159] Figure 52 A DSC thermogram of Form L of Formula (I) is provided.

[0160] Figure 53 A DSC thermogram of Form B of Formula (I) is provided.

[0161] Figure 54 A DSC thermogram of Form A of Formula (I) is provided.

[0162] Figure 55 A DSC thermogram of Form L of Formula (I) is provided.

[0163] Figure 56 A DSC thermogram of Form A of Formula (I) is provided.

[0164] Figure 57 A DSC thermogram of Form D of Formula (I) is provided.

[0165] Figure 58 A DSC thermogram of Form H of Formula (I) is provided.

[0166] Figure 59 A DSC thermogram of Form L of Formula (I) is provided.

[0167] Figure 60 An XRD spectrum of Form I of Formula (I) is provided.

[0168] Figure 61 An XRD spectrum of Form G of Formula (I) is provided.

[0169] Figure 62 An XRD spectrum of Form F of Formula (I) is provided.

[0170] Figure 63 An XRD spectrum of Form E of Formula (I) is provided.

[0171] Figure 64 Representative XRD spectra of Form C of Formula (I) (top), Formula (I) after 1 day incubation in water (middle), and Formula (I) after 7 days incubation in water (bottom) are provided.

[0172] Figure 65 Representative XRD spectra of Form K of Formula (I) (top), Formula (I) after 1 day incubation in MTBE (middle), and Formula (I) after 7 days incubation in MTBE (bottom) are provided.

[0173] Figure 66 Representative XRD spectra are provided for Form D of Formula (I) (top), Form E of Formula (I) (second from the top), Formula (I) after 1 day of incubation in n-heptane (second from the bottom), and Formula (I) after 7 days of incubation in n-heptane (bottom).

[0174] Figure 67 Representative XRD spectra are provided for Form A of formula (I) (top), Form D of formula (I) (second from the top), Formula (I) after one day of incubation in n-heptane at 70°C (second from the bottom), and Formula (I) after seven days of incubation in n-heptane at 70°C (bottom).

[0175] Figure 68 Representative XRD spectra are provided for Form D of formula (I) (top), Form E of formula (I) (second from the top), Formula (I) after one day of incubation in n-heptane at 70°C (second from the bottom), and Formula (I) after seven days of incubation in n-heptane at 70°C (bottom).

[0176] Figure 69 Representative XRD spectra are provided for Form A of Formula (I) (top), Form E of Formula (I) (second from the top), Formula (I) after one day of incubation in n-heptane (second from the bottom), and Formula (I) after seven days of incubation in n-heptane (bottom).

[0177] Figure 70 Representative XRD spectra of Form D of Formula (I) (top), Formula (I) after one day of incubation in n-heptane (middle), and Formula (I) after seven days of incubation in n-heptane (bottom) are provided.

[0178] Figure 71 Representative XRD spectra of Form E of Formula (I) (top), Formula (I) after one day of incubation in n-heptane (middle), and Formula (I) after seven days of incubation in n-heptane (bottom) are provided.

[0179] Figure 72Representative XRD spectra are provided for Form C of Formula (I) (top), Form E of Formula (I) (second from the top), Formula (I) after one day of incubation in n-heptane (second from the bottom), and Formula (I) after seven days of incubation in n-heptane (bottom).

[0180] Figure 73 Representative XRD spectra of Form A of Formula (I) (top), Form A of Formula (I) after incubation at 60°C for 1 day (middle), and Form A of Formula (I) after incubation at 60°C for 7 days (bottom) are provided.

[0181] Figure 74 Representative XRD spectra are provided for Form B of formula (I) (top), Form D of formula (I) (second from the top), Form D of formula (I) after incubation at 60°C bottom for 1 day (second from the bottom), and Form D of formula (I) after incubation at 60°C bottom for 7 days (bottom).

[0182] Figure 75 Representative XRD spectra of Form D of formula (I) (top), Form D of formula (I) after incubation at 60°C for 1 day (middle), and Form D of formula (I) after incubation at 60°C for 7 days (bottom) are provided.

[0183] Figure 76 Representative XRD spectra of Form E of formula (I) (top), Form E of formula (I) after incubation at 60°C for 1 day (middle), and Form E of formula (I) after incubation at 60°C for 7 days (bottom) are provided.

[0184] Figure 77 Representative XRD spectra of Form F of formula (I) (top), Form F of formula (I) after incubation at 60°C for 1 day (middle), and Form F of formula (I) after incubation at 60°C for 7 days (bottom) are provided.

[0185] Figure 78 Representative XRD spectra of Form G of formula (I) (top), Form L of formula (I) (second from the top), Form G of formula (I) after incubation at 60°C bottom for 1 day (middle), and Form G of formula (I) after incubation at 60°C bottom for 7 days (bottom) are provided.

[0186] Figure 79 Representative XRD spectra of Form I of formula (I) (top), Form I of formula (I) after incubation at 60°C for 1 day (middle), and Form I of formula (I) after incubation at 60°C for 7 days (bottom) are provided.

[0187] Figure 80Representative XRD spectra are provided for Form A of formula (I) (top), Form C of formula (I) (second from the top), Form A of formula (I) starting (middle), Form A of formula (I) after incubation at 60°C bottom for 1 day (second from the bottom), and Form A of formula (I) after incubation at 60°C bottom for 7 days (bottom).

[0188] Figure 81 Provided is an HPLC chromatogram of Form D of Formula (I) prior to high temperature incubation.

[0189] Figure 82 Provided is an HPLC chromatogram of Form D of Formula (I) after incubation at 60°C for 1 day.

[0190] Figure 83 Provided is an HPLC chromatogram of Form D of Formula (I) after incubation at 60°C for 7 days.

[0191] Figure 84 XRD spectra of Form D of formula (I) are provided, wherein the top spectrum corresponds to a representative Form D pattern, the second spectrum from the top corresponds to Form D of formula (I) before humidity exposure, the second spectrum from the bottom corresponds to Form D of formula (I) after 4 days of humidity exposure, and the bottom spectrum corresponds to Form D of formula (I) after 14 days of humidity exposure.

[0192] Figure 85 XRD spectra of Form C of formula (I) (top), Form D of formula (I) (second from the top), a mixture of Form C and Form D after incubation in PEG300 containing 75% water (third from the top), a mixture of Form C and Form D after incubation in PEG300 containing 50% water (middle), a mixture of Form C and Form D after incubation in PEG300 containing 25% water (third from the bottom), a mixture of Form C and Form D after incubation in PEG300 containing 10% water (second from the bottom), and a mixture of Form C and Form D after incubation in PEG300 containing 5% water (bottom) are provided.

[0193] Figure 86 A representative HPLC chromatogram of Formula (I) after incubation in diethylene glycol monoethyl ether is provided.

[0194] Figure 87 Representative XRD spectra are provided for Form A of Formula (I) (top), Form C of Formula (I) (second from the top), and three batches of Formula (I) (bottom three spectra).

[0195] Figure 88 A DSC thermogram of Formula (I) is provided.

[0196] Figure 89A TGA thermogram of Formula (I) is provided.

[0197] Figure 90 A modulated DSC thermogram of formula (I) is provided.

[0198] Figure 91 Two polarized light microscopy images of formula (I) are provided.

[0199] Figure 92 A dynamic vapor adsorption diagram of formula (I) is provided.

[0200] Figure 93 A DSC thermogram of Formula (I) is provided.

[0201] Figure 94 A TGA thermogram of Formula (I) is provided.

[0202] Figure 95 Two polarized light microscopy images of formula (I) are provided.

[0203] Figure 96 A dynamic vapor adsorption diagram of formula (I) is provided.

[0204] Figure 97 A DSC thermogram of Formula (I) is provided.

[0205] Figure 98 XRD spectra of Form D of Formula (I) (top) and three separate formulations of Formula (I) (bottom three spectra) are provided.

[0206] Figure 99 XRD spectra of several polymorphs of formula (I) are provided.

[0207] Figure 100 XRD spectra of Form D of Formula (I) (top) and a sample of Formula (I) produced from a crystal seeding experiment are provided.

[0208] Figure 101 XRD spectra of Formula (I) having 2.5% (top), 5% (second from the top), 7.5% (third from the top), 10% (middle), and 15% (second from the bottom) Form C mixed into Form D are provided, along with representative spectra of Form D (second from the bottom) and Form C (bottom).

[0209] Figure 102 Provided from Figure 101 A magnified form of the XRD spectrum.

[0210] Figure 103 XRD data are provided for unmilled Form D of Formula (I) (top and middle) and milled Form D of Formula (I) (bottom).

[0211] Figure 104 A DSC thermogram of milled Form D of Formula (I) is provided.

[0212] Figure 105 Provided are thermograms of Form D of Formula (I) in micronized form (top), Form D of Formula (I) after 5 minutes of milling (second from the top), Form D of Formula (I) after 10 minutes of milling (second from the bottom), and Form D of Formula (I) after 15 minutes of milling (bottom).

[0213] Figure 106 Provided are optical microscopy images of unmilled Form D of Formula (I).

[0214] Figure 107 Provided are optical microscopy images of milled Form D of Formula (I).

[0215] Figure 108 Particle size data is provided for unmilled Form D of Formula (I) using a pressure of 2.5 bar.

[0216] Figure 109 Particle size data is provided for unmilled Form D of Formula (I) using a pressure of 3.0 bar.

[0217] Figure 110 Particle size data is provided for unmilled Form D of Formula (I) using a pressure of 3.5 bar.

[0218] Figure 111 Particle size data is provided for Form D of Formula (I) milled using a pressure of 2.5 bar.

[0219] Figure 112 Particle size data is provided for Form D of Formula (I) milled using a pressure of 3.0 bar.

[0220] Figure 113 Particle size data is provided for Form D of Formula (I) milled using a pressure of 3.5 bar. Figure 114 Particle size data is provided for unmilled Form D of Formula (I) using 2.5 bar pressure and high energy venturi.

[0221] Figure 115 Particle size data is provided for unmilled Form D of Formula (I) using 3.0 bar pressure and a high energy venturi.

[0222] Figure 116 Particle size data is provided for unmilled Form D of Formula (I) using 3.5 bar pressure and high energy venturi.

[0223] Figure 117 Particle size data is provided for Form D of Formula (I) using 2.5 bar pressure and high energy venturi milling.

[0224] Figure 118 Particle size data is provided for Form D of Formula (I) using 3.0 bar pressure and high energy venturi milling.

[0225] Figure 119 Particle size data is provided for Form D of Formula (I) using 3.5 bar pressure and high energy venturi milling.

[0226] Figure 120 XRD spectra of Form C of Formula (I) (top) and amorphous Formula (I) (bottom) are provided.

[0227] Figure 121 A DSC thermogram of the amorphous form of Formula (I) is provided.

[0228] Figures 122 to 123 The kinetic solubility data for sodium lauryl sulfate (SLS) of formula (I) over 180 and 90 minutes are summarized.

[0229] Figure 124 Provided are XRD spectra of Form C of Formula (I) (top), Form (D) of Formula (I) (second from the top), unmilled Form D of Formula (I) after 5 minutes of incubation in SLS (third from the top), unmilled Form D of Formula (I) after 60 minutes of incubation in SLS (third from the bottom), unmilled Form D of Formula (I) after 90 minutes of incubation in SLS (second from the bottom), and unmilled Form D of Formula (I) after 180 minutes of incubation in SLS.

[0230] Figure 125 Provided are XRD spectra of Form C of Formula (I) (top), Form (D) of Formula (I) (second from the top), milled Form D of Formula (I) after 5 minutes of incubation in SLS (third from the top), milled Form D of Formula (I) after 60 minutes of incubation in SLS (third from the bottom), milled Form D of Formula (I) after 90 minutes of incubation in SLS (second from the bottom), and milled Form D of Formula (I) after 180 minutes of incubation in SLS.

[0231] Figure 126 XRD spectra of Form C of Formula (I) (top), Form (D) of Formula (I) (second from the top), amorphous form of Formula (I) after 5 minutes of incubation in SLS (third from the top), amorphous form of Formula (I) after 60 minutes of incubation in SLS (third from the bottom), amorphous form of Formula (I) after 90 minutes of incubation in SLS (second from the bottom), and amorphous form of Formula (I) after 180 minutes of incubation in SLS are provided.

[0232] Figure 127A DSC thermogram of Formula (I) is provided.

[0233] Figure 128 Provided is a compound of formula (I) 1 H NMR spectrum.

[0234] Figure 129 Provided is a compound of formula (I) 13 C NMR spectrum.

[0235] Figure 130 Provided is a compound of formula (I) 19 F NMR spectrum.

[0236] Figures 131A to L Representative X-ray powder diffraction spectra of various polymorphs of Formula (I) are provided. Figure 131A A representative X-ray powder diffraction spectrum (XRD) of Form A of Formula (I) is provided. Figure 131B A representative XRD of Form B of Formula (I) is provided. Figure 131C A representative XRD of Form C of Formula (I) is provided. Figure 131D A representative XRD of Form D of Formula (I) is provided. Figure 131E A representative XRD of Form E of Formula (I) is provided. Figure 131F A representative XRD of Form F of Formula (I) is provided. Figure 131G A representative XRD of Form G of Formula (I) is provided. Figure 131H A representative XRD of Form H of Formula (I) is provided. Figure 131I A representative XRD of Form I of Formula (I) is provided. Figure 131J A representative XRD of Form J of Formula (I) is provided. Figure 131K A representative XRD of Form K of Formula (I) is provided. Figure 131L A representative XRD of Form L of Formula (I) is provided. DETAILED DESCRIPTION

[0237] Soluble epoxide hydrolase (sEH) is the core of various forms of lipid metabolism and may be involved in the degradation of cytochrome P450 oxidation xenobiotics. Although the sEH active site is selective for hydrophobic substances (typically simulating its natural lipid substrate), sEH is mainly located in the cytosol and cytosolic peroxisomal fractions, and therefore can usually only be targeted by aqueous substances. Therefore, sEH inhibitor delivery is usually the main barrier to sEH regulation. As a way to solve this challenge, the present disclosure provides a series of polymorphic forms of sEH inhibitors (Formula (I)), which have physical properties that are very suitable for formulation and therapeutic use.

[0238] The compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0239] As used herein, the terms "a," "an," and "the" include plural referents unless the context dictates otherwise.

[0240] As used herein and in the claims, the terms "comprising," "containing," and "including" are inclusive and open-ended and do not exclude additional, unrecited elements, components, or method steps. Thus, the terms "comprising" and "including" encompass the relatively more restrictive terms "consisting of" and "consisting essentially of."

[0241] As used herein, "soluble epoxide hydrolase" ("sEH") refers to an enzyme that converts EETs into dihydroxy derivatives called dihydroxyeicosatrienoic acids ("DHETs") in endothelial cells, smooth muscle cells, and other cell types. The cloning and sequence of mouse sEH are shown in Grant et al., J. Biol. Chem. 268(23): 17628-17633 (1993). The cloning, sequence, and accession number of the human sEH sequence are shown in Beetham et al., Arch. Biochem. Biophys. 305(1): 197-201 (1993). The amino acid sequence of human sEH is also shown in SEQ ID NO: 2 of U.S. Patent No. 5,445,956; the nucleic acid sequence encoding human sEH is shown in nucleotides 42 to 1703 of SEQ ID NO: 1 of that patent. The evolution and nomenclature of the gene are discussed in Beetham et al., DNA Cell Biol. 14(1):61-71 (1995). Soluble epoxide hydrolase represents a highly conserved gene product with greater than 90% homology between rodents and humans (Arand et al., FEBS Lett., 338:251-256 (1994)).

[0242] As used herein, the terms "active pharmaceutical ingredient," "active ingredient," "API," "drug," "active," "actives," and "therapeutic agent" are used interchangeably to refer to one or more pharmaceutically active compounds in a pharmaceutical composition. This is in contrast to other ingredients in the composition, such as excipients, which are substantially or completely pharmaceutically inert. Suitable APIs according to the present disclosure include those for which patient compliance issues exist or may exist when treating a disease, condition, or disorder. Therapeutic agents, as used herein, include active compounds and salts, prodrugs, and metabolites thereof.

[0243] As used herein, the term "drug" refers to a compound intended for use in the diagnosis, cure, mitigation, treatment and / or prevention of disease in humans or other animals.

[0244] As used herein, the term "subject" includes animals, such as mammals, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some embodiments, the subject is a human.

[0245] As used herein, the terms "treat," "treating," and "treatment" may refer to a method of alleviating or eliminating a disease or its attendant symptoms.

[0246] Unless otherwise indicated, references in this application to "a compound" or "compounds" (such as compounds of Formula (I), Formula (II), Formula (III), and Formula (IV)) include polymorphic forms, amorphous forms, salt forms, free base forms, acid salt forms, cocrystal forms, and solvate forms of these formulae and / or compounds. Thus, appearances of the phrases "compound," "a compound of Formula (I)," "compounds of Formula (I)," etc. include polymorphic forms of compounds of Formula (I), such as Forms A to L of compounds of Formula (I) further disclosed herein.

[0247] "Crystalline form" and "polymorph" are used interchangeably herein and are meant to include all crystalline forms of a compound, including, for example, polymorphs and pseudopolymorphs.

[0248] The term "form" may be understood to encompass the terms "crystalline form" and "polymorph," as well as other descriptions of physical state (e.g., "solvated," "amorphous," etc.). Unless otherwise specified, the term "form" may refer to salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, and mixtures thereof.

[0249] For example, when referring to an X-ray powder diffraction (XRPD) pattern, the term "substantially as shown" includes patterns that are not necessarily identical to those depicted herein but that fall within the limits of experimental error or deviation when considered by one of ordinary skill in the art.

[0250] The relative intensities of XRPD peaks may vary depending on particle size, sample preparation technique, sample mounting procedure, and the specific instrument used.

[0251] In addition, instrument variations and other factors may also affect the 2θ(20) values.

[0252] Thus, when a specified 2θ angle is provided, it is understood that the specified 2θ angle may vary by the specified value of 0.50, such as 0.40, 0.30, 0.20, or 0.10.

[0253] As used herein, the term "major peak" refers to an XRPD peak with a relative intensity greater than 30%, such as greater than 35%. Relative intensity is calculated as the ratio of the peak intensity of the peak of interest to the peak intensity of the largest peak in the XRPD pattern.

[0254] The compounds of the present disclosure include crystalline and amorphous forms of these compounds, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0255] It is further understood that all compounds disclosed herein include all possible isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 12 C. 13 C and 14 C.

[0256] As used herein, the term "dosage form" may refer to the form in which a compound or composition of the disclosure is delivered to a patient and includes physical form (eg, microcrystals, micelles, etc.) and characteristics (eg, powder compressed into a pellet form).

[0257] As used herein, the term "combination therapy" may refer to the use of a compound, composition, or therapy described herein in combination with one or more additional compounds, compositions, or therapies (e.g., radiation therapy). Two or more compounds, compositions, therapies, or combinations thereof may be administered together or provided in different administration regimens and / or dosage forms.

[0258] As used herein, the term "pharmaceutical composition" may refer to the combination of an active agent and a pharmaceutically acceptable excipient (e.g., carrier) that makes the composition suitable or enhances its suitability for in vitro, in vivo, and / or ex vivo diagnostic or therapeutic use.

[0259] As used herein, the term "compound" is intended to include not only the specified molecular entity, but also pharmaceutically acceptable, pharmacologically active derivatives thereof, including but not limited to salts, prodrug conjugates (such as esters and amides), metabolites, and the like.

[0260] As used herein, the term "composition" encompasses a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0261] As used herein, "pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0262] As used herein, the term "alkyl" refers to a saturated hydrocarbon group, which can be a straight chain or branched chain (e.g., ethyl, isopropyl, tert-amyl or 2,5-dimethylhexyl). This definition applies both to the case where the term is used alone and to the case where it is used as part of a composite term, such as "aralkyl", "alkylamino" and similar terms. In some embodiments, the alkyl group is one containing 1 to 24 carbon atoms. All numerical ranges in this specification and claims are intended to include their upper and lower limits. Low alkyl refers to those alkyl groups with 1 to 4 carbon atoms. In addition, alkyl and heteroalkyl groups can be attached to other parts at any position that would otherwise be occupied by hydrogen atoms on the alkyl or heteroalkyl group (e.g., 2-pentyl, 2-methylpent-1-yl and 2-propoxy). Divalent alkyl groups can be referred to as "alkylene", and divalent heteroalkyl groups can be referred to as "heteroalkylene", such as those groups used as joints in the present invention. The alkyl, alkylene and heteroalkyl moieties may also be optionally substituted with halogen atoms or other groups such as oxo, cyano, nitro, alkyl, alkylamino, carboxyl, hydroxy, alkoxy, aryloxy, and the like.

[0263] As used herein, the terms "cycloalkyl" and "cycloalkenyl" refer to saturated hydrocarbon rings, and include bicyclic and polycyclic rings. Similarly, cycloalkyl and cycloalkenyl groups with heteroatoms (such as N, O or S) replacing carbon ring atoms can be referred to as "heterocycloalkyl" and "heterocycloalkylene" respectively. Examples of cycloalkyl and heteroaryl groups are, for example, cyclohexyl, norbornyl, adamantyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, etc. Cycloalkyl and heterocycloalkyl moieties may also be optionally substituted with halogen atoms or other groups (such as nitro, alkyl, alkylamino, carboxyl, alkoxy, aryloxy, etc.). In certain embodiments, cycloalkyl and cycloalkenyl moieties are moieties having 3 to 12 carbon atoms in the ring (for example, cyclohexyl, cyclooctyl, norbornyl, adamantyl, etc.). In certain embodiments, heterocycloalkyl and heterocycloalkylene moieties are moieties having 1 to 3 heteroatoms in the ring (for example, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperidinyl, etc.). Additionally, the term "(cycloalkyl)alkyl" refers to a group in which a cycloalkyl moiety is attached to an alkyl moiety. Examples are cyclohexylmethyl, cyclohexylethyl, and cyclopentylpropyl.

[0264] As used herein, the term "alkenyl" refers to an alkyl group as described above, which contains one or more sites of double bond unsaturation. Similarly, as used herein, the term "alkynyl" refers to an alkyl group as described above, which contains one or more sites of triple bond unsaturation.

[0265] As used herein, the term "alkoxy" refers to an alkyl group as described above, further bearing an oxygen substituent capable of covalently attaching to another hydrocarbyl group (such as, for example, methoxy, ethoxy, aryloxy, and tert-butoxy).

[0266] As used herein, the term "aryl" refers to an aromatic carbocyclic substituent, which can be a monocyclic or fused together, covalently linked or connected to a plurality of rings of a common group (such as an ethylene or methylene moiety). Similarly, an aryl group having a heteroatom (such as N, O or S) replacing a carbon ring atom is referred to as a "heteroaryl". Examples of aryl and heteroaryl groups are, for example, phenyl, naphthyl, biphenyl, diphenylmethyl, 2,2-diphenyl-1-ethyl, thienyl, pyridyl and quinoxalinyl. Aryl and heteroaryl moieties may also be optionally substituted by halogen atoms or other groups (such as nitro, alkyl, alkylamino, carboxyl, alkoxy, aryloxy, etc.). In addition, aryl and heteroaryl groups may be attached to other moieties at any position that would otherwise be occupied by a hydrogen atom on an aryl or heteroaryl group (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl). A divalent aryl group is an "arylene" and a divalent heteroaryl group, such as those groups used as linkers in the present invention, is referred to as a "heteroarylene".

[0267] As used herein, the terms "arylalkyl," "arylalkenyl," and "aryloxyalkyl" refer to aryl groups that are directly attached to an alkyl group, directly attached to an alkenyl group, or directly attached to an oxygen that is attached to an alkyl group, respectively. For simplicity, aryl, as part of the above combined terms, also includes heteroaryl.

[0268] As used herein, unless otherwise indicated, the term "halo" or "halogen," by itself or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "Ci-C6 haloalkyl" is intended to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0269] As used herein, the term "hetero" as used in "heteroatom" refers to any atom other than carbon or hydrogen, such as nitrogen, oxygen, sulfur, phosphorus, or silicon.

[0270] As used herein, the term "hetero" as used in a "heteroatom-containing alkyl group" ("heteroalkyl" group) or a "heteroatom-containing aryl group" ("heteroaryl" group) refers to a molecule, bond, or substituent in which one or more carbon atoms are replaced by atoms other than carbon, such as nitrogen, oxygen, sulfur, phosphorus, or silicon (typically nitrogen, oxygen, or sulfur), or more than one non-carbon atom (e.g., sulfonamide). Similarly, the term "heteroalkyl" refers to a heteroatom-containing alkyl substituent, the term "heterocycle" refers to a heteroatom-containing cyclic substituent, the terms "heteroaryl" and "heteroaromatic" refer to heteroatom-containing "aryl" and "aromatic" substituents, respectively. Examples of heteroalkyl groups include alkoxyaryl, alkyl substituted with alkylsulfanyl, N-alkylated aminoalkyl, and the like. Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, and the like, and examples of heteroatom-containing alicyclic groups are pyrrolidinyl, morpholino, piperazinyl, piperidinyl, and the like.

[0271] As used herein, the terms "hydrophobic radical" and "hydrophobic group" refer to a group that reduces the water solubility of a molecule. In some embodiments, the hydrophobic group is a group containing at least 3 carbon atoms.

[0272] As used herein, the term "carboxylic acid analogue" refers to various groups having an acidic portion that can mimic a carboxylic acid residue. Examples of such groups include sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid, phosphinic acid, sulfonamide, and heterocyclic moieties such as, for example, imidazole, triazole, and tetrazole.

[0273] As used herein, the term "substituted" means that an atom or group of atoms in a compound is replaced by another atom or group of atoms. For example, an atom or group of atoms can be substituted by one or more of the following substituents or groups: halo, cyano, nitro, alkyl, alkylamino, hydroxyalkyl, haloalkyl, carboxyl, hydroxy, alkoxy, alkoxyalkoxy, haloalkoxy, thioalkyl, aryl, aryloxy, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl optionally substituted by 1 or more (preferably 1 to 3) substituents selected from halo, haloalkyl and alkyl, aralkyl, heteroaralkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, alk(en)(yn)yl groups, halo, cyano, hydroxy, haloalkyl and polyhaloalkyl (preferably halo lower alkyl, especially trifluoromethyl), formyl, alkylcarbonyl, optionally substituted by 1 or more (preferably 1 to 3) substituents selected from halo, haloalkyl and alkyl substituted arylcarbonyl, heteroarylcarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, aralkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, arylalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, amino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkylcarbonylamino, arylcarbonylamino, azido, nitro, thiol, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfamoyl, alkylsulfonyl, arylsulfamoyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl and arylaminosulfonyl. When the term "substituted" appears before a list of possible substituent groups, it is meant that the term applies to every member of that group.

[0274] The term "unsubstituted" refers to a naturally occurring compound that lacks replacement atoms or groups of atoms.

[0275] Soluble epoxide hydrolase inhibitors

[0276] The present disclosure provides soluble epoxide hydrolase inhibitors (sEH) of formula (I) that are effective for treating sEH-mediated diseases and disorders.

[0277] Formula (I)

[0278]

[0279] Soluble epoxide hydrolases are configured to bind a range of epoxidized fatty acid substrates and can include a binding site with two hydrophobic pockets and a hydrophilic core that can include a dual tyrosine substrate hydrogen bonding motif and an aspartate-histidine-aspartate salt bridge. Formula (I) effectively binds to these hydrophobic and hydrophilic regions and has sufficient hydrophobicity to reach these regions through the hydrophobic sEH substrate channel. Exemplifying these features, Formula (I) exhibits an sEH inhibitor constant (Ki) of less than 50 pM and a t for sEH inhibition of 22 minutes. 1 / 2 .

[0280] Formula (I) also has a relatively low aqueous solubility of 11 μg / mL, which may pose a challenge to formulations for cellular uptake and sEH co-localization. Since sEH is primarily present in peroxisomes and the cytoplasm, effective delivery of Formula (I) may require a formulation that promotes aqueous localization. To overcome this obstacle, Formula (I) can be formulated and crystallized to enhance its activity and solubility.

[0281] Polymorphic forms of formula (I)

[0282] Disclosed herein is the unexpected discovery that formula (I) can be prepared in a variety of crystalline forms (hereinafter "forms" or "polymorphs"), each of which has a unique solubility and stability and is therefore useful for customizing formulations for specific treatments and delivery methods. Aspects of the present disclosure are polymorphic forms A, B, C, D, E, F, G, H, I, J, K, and L of formula (I). Each of these forms has a unique physical structure and properties, including different solubility and stability in various conditions and solvents. Forms A to L are each different from amorphous formula (I) (e.g., as summarized in Examples 4 to 6), and thus expand the options for formulating formula (I) beyond those previously available.

[0283] The composition may comprise a single, non-amorphous form of Formula (I). In some cases, the composition comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% by weight of any one of Forms A to L. The composition may comprise a mixture of non-amorphous forms of Formula (I) (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% by weight of two or more of Forms A to L). In some cases, the composition comprises less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 2%, less than 1%, less than 0.5%, or less than 0.1% amorphous Formula (I).

[0284] Form C is a hydrate, unlike Forms A, B, and D to L, which are anhydrous or substantially anhydrous (e.g., containing less than about 3% water by weight). In some cases, a composition having formula (I) comprises at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% anhydrous formula (I) by weight. In some cases, formula (I) (a single form or a mixture of multiple forms) comprises less than 5%, less than 4%, less than 3%, less than 2%, less than 1.5%, less than 1%, less than 0.5%, less than 0.25%, or less than 0.1% water by weight. In some cases, formula (I) is at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.5% Form A, B, D, E, F, G, H, I, J, K, L, or a combination thereof.

[0285] In certain aspects, the present disclosure provides Form A of Formula (I) (hereinafter "Form A"), such as by substantially Figure 1 Thumbnail A or Figure 131A In some aspects, the present disclosure provides Form A of formula (I), such as by including an X-ray powder diffraction pattern of a peak at 3.3 ± 0.3 ° 2θ, 30.3 ± 0.3 ° 2θ, and 20.0 ± 0.3 ° 2θ. In some cases, the relative intensity of the peak at 3.3 ± 0.3 ° 2θ, 30.3 ± 0.3 ° 2θ, and 20.0 ± 0.3 ° 2θ is no more than 20%, no more than 18%, no more than 16%, no more than 14%, no more than 12%, no more than 10%, no more than 8%, no more than 6%, or no more than 5% (e.g., as determined by Gaussian or Lorentzian fitting peaks in an X-ray powder diffraction pattern). In some cases, the peaks at 3.3 ± 0.3 ° 2θ, 30.3 ± 0.3 ° 2θ, and 20.0 ± 0.3 ° 2θ each have an intensity at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 1.6 times, at least 1.7 times, at least 1.8 times, or at least 1.9 times greater than the fourth most intense peak in the X-ray powder diffraction pattern. In some cases, the X-ray powder diffraction pattern further includes at least one, at least two, or at least three peaks selected from the group consisting of 12.1 ± 0.3 ° 2θ, 15.6 ± 0.3 ° 2θ, and 6.0 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further includes at least one, at least two, or at least three peaks selected from the group consisting of 21.7 ± 0.3 ° 2θ, 10.6 ± 0.3 ° 2θ, and 21.6 ± 0.3 ° 2θ. In some cases, Formula (I) is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% Form A by weight.

[0286] Form A of formula (I) may exhibit Figure 131A The X-ray powder diffraction pattern of is shown in , wherein peaks 1 to 28 correspond to the peak numbers in Table 27. Figure 131A The peaks in (numbered sequentially 1 to 28 from left to right) and Table 27 are provided as relative intensities (Relative Intensity %) normalized to Peak 1 (the peak with the highest intensity).

[0287] Table 27

[0288]

[0289] In certain aspects, the present disclosure provides Form B of Formula (I) (hereinafter "Form B"), such as by substantially Figure 1 Thumbnail B or Figure 131B In some aspects, the present disclosure provides Form B of formula (I), such as characterized by an X-ray powder diffraction pattern including peaks at 12.2 ± 0.3 ° 2θ, 3.5 ± 0.3 ° 2θ, and 17.2 ± 0.3 ° 2θ. In some cases, the relative intensity of the peaks at 12.2 ± 0.3 ° 2θ and 3.5 ± 0.3 ° 2θ is at least 10%, at least 9%, at least 8%, at least 7%, at least 6%, at least 5%, at least 4% or at least 3%. In some cases, the peak at 12.2 ± 0.3 ° 2θ has a relative intensity of 4% to 30% greater than the peak at 17.2 ± 0.3 ° 2θ, a relative intensity of 5% to 25%, a relative intensity of 6% to 15%, or a relative intensity of 7.5% to 12.5%. In some cases, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 19.6 ± 0.3 ° 2θ, 13.1 ± 0.3 ° 2θ, and 18.0 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further comprises at least one, at least two, at least three, or at least four peaks selected from the group consisting of 20.2 ± 0.3 ° 2θ, 14.1 ± 0.3 ° 2θ, 17.6 ± 0.3 ° 2θ, and 14.8 ± 0.3 ° 2θ. In some cases, Formula (I) is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% Form B by weight.

[0290] Form B of formula (I) may exhibit Figure 131B The X-ray powder diffraction pattern of is shown in , wherein peaks 1 to 29 correspond to the peak numbers in Table 28. Figure 131B (numbered sequentially 1 to 29 from left to right) and in Table 28 are provided as relative intensities (Relative Intensity %) normalized to Peak 5 (the peak with the highest intensity).

[0291] Table 28

[0292]

[0293] In certain aspects, the present disclosure provides Form C of Formula (I) (hereinafter "Form C"), such as by substantially Figure 1 Small Figure C or Figure 131C In some aspects, the present disclosure provides Form C of formula (I), such as by including an X-ray powder diffraction pattern of a peak at 16.3 ± 0.3 ° 2θ, 16.1 ± 0.3 ° 2θ, and 3.2 ± 0.3 ° 2θ. In some cases, the relative intensity of the peak at 16.3 ± 0.3 ° 2θ, 16.1 ± 0.3 ° 2θ, and 3.2 ± 0.3 ° 2θ is at least 10%, at least 9%, at least 8%, at least 7%, at least 6%, at least 5%, at least 4%, or at least 3%. In some cases, the peak at 16.3 ± 0.3 ° 2θ, 16.1 ± 0.3 ° 2θ, and 3.2 ± 0.3 ° 2θ is each at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% greater than the intensity of the second strongest peak in the X-ray powder diffraction pattern. In some cases, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from 21.6 ± 0.3 ° 2θ, 23.2 ± 0.3 ° 2θ, and 21.7 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from 16.5 ± 0.3 ° 2θ, 21.4 ± 0.3 ° 2θ, and 10.7 ± 0.3 ° 2θ. In some cases, Formula (I) is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% Form C by weight.

[0294] Form C of formula (I) may exhibit Figure 131C The X-ray powder diffraction pattern of is shown in , wherein peaks 1 to 35 correspond to the peak numbers in Table 29. Figure 131C The peaks in (numbered sequentially 1 to 35 from left to right) and Table 29 are provided as relative intensities (Relative Intensity %) normalized to Peak 12 (the peak with the highest intensity).

[0295] Table 29

[0296]

[0297]

[0298] In certain aspects, the present disclosure provides Form D of Formula (I) (hereinafter "Form D"), such as by substantially Figure 1 Thumbnail D or Figure 131D In some aspects, the present disclosure provides Form D of formula (I), such as by including an X-ray powder diffraction pattern of a peak at 20.1 ± 0.3 ° 2θ, 18.3 ± 0.3 ° 2θ, and 18.1 ± 0.3 ° 2θ. In some cases, the relative intensity of the peak at 20.1 ± 0.3 ° 2θ, 18.3 ± 0.3 ° 2θ, and 18.1 ± 0.3 ° 2θ is at least 8%, at least 7%, at least 6%, at least 5%, at least 4%, at least 3%, at least 2%, at least 1.5% or at least 1%. In some cases, the X-ray powder diffraction pattern further includes at least one or at least two peaks selected from the following items: 20.3 ± 0.3 ° 2θ and 17.1 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further comprises at least one, at least two, at least three, or at least four peaks selected from 3.4 ± 0.3 ° 2θ, 19.6 ± 0.3 ° 2θ, 23.4 ± 0.3 ° 2θ, and 25.1 ± 0.3 ° 2θ. In some cases, Formula (I) is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% Form D by weight.

[0299] Form D of formula (I) may exhibit Figure 131D The X-ray powder diffraction pattern of is shown in , wherein peaks 1 to 45 correspond to the peak numbers in Table 30. Figure 131D The peaks in (numbered sequentially 1 to 45 from left to right) and Table 30 are provided as relative intensities (Relative Intensity %) normalized to Peak 14 (the peak with the highest intensity).

[0300] Table 30

[0301]

[0302]

[0303] In certain aspects, the present disclosure provides Form E of Formula (I) (hereinafter "Form E"), such as by substantially Figure 1 Thumbnail E or Figure 131EIn some aspects, the present disclosure provides Form E of formula (I), such as by including an X-ray powder diffraction pattern of a peak at 13.4 ± 0.3 ° 2θ, 11.2 ± 0.3 ° 2θ, and 3.1 ± 0.3 ° 2θ. In some cases, the peak at 13.4 ± 0.3 ° 2θ, 11.2 ± 0.3 ° 2θ, and 3.1 ± 0.3 ° 2θ has a relative intensity within 20%, within 18%, within 16%, within 14%, within 12%, or within 10%. In some cases, the X-ray powder diffraction pattern further includes at least one, at least two, or at least three peaks selected from the following: 9.0 ± 0.3 ° 2θ, 22.2 ± 0.3 ° 2θ, and 14.3 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from 14.9 ± 0.3 ° 2θ, 18.4 ± 0.3 ° 2θ, and 16.8 ± 0.3 ° 2θ. In some cases, Formula (I) is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% Form E by weight.

[0304] Form E of formula (I) may exhibit Figure 131E The X-ray powder diffraction pattern of is shown in , wherein peaks 1 to 42 correspond to the peak numbers in Table 31. Figure 131E (numbered sequentially 1 to 42 from left to right) and in Table 31 are provided as relative intensities (Relative Intensity %) normalized to Peak 8 (the peak with the highest intensity).

[0305] Table 31

[0306]

[0307] In certain aspects, the present disclosure provides Form F of Formula (I) (hereinafter "Form F"), such as by substantially Figure 1 Thumbnail F or Figure 131FIn some aspects, the present disclosure provides Form F of formula (I), as characterized by an X-ray powder diffraction pattern shown in . In some aspects, the present disclosure provides Form F of formula (I), as characterized by an X-ray powder diffraction pattern including peaks at 14.6 ± 0.3 ° 2θ, 3.4 ± 0.3 ° 2θ, and 9.7 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further includes at least one, at least two, or at least three peaks selected from the following items: 18.1 ± 0.3 ° 2θ, 20.2 ± 0.3 ° 2θ, and 16.7 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further includes at least one, at least two, or at least three peaks selected from the following items: 17.6 ± 0.3 ° 2θ, 19.2 ± 0.3 ° 2θ, and 17.3 ± 0.3 ° 2θ. In some cases, Formula (I) is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% Form F by weight.

[0308] Form F of formula (I) may exhibit Figure 131F The X-ray powder diffraction pattern of is shown in , wherein peaks 1 to 42 correspond to the peak numbers in Table 32. Figure 131F The peaks in (numbered sequentially 1 to 42 from left to right) and Table 32 are provided as relative intensities (Relative Intensity %) normalized to Peak 10 (the peak with the highest intensity).

[0309] Table 32

[0310]

[0311]

[0312] In certain aspects, the present disclosure provides Form G of Formula (I) (hereinafter "Form G"), such as by substantially Figure 1 Thumbnail G or Figure 131G In some aspects, the present disclosure provides Form G of formula (I), as characterized by an X-ray powder diffraction pattern shown in . In some aspects, the present disclosure provides Form G of formula (I), as characterized by an X-ray powder diffraction pattern including peaks at 18.2 ± 0.3 ° 2θ, 3.2 ± 0.3 ° 2θ, and 18.0 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further includes at least one, at least two, or at least three peaks selected from the following items: 10.8 ± 0.3 ° 2θ, 19.2 ± 0.3 ° 2θ, and 5.4 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further includes at least one or at least two peaks selected from the following items: 10.6 ± 0.3 ° 2θ and 21.7 ± 0.3 ° 2θ. In some cases, Formula (I) is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% Form G by weight.

[0313] Form G of formula (I) may exhibit Figure 131G The X-ray powder diffraction pattern of is shown in , wherein peaks 1 to 50 correspond to the peak numbers in Table 33. Figure 131G (numbered sequentially 1 to 50 from left to right) and in Table 33 are provided as relative intensities (Relative Intensity %) normalized to Peak 24 (the peak with the highest intensity).

[0314] Table 33

[0315]

[0316]

[0317] In certain aspects, the present disclosure provides Form H of Formula (I) (hereinafter "Form H"), such as by substantially Figure 1 Thumbnail H or Figure 131H In some aspects, the present disclosure provides Form H of formula (I), as characterized by an X-ray powder diffraction pattern shown in . In some aspects, the present disclosure provides Form H of formula (I), as characterized by an X-ray powder diffraction pattern including a peak at 8.8 ± 0.3 ° 2θ, 3.4 ± 0.3 ° 2θ, and 21.4 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further includes at least one, at least two, at least three, or at least four peaks selected from the following items: 17.9 ± 0.3 ° 2θ, 14.5 ± 0.3 ° 2θ, 12.7 ± 0.3 ° 2θ, and 8.7 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further includes at least one, at least two, or at least three peaks selected from the following items: 14.8 ± 0.3 ° 2θ, 12.8 ± 0.3 ° 2θ, and 21.2 ± 0.3 ° 2θ. In some cases, Formula (I) is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% Form H by weight.

[0318] Form H of formula (I) may exhibit Figure 131H The X-ray powder diffraction pattern of is shown in , wherein peaks 1 to 45 correspond to the peak numbers in Table 34. Figure 131H The peaks in (numbered sequentially 1 to 45 from left to right) and Table 34 are provided as relative intensities (Relative Intensity %) normalized to Peak 5 (the peak with the highest intensity).

[0319] Table 34

[0320]

[0321] In certain aspects, the present disclosure provides Form I of Formula (I) (hereinafter "Form I"), such as by substantially Figure 1Thumbnail I or Figure 131I In some aspects, the present disclosure provides Form I of formula (I), such as by including the X-ray powder diffraction pattern of the peak at 12.0 ± 0.3 ° 2θ, 12.3 ± 0.3 ° 2θ and 3.2 ± 0.3 ° 2θ. In some cases, the peak at 12.0 ± 0.3 ° 2θ, 12.3 ± 0.3 ° 2θ and 3.2 ± 0.3 ° 2θ is at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9 or at least 2 times the intensity of the second strongest peak. In some cases, the X-ray powder diffraction pattern further includes at least one, at least two or at least three peaks selected from the following items: 14.5 ± 0.3 ° 2θ, 18.1 ± 0.3 ° 2θ and 13.4 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from 18.6 ± 0.3 ° 2θ, 24.8 ± 0.3 ° 2θ, and 19.1 ± 0.3 ° 2θ. In some cases, Formula (I) is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% Form I by weight.

[0322] Form I of formula (I) may exhibit Figure 131I The X-ray powder diffraction pattern of is shown in , wherein peaks 1 to 41 correspond to the peak numbers in Table 35. Figure 131I The peaks in (numbered sequentially 1 to 41 from left to right) and Table 35 are provided as relative intensities (Relative Intensity %) normalized to Peak 5 (the peak with the highest intensity).

[0323] Table 35

[0324]

[0325]

[0326] In certain aspects, the present disclosure provides Form J of Formula (I) (hereinafter "Form J"), such as by substantially Figure 1 Thumbnail J or Figure 131JIn some aspects, the present disclosure provides Form J of formula (I), as characterized by an X-ray powder diffraction pattern shown in . In some aspects, the present disclosure provides Form J of formula (I), as characterized by an X-ray powder diffraction pattern including a peak at 15.5 ± 0.3 ° 2θ, 15.7 ± 0.3 ° 2θ, and 17.6 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further includes at least one, at least two, or at least three peaks selected from the following items: 15.1 ± 0.3 ° 2θ, 11.4 ± 0.3 ° 2θ, and 15.0 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further includes at least one, at least two, or at least three peaks selected from the following items: 3.4 ± 0.3 ° 2θ, 20.2 ± 0.3 ° 2θ, and 21.0 ± 0.3 ° 2θ. In some cases, Formula (I) is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% Form J by weight.

[0327] Form J of formula (I) may exhibit Figure 131J The X-ray powder diffraction pattern of is shown in , wherein peaks 1 to 44 correspond to the peak numbers in Table 36. Figure 131J (numbered sequentially 1 to 44 from left to right) and in Table 36 are provided as relative intensities (Relative Intensity %) normalized to Peak 11 (the peak with the highest intensity).

[0328] Table 36

[0329]

[0330]

[0331] In certain aspects, the present disclosure provides Form K of Formula (I) (hereinafter "Form K"), such as by substantially Figure 1 Thumbnail K or Figure 131KIn some aspects, the present disclosure provides Form K of formula (I), as characterized by an X-ray powder diffraction pattern including a peak at 5.3 ± 0.3 ° 2θ, 14.5 ± 0.3 ° 2θ, and 7.3 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further includes at least one, at least two, at least three, at least four, or at least five peaks selected from the following: 20.9 ± 0.3 ° 2θ, 3.4 ± 0.3 ° 2θ, 21.1 ± 0.3 ° 2θ, 7.4 ± 0.3 ° 2θ, and 14.8 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further includes a peak at 17.4 ± 0.3 ° 2θ. In some cases, the relative intensity of the peak at 17.4 ± 0.3° 2θ is 30% to 80%, 35% to 75%, 40% to 70%, 45% to 65%, or 50% to 60% of the intensity of the peak at 5.3 ± 0.3° 2θ. In some cases, Formula (I) is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% Form K by weight.

[0332] Form K of formula (I) may exhibit Figure 131K The X-ray powder diffraction pattern shown in , wherein peaks 1 to 36 correspond to the peak numbers in Table 37. Figure 131K (numbered sequentially 1 to 36 from left to right) and in Table 37 are provided as relative intensities (Relative Intensity %) normalized to Peak 2 (the peak with the highest intensity).

[0333] Table 37

[0334]

[0335] In certain aspects, the present disclosure provides Form L of Formula (I) (hereinafter "Form L"), such as by substantially Figure 1 Small Figure L or Figure 131LIn some aspects, the present disclosure provides Form L of formula (I), as characterized by an X-ray powder diffraction pattern shown in . In some aspects, the present disclosure provides Form L of formula (I), as characterized by an X-ray powder diffraction pattern including a peak at 8.9 ± 0.3 ° 2θ, 3.4 ± 0.3 ° 2θ, and 18.3 ± 0.3 ° 2θ. In some cases, the peak at 8.9 ± 0.3 ° 2θ has an intensity of about 10% to 45%, about 15% to 40%, about 20% to 35%, or about 23% to 31% greater than the peak at 18.3 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further includes at least one, at least two, or at least three peaks selected from the following: 14.4 ± 0.3 ° 2θ, 21.9 ± 0.3 ° 2θ, and 18.0 ± 0.3 ° 2θ. In some cases, the X-ray powder diffraction pattern further comprises at least one, at least two, at least three, at least four, or at least five peaks selected from 14.3 ± 0.3 ° 2θ, 13.2 ± 0.3 ° 2θ, 20.0 ± 0.3 ° 2θ, 19.3 ± 0.3 ° 2θ, and 14.9 ± 0.3 ° 2θ. In some cases, Formula (I) is at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% Form L by weight.

[0336] Form L of formula (I) may exhibit Figure 131L The X-ray powder diffraction pattern shown in , wherein peaks 1 to 36 correspond to the peak numbers in Table 38. Figure 131L The peaks in (numbered sequentially 1 to 36 from left to right) and Table 38 are provided as relative intensities (Relative Intensity %) normalized to Peak 4 (the peak with the highest intensity).

[0337] Table 38

[0338]

[0339]

[0340] Synthesis method

[0341] Aspects of the present disclosure provide methods for the synthetic preparation of (S)-1-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-(1-(2-methylbutanoyl)piperidin-4-yl)urea (Formula (I)). Stable Formula (I) can be prepared according to Schemes 1 to 2 as described below and in Examples 1 to 3.

[0342] Synthesis Route 1

[0343] As disclosed herein, Formula (I) can be produced using one, two, three, or all four of Steps 1 to 4 of Scheme 1.

[0344] Solution 1

[0345]

[0346] Step 1 – Isocyanate Activation

[0347] Formula (I) synthesis can include 3-fluoro-4-(trifluoromethoxy) aniline activation to form reactive isocyanide 2-fluoro-4-isocyanato-1-(trifluoromethoxy) benzene.In this step, 3-fluoro-4-(trifluoromethoxy) aniline and 1 triethylamine can be dissolved in CH cl in and stir at-78 ℃.Then triphosgene can be dissolved in CH cl in and dropwise add.Reaction can be warmed to room temperature and stirred for 30 minutes and then cooled to 0 ℃.Gained isocyanato product can be directly used in subsequent synthesis steps.

[0348] Step 2 – Urea formation

[0349] Formula (I) synthesis can comprise the urea between the fluoro-4-isocyanato-1-(trifluoromethoxy) benzene and 4-amino piperidine-1-t-butyl formate and forms, by by these materials and triethylamine (for example, with the ratio of about 2:3:3) at CH cl in merge and at room temperature stirred 12 hours.Can come cancellation reaction with adding acid (for example, 2M HCl).Can be collected from organic layer and further extracted from water layer intermediate compound 4-(3-(3-fluoro-4-(trifluoromethoxy) phenyl) urea radicals) piperidines-1-t-butyl formate (compound S1), and can optionally be dried and concentrated (for example, in a vacuum) for further use.

[0350] Step 3 – Deprotection

[0351] Formula (I) synthesis can include by refluxing in acid and removing Boc protecting group from compound S1.In this step, compound S1 can be dissolved in the MeOH of 2M HCl (for example, to a concentration of about 186mM) and refluxed for 2 hours, forming 1-(3-fluoro-4-(trifluoromethoxy) phenyl)-3-(piperidin-4-yl) urea (compound S2).Can optionally remove (for example, in a vacuum) solvent, and improve the pH (for example, being adjusted to pH 12) of crude reaction product.Precipitate can be filtered, dried and collected.

[0352] Step 4 – Piperidine functionalization

[0353] Formula (I) synthesis can include the functionalization of piperidylamine in compound S2 or its analogue.This step can be included in CH cl in the presence of compound S2, by (S)-2-methylbutyric acid (S)-2-methylbutyric acid (EDCI) and 4-dimethylaminopyridine (DMAP) activation.Reactant mixture can be stirred at room temperature overnight, and then by adding acid (for example, 1M HCl) cancellation.Can be collected from organic layer and from water layer extraction gained formula (I), and can optionally make it stand further purification.

[0354] Synthesis Route 2

[0355] As disclosed herein, one or both of Steps 1 to 2 of Scheme 2 can be utilized to produce Formula (I).

[0356] Option 2

[0357]

[0358] Step 1 – Isocyanate Activation

[0359] The synthesis of formula (I) can include activation of 3-fluoro-4-(trifluoromethoxy)aniline to form a reactive isocyanate group, as outlined above for Scheme 1, Step 1. In this step, 3-fluoro-4-(trifluoromethoxy)aniline and 1-triethylamine can be dissolved in CHCl and combined with triphosgene to form 2-fluoro-4-isocyanato-1-(trifluoromethoxy)benzene.

[0360] Step 2 – Urea formation

[0361] Formula (I) synthesis can comprise the urea formation between 2-fluoro-4-isocyanato-1-(trifluoromethoxy) benzene and (S)-1-(4-amino piperidine-1-yl)-2-methyl butan-1-ketone.This step can comprise by these materials and triethylamine (in CH Cl In) merge and at room temperature stir.Can come cancellation reaction with adding acid (for example, 2M HCl).Can collect from organic layer and from water layer further extract product material formula (I), and can optionally be dried, concentrated and make it stand further purification.

[0362] Method for producing polymorphs

[0363] The unexpected discovery disclosed herein is that formula (I) can be prepared in a variety of polymorphic forms, each with unique solubility and physical properties. Among the determinants of formula (I) form, solvent system, temperature, cooling rate and evaporation rate may affect the form of formula (I) produced from the crystallization procedure. Typically, crystallization disclosed herein will produce a single form of formula (I), for example, at least 90%, at least 95%, at least 98%, at least 99% or at least 99.5% single form by weight. In some cases, crystallization produces a negligible amount of amorphous formula (I), for example, less than 5%, less than 2%, less than 1% or less than 0.5% by weight. In some cases, after crystallization, selective removal of non-targeted form of formula (I) is performed, for example, by grinding soluble impurities.

[0364] Although formula (I) is soluble in multiple solvents, solvent type may significantly affect the form and the purity of the formula (I) obtained from crystallization. In some cases, the primary solvent for crystallization is an organic solvent. In some cases, the organic solvent is a protonic organic solvent. In other cases, the organic solvent is aprotic. In some cases, the organic solvent is acetone, acetonitrile, methylene chloride, dioxane, isopropyl alcohol, isopropyl acetate, methanol, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ether, n-butyl alcohol, tetrahydrofuran (THF), 2-methyltetrahydrofuran (MTB), toluene or its combination. In some cases, formula (I) comprises at least about 5mg / mL, at least about 10mg / mL, at least about 20mg / mL, at least about 30mg / mL, at least about 40mg / mL or at least about the solubility of 50mg / mL (for example, as outlined in the table 4 of form A) in the primary solvent.

[0365] Formula (I) crystallization can utilize a single solvent or a solvent mixture. In many cases, formula (I) crystallization utilizes a solvent system with at least two solvents. In some cases, the two solvents used for crystallization are miscible, such as methanol and water. In some cases, formula (I) has a solubility of at least 5mg / mL in a secondary solvent. However, in many cases, formula (I) crystallization utilizes a primary solvent with a high solubility of formula (I) and an antisolvent with a low solubility of formula (I). As used herein, the term "antisolvent" can represent a solvent in which the analyte (e.g., formula (I)) has a relatively low solubility. In some cases, formula (I) has a solubility of at most 5mg / mL, at most 3mg / mL, at most 2mg / mL, or at most 1mg / mL in a secondary solvent. In some cases, the secondary solvent is water or hexane. In some cases, the solvent system used for formula (I) crystallization only contains a solvent in which formula (I) has a solubility of at least 5mg / ml, 10mg / ml, or 20mg / ml. In some cases, the solvent system used for crystallization of Formula (I) comprises a first solvent in which Formula (I) has a solubility of at least 10 mg / ml and a second solvent in which Formula (I) has a solubility of at most 5 mg / ml at room temperature. In some cases, the solvent system used for crystallization of Formula (I) comprises a first solvent in which Formula (I) has a solubility of at least 20 mg / ml and a second solvent in which Formula (I) has a solubility of at most 2 mg / ml at room temperature.

[0366] In some cases, formula (I) crystallization utilizes a multisolvent system comprising water and an organic solvent. In some cases, the organic solvent is selected from the group consisting of: methanol, ethanol, acetonitrile, isopropyl alcohol, tetrahydrofuran, acetone, dimethyl sulfoxide, dimethylformamide, NMP, n-propyl alcohol and dioxane. In some cases, the organic solvent is selected from the group consisting of: ethanol, acetonitrile, isopropyl alcohol, tetrahydrofuran, acetone, dimethyl sulfoxide, dimethylformamide, NMP, n-propyl alcohol and dioxane. In some cases, the ratio of water to the organic solvent is between 10:1 and 1:10, between 10:1 and 1:1, between 5:1 and 1:5, between 5:2 and 2:5, between 3:2 and 2:3 or between 1:1 and 1:10.

[0367] In some cases, formula (I) crystallization comprises heptane and other organic solvent.In some cases, heptane is normal heptane.In some cases, organic solvent is selected from the group consisting of the following: methanol, ethanol, acetonitrile, isopropyl alcohol, tetrahydrofuran (THF), acetone, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), NMP, n-propyl alcohol and dioxane.In some cases, the ratio of heptane to methanol, ethanol, acetonitrile, isopropyl alcohol, dimethyl sulfoxide (DMSO), NMP, n-propyl alcohol or dioxane is between 5:1 and 200:1, between 10:1 and 200:1, between 5:1 and 100:1 or between 10:1 and 300:1.In some cases, the ratio of heptane to tetrahydrofuran (THF) or acetone is between 20:1 and 1:1, between 10:1 and 1:1, between 5:1 and 1:5 or between 5:1 and 1:1.

[0368] In some cases, formula (I) crystallization comprises hexane and other organic solvent.In some cases, hexane is hexamethylene.In some cases, organic solvent is selected from the group consisting of: methanol, ethanol, acetonitrile, isopropyl alcohol, tetrahydrofuran (THF), acetone, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), NMP, n-propyl alcohol and dioxane.In some cases, the ratio of hexane to methanol, ethanol, acetonitrile, isopropyl alcohol, dimethyl sulfoxide (DMSO), NMP or n-propyl alcohol is between 5:1 and 200:1, between 10:1 and 200:1, between 5:1 and 100:1 or between 10:1 and 300:1.In some cases, the ratio of hexane to tetrahydrofuran (THF), acetone or dioxane is between 20:1 and 1:1, between 10:1 and 1:1, between 5:1 and 1:5 or between 5:1 and 1:1.

[0369] In some cases, formula (I) is dissolved at a temperature of at least 30°C and then cooled for crystallization. In some cases, formula (I) is dissolved at a temperature of at least 40°C, at least 50°C, at least 60°C, or at least 70°C and then cooled for crystallization. In some cases, formula (I) is dissolved at a temperature of up to 70°C, up to 60°C, up to 50°C, up to 40°C, or up to 30°C and then cooled for crystallization. In some cases, formula (I) is dissolved at a temperature between about 30°C and 90°C, between about 40°C and 80°C, or about 50°C and 75°C and then cooled for crystallization.

[0370] The rate of cooling after the solution of formula (I) is dissolved in the solvent system may affect one or more polymorphs produced during crystallization. Cooling can be slow, for example, at most about 0.1°C / hour, at most about 1°C / hour, at most about 2°C / hour, at most about 4°C / hour, at most about 8°C / hour, at most about 12°C / hour, at most about 15°C / hour, at most about 20°C / hour, at most about 25°C / hour, at most about 30°C / hour or at most about 40°C / hour. The cooling rate can be between about 0.1°C / hour and 40°C / hour, between about 1°C / hour and 40°C / hour, between about 4°C / hour and 20°C / hour, between about 4°C / hour and 30°C / hour, between about 8°C / hour and 25°C / hour, or between about 15°C / hour and 40°C / hour / hour. The cooling rate can also be fast, for example, between 60°C / hour and 600°C / hour, greater than about 60°C / hour, greater than about 100°C / hour, or greater than about 200°C / hour. In some cases, cooling reduces the temperature of the solvent system to less than 30°C. In some cases, cooling reduces the temperature of the solvent system to less than 27°C. In some cases, cooling reduces the temperature of the solvent system to less than 20°C. In some cases, cooling reduces the temperature of the solvent system to less than 10°C. In some cases, cooling reduces the temperature of the solvent system to less than 5°C.

[0371] In some cases, formula (I) is added to a solvent system at a first temperature and then cooled to a second temperature, at which temperature, formula (I) has a lower solubility in the solvent system. In some cases, the solvent system is saturated with formula (I) at a first temperature. In some cases, formula (I) is added to a solvent system to a saturation of about 60% to 90% at a first temperature. In some cases, formula (I) is added to a solvent system to a saturation of about 40% to 80% at a first temperature. In some cases, formula (I) is added to a solvent system to a saturation of about 30% to 60% at a first temperature. In some cases, formula (I) is added to a solvent system to a saturation of about 75% to greater than 100% at a first temperature.

[0372] After dissolution, the solvent system containing Formula (I) can be seeded with solid Formula (I). In some cases, Formula (I) is in a single polymorphic form. In some cases, Formula (I) is in Form A, B, C, D, E, F, G, H, I, J, K, or L. In some cases, Formula (I) is added in milligram quantities (e.g., 1 mg to 5 mg).

[0373] Crystallization can also include adding a solvent (e.g., an anti-solvent) with low solubility of formula (I). Compared with the main solvent for crystallization, the added solvent may have a lower solubility of formula (I), so its addition can reduce the solubility of formula (I) in the solvent system. In many cases, crystallization method can include adding an anti-solvent (e.g., water) gradually to a solvent system with a main solvent (formula (I) comprising high solubility therein). For example, some crystallization methods disclosed herein include adding water, n-heptane, cycloheptane or formula (I) under conditions for crystallization with another solvent having a solubility of less than about 5 mg / ml therein.

[0374] In some cases, formula (I) is added to the solvent system before adding the anti-solvent. In some cases, the solvent system is saturated with formula (I) before adding the anti-solvent. In some cases, formula (I) is added to the solvent system to a saturation of about 60% to 90% before adding the anti-solvent. In some cases, formula (I) is added to the solvent system to a saturation of about 40% to 80% before adding the anti-solvent. In some cases, formula (I) is added to the solvent system to a saturation of about 30% to 60% before adding the anti-solvent. In some cases, formula (I) is added to the solvent system to a saturation of about 75% to greater than 100% before adding the anti-solvent.

[0375] (i) Method for making Form A

[0376] In some cases, Form A is formed during rapid cooling in a single solvent or substantially single solvent system. As used herein, a single solvent or substantially single solvent system can comprise at least 90%, at least 95%, or at least 99% of a primary solvent. In some cases, the solvent is methanol or toluene.

[0377] In some cases, Form A is formed during slow cooling in a multi-solvent system (e.g., a solvent system comprising at least 90%, at least 95%, or at least 99% by volume of a specified solvent). In some cases, the solvent system comprises water and a solvent selected from the group consisting of acetonitrile and acetone.

[0378] In some cases, Form A is formed during rapid cooling in a multi-solvent system. In some cases, the solvent system comprises water, acetonitrile, and at least 0.25 mg / ml of Formula (I) in the multi-solvent system.

[0379] In some cases, Form A is formed by heating Form C. As shown in Table 15, when incubated at 60°C, Form C achieves 100% conversion to Form A in less than 1 day. Methods for producing Form A can comprise incubating Form C at a temperature of at least 40°C, at least 50°C, at least 60°C, or between 40°C and 90°C for at least 1 hour, at least 6 hours, at least 12 hours, or at least 1 day. Incubation can be performed under low humidity or strictly anhydrous conditions.

[0380] (ii) Method for making Form B

[0381] In some cases, Form B forms during slow cooling in a single solvent or substantially a single solvent. In some cases, the single solvent is methanol, ethanol, isopropanol, or n-butanol.

[0382] In some cases, Form B forms during rapid cooling in a single solvent or substantially single solvent system. In some cases, the solvent is ethanol, isopropanol, or n-butanol.

[0383] In some cases, Form B forms during rapid cooling in a multi-solvent system. In some cases, the solvent system comprises water and n-propanol.

[0384] In some cases, Form B is formed during slow cooling in a multi-solvent system. In some cases, the multi-solvent system comprises an organic solvent in which Formula (I) has a solubility of less than 5 mg / ml at room temperature. In some cases, the multi-solvent system comprises an alkane in which Formula (I) has a solubility of less than 5 mg / ml at room temperature. In some cases, the multi-solvent system comprises cyclohexane and dioxane. In some cases, the multi-solvent system comprises cyclohexane and acetonitrile, and crystallization utilizes up to about 0.1 mg / ml Formula (I).

[0385] (iii) Method for making Form C

[0386] In some cases, Form C forms during rapid cooling in a multi-solvent system. In some cases, the solvent system comprises water and methanol.

[0387] In some cases, Form C is formed by incubating a polymorph of Formula (I) in water. In some cases, the polymorph of Formula (I) is one or more of Forms A to L. In some cases, the incubation is performed at or near room temperature (e.g., between 15° C. and 35° C.). In some cases, the incubation is performed for at least 1 hour, at least 6 hours, at least 12 hours, at least 1 day, at least 2 days, or at least 5 days. In some cases, the polymorph of Formula (I) is an anhydrous polymorph.

[0388] In some cases, Form C is formed by incubating a polymorph of Formula (I) in a polyethylene glycol (PEG): water mixture containing at least 50% water by volume. In some cases, the PEG has a molecular weight of at least about 50, at least about 100, at least about 200, at least about 300, at least about 500, or at least about 1000. In some cases, the incubation is for at least 1 hour, at least 6 hours, at least 12 hours, at least 1 day, at least 2 days, or at least 5 days. In some cases, the polymorph of Formula (I) is an anhydrous polymorph.

[0389] In some cases, Form C is formed by incubating another form of Formula (I) in a micellar system. In some cases, the micellar system comprises a nonionic surfactant. In some cases, the nonionic surfactant is polysorbate 80 ("Tween 80") or sodium lauryl sulfate. In some cases, the critical micelle concentration of the micellar system is between about 0.1 and 150, or between about 1 and 100.

[0390] (iv) Method for making Form D

[0391] In some cases, Form D is formed during rapid cooling in a multi-solvent system. In some cases, the solvent system comprises an organic solvent in which Formula (I) has a solubility of less than 5 mg / ml at room temperature and a solvent selected from the group consisting of dimethyl sulfoxide and NMP. In some cases, the organic solvent in which Formula (I) has a solubility of less than 5 mg / ml at room temperature is n-heptane.

[0392] In some cases, form D is formed during slow cooling in a multi-solvent system. In some cases, the solvent system comprises water and dimethylformamide, and crystallization utilizes up to about 0.25mg / ml formula (I). In some cases, the solvent system comprises an organic solvent, and at room temperature formula (I) has less than 5mg / ml solubility in this organic solvent. In some cases, the solvent system comprises normal heptane and a solvent selected from the group consisting of dimethylformamide and NMP. In some cases, the solvent system comprises normal heptane isopropyl alcohol, and at least about 0.4mg / ml formula (I) is used for crystallization. In some cases, the solvent system comprises normal heptane and a solvent selected from the group consisting of ethanol, isopropyl alcohol and ethyl acetate, and crystallization includes seeding with form D crystals. In some cases, the solvent system comprises cyclohexane and dimethyl sulfoxide.

[0393] In some cases, Form D is formed by incubating a polymorph of Formula (I) in n-heptane. In some cases, the polymorph of Formula (I) is one or more of Forms A to L. In some cases, the incubation is performed at or near room temperature (e.g., between 15° C. and 35° C.). In some cases, the incubation is performed for more than one day.

[0394] In some cases, Form D is formed by heating Form B. For example, as summarized in Table 15, Form B rapidly converts to Form D at 60°C, reaching 100% conversion after one day of incubation. Based on this observation, methods for making Form D can comprise incubating Form B at a temperature of at least 40°C, at least 50°C, or at least 60°C for at least 1 hour, at least 6 hours, at least 12 hours, or at least 1 day.

[0395] In some cases, Form D is formed by incubating Form C in a PEG:water mixture containing greater than 50% PEG by volume. In some cases, the mixture contains at least 60% PEG, at least 70% PEG, at least 75% PEG, at least 80% PEG, or at least 90% PEG by volume. In some cases, the PEG has a molecular weight of at least about 50, at least about 100, at least about 200, at least about 300, at least about 500, or at least about 1000.

[0396] (v) Method for making Form E

[0397] In some cases, Form E is formed during rapid cooling in a multi-solvent system. In some cases, the solvent system comprises an organic solvent in which Formula (I) has a solubility of less than 5 mg / ml at room temperature and a solvent selected from the group consisting of methanol, ethanol, acetonitrile, isopropanol, acetone, and n-propanol. In some cases, the organic solvent in which Formula (I) has a solubility of less than 5 mg / ml at room temperature is n-heptane.

[0398] In some cases, Form E is formed during slow cooling in a multi-solvent system. In some cases, the solvent system comprises an organic solvent in which formula (I) has a solubility of less than 5 mg / ml at room temperature. In some cases, the solvent system comprises n-heptane and a solvent selected from the group consisting of methanol, ethanol, acetonitrile and n-propyl alcohol. In some cases, the solvent system comprises n-heptane and methyl ethyl ketone, and crystallization comprises seeding with Form E crystals. In some cases, the solvent system comprises cyclohexane and methanol. In some cases, the solvent system comprises n-heptane and isopropyl alcohol, and crystallization utilizes up to about 0.25 mg / ml formula (I).

[0399] For many of the slurry-based conversions disclosed herein, non-Form D is first converted to Form E and then converted to Form D during incubation in heptane for less than one day. In some cases, the heptane is n-heptane. In some cases, the polymorph of Formula (I) is one or more of Forms A to C. In some cases, incubation is performed at or near room temperature (e.g., between 15° C. and 35° C.). In some cases, incubation is performed for up to one day.

[0400] (vi) Method for making Form F

[0401] In some cases, Form F is formed during rapid cooling in a multi-solvent system. In some cases, the solvent system comprises water and a solvent selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dimethyl sulfoxide, dimethylformamide, N-methyl and -2-pyrrolidone (NMP). In some cases, the solvent system comprises water and acetonitrile, and crystallization utilizes up to about 0.25mg / ml formula (I). In some cases, the solvent system comprises an organic solvent, and at room temperature formula (I) has less than 5mg / ml solubility in the organic solvent. In some cases, the solvent system comprises n-heptane and dimethylformamide. In some cases, the solvent system comprises cyclohexane and a solvent selected from the group consisting of ethanol, NMP, n-propyl alcohol and dioxane.

[0402] In some cases, Form F is formed during slow cooling in a multi-solvent system. In some cases, the solvent system comprises water and a solvent selected from the group consisting of ethanol, tetrahydrofuran, dimethylformamide, and n-propyl alcohol. In some cases, the solvent system comprises an organic solvent in which Formula (I) has a solubility of less than 5 mg / ml at room temperature. In some cases, the solvent system comprises n-heptane and dimethyl sulfoxide. In some cases, the solvent system comprises cyclohexane and a solvent selected from the group consisting of methanol, isopropyl alcohol, dimethylformamide, and n-propyl alcohol.

[0403] (vii) Method for making Form G

[0404] In some cases, Form G forms during slow cooling in a single solvent or substantially single solvent system. In some cases, the single solvent is tetrahydrofuran (THF), methyl ethyl ketone (MEK), or dioxane.

[0405] In some cases, Form G forms during rapid cooling in a single solvent or substantially single solvent system. In some cases, the solvent is tetrahydrofuran or dioxane.

[0406] In some cases, Form G is formed during rapid cooling in a multi-solvent system. In some cases, the solvent system comprises water and dioxane. In some cases, the solvent system comprises an organic solvent in which Formula (I) has a solubility of less than 5 mg / ml at room temperature. In some cases, the solvent system comprises n-heptane and a solvent selected from the group consisting of tetrahydrofuran and dioxane. In some cases, the solvent system comprises cyclohexane and acetone, and crystallization utilizes up to about 0.25 mg / ml Formula (I).

[0407] In some cases, Form G is formed during slow cooling in a multi-solvent system. In some cases, the solvent system comprises water and dioxane. In some cases, the solvent system comprises an organic solvent in which Formula (I) has a solubility of less than 5 mg / ml at room temperature. In some cases, the solvent system comprises n-heptane and dioxane. In some cases, the solvent system comprises cyclohexane and tetrahydrofuran. In some cases, the solvent system comprises cyclohexane, dioxane, and at least about 0.4 mg / ml of Formula (I) is in the solvent system.

[0408] (viii) Method for making Form H

[0409] In some cases, Form H forms during slow cooling in a single solvent or substantially single solvent system. In some cases, the single solvent is 2-methyltetrahydrofuran (2-MeTHF), isopropyl acetate (IPAc), or methyl isobutyl ketone (MIBK).

[0410] In some cases, Form H forms during rapid cooling in a single solvent or substantially single solvent system. In some cases, the solvent is isopropyl acetate or 2-methyltetrahydrofuran.

[0411] In some cases, Form H is formed during rapid cooling in a multi-solvent system. In some cases, the multi-solvent system comprises an organic solvent in which Formula (I) has a solubility of less than 5 mg / ml at room temperature. In some cases, the multi-solvent system comprises cyclohexane and a solvent selected from the group consisting of acetonitrile and tetrahydrofuran. In some cases, the solvent system comprises cyclohexane and acetone, and at least about 0.4 mg / ml of Formula (I) is in the solvent system.

[0412] In some cases, Form H is formed during slow cooling in a multi-solvent system. In some cases, the multi-solvent system comprises an organic solvent in which Formula (I) has a solubility of less than 5 mg / ml at room temperature. In some cases, the multi-solvent system comprises cyclohexane and acetone. In some cases, the multi-solvent system comprises cyclohexane and acetonitrile, and at least about 0.4 mg / ml of Formula (I) is in the solvent system.

[0413] (ix) Method for producing Form I

[0414] In some cases, Form I forms during slow cooling in a single solvent or substantially single solvent system. In some cases, the single solvent is dichloromethane.

[0415] In some cases, Form I is formed during rapid cooling in a single solvent or substantially single solvent system. In some cases, the solvent is dichloromethane. In some cases, the solvent is acetonitrile, and crystallization utilizes up to about 0.25 mg / ml of Formula (I).

[0416] (x) Method for making Form J

[0417] In some cases, Form J forms during slow cooling in a single solvent or substantially single solvent system. In some cases, the single solvent is toluene.

[0418] (xi) Method for making Form K

[0419] In some cases, Form K forms during slow cooling in a single solvent or substantially single solvent system. In some cases, the single solvent is methyl tert-butyl ether (MTBE).

[0420] In some cases, Form K forms during rapid cooling in a single solvent or substantially single solvent system. In some cases, the single solvent is methyl tert-butyl ether (MTBE).

[0421] In some cases, Form K is formed by incubating a polymorph of Formula (I) in methyl tert-butyl ether. In some cases, the polymorph of Formula (I) is one or more of Forms A to L. In some cases, the incubation is performed at or near room temperature (e.g., between 15° C. and 35° C.). In some cases, the incubation is performed for at least one day.

[0422] (xii) Method for making Form L

[0423] In some cases, Form L is formed during slow cooling in a multi-solvent system. In some cases, the multi-solvent system comprises water and isopropanol, and at least about 0.4 mg / mL of Formula (I) is used for crystallization. In some cases, the multi-solvent system comprises cyclohexane and acetonitrile, and at least about 0.2 mg / mL of Formula (I) is used for crystallization.

[0424] In some cases, Form L is formed during rapid cooling in a multi-solvent system. In some cases, the solvent system comprises an organic solvent in which Formula (I) has a solubility of less than 5 mg / ml at room temperature. In some cases, the solvent system comprises n-heptane and tetrahydrofuran.

[0425] Preparations

[0426] Formula (I) can be formulated for a variety of delivery routes, including oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including transdermal, buccal, sublingual and intraocular) administration. Formula (I) as disclosed herein can be prepared in a variety of polymorphic forms, each with unique solubility, stability and activity. According to these findings, formula (I) formulations can not only be customized according to a specific delivery route, but also optimize the form of formula (I) and the suitability of a specific delivery system. For example, as outlined in Example 17, by appropriately selecting formula (I) polymorphic forms, its solubility and stability in PEG-water mixtures can be enhanced. Therefore, the best formulation not only includes a delivery form (e.g., solid pill or micellar suspension), but also includes a polymorph of formula (I) selected for delivery and a desired activity level.

[0427] Formula (I) can be formulated as a raw material or as a component of a pharmaceutical formulation. In many cases, the formulation of formula (I) comprises one or more pharmaceutically acceptable carriers. As used herein, a pharmaceutically acceptable carrier can represent a non-therapeutic active ingredient that is compatible with other ingredients in a pharmaceutical formulation. The pharmaceutical compositions disclosed herein can be manufactured in any manner known in the art, for example, by conventional mixing, dissolving, granulating, preparing dragees, grinding, emulsifying, encapsulating, embedding or tableting processes. A pharmaceutically acceptable carrier can be a solid, a liquid, an emulsifier or a combination thereof. In some cases, the formulation of formula (I) comprises polyethylene glycol, polypropylene glycol, sulfobutyl ether, vitamin E, castor oil, hydrogenated castor oil, soybean oil, corn oil, canola oil, Miglyol 810, Miglyol 812, Capmul MCM, Kolliphor P188, Kolliphor EL, oleic acid, plurololeique, pecceol, labrasol, labrafil M1944CS, Felucire 44 / 14, Captex 355, PlurolOleique CC 497, triacetin, transcutol HP, glycerol, intralipid or a combination thereof. In some cases, the formulation of formula (I) comprises a surfactant. In some cases, the surfactant is an ionic surfactant. In some cases, the surfactant is a nonionic surfactant.

[0428] The size of formula (I) is an important determinant of formula (I) characteristics (for example, dissolution rate in a specific solvent). In preparation, formula (I) can have size uniformity or be polydisperse. In some cases, the particle size (for example, crystal diameter) standard deviation of formula (I) is about 0.1 times of average particle size, about 0.2 times of average particle size, about 0.4 times of average particle size, about 0.75 times of average particle size, about equal to average particle size or greater than average particle size. For some preparations disclosed herein, the average particle size (for example, the average diameter of single crystals) of formula (I) is between about 0.1 micron and 500 microns. In some cases, the average particle size of formula (I) is between about 10 microns and 50 microns, between about 10 microns and 100 microns, between about 10 microns and 200 microns, between about 20 microns and 100 microns, between about 50 microns and 100 microns, between about 50 microns and 250 microns or between about 100 microns and about 500 microns. In some cases, the average particle size of Formula (I) is between about 0.1 and 25 microns, between about 0.1 and 0.5 microns, between about 0.1 and 1 micron, between about 0.1 and 2 microns, between about 0.25 and 1 micron, between about 0.25 and 2 microns, between about 0.25 and 4 microns, between about 0.5 and 2 microns, between about 0.5 and 5 microns, between about 1 and 5 microns, between about 2 and 6 microns, between about 2 and 9 microns, between about 2 and 12 microns, between about 4 and 12 microns, between about 4 and 20 microns, between about 6 and 12 microns, between about 6 and 20 microns, between about 8 and 25 microns, or between about 10 and 30 microns.

[0429] The most suitable approach may depend on, for example, the illness and disorder of the recipient. The formulation can be conveniently presented in unit dosage form and can be prepared by any method known in pharmaceutical formulations. Typically, these methods include the step of associating the compound of the present invention or its pharmaceutically acceptable salt, ester, amide, prodrug or solvate ("active ingredient") with a carrier constituting one or more auxiliary ingredients. Typically, the formulation is prepared by uniformly and closely associating the active ingredient with a liquid carrier or a finely dispersed solid carrier or both and then, if necessary, shaping the product into the desired formulation.

[0430] Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0431] Pharmaceutical formulations for oral administration include tablets, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). Tablets can be manufactured by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (such as a powder or granules) optionally mixed with a binder, an inert diluent or lubricant, a surfactant, or a dispersant in a suitable machine. Molded tablets can be manufactured by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored and are optionally formulated to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in a dosage suitable for such administration. Such push-fit capsules can contain the active ingredient, which is mixed with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or magnesium stearate), and optionally a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid (such as fatty oil, liquid paraffin or liquid polyethylene glycol). In addition, a stabilizing agent can be added. Suitable coating is provided for dragee cores. For this purpose, concentrated sugar solution can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture. Coloring agent or pigment can be added to tablet or dragee coating for the identification or characterization of the different combinations of active compound dosage.

[0432] The compound can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Preparations for injection can be present in unit dosage form, for example, in ampoules or in multi-dose containers, with the addition of preservatives. These compositions can be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain preparatons such as suspending agents, stabilizers, and / or dispersants. These preparations can be present in unit doses or multi-dose containers, such as sealed ampoules and vials, and can be stored in powder form or stored under freeze-dried (lyophilized) conditions requiring only the addition of a sterile liquid carrier (e.g., saline or water for injection) immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the aforementioned types.

[0433] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils (such as sesame oil) or synthetic fatty acid esters (such as ethyl oleate or triglycerides) or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow the preparation of high concentration solutions.

[0434] In addition to the aforementioned preparations, the compound can also be formulated into a depot preparation. Such long-acting preparations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Therefore, for example, the compound can be formulated with a suitable polymeric material or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or be formulated as a slightly soluble derivative, for example, as a slightly soluble salt.

[0435] For buccal or sublingual administration, the composition may take the form of tablets, lozenges, pastilles or gels formulated in conventional manner.Such compositions may contain the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0436] Formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0437] Formula (I) can be formulated for topical application, i.e., by non-systemic administration. This includes applying a compound disclosed herein to the epidermis or oral cavity from the outside, and dripping this compound into the ears, eyes, and nose so that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration. Preparations suitable for topical application include liquid or semi-liquid preparations suitable for penetrating the skin into the site of inflammation, such as gels, liniments, lotions, creams, ointments, or pastes, and drops suitable for application to the eyes, ears, or noses. The active ingredient for topical application can include, for example, 0.001% to 10% w / w (by weight) of the preparation. In certain embodiments, the active ingredient can include up to 10% w / w. In other embodiments, it can include less than 5% w / w. In certain embodiments, the active ingredient can include 2% w / w to 5% w / w. In other embodiments, it can include 0.1% to 1% w / w of the preparation.

[0438] The topical ophthalmic, otological, and nasal formulations of the present invention may also contain excipients in addition to the active ingredient. Excipients commonly used in such formulations include, but are not limited to, tonicity agents, preservatives, chelating agents, buffers, and surfactants. Other excipients include solubilizers, stabilizers, comfort enhancers, polymers, emollients, pH adjusters, and / or lubricants. Any of a variety of excipients may be used in the formulations of the present invention, including water, mixtures of water and water-miscible solvents (such as C1-C7-alkanols), vegetable or mineral oils containing 0.5% to 5% non-toxic water-soluble polymers, natural products (such as alginates, pectins, tragacanth gum, carrageenan, guar gum, xanthan gum, carrageenan, agar, and gum arabic), starch derivatives (such as starch acetate and hydroxypropyl starch), and other synthetic products (such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably cross-linked polyacrylic acid, and mixtures of these products). The concentration of the excipient is typically 1 to 100,000 times the concentration of the active ingredient.In preferred embodiments, the excipients included in the formulation are typically selected based on the inertness of the excipient toward the active ingredient component of the formulation.

[0439] With respect to ophthalmic, otological and nasal formulations, suitable tonicity adjusting agents include, but are not limited to, mannitol, sodium chloride, glycerol, sorbitol, and the like. Suitable buffers include, but are not limited to, phosphates, borates, acetates, and the like. Suitable surfactants include, but are not limited to, ionic and nonionic surfactants (although nonionic surfactants are preferred), RLM100, POE 20 cetyl stearyl ether (such as CS20) and poloxamers (such as F68).

[0440] The formulations described herein may contain one or more preservatives. Examples of such preservatives include parabens, sodium perborate, sodium chlorite, alcohols (such as chlorobutanol, benzyl alcohol, or phenylethyl alcohol), guanidine derivatives (such as polyhexamethylene biguanide), sodium perborate, polyquaternium-1, amino alcohols (such as AMP-95), or sorbic acid. In certain embodiments, the formulations may be self-preserving and therefore do not require a preservative.

[0441] For ophthalmic, otological or nasal administration, the formulation can be a solution, suspension or gel. In a preferred aspect, the formulation is applied topically to the eye, nose or ear in the form of an aqueous solution in the form of drops. The term "aqueous" generally refers to an aqueous formulation, wherein the formulation contains >50%, more preferably >75%, and especially >90% water by weight. These drops can be delivered from a single-dose ampoule, which can preferably be sterile and therefore no antibacterial component is required in the formulation. Alternatively, the drops can be delivered from a multi-dose bottle, which preferably includes a device for removing any preservatives from the formulation upon delivery, such devices being known in the art. For ophthalmic disorders, the components of the present invention can be delivered to the eye in the form of a concentrated gel or similar vehicle or in the form of a dissolvable insert placed under the eyelid.

[0442] The formulations of the present invention suitable for topical application to the eye are preferably isotonic or slightly hypotonic to counteract any tear hyperosmolarity caused by evaporation and / or disease. This may require a tonicity agent to adjust the osmolality of the formulation to or near 210 to 320 milliosmoles / kilogram (mOsm / kg). The formulations of the present invention typically have an osmolality in the range of 220 to 320 mOsm / kg, preferably an osmolality in the range of 235 to 300 mOsm / kg. Ophthalmic formulations will typically be formulated into sterile aqueous solutions.

[0443] In certain ophthalmic embodiments, the compositions of the present invention are formulated with one or more tear substitutes. A variety of tear substitutes are known in the art and include, but are not limited to: monomeric polyols such as glycerol, propylene glycol, and ethylene glycol; polymeric polyols such as polyethylene glycol; cellulose esters such as hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and hydroxypropyl cellulose; dextran such as dextran 70; vinyl polymers such as polyvinyl alcohol; and carbomers such as carbomer 934P, carbomer 941, carbomer 940, and carbomer 974P. Certain formulations of the present invention can be used with contact lenses or other ophthalmic products. Preferred tear substitute formulations are prepared using a buffer system that maintains the formulation at a pH of about 4.5 to a pH of about 8. The most preferred formulations have a pH of 6 to 8.

[0444] Gels for topical or transdermal administration typically comprise a mixture of a volatile solvent, a non-volatile solvent, and water. In certain embodiments, the volatile solvent component of the buffered solvent system may include lower (Ci-C6) alkyl alcohols, lower alkyl glycols, and lower glycol polymers. In other embodiments, the volatile solvent is ethanol. The volatile solvent component is believed to act as a penetration enhancer while also having a cooling effect on the skin upon evaporation. The non-volatile solvent portion of the buffered solvent system is selected from lower alkylene glycols and lower glycol polymers. In certain embodiments, propylene glycol is used. The non-volatile solvent slows the evaporation of the volatile solvent and reduces the vapor pressure of the buffered solvent system. As with the volatile solvent, the amount of this non-volatile solvent component is determined by the drug compound or drug being used. When there is too little non-volatile solvent in the system, the drug compound may crystallize due to evaporation of the volatile solvent, while an excess may result in reduced bioavailability due to poor release of the drug from the solvent mixture. The buffer component of the buffered solvent system can be selected from any buffer commonly used in the art; in certain embodiments, water is used. A common ratio of ingredients is about 20% non-volatile solvent, about 40% volatile solvent, and about 40% water. There are several optional ingredients that can be added to the topical composition. These ingredients include, but are not limited to, chelating agents and gelling agents. Suitable gelling agents can include, but are not limited to, semisynthetic cellulose derivatives (such as hydroxypropyl methylcellulose), synthetic polymers, galactomannan polymers (such as guar gum and its derivatives), and cosmetic agents.

[0445] Lotions include those suitable for application to the skin or eyes. Eye lotions may comprise sterile aqueous solutions (optionally containing a bactericide) and may be prepared by methods similar to those used for drops. Lotions or liniments for application to the skin may also contain an agent (such as alcohol or acetone) and / or a moisturizer (such as glycerol) or oil (such as castor oil or peanut oil) to accelerate drying and cool the skin.

[0446] Creams, ointments or pastes are semisolid formulations of active ingredients for external application. They can be made by mixing the active ingredient in fine powder or powder form (alone or in the form of a solution or suspension in an aqueous or non-aqueous fluid) with an oily or non-oily base with the help of a suitable machine. The base may include hydrocarbons such as hard paraffin, soft paraffin or liquid paraffin, glycerol, beeswax, metallic soaps; viscose; oils of natural origin such as almond oil, corn oil, peanut oil, castor oil or olive oil; lanolin or its derivatives or fatty acids such as stearic acid or oleic acid, and alcohols such as propylene glycol or macrogol. The formulation may incorporate any suitable surfactant, such as anionic, cationic or nonionic surfactants, such as sorbitan or its polyoxyethylene derivatives. It may also contain suspending agents (such as natural gums, cellulose derivatives or inorganic materials such as siliceous silica) and other ingredients (such as lanolin).

[0447] Drops can comprise sterile aqueous solutions or oily solutions or suspensions, and can be prepared by dissolving the active ingredient in an aqueous solution of a suitable bactericide and / or fungicide and / or any other suitable preservative (and in certain embodiments, comprising a surfactant). The resulting solution can then be clarified by filtration, transferred to a suitable container, which is then sealed and sterilized by autoclaving or maintaining at 98°C to 100°C for half an hour. Alternatively, the solution can be sterilized by filtration and transferred to a container by aseptic technique. Examples of bactericides and fungicides suitable for inclusion in drops are phenylmercuric nitrate or phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%), and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of oily solutions include glycerol, dilute alcohol, and propylene glycol. Formulations for topical administration in the mouth (e.g., buccally or sublingually) include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, as well as confectionery lozenges comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.

[0448] For administration by inhalation, the compound can be delivered by an insufflator, a nebulizer pressurized package or other convenient aerosol spray mode. The pressurized package can include a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compound according to the present invention can take the form of a dry powder composition, for example a powder mixture of the compound and a suitable powder base (such as lactose or starch). The powder composition can be in a unit dose form (e.g., in capsules, cartridges, gelatin or blister packs, from which the powder can be administered with the help of an insufflator or insufflator).

[0449] In some cases, the formula (I) formulation is provided together with one or more additional therapeutic ingredients. By way of example only, if one of the side effects experienced by a patient after receiving one of the compounds herein is hypertension, it may be appropriate to administer an antihypertensive agent in combination with the initial therapeutic agent. Alternatively, by way of example only, the therapeutic effectiveness of one of the compounds described herein can be enhanced by administering an adjuvant (i.e., the adjuvant itself may have only minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefit experienced by the patient can be increased by administering one of the compounds described herein together with another therapeutic agent (which also includes a treatment regimen) that also has a therapeutic benefit. By way of example only, in the treatment of diabetic neuropathic pain involving the administration of one of the compounds described herein, the increased therapeutic benefit can be generated by also providing the patient with another diabetes therapeutic agent. In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may be a simple addition of the two therapeutic agents, or the patient may experience a synergistic benefit. Multiple therapeutic agents (at least one of which is a compound disclosed herein) can be administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, as a single pill or as two separate pills). One of the therapeutic agents may be administered in multiple doses, or both therapeutic agents may be administered in multiple doses. If administered non-simultaneously, the time between multiple doses may be any duration ranging from a few minutes to four weeks.

[0450] How to use

[0451] Formula (I) (e.g., a single polymorph or a mixture of forms A to L) is effective as a soluble epoxide hydrolase inhibitor. The present disclosure provides methods for inhibiting soluble epoxide hydrolase inhibitors with formula (I). In many cases, such methods include using one or more of forms A to L to inhibit soluble epoxide hydrolase.

[0452] Among other uses, Formula (I) can be used to modulate disorders or diseases in which modulation of sEH has some effect on the underlying condition or disease (e.g., sEH inhibitors or antagonists cause some improvement in patient health in at least some patients). Such disorders and diseases can include epileptic disorders (such as epilepsy), nephropathy, cardiomyopathy, hypertension, pain, inflammation, inflammatory pain, postoperative pain, neuropathic pain, diabetic neuropathic pain, tissue wounds or pain caused thereby, acute inflammation, inflammation caused by sepsis, pancreatitis, multiple trauma (such as brain injury and tissue damage, such as muscle tissue tears, brain surgery, hemorrhagic shock, and immune-mediated organ damage), adult respiratory distress syndrome, emphysema, chronic bronchitis, obstructive lung disease, chronic obstructive pulmonary disease (COPC), small airway disease, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, burns or pain in skin diseases (such as dermatitis, chemical burns, thermal burns, redness of the skin, and chemically induced lesions), neuralgia, pain caused by trauma or irritation of peripheral nerves near the surface of the skin.

[0453] In many cases, Formula (I) inhibits sEH without or with negligible inhibition of microsomal epoxide hydrolase (hereinafter "mEH"), which is essential for sodium transport and xenobiotic degradation. The favorable solubility of Forms A to L makes them easy to formulate for cytosol and peroxisomal delivery (where sEH is normally located), and has minimal effect on the delivery of mEH, which is primarily anchored to the cell membrane.

[0454] In a specific embodiment, the preparation of the present invention is used once a day. However, the preparation may also be formulated for use with any frequency of administration (comprising once a week, once every 5 days, once every 3 days, once every 2 days, twice a day, three times a day, four times a day, five times a day, six times a day, eight times a day, per hour or any higher frequency). This type of administration frequency may also maintain different durations according to the treatment regimen. The duration of a specific treatment regimen may vary from a one-time administration to the scheme that lasts for several months or years. The preparation is used with the dosage that varies, but conventional dosage is for each use of one to two drops, or a considerable amount of gel or other preparations. Those skilled in the art will be familiar with the treatment regimen determined for specific indications.

[0455] Formula (I) can be orally, topically or via injection with a dosage of 0.1 to 500mg / kg / days. The dosage range of adults is generally 5mg to 2g / days. Tablet or other presentation forms provided in discrete units can conveniently contain a certain amount of one or more compounds, which are effective at this dosage, or with their multiples (for example, containing 5mg to 500mg, typically about 10mg to 200mg units) effective.

[0456] Examples

[0457] The following examples are provided to further illustrate embodiments of the present invention and are not intended to limit the scope of the present invention. Although they are typical examples that may be used, other procedures, methods or techniques known to those skilled in the art may also be used alternatively.

[0458] Experimental methods

[0459] Differential Scanning Calorimetry (DSC)

[0460] Differential Scanning Calorimetry analysis was performed on each sample "as received." Unless otherwise stated, samples were weighed into aluminum pans, covered with perforated lids, press-fitted, and sealed and analyzed by heating from 30°C to 300°C at 10°C / min.

[0461] Thermogravimetric analysis (TGA)

[0462] Thermogravimetric analysis was performed on each sample “as received.” Unless otherwise stated, samples were weighed in alumina crucibles and analyzed at 10°C / min from 30°C to 350°C.

[0463] X-ray powder diffraction (XRD)

[0464] X-ray powder diffraction was performed on each sample "as received" on a Si zero-reset microsample holder and analyzed using a 10 mm irradiation width and the parameters outlined in Table 1. After analysis, the data were converted from an adjustable slit to a fixed slit using X'Pert HighScorePlus software using a fixed divergence slit size of 1.00° (1.59 mm) and a crossover point of 44.3°Ω.

[0465] Table 1

[0466] X-ray tube: Cu KEICu KKKube: Detector: X'Celerator ASS main slit: Fixed 1° Diverging slit (Prog): Automatic-5mm irradiation length Soller Slit: 0.02 radians Scattering slit (PASS): Automatic-5mm observation length Scan range: 3.0°-45.0°0 Scan Mode: continuous Step length: 0.02° Time per step: 10s Effective length: 2.54°

[0467] Water Sorption Analysis (DVS)

[0468] All materials were subjected to a gravimetric moisture adsorption experiment. The samples were first maintained at 40% RH and 25°C for a period of up to 4 hours. The samples were then subjected to an isothermal (25°C) adsorption scan with a step length of 10% RH from 40% to 90% RH. The samples were allowed to balance to asymptotic weight for a period of up to 4 hours at each point. After adsorption, a desorption scan was run from 90% to 0% RH (at 25°C) with a step length of -10% RH, requiring a maximum of 4 hours to balance to asymptotic weight. The adsorption scan was then carried out from 0% RH to 40% RH with a step length of +10% RH. The samples were then dried for more than 2 hours at 60°C 0% RH, and the resulting solid was analyzed by XRD.

[0469] Nuclear magnetic resonance imaging

[0470] The samples were dissolved in DMSO-d6. 1H NMR spectra were acquired at 300 MHz or 500 MHz using a 5 mm broadband (1H-X) Z gradient probe. Spectra were acquired using a 30 degree pulse, 20 ppm spectral width, 1.0 s repetition rate, and 32 transients.

[0471] Polarized light microscopy

[0472] The samples were examined using a polarizing microscope combined with a digital camera (1600×1200 resolution). A small amount of sample was spread on a glass slide and a small amount of mineral oil was added at a magnification of 100× or 200×. The parameters measured by the polarizing microscope are provided in Table 2. The calibration curve at 254 nm is provided in Figure 38 middle.

[0473] Table 2

[0474]

[0475]

[0476] Example 1

[0477] Synthesis of tert-butyl 4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)piperidine-1-carboxylate (Compound S1)

[0478]

[0479] Meta-fluoro-4-(trifluoromethoxy) aniline (500mg, 2.56mmol) and triethylamine (388mg, 3.84mmol) are dissolved in CH cl (4mL) and at-78 ℃, it is dropwise added to triphosgene (341mg, 1.15mmol) and is dissolved in CH cl (5mL) in solution.Reaction mixture is stirred at 0 ℃ for 1 hour and then is cooled to-78 ℃.4-amino-1-Boc-piperidines (769mg, 3.84mmol) and triethylamine (388mg, 3.84mmol) are dissolved in CH cl (4mL) and at-78 ℃, suspension is dropwise added to reaction mixture.Reaction mixture is stirred 2 hours under room temperature (RT).Reaction is quenched by adding water.Separate organic layer, and organic layer is washed 4 times with HCl solution (1M). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to give the final crude product (1.05 g, 86% pure, 2.13 mmol, 83.4% yield). Impurities including 1,3-bis(3-fluoro-4-(trifluoromethoxy)phenyl)urea were removed by column chromatography using EtOAc:Hex (1:1).

[0480] 1H NMR(dg-DMSO,300Mhz):A:d 8.77(s,1H),7.66(dd,J=13.5,2.4Hz,1H),7.38(t,J=8.1Hz,1H),7.10(d,J=9Hz,1H),6.33(d,J=7.5Hz,1H),3.81(d ,J=12.9Hz,2H),3.6-3.8(m,1H),2.8-3.0(m,2H),1.78(dd,J=12.3Hz,3.3Hz,2H),1.40(s,9H),1.2-1.4(m,2H); 38:d 9.28(s,1H),7.69(dd,J=14.9,2.4Hz,1H),7.46(t,J=9Hz,1H),7.2-7.3(m,1H).

[0481] Example 2

[0482] Synthesis of 1-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-(piperidin-4-yl)urea (Compound S2)

[0483]

[0484] Compound S1 (186 mM) was dissolved in HCl solution (2 M, MeOH) to prepare a reaction mixture. The resulting solution was refluxed for 2 hours. The solvent was removed under vacuum and the crude reaction product was subjected to a pH of 12 with NaOH. The precipitated product S2 was filtered and dried under high vacuum.

[0485] Example 3

[0486] Synthesis of (S)-1-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-(1-(2-methylbutyryl)piperidin-4-yl)urea (Formula (I))

[0487]

[0488] (S) -2-methylbutanoic acid (14 mg, 140 μ mol) was activated with 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) and 4-dimethylaminopyridine (DMAP) in a molar equivalent of CH2CL2 and then merged with compound S2 (30 mg, 93.4 μ mol). The reaction was stirred at room temperature for 12 hours and then quenched by adding 1M HCl. The organic layer was collected and the aqueous layer was extracted 4 times with EtOAc. The organic layer and EtOAc were merged and dried over anhydrous magnesium sulfate and then concentrated in vacuo. The product was purified by flash chromatography and eluted with ethyl acetate. The collected fractions were dried in vacuo to obtain a white solid formula (I). The product was further purified (30 mg, 83.9 μ mol, 79.2% yield, purity (H-NMR):>95%) by recrystallization using methanol and water.

[0489] MP: 147°C to 147.8°C. 1H NMR (de-DMSO, 600 MHz): d 8.78(d,J=17.4Hz,1H),7.66(dd,J=13.8Hz,2.4Hz,1H),7.39(t,J=9Hz,1H),7.1 1(dd,J=9Hz,1.2Hz,1H),6.3-6.4(m,1H),4.23(t,J=13.2Hz,1H),3.88(d,J=10. 8Hz,1H),3.6-3.8(m,1H),3.1-3.2(m,1H),2.6-2.8(m,2H),1.8-1.9(br,1H),1. 7-1.8(m,1H),1.5-1.6(m,1H),1.1-1.4(m,3H),0.9-1.0(m,3H),0.7-0.9(m,3H).

[0490] Example 4

[0491] Evaluation of various crystallization conditions

[0492] This example covers the crystallization of formula (I) in a variety of solvent systems. Across a range of polarity, functionality and according to the International Conference on Harmonization (ICH) classification, solvents are selected, with preference given to Class II and Class III solvents. Solvents also differ in terms of solubility of formula (I). For these analyses, approximately 4 mg to 6 mg of formula (I) are dispensed into 7 mL glass vials, and selected solvents are added in 100 μL aliquots to completely dissolve at room temperature. After each addition of solvent, the vial is shaken and visually inspected for residual solids. If necessary, it is heated to 50 ° C or heated to reflux (for low boiling point solvents) for approximately two minutes to ensure complete dissolution. If there are residual solids, additional solvent aliquots are added. Solvent addition is stopped when complete dissolution is complete.

[0493] Table 3 summarizes the solvents used for crystallization and the corresponding solubility of formula (I) at room temperature (RT) and 50°C. Based on these solubility data, sixteen solvents were selected as the main solvents: methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA), n-BuOH, acetonitrile (ACN), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), ethyl acetate (EtOAc), isopropyl acetate (IPAc), acetone, 2-butanone (methyl ethyl ketone, MEK), methyl isobutyl ketone (MIBK), dichloromethane (DCM), toluene, methyl tert-butyl ether (MTBE) and dioxane. Three solvents (water, n-heptane and cyclohexane) were selected as anti-solvents for crystallization. Figure 1 A total of twelve unique XRD patterns were identified from the single-solvent and binary-solvent crystals, presented in panels A to L.

[0494] Table 3 - Summary of solubility screening of formula (I)

[0495]

[0496] First, the crystallization of formula (I) was analyzed in a single solvent system lacking an anti-solvent. For these analyses, approximately 30 mg to 70 mg of formula (I) was weighed into a 7 mL transparent glass vial equipped with a stirring rod and dissolved with the minimum amount of solvent (minimum 0.1 mL) required for dissolution. Rapid cooling was performed by placing the vial in a 4 ° C refrigerator for 24 hours, while slowly cooling was performed by lowering the vial temperature at 20 ° C / h under stirring. The obtained solid was separated by centrifugation through a 0.45 μm centrifugal filter. When no solid was produced, the solution was evaporated under nitrogen as another attempt to obtain a solid. All obtained solids were analyzed by XRD to determine the solid form. For each recrystallization, formula (I) was dissolved in a solvent and recrystallized from 40 ° C, 50 ° C or 70 ° C according to the boiling point of the main solvent. In total, eight unique XRD patterns of the crystals produced by crystallization were observed, and the results of the slow cooling experiment and the fast cooling experiment are summarized in Table 4.

[0497] Table 4

[0498]

[0499]

[0500] Then, the recrystallization of formula (I) was tested using a binary solvent system containing water, n-heptane or cyclohexane as an anti-solvent. For these analyses, approximately 30 mg to 40 mg of formula (I) was weighed into a 7 mL transparent glass vial equipped with a stirring rod and dissolved with the minimum amount of each primary solvent (minimum 0.1 mL) required for dissolution. Anti-solvent was added dropwise at the same temperature until precipitation was observed or the vial volume (approximately 7 mL) was reached. The vial was quickly cooled to 4 ° C or slowly cooled at 20 ° C / hour, as described in single solvent recrystallization. The resulting solid was separated by centrifugal filtration. The sample that did not precipitate was evaporated to dryness under a gentle nitrogen stream as another attempt to obtain a solid. All obtained solids were analyzed by XRD to determine the solid form. The selection of the primary solvent was based on the high solubility of formula (I) and its miscibility with the anti-solvent. For each binary solvent system, formula (I) was recrystallized from 50 ° C or 70 ° C. Ten unique XRD patterns were identified from the resulting crystals and are summarized in Tables 5 to 7 below.

[0501] Table 5

[0502]

[0503]

[0504] Table 6

[0505]

[0506]

[0507] Table 7

[0508]

[0509]

[0510] Example 5

[0511] Polymorph characterization

[0512] This example covers the characterization of the twelve polymorphs identified in Example 4. Each polymorph was characterized by XRD ( Figure 1 Panels A to L), differential scanning calorimetry ( Figures 2 to 13 )、Thermogravimetric analysis( Figures 14 to 25 ) were analyzed for polymorph and pseudopolymorph identification and NMR ( Figures 26 to 37 ) were analyzed to confirm chemical integrity and residual solvent. Exemplary conditions and physical characteristics for producing each of the twelve polymorphs are summarized in Table 8.

[0513] The DSC results for each of Forms A to L are provided in Figures 2 to 13 Although each sample exemplifies a single polymorph, some samples show evidence of trace amounts of additional forms. In particular, DSC indicated the presence of small amounts of Form D in some preparations of Forms A, B, E, G, H, K, and L, and the absence of additional polymorphs in Forms D, F, and I. Hydrated Form C was not detected in any of the other polymorphs by DSC.

[0514] Thermogravimetric analysis results for Forms A to L are provided in Figures 14 to 25 All forms exhibited weight loss above 150°C, corresponding to decomposition of Formula (I). Only Forms C, E, H, J, K, and L exhibited weight changes below 150°C, indicating solvent loss. The weight loss of Form C between 39°C and 50°C likely reflects methanol loss. Forms E, H, J, K, and L exhibited weight loss at approximately 120°C, corresponding to loss of organic solvent.

[0515] Figures 26 to 37 NMR spectra are provided for Forms A through L. In addition to Formula (I), NMR also identified approximately 2.5% methanol in Form C, approximately 0.9% isopropanol in Form E, approximately 0.04% acetone in Form G, approximately 7.1% cyclohexane in Form H, approximately 8.8% toluene in Form J, approximately 8.8% MTBE in Form K, and approximately 0.2% THF in Form L.

[0516] Table 8

[0517]

[0518]

[0519]

[0520]

[0521] Example 6

[0522] Scale-up method for polymorph production

[0523] In order to produce sufficient quantities of each polymorph (e.g., Forms A, B, D, E, etc.) for further physical characterization, Formula (I) was produced according to Examples 1 to 3 and then recrystallized using the solvent system and conditions outlined in Example 5. The parameters for the scaled-up recrystallization are summarized in Table 9. Briefly, the scaled-up recrystallization utilized between about 330 mg and 450 mg (about 10 times the amount used in the recrystallization of Example 4) of Formula (I).

[0524] Table 9

[0525]

[0526] The X-ray powder diffraction data of the obtained polymorphs are presented in Figures 39 to 45 In each figure, the top spectrum corresponds to a previously produced polymorph with a similar XRD pattern, and the bottom spectrum corresponds to the XRD of the polymorph produced in the scale-up experiment. The DSC and TGA of the polymorph produced in the scale-up recrystallization are presented in Figures 46 to 52 and Figures 53 to 59 middle.

[0527] DSC data was used to determine the heat of fusion of Forms A, B, D, and F based on their heat of fusion measured during conversion from Form C. As summarized in Table 10, each of Forms A, B, D, and F is thermodynamically stable, with Form D having the highest stability of the four forms.

[0528] Table 10

[0529] form Heat of fusion Melting temperature, °C A 29，.73 Start: 106; Peak: 111 B 53.14 Start: 144; Peak: 147 D 67.51 Start: 141; Peak: 143 F 57.06 Start: 148; Peak: 150

[0530] Since no forms E, F, G and I were obtained, the materials from the preliminary screening experiments were combined and used. The data for the combined materials are summarized in Table 11. The XRD patterns of these crystals (yielding forms I, G, F and E, respectively) are shown in Table 11. Figures 60 to 63 , where the standard XRD of the target form is provided as the top spectrum in each figure and the obtained spectrum is shown at the bottom of each figure.

[0531] Table 11

[0532]

[0533] Example 7

[0534] Competitive slurry experiments

[0535] Adopt competitive slurry experiment to analyze polymorph stability and interconversion.For the form A, B, D, E, F, G and I (summarized in Table 11) produced by amplifying crystallization, carried out competitive slurry (solvent-mediated conversion) experiment.Adopt water, MTBE and normal heptane (for their low solubility to formula (I) and select) to carry out competitive slurry experiment.In brief, by the formula (I) of one or more forms being suspended in 1.0mL solvent and at room temperature following stirring hatching to carry out competitive slurry experiment.Suspension is divided equally on the first day and the seventh day, and filtered to separate solid.Remaining solid is analyzed by XRD when not being dried.

[0536] The XRD data of the polymorphs in these solvents (water, MTBE and n-heptane) are shown in Figures 64 to 66 middle. Figures 64 to 66 The top spectra in the figure correspond to Form C ( Figure 64 )、K( Figure 65 ) and D and E( Figure 66 ), while the second and bottom spectra from the bottom of each panel correspond to formula (I) after 1 day and 7 days at room temperature in the various solvent systems shown. Figure 66 The second spectrum from the top corresponds to Form E. These XRD data confirm that Forms C, K, and D were obtained in these solvents. The data are summarized in Table 12.

[0537] Table 12

[0538]

[0539] Competitive slurry experiments showed that Form C (formed in water) is an unstable hydrate. Form K from MTBE slurry showed that it is an MTBE solvate because it was only produced by slow cooling and fast cooling processes in single solvent crystallization using MTBE as solvent, and residual MTBE was detected by NMR. Conversion from a mixture of polymorphs to a single Form D (anhydrous form of Formula (I)) in n-heptane showed that Form D is the most stable form at RT.

[0540] To further confirm the stability ranking of the selected forms and to extend the temperature range of the stability relationship to 70°C (covering potential API process conditions), binary form slurries were performed with starting mixtures of (1) Forms A and D and (2) Forms D and E. The resulting polymorphs were characterized by XRD after 1 and 7 days, and the analytical results are shown in Figures 67 to 68 The results are summarized in Table 13. After seven days of stirring at elevated temperature, Form D emerged from the slurries of binary mixtures of A and D, and D and E. Therefore, it was concluded that Form D is the most thermodynamically stable between room temperature and 70°C.

[0541] Table 13

[0542]

[0543] Additional single form slurry experiments were conducted on Forms A, D, and E in water or heptane at room temperature. The resulting polymorphs were analyzed by XRD after 1 and 7 days, and the results are provided in Figures 69 to 72 In. Figure 69 In the figure, the top two spectra correspond to the formula (I) starting material (Form A) and the product Form E, respectively, while the bottom two spectra correspond to the XRD spectra of formula (I) after 1 day and 7 days in n-heptane, respectively. Figure 70 In the top spectrum corresponds to the formula (I) starting material (Form A), the middle spectrum corresponds to the formula (I) after 1 day in n-heptane, and the bottom spectrum corresponds to the formula (I) after 7 days in n-heptane. Figure 71In the top spectrum corresponds to the formula (I) starting material (Form E), the middle spectrum corresponds to the formula (I) after 1 day in n-heptane, and the bottom spectrum corresponds to the formula (I) after 7 days in n-heptane. Figure 72 In the Figure 14, the top spectrum corresponds to the XRD pattern of the product (Form C), the second spectrum from the top corresponds to the formula (I) starting material (Form E), the second spectrum from the bottom corresponds to the formula (I) after 1 day in n-heptane, and the bottom spectrum corresponds to the formula (I) after 7 days in n-heptane. The competitive slurry experiments and the resulting polymorphs are summarized in Table 14. Consistent with the previous competitive slurry experiments, Form D is stable at room temperature in n-heptane. Form E is obtained from the slurry in n-heptane starting with Forms A and E. As expected, Form C is formed by Form E slurry in water.

[0544] Table 14

[0545]

[0546] Example 8

[0547] Thermal stress research

[0548] This example covers the thermal stability of multiple polymorphs of formula (I). Seven forms of formula (I) were incubated at elevated temperatures to study polymorph stability and heat-mediated polymorph conversion. Briefly, 20 mg of solid forms A, B, C, D, E, F, G, and I were weighed into 7 mL glass vials. The vials were covered with tissue paper and stored in an oven set to 60 ° C and ambient pressure. After 1 day and 7 days of incubation, solids were collected for XRD analysis.

[0549] The results of the thermal stress analysis are summarized in Table 15. The XRD data of the polymorphs before and after thermal stress are shown in Figures 73 to 80 wherein the top spectrum of each figure corresponds to the XRD before thermal stress, the middle spectrum of each figure provides the XRD after thermal stress for 1 day, and the bottom spectrum of each figure provides the XRD after thermal stress for 7 days at the temperature shown in Table 15, and Figures 73 to 80 The thermal stress progression of the starting formula (I) forms A, D, D, E, F, G, I, and A is provided, respectively. As shown in these figures, forms B and C are converted to forms D and A, respectively, while the other forms are unchanged.

[0550] Table 15

[0551]

[0552] The starting material, intermediates (heat stress for 1 day) and products (heat stress for 7 days) were analyzed by HPLC. A representative chromatogram of the heat stress analysis of Form D is shown in Figures 81 to 83These data indicate that no impurities were observed in any of the samples during the seven-day thermal stress at 60°C.

[0553] Example 9

[0554] Hygroscopicity analysis

[0555] To further evaluate physical stability, Form D was tested for stability under humid conditions. Form D was placed in an open vial and equilibrated at 75% relative humidity and 40°C. Figure 84 The XRD analysis used to monitor the polymorphs during the 14-day experiment is summarized. In this figure, the top panel provides a representative XRD spectrum of Form D, the second panel from the top is the XRD spectrum of the starting material, the third panel from the top is the XRD spectrum of the starting material after 4 days of humidity exposure, and the bottom panel is the XRD spectrum of the starting material after 14 days of humidity exposure. The XRD data showed that Form D was unchanged after 4 and 14 days of equilibration and indicates that Form D has extended air and humidity stability.

[0556] Example 10

[0557] PEG stability analysis

[0558] Since formula (I) can be prepared in PEG (for example, with suspension or solution), the stability of various formula (I) in PEG300 was evaluated. It is particularly noteworthy that whether form D can be converted into a hydrate (for example, form C) in the presence of water. In order to study the critical water concentration of the mutual change between form C and form D, a series of experiments (as summarized in Table 16) were designed. A 1: 1 mixture of form C and form D was prepared, and they were made into slurry in PEG300 with different levels of water concentration. Phase conversion was monitored by XRD, and it is summarized in Figure 85 In the figure (from top to bottom) provides the XRD of the following items: Form C, Form D, a mixture after incubation in PEG300 containing 75% water, a mixture after incubation in PEG300 containing 50% water, a mixture after incubation in PEG300 containing 25% water, a mixture after incubation in PEG300 containing 10% water, and a mixture after incubation in PEG300 containing 5% water. The data show that the critical water concentration is 50%. Form D is a stable form in PEG300 containing less than 50% water. However, in PEG300 solutions with 50% or higher water content, Form C becomes more stable and is observed to convert to Form C, resulting in a mixture of Form C and Form D or pure Form C.

[0559] Table 16

[0560] medium Initial XRD pattern XRD pattern at equilibrium <![CDATA[H2O:PEG 300=75%:25%]]> C(50%)+D(50%) C <![CDATA[H2O:PEG 300=50%:50%]]> C(50%)+D(50%) C (mainly) + D (small amount) <![CDATA[H2O:PEG 300=25%:75%]]> C(50%)+D(50%) D <![CDATA[H2O:PEG 300=10%:90%]]> C(50%)+D(50%) D <![CDATA[H2O:PEG 300=5%:95%]]> C(50%)+D(50%) D

[0561] Example 11

[0562] Chemical stability analysis

[0563] Chemical stability studies of Form D of Formula (I) were conducted in various pH media and selected excipients at RT and 50°C for up to 1 week. For pH stability analysis, approximately 2 mg to 3 mg of Form D were incubated in 1.0 mL of aqueous pH 1.0 (0.1 M HCl), pH 6.8 (water adjusted with 0.1 M NaOH and 0.1 M HCl), and pH 10.0 solutions. No impurities were detected after incubation for 4 or 7 days at room temperature or 50°C at any pH tested.

[0564] For excipient stability analysis, approximately 10 mg to 20 mg of Form D was mixed in a mixture of PEG400, propylene glycol, D-α-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), 44 / 14, Hydrogenated Castor Oil, Caprylic / Capric Glycerides ( MCM), ethoxylated solubilizers ( HS15, EL), nonionic surfactant and diethylene glycol monoethyl ether ( The impurities produced during the incubation were monitored by HPLC chromatography and are summarized in Tables 17 to 18. Representative HPLC chromatograms are shown in Figure 86 No impurities were observed after incubation for 4 or 7 days at room temperature or 50°C. These data demonstrate that Form D of Formula (I) is chemically compatible with a wide range of pH media and pharmaceutically acceptable excipients.

[0565] Table 17

[0566]

[0567]

[0568] Table 18

[0569]

[0570] Example 12

[0571] Characterization of the starting materials of formula (I)

[0572] Prior to crystallization and polymorph analysis (as presented in the previous examples), three batches of Formula (I) were analyzed for purity. Each batch contained either Form A or Form C. Baseline characterization of each batch included DSC, TGA, microscopic analysis, and vapor sorption, the results of which are summarized in Table 19. Figure 87 The XRD of three batches of Formula (I) are provided above for representative Form A and Form C batches (top and second from the top, respectively). Batch 1 contained primarily Form A, while batches 2 and 3 contained primarily Form C.

[0573] Figures 88 to 92 A physical analysis of Batch 1 is provided. Briefly, Figure 88 (DSC thermogram of batch 1) Contains peaks corresponding to Forms A and B. Figure 89 A TGA thermogram of Batch 1 is provided, with 0% weight change below 100°C and 99% weight change at 233°C indicating high purity and low water content. Figure 90 A modulated DSC thermogram of Batch 1 is provided, and a glass transition temperature of approximately 48.5°C was identified. Figure 91 Two polarized light microscopy images of Batch 1 are provided and show that Formula (I) is predominantly microcrystallized with crystals of about 1 μm to 50 μm. Figure 92 A dynamic vapor sorption plot for Batch 1 is provided, showing 2.49 wt% water vapor sorption at 90% relative humidity, 1.25 wt% water vapor sorption at 60% relative humidity, and nearly complete water vapor desorption at 0% relative humidity.

[0574] Figures 93 to 96 Physical analysis of Batch B is provided. Figure 93 The DSC thermogram of Batch 2 is provided, exhibiting a low temperature peak corresponding to the desorption of bound water (from Form C), and higher temperature peaks corresponding to the melting of Forms A and B. Figure 94 A TGA thermogram for Batch 2 is provided, showing a 2.9% weight change below 100°C corresponding to water desorption and a 96% weight change at 233°C corresponding to the melting of Formula (I), confirming the presence of Form C and indicating the high purity of Formula (I). Figure 95 Polarized light microscopy images of Batch 2 at 200x magnification are provided, with scales of 50 μm and 100 μm shown. The images show that Batch 2 contains a mixture of crystallites, ranging in size from a few microns to hundreds of microns. Figure 96 A dynamic vapor sorption plot for Batch 2 is provided, showing 3.99 wt% water vapor sorption at 60% relative humidity, 4.12 wt% water vapor sorption at 90% relative humidity, and nearly complete water vapor desorption at 0% relative humidity.

[0575] Figure 97 The DSC thermogram of Batch 3 is provided and includes a large endotherm at 84°C corresponding to water desorption, as well as melting and crystallization peaks of Forms A and B, indicating that Batch 3 contains a mixture of Forms A, B, and C.

[0576] Table 19

[0577]

[0578]

[0579] Example 13

[0580] Characterization of the starting materials of formula (I)

[0581] This example covers the thermal conversion of Form B to Form D as a scalable route to manufacture Form D. In Example 4, Form D was produced by evaporation, which for some crystallizations is not as easily scalable as other alternative crystallization methods. The results of the thermal stress studies summarized in Example 8 indicate that Form D can be obtained from the solid phase conversion of Form B by incubation at elevated temperatures.

[0582] Several scaled-up crystallization conditions are summarized in Table 20, each utilizing Form C as the starting material. In one crystallization, rapid cooling crystallization in ACN afforded Form B. Therefore, further attempts were made to prepare Form B in rapid cooling ACN. However, as shown in Table 20, rapid cooling crystallization in ACN directly afforded Form D.

[0583] Table 20

[0584]

[0585] Since rapid cooling may be difficult to scale up, slow cooling was used to optimize crystallization in ACN. Figure 98 The results of various ACN crystallizations in the XRD spectra of Table 20 (shown from top to bottom as Form D, Table 20 Preparation 4, Table 20 Preparation 5, and Table 20 Preparation 6) show that Form D can be produced by crystallization from ACN solvent by rapid cooling and slow cooling. However, from a method development perspective, the ACN method has two disadvantages. One is that the solvent to API volume ratio is generally low, which may lead to excessive method concentration, low material transfer and recovery. The other is that ACN is an ICH II solvent with a low residual solvent limit. Therefore, in some pharmaceutical formulations, it may be preferred to use ICH III solvents instead of ACN.

[0586] Several additional crystallization conditions using seed crystals and a binary solvent system were tested. As shown in Table 21, these crystallizations utilized ethanol, isopropanol, methyl ethyl ketone, and ethyl acetate as primary solvents, n-heptane as an antisolvent, an initial temperature of 70°C, and a cooling rate of 20°C / hour. Two replicates were performed for each condition. The XRD patterns of the resulting polymorphs are shown in Table 21. Figure 99In the figure, from top to bottom, the XRD of the following items is provided: Form D, Form E, two repeats of ethanol recrystallization, two repeats of isopropanol recrystallization, two repeats of methyl ethyl ketone recrystallization, and two repeats of ethyl acetate recrystallization. Using EtOH, IPA and EtOAc as the primary solvents and n-heptane as the anti-solvent, Form D solid was successfully produced from the system. Using methyl ethyl ketone as the primary solvent and n-heptane as the secondary solvent, Form E was produced.

[0587] Table 21

[0588]

[0589] The solubility of Form C of Formula (I) in the binary solvent systems of Table 21 is summarized in Table 22. When ethanol was used as the primary solvent, the solubility of Formula (I) decreased with increasing n-heptane solvent content. For isopropanol, methyl ethyl ketone, and ethyl acetate, the solubility of Formula (I) increased with increasing n-heptane solvent content.

[0590] Table 22

[0591]

[0592] Example 14

[0593] Gram-scale polymorph stability

[0594] In order to obtain a sufficient amount of form D for solubility testing and micronization, seed crystallization is carried out in grams. Specifically, 27g form C is dissolved in EtOH (15mL) at 70°C in a 500mL flask equipped with a stirring rod. N-heptane is added with 20mL aliquots until the solution becomes slightly turbid (adding 220mL n-heptane in total). The mixture is stirred at 70°C to form a clear solution. The mixture is cooled to room temperature at 20°C / hour, down to a final temperature of 40°C. Meanwhile, 2 milligrams to 3 milligrams of form D seed crystals are added at five minute intervals until precipitation is observed. Solid is separated by filtration, and dried in a vacuum drying oven at RT to obtain 18.17g solid (67% yield). Figure 100 Provided are the XRD of Form D (top) and crystals obtained from a magnified seed crystallization (bottom). As shown in this figure, the XRD of the resulting crystals is consistent with Form D.

[0595] Example 15

[0596] X-ray powder diffraction detection limit

[0597] The XRD detection limit of Form C in Form D was evaluated to determine the minimum purity of Form D produced in scaled-up crystallization. To perform these analyses, a series of blends having varying levels of Form C ranging from 2.5% to 15% were analyzed by XRD. The characteristic peak of Form C at 22.2° 2θ was used to quantify the amount of Form C in each mixture. The XRD patterns of the Form C, Form D mixtures are provided at Figure 101 and 102 In each figure, from top to bottom, the XRD spectra correspond to 2.5% Form C and 97.5% Form D (top), 5% Form C and 95% Form D (second from the top), 7.5% Form C and 92.5% Form D (third from the top), 10% Form C and 90% Form D (fourth from the top), 15% Form C and 85% Form D (fifth from the top), pure Form D (second from the bottom), and pure Form C (bottom). Figure 102 Provided Figure 101 Because the 22.2° 2θ peak (corresponding to Form C) is discernible in mixtures with 7.5% and higher proportions of Form C, additional physical characterization techniques (e.g., monitoring low-temperature water desorption in differential scanning calorimetry) may be required to quantify low levels of Form C in Form D formulations.

[0598] Example 16

[0599] Solubility enhancement screening

[0600] This example covers the solubility of polymorphs of Formula (I) in different solvent systems. Since Formula (I) generally has limited water solubility, strategies to increase its solubility can be used to enhance dissolution and bioavailability after administration. On this basis, multiple experiments (including particle size reduction and amorphous formulations) were performed to evaluate various solubility enhancement methods to optimize drug delivery.

[0601] Equilibrium solubility screening

[0602] Formula (I) equilibrium solubility is tested in a series of solvents and excipient systems. For these analyses, Form D or Form C are mixed with 0.5mL or 1.0mL solvent, and balance for approximately 24 hours. The mixture is filtered by a 0.45 μm centrifugal filter. The solid formula (I) collected during the filtration is analyzed by XRD, to determine the remaining solid polymorphic form, while collecting the filtrate for analyzing by HPLC to determine its solubility in each solvent.

[0603] Equilibrium solubility data are summarized in Table 23.As expected, compound is difficult for ionization under physiological relevant pH.However, many excipients with greater than 20mg / mL formula (I) solubility have been identified, including PEG300, PEG400, propylene glycol, vitamin E TPGS, Gelucire 44 / 14, hydrogenated castor oil, Capmul MCM, NF, Capmul MCM, EP, Kolliphor HS-15, Kolliphor EL, Labrasol and Transcutol HP.In addition, these excipients include surfactant, cosolvent and lipid, which are suitable for self-emulsifying drug delivery system (SEDDS).After equilibrium, the XRD pattern of the parent material of every kind of sample is kept.

[0604] Table 23

[0605]

[0606]

[0607] Supersaturation Monitoring in PEG300

[0608] Supersaturated solubility of both Form D and Form C of Formula (I) was prepared in PEG300 at 100 mg / mL and 200 mg / mL, a selected solvent for Formula (I) exhibiting high solubility. The experimental details and the results of these analyses are summarized in Table 24. 100 mg / mL of Formula (I) was stable in PEG300, with visible precipitation occurring only after 9 days of incubation at room temperature, indicating long-term stability under these conditions. When prepared in PEG300 at 200 mg / mL, Formula (I) readily precipitated overnight, indicating that Formula (I) was unstable at this higher concentration in PEG300.

[0609] Table 24

[0610]

[0611]

[0612] Particle size analysis

[0613] In order to explore the effect of particle size reduction of formula (I) on apparent solubility / dissolution for the convenience of formulation development, the solubility of Form D of Formula (I) was tested after grinding to a smaller particle size. Before grinding, Form D was sieved through a 30-micron mesh sieve. Then, Form D was micronized using a 2-inch airflow mill with a feed pressure of 70 psig, a grinding pressure of 40 psig, and a powder feed rate of 4.3 g / min. Relative to unground material, the micronization process provided a 69% yield and 95.6% crystallinity. The bulk density and tap density of Form D (including unground and ground) before and after tapping were measured by a tap density tester, and it was shown that the density decreased after micronization. The unground form showed a bulk density of 0.54 g / mL and a tap density of 0.61 g / mL, while the micronized form showed a bulk density of 0.20 g / mL and a tap density of 0.22 g / mL.

[0614] XRD and DSC were performed on the micronized compound of formula (I) to confirm that the compound remained unchanged during micronization. Figure 103 The results of XRD analysis are provided, where the top spectrum corresponds to the XRD of pure Form D, the middle spectrum corresponds to the starting material, and the bottom spectrum provides the XRD of the micronized product. Figure 104 A DSC thermogram of the micronized material is provided. No changes were detected by either XRD or DSC after micronization.

[0615] However, two new endothermic peaks (at 147°C and 150°C) were detected in small amounts by DSC in the micronized material. The appearance of the two endothermic peaks is likely due to melting of the crystalline phase during the DSC scan. To verify the hypothesis of conversion of the amorphous component (two endothermic peaks) in DSC, Form D material was ground to varying degrees using a mortar and pestle to produce different levels of amorphous components and analyzed by DSC. Figure 105 The results of these analyses are presented in Figure 2, where the top thermogram corresponds to micronized Form D, the second thermogram from the top corresponds to Form D ground for 5 minutes (in a mortar and pestle), the second thermogram from the bottom corresponds to Form D ground for 10 minutes, and the bottom thermogram corresponds to Form D ground for 15 minutes. The DSC endotherm of ground Form D exhibits a similar endotherm at 150°C. The intensity of this endotherm correlates with the grinding time, supporting its identification as a melt-crystalline phase.

[0616] The particle size was first analyzed using an optical microscope. Representative optical microscope images of unground Form D at 200x magnification are shown in Figure 106 Representative optical microscope images of micronized Form D at 200x magnification are shown in Figure 107 As can be seen from these images, micronization effectively reduced the particle size of the sample.

[0617] Particle size was also analyzed using a dry method using a Malvern 300 particle sizer equipped with a standard energy venturi and using 2.5 bar, 3.0 bar and 3.5 bar gas pressures. The results of these analyses are provided in Figures 108 to 113 middle. Figures 108 to 110 The results obtained for the unground Form D at 2.5, 3.0 and 3.5 bar are presented, while Figures 111 to 113 The results obtained at 2.5, 3.0 and 3.5 bar, respectively, are presented for micronized Form D. For both unmilled and micronized Form D, the 10th, 50th and 90th percentile particle sizes (D, respectively) were determined at each pressure. 10 、D 50 and D 90 ) are summarized in Table 25. It is noteworthy that the size data obtained with the particle size analyzer are inconsistent with the particle size determined by optical microscopy. One possible explanation is that the energy provided is insufficient to break up the particle agglomerates. D of micronized form D from three air pressure titrations 90 The significant changes in and the bimodal curve of the particle size results support this model and indicate that Form D particles form relatively strong aggregates.

[0618] Table 25

[0619]

[0620] Based on these results, the particle size analysis was repeated using a higher energy venturi at 2.5, 3.0 and 3.5 bar pressures to ensure the breakdown of potential agglomerates. Detailed particle size data using the high energy venturi are summarized in Tables 26 and Figures 114 to 119 Among them, respectively, Figures 114 to 116 corresponding to the 2.5, 3.0 and 3.5 bar assays of unmilled Form D, and Figures 117 to 119 The 2.5, 3.0 and 3.5 bar analyses correspond to micronized form D. Although the data remain bimodal, indicating that the particle agglomerates are not completely broken down, the D of the micronized material was measured to be 90 Below 6 μm, it is more closely consistent with the optical analysis.

[0621] Table 26

[0622]

[0623] Example 17

[0624] Analysis of amorphous phase transition

[0625] This example covers the generation of amorphous forms of formula (I) under different temperatures and conditions. As presented previously, the glass transition temperature (Tg) of the amorphous form of formula (I) generated in situ in DSC is 48°C ( Figure 90and Table 19), which indicates that thermal generation of the amorphous form (I) is feasible.

[0626] As an alternative to the production of amorphous Formula (I), bulk amorphous material was reconstituted by spray drying. 2% Form C (solids concentration) in ethanol was spray dried at an inlet temperature of 115°C to 120°C, an outlet temperature of 39°C to 35°C, a pumping rate of 90% to 95%, and a pump rate of 50% to 54%. The XRD of the resulting material is provided in Figure 120 , where the top spectrum corresponds primarily to Form C starting material and the bottom spectrum provides the spray-dried material, wherein the lack of peaks in the bottom spectrum indicates that the spray-dried material is in an amorphous state. DSC of the spray-dried material ( Figure 121 ) indicates a glass transition temperature (Tg) of about 43°C, which is comparable to the Tg of amorphous materials generated in situ in DSC.

[0627] Example 18

[0628] Kinetic solubility analysis

[0629] The kinetic solubility of Formula (I) provided as unground Form D, micronized Form D, and amorphous form was measured at a nominal concentration of approximately 4 mg / mL in 60 mM sodium lauryl sulfate (SLS) (7 x critical micelle concentration) (non-sink conditions; for Formula (I) SLS solubility, see Table 23). The mixture was stirred with a stir bar at room temperature. Samples (n=3) were collected at each predetermined time point (5, 10, 15, 20, 30, 60, 90, 120, and 180 minutes) and centrifuged. The filtrate was analyzed by HPLC to determine solubility, and the remaining solid (as appropriate) was analyzed by XRD. Three replicates were performed for each condition.

[0630] Figures 122 to 123 SLS kinetic solubility data for 180 and 90 minutes are summarized, with each trace corresponding to the average of three replicates. Milled, unmilled, and amorphous forms of Formula (I) exhibit similar kinetic solubility in SLS. The advantages of achieving a higher degree of supersaturation with milled material (by providing greater surface area) and amorphous material (by providing higher solubility) are offset by the phase transition from Form D to Form C (i.e., the hydrate form).

[0631] XRD was used to monitor the conversion of Form D and amorphous Formula (I) during the kinetic solubility analysis. Figures 124 to 126The XRD spectra of unground form D, ground form D and amorphous formula (I) during 180 minutes of dissolution are provided respectively. In each figure, the top spectrum corresponds to pure form C, the second figure from the top of the figure corresponds to pure form D, the third spectrum from the top of the figure corresponds to the solid collected after dissolving for 5 minutes, the fourth spectrum from the top corresponds to the solid collected after dissolving for 60 minutes, the fifth spectrum from the top corresponds to the solid collected after dissolving for 90 minutes, and the bottom spectrum corresponds to the solid collected after dissolving for 180 minutes. As indicated by these XRD data, ground material and amorphous material are converted into form C within 5min after being exposed to the dissolution medium. It may be due to the relatively large particle size of the unground material that the unground material shows a slower rate of conversion to form C, and is completely converted into a hydrate form after dissolving for 60 minutes. This may explain the reason why the unground material supersaturation state maintains a slightly longer time. As a mitigation formulation strategy, if needed in future formulation work, amorphous material can be stabilized in the dissolution medium by solid dispersion. In the kinetic solubility studies, the advantages of the milling and amorphous methods in achieving high supersaturation were offset by a phase transition to the hydrated form. In future work, if the amorphous form is required to enhance solubility, it could be possible to maintain the amorphous state through amorphous solid dispersions by selecting the optimal polymer.

[0632] Although the present invention has been described with reference to presently preferred embodiments, it will be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the present invention is limited only by the following claims.

Claims

1. A composition comprising an anhydrous crystalline form of formula (I): or a pharmaceutically acceptable salt thereof.

2. The composition of claim 1, wherein the anhydrous crystalline form of formula (I) comprises a water content of less than 2.9%.

3. A composition according to claim 1 or claim 2, wherein the anhydrous crystalline form of formula (I) comprises a water content of less than 1.0%.

4. The composition of any one of claims 1 to 3, wherein the anhydrous crystalline form of formula (I) has a purity of at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% by weight.

5. The composition of any one of claims 1 to 4, wherein the composition comprises less than 5% by weight of degradation products of formula (I), less than 3% by weight of degradation products of formula (I), less than 2% by weight of degradation products of formula (I), or less than 1% by weight of degradation products of formula (I).

6. A composition according to any one of claims 1 to 5, wherein the anhydrous crystalline form of formula (I) is characterised by an X-ray powder diffraction pattern substantially as shown in any one of Panels A to L of Figure 1 .

7. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, Wherein said crystalline forms of Formula (I) include Form D as characterised by X-ray powder diffraction substantially as shown in Figure 1, Panel D.

8. The composition of claim 7, wherein at least 80% of Formula (I) of the composition is in Form D, at least 85% of Formula (I) of the composition is in Form D, at least 90% of Formula (I) of the composition is in Form D, at least 95% of Formula (I) of the composition is in Form D, at least 98% of Formula (I) of the composition is in Form D, or at least 99% of Formula (I) of the composition is in Form D.

9. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, Wherein said crystalline forms of Formula (I) include Form A as characterised by an X-ray powder diffraction pattern substantially as shown in Panel A of Figure 1 .

10. The composition of claim 9, wherein at least 80% of Formula (I) of the composition is in Form A, at least 85% of Formula (I) of the composition is in Form A, at least 90% of Formula (I) of the composition is in Form A, at least 95% of Formula (I) of the composition is in Form A, at least 98% of Formula (I) of the composition is in Form A, or at least 99% of Formula (I) of the composition is in Form A.

11. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, Wherein said crystalline form of Formula (I) includes Form B as characterised by an X-ray powder diffraction pattern substantially as shown in Figure 1, Panel B.

12. The composition of claim 11, wherein at least 80% of Formula (I) of the composition is in Form B, at least 85% of Formula (I) of the composition is in Form B, at least 90% of Formula (I) of the composition is in Form B, at least 95% of Formula (I) of the composition is in Form B, at least 98% of Formula (I) of the composition is in Form B, or at least 99% of Formula (I) of the composition is in Form B.

13. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, Wherein said crystalline forms of Formula (I) include Form C as characterised by an X-ray powder diffraction pattern substantially as shown in Figure 1, Panel C.

14. The composition of claim 13, wherein at least 80% of Formula (I) of the composition is in Form C, at least 85% of Formula (I) of the composition is in Form C, at least 90% of Formula (I) of the composition is in Form C, at least 95% of Formula (I) of the composition is in Form C, at least 98% of Formula (I) of the composition is in Form C, or at least 99% of Formula (I) of the composition is in Form C.

15. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, Wherein said crystalline forms of Formula (I) include Form E as characterised by an X-ray powder diffraction pattern substantially as shown in Panel E of Figure 1 .

16. The composition of claim 15, wherein at least 80% of Formula (I) of the composition is in Form E, at least 85% of Formula (I) of the composition is in Form E, at least 90% of Formula (I) of the composition is in Form E, at least 95% of Formula (I) of the composition is in Form E, at least 98% of Formula (I) of the composition is in Form E, or at least 99% of Formula (I) of the composition is in Form E.

17. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, Wherein said crystalline forms of Formula (I) include Form F as characterised by an X-ray powder diffraction pattern substantially as shown in Figure 1, Panel F.

18. The composition of claim 17, wherein at least 80% of the composition of Formula (I) is in Form F, at least 85% of the composition of Formula (I) is in Form F, at least 90% of the composition of Formula (I) is in Form F, at least 95% of the composition of Formula (I) is in Form F, at least 98% of the composition of Formula (I) is in Form F, or at least 99% of the composition of Formula (I) is in Form F.

19. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, Wherein said crystalline forms of Formula (I) include Form G as characterised by an X-ray powder diffraction pattern substantially as shown in Panel G of Figure 1 .

20. The composition of claim 19, wherein at least 80% of Formula (I) of the composition is in Form G, at least 85% of Formula (I) of the composition is in Form G, at least 90% of Formula (I) of the composition is in Form G, at least 95% of Formula (I) of the composition is in Form G, at least 98% of Formula (I) of the composition is in Form G, or at least 99% of Formula (I) of the composition is in Form G.

21. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, Wherein said crystalline forms of Formula (I) include Form H as characterised by an X-ray powder diffraction pattern substantially as shown in Panel H of Figure 1 .

22. The composition of claim 21, wherein at least 80% of Formula (I) of the composition is in Form H, at least 85% of Formula (I) of the composition is in Form H, at least 90% of Formula (I) of the composition is in Form H, at least 95% of Formula (I) of the composition is in Form H, at least 98% of Formula (I) of the composition is in Form H, or at least 99% of Formula (I) of the composition is in Form H.

23. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, Wherein said crystalline forms of Formula (I) include Form I as characterised by an X-ray powder diffraction pattern substantially as shown in Panel I of Figure 1 .

24. The composition of claim 23, wherein at least 80% of Formula (I) of the composition is in Form I, at least 85% of Formula (I) of the composition is in Form I, at least 90% of Formula (I) of the composition is in Form I, at least 95% of Formula (I) of the composition is in Form I, at least 98% of Formula (I) of the composition is in Form I, or at least 99% of Formula (I) of the composition is in Form I.

25. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, Wherein said crystalline forms of Formula (I) include Form J as characterised by an X-ray powder diffraction pattern substantially as shown in Panel J of Figure 1 .

26. The composition of claim 25, wherein at least 80% of Formula (I) of the composition is in Form J, at least 85% of Formula (I) of the composition is in Form J, at least 90% of Formula (I) of the composition is in Form J, at least 95% of Formula (I) of the composition is in Form J, at least 98% of Formula (I) of the composition is in Form J, or at least 99% of Formula (I) of the composition is in Form J.

27. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, Wherein said crystalline form of Formula (I) includes Form K as characterised by an X-ray powder diffraction pattern substantially as shown in Figure 1, Panel K.

28. The composition of claim 27, wherein at least 80% of Formula (I) of the composition is in Form K, at least 85% of Formula (I) of the composition is in Form K, at least 90% of Formula (I) of the composition is in Form K, at least 95% of Formula (I) of the composition is in Form K, at least 98% of Formula (I) of the composition is in Form K, or at least 99% of Formula (I) of the composition is in Form K.

29. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, Wherein said crystalline forms of Formula (I) include Form L as characterised by an X-ray powder diffraction pattern substantially as shown in Panel L of Figure 1 .

30. The composition of claim 29, wherein at least 80% of Formula (I) of the composition is in Form L, at least 85% of Formula (I) of the composition is in Form L, at least 90% of Formula (I) of the composition is in Form L, at least 95% of Formula (I) of the composition is in Form L, at least 98% of Formula (I) of the composition is in Form L, or at least 99% of Formula (I) of the composition is in Form L.

31. A composition according to any one of claims 1 to 30, wherein the crystalline form of formula (I) comprises at least 98% by weight of formula (I).

32. A composition according to any one of claims 1 to 31 wherein the crystalline form of formula (I) comprises at least 99% by weight of formula (I).

33. The composition of any one of claims 1 to 32, wherein the crystalline form of formula (I) has an average particle size of between about 10 and about 100 microns.

34. The composition of any one of claims 1 to 33, wherein the crystalline form of formula (I) has an average particle size of between about 2 and about 12 microns.

35. The composition of any one of claims 1 to 34, wherein the crystalline form of formula (I) has a melting temperature between 140°C and 145°C.

36. The composition of any one of claims 1 to 35, wherein the crystalline form of formula (I) has a melting temperature between 145°C and 150°C.

37. A composition according to any one of claims 1 to 36, wherein the crystalline form of formula (I) has a heat of fusion of at least 25 J / g.

38. A composition according to any one of claims 1 to 37, wherein the crystalline form of formula (I) has a heat of fusion of at least 50 J / g.

39. A composition according to any one of claims 1 to 38, wherein the crystalline form of formula (I) has a heat of fusion of at least 55 J / g.

40. A composition according to any one of claims 1 to 39, wherein the crystalline form of formula (I) has less than 10% by weight solvent.

41. A composition according to any one of claims 1 to 40, wherein the crystalline form of formula (I) has less than 5% by weight solvent.

42. The composition of any one of claims 1 to 41, wherein the crystalline form of formula (I) is stable at 25°C and 0% humidity for at least 28 days.

43. The composition of any one of claims 1 to 42, wherein the crystalline form of formula (I) is stable at 25°C and 0% humidity for at least 180 days.

44. A method for producing a crystalline form of formula (I), the method comprising: In a solvent system, formula (I) is dissolved in a solvent system at a temperature between 35° C. and 80° C., wherein the solvent system comprises acetone, acetonitrile, dichloromethane, dioxane, isopropanol, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ether, n-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene or a combination thereof, and The solvent system was cooled to a temperature between 0°C and 30°C.

45. The method of claim 44, wherein the dissolving is performed at a temperature between 50°C and 75°C.

46. ​​A method according to claim 44 or claim 45, wherein the cooling brings the solvent to a temperature between 27°C and -20°C.

47. The method of any one of claims 44 to 46, wherein the cooling brings the solvent system to a temperature between 10°C and -20°C.

48. A method according to any one of claims 44 to 47, wherein the cooling is at a rate between 0.1°C / hour and 600°C / hour.

49. The method of any one of claims 44 to 48, wherein the solvent system comprises a secondary solvent in which formula (I) has a solubility of at most 5 mg / mL.

50. The method according to any one of claims 44 to 49, wherein the secondary solvent is water or a C5-C 12 Alkanes.

51. The method of any one of claims 44 to 50, wherein the secondary solvent is hexane or heptane.

52. The method of any one of claims 44 to 51, wherein the secondary solvent is cyclohexane or n-heptane.

53. The method of any one of claims 44 to 52, further comprising seeding the solvent system with solid Formula (I) after the dissolving.

54. The method of any one of claims 44 to 53, wherein the solid Formula (I) is any one of Forms A to L.

55. The method of any one of claims 44 to 54, further comprising adding an additional volume of the secondary solvent during or after the cooling.

56. A method for producing a crystalline form of formula (I), comprising: (i) dissolving the compound of formula (I) in a solvent system comprising at least 90% methanol or at least 90% toluene, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 60°C / hour and 600°C / hour; (ii) dissolving formula (I) in a solvent system comprising water and a solvent selected from the group consisting of acetonitrile and acetone, and cooling the solvent system to a temperature between 0°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (iii) dissolving Formula (I) in a solvent system comprising water and acetonitrile to a concentration of at least about 0.4 mg / ml, and cooling the solvent system to a temperature between 0° C. and 30° C. at a rate between 60° C. / hour and 600° C. / hour; (iv) incubating Form C of Formula (I) at a temperature between 40°C and 90°C for at least 1 hour; or (v) combinations thereof.

57. The method of claim 56, wherein (i) and (iii) comprise cooling the solvent system to a temperature between -20°C and 30°C at a rate between 60°C / hour and 150°C / hour.

58. The method of claim 56 or claim 57, wherein (ii) comprises cooling the solvent system to a temperature between 0°C and 30°C at a rate between 1°C / hour and 30°C / hour.

59. The method of any one of claims 56 to 58, wherein the solvent system of (ii) comprises water and the solvent selected from the group consisting of acetonitrile and acetone in a ratio of between 5:1 and 1:

5.

60. The method of any one of claims 56 to 59, wherein the solvent system of (ii) comprises water and the solvent selected from the group consisting of acetonitrile and acetone in a ratio of between 2:1 and 1:

2.

61. The method of any one of claims 56 to 60, wherein the crystalline form is at least 80% Form A, at least 85% Form A, at least 90% Form A, at least 95% Form A, at least 98% Form A, or at least 99% Form A.

62. A method for producing a crystalline form of formula (I) comprising: (i) dissolving the compound of formula (I) in a solvent system comprising at least 90% methanol, at least 90% ethanol, at least 90% isopropanol, or at least 90% n-butanol, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (ii) dissolving the compound of formula (I) in a solvent system comprising at least 90% ethanol, at least 90% isopropanol, or at least 90% n-butanol, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 60°C / hour and 600°C / hour; (iii) dissolving the compound of formula (I) in a solvent system comprising water and n-propanol, and cooling the solvent system to a temperature between 0° C. and 30° C. at a rate between 60° C. / hour and 600° C. / hour; (iv) dissolving the compound of formula (I) in a solvent system comprising hexane and dioxane and cooling to a temperature between 12°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (v) dissolving formula (I) in a solvent system comprising hexane and acetonitrile to a concentration of up to 0.1 mg / ml and cooling to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; or (vi) combinations thereof.

63. The method of claim 62, wherein (i) and (v) comprise cooling the solvent system to a temperature between 0°C and 30°C at a rate between 1°C / hour and 30°C / hour.

64. The method of claim 62 or claim 63, wherein (ii) and (iii) comprise cooling the solvent system to a temperature of between 4°C and 30°C at a rate of between 60°C / hour and 150°C / hour.

65. The method of any one of claims 62 to 64, wherein the solvent system of (iii) comprises water and n-propanol in a volume to volume ratio of between 5:1 and 1:

5.

66. The method of any one of claims 62 to 65, wherein the solvent system of (iv) comprises hexane and dioxane in a volume to volume ratio of between 5:1 and 1:

5.

67. The method of any one of claims 62 to 66, wherein the solvent system of (v) comprises hexane and acetonitrile in a volume to volume ratio of between 10:1 and 150:

1.

68. The method of any one of claims 62 to 67, wherein the crystalline form is at least 80% Form B, at least 85% Form B, at least 90% Form B, at least 95% Form B, at least 98% Form B, or at least 99% Form B.

69. A method for producing a crystalline form of formula (I) comprising: (i) dissolving formula (I) in a solvent system comprising water and methanol, and cooling the solvent system to a temperature between 0° C. and 30° C. at a rate between 60° C. / hour and 600° C. / hour; (ii) incubating the compound of formula (I) in water for at least one hour; (iii) incubating the compound of formula (I) in a polyethylene glycol (PEG) water mixture comprising at least 50% by volume of water for at least one hour; or (iv) combinations thereof.

70. The method of claim 69, wherein (i) comprises cooling the solvent system to a temperature between 0°C and 15°C at a rate between 60°C / hour and 150°C / hour.

71. The method of claim 69 or claim 70, wherein (ii) comprises incubating Formula (I) in water for at least one day.

72. The method of any one of claims 69 to 71, wherein (iii) comprises incubating Formula (I) in a polyethylene glycol (PEG) water mixture comprising at least 50% water by volume for at least one day.

73. The method of any one of claims 69 to 72, wherein (ii) and (iii) comprise incubating solid Formula (I).

74. The method of any one of claims 69 to 73, wherein the crystalline form is at least 80% Form C, at least 85% Form C, at least 90% Form C, at least 95% Form C, at least 98% Form C, or at least 99% Form C.

75. A method for producing a crystalline form of formula (I) comprising: (i) dissolving formula (I) in a solvent system comprising heptane and a solvent selected from the group consisting of dimethyl sulfoxide and n-methyl-2-pyrrolidone, and cooling the formula (I) to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 600°C / hour; (ii) dissolving formula (I) in a solvent system comprising water and dimethylformamide to a concentration of up to 0.25 mg / ml, and cooling to a temperature between 0°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (iii) dissolving the compound of formula (I) in a solvent system comprising heptane and a solvent selected from the group consisting of ethanol, isopropanol, and ethyl acetate, and cooling to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (iv) dissolving the compound of formula (I) in a solvent system comprising hexane and dimethyl sulfoxide and cooling to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (v) dissolving formula (I) in a solvent system comprising heptane and isopropanol to a concentration of at least 0.4 mg / ml, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (vi) incubating the compound of formula (I) in heptane for at least 1 day; (vii) incubating the compound of formula (I) in a polyethylene glycol:water mixture comprising greater than 50% by volume of polyethylene glycol for at least 1 hour; or (viii) combinations thereof.

76. The method of claim 75, wherein (i) comprises cooling the solvent system to a temperature between -10°C and 15°C at a rate between 60°C / hour and 150°C / hour.

77. The method of claim 75 or claim 76, wherein (ii) to (v) comprise cooling the solvent system to a temperature between 10°C and 30°C at a rate between 1°C / hour and 30°C / hour.

78. The method of any one of claims 75 to 77, wherein the solvent system of (i) comprises heptane and the solvent selected from the group consisting of dimethyl sulfoxide and n-methyl-2-pyrrolidone in a ratio of between 10:1 and 200:

1.

79. The method of any one of claims 75 to 78, wherein the solvent system of (ii) comprises water and dimethylformamide in a ratio of between 5:1 and 1:

5.

80. The method of any one of claims 75 to 79, wherein the solvent system of (iii) comprises heptane and the solvent selected from the group consisting of ethanol, isopropanol, and ethyl acetate in a ratio of between 5:1 and 1:

5.

81. The method of any one of claims 75 to 80, wherein the solvent system of (iv) comprises hexane and dimethyl sulfoxide in a ratio of between 10:1 and 200:

1.

82. The method of any one of claims 75 to 81, wherein the solvent system of (v) comprises heptane and isopropanol in a ratio of between 3:1 and 40:

1.

83. The method of any one of claims 75 to 82, wherein the crystalline form is at least 80% Form E, at least 85% Form D, at least 90% Form D, at least 95% Form D, at least 98% Form D, or at least 99% Form D.

84. A method for producing a crystalline form of formula (I) comprising: (i) dissolving the compound of formula (I) in a solvent system comprising heptane and a solvent selected from the group consisting of methanol, ethanol, acetonitrile, isopropanol, acetone, and n-propanol, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 60°C / hour and 600°C / hour; (ii) dissolving the compound of formula (I) in a solvent system comprising heptane and a solvent selected from the group consisting of methanol, ethanol, acetonitrile and n-propanol, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (iii) dissolving Formula (I) in a solvent system comprising heptane and methyl ethyl ketone, seeding the solvent system with Form E, and cooling the solvent system at a rate between 0.1°C / hour and 40°C / hour to a temperature between -20°C and 30°C; (iv) dissolving formula (I) in a solvent system comprising heptane and isopropanol to a concentration of up to 0.25 mg / ml, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (v) dissolving Formula (I) in a solvent system comprising hexane and methanol, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (vi) incubating the compound of formula (I) in heptane for less than one day; or (vii) combinations thereof.

85. The method of claim 84, wherein (i) comprises cooling the solvent system to a temperature between -10°C and 15°C at a rate between 60°C / hour and 150°C / hour.

86. The method of claim 84 or claim 85, wherein (ii) to (v) comprise cooling the solvent system to a temperature between 10°C and 30°C at a rate between 1°C / hour and 30°C / hour.

87. The method of any one of claims 84 to 86, wherein the solvent system of (i) comprises heptane and methanol, ethanol, acetonitrile, isopropanol, or n-propanol in a ratio of between 5:1 and 200:

1.

88. The method of any one of claims 84 to 87, wherein the solvent system of (i) comprises heptane and acetone in a ratio of between 1 :1 and 15:

1.

89. The method of any one of claims 84 to 88, wherein the solvent system of (ii) comprises heptane and methanol, ethanol, acetonitrile or n-propanol in a ratio of between 5:1 and 200:

1.

90. The method of any one of claims 84 to 89, wherein the solvent system of (iii) comprises heptane and methyl ethyl ketone in a ratio of between 1 :1 and 15:

1.

91. The method of any one of claims 84 to 90, wherein the solvent system of (iv) comprises heptane and isopropanol in a ratio of between 5:1 and 100:

1.

92. The method of any one of claims 84 to 91, wherein the solvent system of (v) comprises hexane and methanol in a ratio of between 10:1 and 200:

1.

93. The method of any one of claims 84 to 92, wherein (vi) comprises incubating solid Formula (I) in heptane for less than one day.

94. The method of any one of claims 84 to 93, wherein the crystalline form is at least 80% Form E, at least 85% Form E, at least 90% Form E, at least 95% Form E, at least 98% Form E, or at least 99% Form E.

95. A method for producing a crystalline form of formula (I), comprising: (i) dissolving the compound of formula (I) in a solvent system comprising water and a solvent selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dimethyl sulfoxide, dimethylformamide, N-methyl-2-pyrrolidone (NMP), and cooling the solvent system to a temperature between 0° C. and 30° C. at a rate between 60° C. / hour and 600° C. / hour; (ii) dissolving formula (I) in a solvent system to a concentration of up to 0.25 mg / ml, the solvent system comprising water and acetonitrile, and cooling the solvent system to a temperature between 0° C. and 30° C. at a rate between 60° C. / hour and 600° C. / hour; (iii) dissolving the compound of formula (I) in a solvent system comprising heptane and dimethylformamide, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 60°C / hour and 600°C / hour; (iv) dissolving the compound of formula (I) in a solvent system comprising hexane and a solvent selected from the group consisting of ethanol, NMP, and n-propanol, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 60°C / hour and 600°C / hour; (v) dissolving Formula (I) in a solvent system comprising hexane and dioxane, and cooling the solvent system to a temperature between 4° C. and 30° C. at a rate between 60° C. / hour and 600° C. / hour; (vi) dissolving formula (I) in a solvent system comprising water and a solvent selected from the group consisting of ethanol, tetrahydrofuran, dimethylformamide, and n-propanol, and cooling the solvent system to a temperature between 0°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (vii) dissolving formula (I) in a solvent system comprising heptane and dimethyl sulfoxide, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (viii) dissolving the compound of formula (I) in a solvent system comprising hexane and a solvent selected from the group consisting of methanol, isopropanol, dimethylformamide, and n-propanol, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; or (ix) combinations thereof.

96. The method of claim 95, wherein (i) to (iv) comprises cooling the solvent system to a temperature between 0°C and 15°C at a rate between 60°C / hour and 150°C / hour.

97. The method of claim 95 or claim 96, wherein (v) comprises cooling the solvent system to a temperature of between 4°C and 15°C at a rate of between 60°C / hour and 150°C / hour.

98. The method of any one of claims 95 to 97, wherein (vi) to (viii) comprises cooling the solvent system to a temperature between 10°C and 30°C at a rate between 1°C / hour and 30°C / hour.

99. The method of any one of claims 95 to 98, wherein the solvent system of (i) comprises water and methanol, ethanol, isopropanol, tetrahydrofuran, acetone, dimethyl sulfoxide, dimethylformamide, or NMP in a ratio of between 5:1 and 1:

5.

100. The method of any one of claims 95 to 99, wherein the solvent system of (ii) comprises water and acetonitrile in a ratio of between 5:1 and 1:

5.

101. The method of any one of claims 95 to 100, wherein the solvent system of (iii) comprises heptane and dimethylformamide in a ratio of between 10:1 and 200:

1.

102. The method of any one of claims 95 to 101, wherein the solvent system of (iv) comprises hexane and ethanol, NMP, or n-propanol in a ratio of between 5:1 and 100:

1.

103. The method of any one of claims 95 to 102, wherein the solvent system of (v) comprises hexane and dioxane in a ratio of between 5:1 and 1:

5.

104. The method of any one of claims 95 to 103, wherein the solvent system of (vi) comprises water and ethanol, tetrahydrofuran, dimethylformamide, or n-propanol in a ratio of between 5:1 and 1:

5.

105. The method of any one of claims 95 to 104, wherein the solvent system of (vii) comprises heptane and dimethyl sulfoxide in a ratio of between 10:1 and 200:

1.

106. The method of any one of claims 95 to 105, wherein the solvent system of (viii) comprises between 10:1 and 200:1 hexane to methanol, isopropanol, dimethylformamide, or n-propanol.

107. The method of any one of claims 95 to 106, wherein the crystalline form is at least 80% Form F, at least 85% Form F, at least 90% Form F, at least 95% Form F, at least 98% Form F, or at least 99% Form F.

108. A method for producing a crystalline form of formula (I), comprising: (i) dissolving the compound of formula (I) in a solvent system comprising at least 90% tetrahydrofuran or at least 90% methyl ethyl ketone, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (ii) dissolving the compound of formula (I) in a solvent system comprising at least 90% dioxane, and cooling the solvent system to a temperature between 12° C. and 30° C. at a rate between 0.1° C. / hour and 600° C. / hour; (iii) dissolving the compound of formula (I) in a solvent system comprising at least 90% tetrahydrofuran, and cooling the solvent system at a rate between 60°C / hour and 600°C / hour to a temperature between -20°C and 30°C; (iv) dissolving the compound of formula (I) in a solvent system comprising water and dioxane, and cooling the solvent system to a temperature between 12° C. and 30° C. at a rate between 0.1° C. / hour and 600° C. / hour; (v) dissolving formula (I) in a solvent system comprising heptane and dioxane, and cooling the solvent system to a temperature between 4°C and 30°C at a rate between 0.1°C / hour and 600°C / hour; (vi) dissolving Formula (I) in a solvent system comprising heptane and tetrahydrofuran, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 60°C / hour and 600°C / hour; (vii) dissolving formula (I) in a solvent system to a concentration of up to 0.25 mg / ml, the solvent system comprising hexane and acetone, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 60°C / hour and 600°C / hour; (viii) dissolving Formula (I) in a solvent system comprising hexane and tetrahydrofuran, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (ix) dissolving formula (I) in a solvent system comprising hexane and dioxane to a concentration of at least 0.4 mg / ml, and cooling the solvent system to a temperature between 12°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; or (x) combinations thereof.

109. The method of claim 108, wherein (i) comprises cooling the solvent system to a temperature between 0°C and 30°C at a rate between 1°C / hour and 30°C / hour.

110. The method of claim 108 or claim 109, wherein (iv) comprises water and dioxane in a ratio of between 5:1 and 1:

5.

111. The method of any one of claims 108 to 110, wherein (v) comprises heptane to dioxane in a ratio of between 3:1 and 60:

1.

112. The method of any one of claims 108 to 111, wherein (vi) comprises heptane and tetrahydrofuran in a ratio of between 5:1 and 1:

5.

113. The method of any one of claims 108 to 112, wherein (vii) comprises hexane and acetone in a ratio of between 5:1 and 1:

5.

114. The method of any one of claims 108 to 113, wherein (viii) comprises hexane and tetrahydrofuran in a ratio of between 5:1 and 1:

5.

115. The method of any one of claims 108 to 114, wherein (ix) comprises hexane and dioxane in ratios of 5:1 and 1:

5.

116. The method of any one of claims 108 to 115, wherein the crystalline form is at least 80% Form G, at least 85% Form G, at least 90% Form G, at least 95% Form G, at least 98% Form G, or at least 99% Form G.

117. A method for producing a crystalline form of formula (I), comprising: (i) dissolving the compound of formula (I) in a solvent system comprising at least 90% 2-methyltetrahydrofuran or at least 90% isopropyl acetate, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 600°C / hour; (ii) dissolving the compound of formula (I) in a solvent system comprising at least 90% methyl isobutyl ketone, and Cooling the solvent system at a rate between 0.1°C / hour and 40°C / hour to a temperature between -20°C and 30°C; (iii) dissolving the compound of formula (I) in a solvent system comprising hexane and a solvent selected from the group consisting of acetonitrile and tetrahydrofuran, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 60°C / hour and 600°C / hour; (iv) dissolving the compound of formula (I) in a solvent system comprising hexane and acetone to a concentration of at least 0.4 mg / ml, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 60°C / hour and 600°C / hour; (v) dissolving formula (I) in a solvent system comprising hexane and acetone, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (vi) dissolving formula (I) to a concentration of at least 0.5 mg / ml in a solvent system comprising hexane and acetonitrile, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; or (vii) combinations thereof.

118. The method of claim 117, wherein (i), (ii), (v) and (vi) comprise cooling the solvent system to a temperature between 0°C and 30°C at a rate between 1°C / hour and 30°C / hour.

119. The method of claim 117 or claim 118, wherein (i), (iii) and (iv) comprise cooling the solvent system to a temperature between 0°C and 30°C at a rate between 60°C / hour and 150°C / hour.

120. The method of any one of claims 117 to 119, wherein (iii) or (vi) comprises hexane and acetonitrile in a ratio of between 5:1 and 100:

1.

121. The method of any one of claims 117 to 120, wherein (iii) comprises hexane and tetrahydrofuran in a ratio of between 5:1 and 1:

5.

122. The method of any one of claims 117 to 121, wherein (iv) or (v) comprises hexane and acetone in a ratio of between 5:1 and 1:

5.

123. The method of any one of claims 117 to 122, wherein the crystalline form is at least 80% Form H, at least 85% Form H, at least 90% Form H, at least 95% Form H, at least 98% Form H, or at least 99% Form H.

124. A method for producing a crystalline form of formula (I), comprising: (i) dissolving the compound of formula (I) in a solvent system comprising at least 90% dichloromethane, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 600°C / hour; (ii) dissolving the compound of formula (I) in a solvent system comprising at least 90% acetonitrile to a concentration of up to 0.25 mg / ml, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 60°C / hour and 600°C / hour; or (iii) combinations thereof.

125. The method of claim 124, wherein (i) and (ii) comprise cooling to a temperature between 0°C and 30°C at a rate between 60°C / hour and 150°C / hour.

126. The method of claim 124 or claim 125, wherein the crystalline form is at least 80% Form I, at least 85% Form I, at least 90% Form I, at least 95% Form I, at least 98% Form I, or at least 99% Form I.

127. A method for producing a crystalline form of formula (I), the method comprising: Formula (I) is dissolved in a solvent system comprising at least 90% toluene, and the solvent system is cooled to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour.

128. The method of claim 127, comprising cooling the solvent system to a temperature between 0°C and 30°C at a rate between 1°C / hour and 30°C / hour.

129. The method of claim 127 or claim 128, wherein the crystalline form is at least 80% Form J, at least 85% Form J, at least 90% Form J, at least 95% Form J, at least 98% Form J, or at least 99% Form J.

130. A method for producing a crystalline form of formula (I), comprising: (i) dissolving the compound of formula (I) in a solvent system comprising at least 90% methyl tert-butyl ether, and Cooling the solvent system at a rate between 0.1°C / hour and 600°C / hour to a temperature between -20°C and 30°C; (ii) incubating the compound of formula (I) in methyl tert-butyl ether for at least one hour; or (iii) combinations thereof.

131. The method of claim 130, comprising cooling the solvent system to a temperature between 0°C and 30°C at a rate between 1°C / hour and 150°C / hour.

132. The method of claim 130 or claim 131, wherein the crystalline form is at least 80% Form K, at least 85% Form K, at least 90% Form K, at least 95% Form K, at least 98% Form K, or at least 99% Form K.

133. A method for producing a crystalline form of formula (I), comprising: (i) dissolving formula (I) in a solvent system comprising water and isopropanol to a concentration of at least 0.4 mg / ml, and cooling the solvent system to a temperature between 0°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (ii) dissolving Formula (I) in a solvent system comprising hexane and acetonitrile to a concentration of at least about 0.2 mg / ml, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 0.1°C / hour and 40°C / hour; (iii) dissolving formula (I) in a solvent system comprising heptane and tetrahydrofuran, and cooling the solvent system to a temperature between -20°C and 30°C at a rate between 60°C / hour and 600°C / hour; or (iv) combinations thereof.

134. The method of claim 133, wherein (i) and (ii) comprise cooling the solvent system to a temperature between 10°C and 30°C at a rate between 1°C / hour and 40°C / hour.

135. The method of claim 133 or claim 134, wherein (iii) comprises cooling the solvent system to a temperature between 0°C and 30°C at a rate between 60°C / hour and 150°C / hour.

136. The method of any one of claims 133 to 135, wherein (i) comprises water to isopropyl alcohol in a ratio of between 5:1 and 1:

5.

137. The method of any one of claims 133 to 136, wherein (ii) comprises hexane and acetonitrile in a ratio of between 5:1 and 1:

5.

138. The method of any one of claims 133 to 137, wherein the crystalline form is at least 80% Form L, at least 85% Form L, at least 90% Form L, at least 95% Form L, at least 98% Form L, or at least 99% Form L.

139. A method of treating a soluble epoxide hydrolase (sEH)-mediated disorder or disease in a subject, comprising administering to the subject a composition according to any one of claims 1 to 43, thereby treating the disorder or disease in the subject.

140. The method of claim 139, wherein the sEH-mediated disorder or disease is selected from the group consisting of pain, epileptic disorders, epilepsy, Parkinson's disease, Alzheimer's disease, depression, spinal cord injury, peripheral nerve injury, stroke, multiple sclerosis, cognitive dysfunction, kidney disease, cardiomyopathy, wound healing, and inflammation.

141. The method of claim 140, wherein the pain is neuropathic pain.

142. The method of claim 141, wherein the neuropathic pain is associated with nerve damage.

143. The method of claim 142, wherein the nerve damage is caused by diabetes or other disease.

144. The method of claim 140, wherein the pain is diabetic neuropathic pain.

145. The method of claim 140, wherein the pain is inflammatory pain.

146. The method of claim 140, wherein the epileptic disorder is epilepsy.

147. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form A, as characterized by an X-ray powder diffraction pattern comprising peaks at 3.3±0.3°2θ, 30.3±0.3°2θ, and 20.0±0.3°2θ.

148. The composition of claim 147, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 12.1 ± 0.3° 2θ, 15.6 ± 0.3° 2θ, and 6.0 ± 0.3° 2θ.

149. The composition of claim 147 or claim 148, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from 21.7 ± 0.3 °2θ, 10.6 ± 0.3 °2θ, and 21.6 ± 0.3 °2θ.

150. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form B, as characterized by an X-ray powder diffraction pattern comprising peaks at 12.2±0.3°2θ, 3.5±0.3°2θ, and 17.2±0.3°2θ.

151. The composition of claim 150, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 19.6 ± 0.3° 2θ, 13.1 ± 0.3° 2θ, and 18.0 ± 0.3° 2θ.

152. The composition of claim 151, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, at least three, or at least four peaks selected from the group consisting of 20.2±0.3°2θ, 14.1±0.3°2θ, 17.6±0.3°2θ, and 14.8±0.3°2θ.

153. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form C, as characterized by an X-ray powder diffraction pattern comprising peaks at 16.3±0.3°2θ, 16.1±0.3°2θ, and 3.2±0.3°2θ.

154. The composition of claim 153, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 21.6±0.3°2θ, 23.2±0.3°2θ, and 21.7±0.3°2θ.

155. The composition of claim 154, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 16.5 ± 0.3° 2θ, 21.4 ± 0.3° 2θ, and 10.7 ± 0.3° 2θ.

156. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form D, as characterized by an X-ray powder diffraction pattern comprising peaks at 20.1±0.3°2θ, 18.3±0.3°2θ, and 18.1±0.3°2θ.

157. The composition of claim 156, wherein the X-ray powder diffraction pattern further comprises at least one or at least two peaks selected from the group consisting of 20.3 ± 0.3 °2Θ and 17.1 ± 0.3 °2Θ.

158. The composition of claim 157, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, at least three, or at least four peaks selected from the group consisting of 3.4±0.3°2θ, 19.6±0.3°2θ, 23.4±0.3°2θ, and 25.1±0.3°2θ.

159. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form E, as characterized by an X-ray powder diffraction pattern comprising peaks at 13.4±0.3°2θ, 11.2±0.3°2θ, and 3.1±0.3°2θ.

160. The composition of claim 159, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 9.0 ± 0.3° 2θ, 22.2 ± 0.3° 2θ, and 14.3 ± 0.3° 2θ.

161. The composition of claim 160, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 14.9 ± 0.3° 2θ, 18.4 ± 0.3° 2θ, and 16.8 ± 0.3° 2θ.

162. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form F, as characterized by an X-ray powder diffraction pattern comprising peaks at 14.6±0.3°2θ, 3.4±0.3°2θ, and 9.7±0.3°2θ.

163. The composition of claim 162, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 18.1 ± 0.3° 2θ, 20.2 ± 0.3° 2θ, and 16.7 ± 0.3° 2θ.

164. The composition of claim 163, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 17.6±0.3°2θ, 19.2±0.3°2θ, and 17.3±0.3°2θ.

165. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form G, as characterized by an X-ray powder diffraction pattern comprising peaks at 18.2±0.3°2θ, 3.2±0.3°2θ, and 18.0±0.3°2θ.

166. The composition of claim 165, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 10.8±0.3°2θ, 19.2±0.3°2θ, and 5.4±0.3°2θ.

167. The composition of claim 166, wherein the X-ray powder diffraction pattern further comprises at least one or at least two peaks selected from the group consisting of 10.6 ± 0.3° 2θ and 21.7 ± 0.3° 2θ.

168. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form H, as characterized by an X-ray powder diffraction pattern comprising peaks at 8.8±0.3°2θ, 3.4±0.3°2θ, and 21.4±0.3°2θ.

169. The composition of claim 168, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, at least three, or at least four peaks selected from the group consisting of 17.9 ± 0.3 °2θ, 14.5 ± 0.3 °2θ, 12.7 ± 0.3 °2θ, and 8.7 ± 0.3 °2θ.

170. The composition of claim 169, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 14.8 ± 0.3° 2θ, 12.8 ± 0.3° 2θ, and 21.2 ± 0.3° 2θ.

171. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form I, as characterized by an X-ray powder diffraction pattern comprising peaks at 12.0±0.3°2θ, 12.3±0.3°2θ, and 3.2±0.3°2θ.

172. The composition of claim 171, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 14.5 ± 0.3° 2θ, 18.1 ± 0.3° 2θ, and 13.4 ± 0.3° 2θ.

173. The composition of claim 172, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 18.6±0.3°2θ, 24.8±0.3°2θ, and 19.1±0.3°2θ.

174. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form J, as characterized by an X-ray powder diffraction pattern comprising peaks at 15.5±0.3°2θ, 15.7±0.3°2θ, and 17.6±0.3°2θ.

175. The composition of claim 174, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 15.1 ± 0.3° 2θ, 11.4 ± 0.3° 2θ, and 15.0 ± 0.3° 2θ.

176. The composition of claim 175, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 3.4±0.3°2θ, 20.2±0.3°2θ, and 21.0±0.3°2θ.

177. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form K, as characterized by an X-ray powder diffraction pattern comprising peaks at 5.3±0.3°2θ, 14.5±0.3°2θ, and 7.3±0.3°2θ.

178. The composition of claim 177, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, at least three, at least four, or at least five peaks selected from the group consisting of 20.9 ± 0.3 °2θ, 3.4 ± 0.3 °2θ, 21.1 ± 0.3 °2θ, 7.4 ± 0.3 °2θ, and 14.8 ± 0.3 °2θ.

179. The composition of claim 178, wherein the X-ray powder diffraction pattern further comprises a peak at 17.4 ± 0.3° 2Θ.

180. A composition comprising a crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form L, as characterized by an X-ray powder diffraction pattern comprising peaks at 8.9±0.3°2θ, 3.4±0.3°2θ, and 18.3±0.3°2θ.

181. The composition of claim 180, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from the group consisting of 14.4±0.3°2θ, 21.9±0.3°2θ, and 18.0±0.3°2θ.

182. The composition of claim 181, wherein the X-ray powder diffraction pattern further comprises at least one, at least two, at least three, at least four, or at least five peaks selected from the group consisting of 14.3 ± 0.3 °2θ, 13.2 ± 0.3 °2θ, 20.0 ± 0.3 °2θ, 19.3 ± 0.3 °2θ, and 14.9 ± 0.3 °2θ.

183. A composition comprising an amorphous form of formula (I): or a pharmaceutically acceptable salt thereof.

184. A method of producing an amorphous form of formula (I): This involves converting a non-amorphous form of formula (I) into an amorphous form of said formula (I).

185. The method of claim 184, wherein the converting comprises an amorphous solid dispersion method.

186. The method of claim 185, wherein the amorphous solid dispersion method comprises hot melt extrusion or spray drying.

187. The method of claim 184, wherein the non-amorphous form of Formula (I) comprises a crystalline form of Formula (I).

188. The method of claim 187, wherein the crystalline form of Formula (I) is any one of Forms A to L.

189. The method of claim 188, wherein the crystalline form of Formula (I) is Form D.

190. The composition of any one of claims 1 to 43 or 147 to 183, wherein at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% of Formula (I) is amorphous.

191. The composition of any one of claims 1 to 43 or 147 to 183, wherein at most about 50%, at most about 45%, at most about 40%, at most about 35%, at most about 30%, at most about 25%, at most about 20%, at most about 15%, at most about 10%, at most about 5%, at most about 4%, at most about 3%, at most about 2%, at most about 1% or at most about 0.5% of Formula (I) is amorphous.

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