Polymorphic forms of soluble epoxide hydrolase inhibitors and their formulations.

Abstract

In embodiments, the present disclosure encompasses crystalline forms of soluble epoxide hydrolase inhibitors that have a range of advantageous properties for 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 present invention.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 421,961, filed November 2, 2022, and U.S. Provisional Application No. 63 / 457,722, filed April 6, 2023. The disclosures of the prior applications are considered part of the disclosure of this application and are incorporated herein by reference in their entireties.

[0002] Government Rights Statement This disclosure was made in part with funding from the National Institute of Neurological Disorders and Stroke (NINDS) Blueprint Neurotherapeutics Network UC3 / UH3NS094258. The government has certain rights in this invention. [Background technology]

[0003] background Soluble epoxide hydrolase (sEH, EC 3.3.2.10) is a dual-function enzyme found in mammalian cytosol and cytosolic peroxisomal fractions. sEH performs the dual function of hydrolyzing biological epoxides and lipid phosphoryl groups, thereby playing a central role in numerous lipid anabolic, catabolic, and signaling pathways. Therefore, sEH dysregulation can exacerbate or manifest as metabolic, inflammatory, systemic, and cardiovascular disorders. Of particular clinical relevance, alterations in sEH expression appear to contribute to many diseases, including certain cancers, neurodegenerative disorders, and forms of diabetes. Therefore, controlling sEH activity in diseased and at-risk patients may provide a means for controlling the pathogenesis of various diseases.

[0004] Nevertheless, targeted sEH inhibition remains a major challenge. The design of sEH inhibitors is simultaneously challenged by the requirement for water solubility necessary for sEH delivery and an extended hydrophobic structure critical for sEH binding affinity. The sEH active site, configured to bind a range of fatty acid substrates, contains two deep hydrophobic pockets adjacent to a hydrophilic epoxide-binding core. Due to these constraints, drug delivery is often limited for sEH. Summary of the Invention

[0005] overview The present disclosure provides a crystalline form of Formula (I) with high purity, stability, and comfort for use in drug delivery platforms, thus providing an improved means for selectively targeting sEH. While Formula (I) is an effective sEH inhibitor, its amorphous form can have limited solvent compatibility, a relatively slow dissolution rate, and can be difficult to prepare in a homogeneous, uniform manner in pharmaceutical formulations. The properties of the crystalline form of Formula (I) disclosed herein differ from those of amorphous Formula (I), thereby expanding the options for formulating Formula (I) beyond those previously available.

[0006] An embodiment of the present disclosure is a compound of formula (I) in an anhydrous crystalline form: TIFF2025540598000002.tif22128 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 decomposition products of Formula (I), less than 3% by weight of decomposition products of Formula (I), less than 2% by weight of decomposition products of Formula (I), or less than 1% by weight of decomposition products of Formula (I). In some embodiments, the anhydrous crystalline form of Formula (I) is characterized by an X-ray powder diffraction pattern substantially as set forth in any one of panels A-L of FIG. 1 .

[0007] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: TIFF2025540598000003.tif22128 or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form D characterized by an X-ray powder diffraction pattern substantially as depicted in Panel D of Figure 1. In some embodiments, at least 80% of Formula (I) in the composition is Form D, at least 85% of Formula (I) in the composition is Form D, at least 90% of Formula (I) in the composition is Form D, at least 95% of Formula (I) in the composition is Form D, at least 98% of Formula (I) in the composition is Form D, or at least 99% of Formula (I) in the composition is Form D.

[0008] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: TIFF2025540598000004.tif22128 or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form A characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1, panel A. In some embodiments, at least 80% of Formula (I) in the composition is Form A, at least 85% of Formula (I) in the composition is Form A, at least 90% of Formula (I) in the composition is Form A, at least 95% of Formula (I) in the composition is Form A, at least 98% of Formula (I) in the composition is Form A, or at least 99% of Formula (I) in the composition is Form A.

[0009] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: TIFF2025540598000005.tif22128 or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) includes Form B characterized by an X-ray powder diffraction pattern substantially as depicted in Panel B of Figure 1. In some embodiments, at least 80% of Formula (I) in the composition is Form B, at least 85% of Formula (I) in the composition is Form B, at least 90% of Formula (I) in the composition is Form B, at least 95% of Formula (I) in the composition is Form B, at least 98% of Formula (I) in the composition is Form B, or at least 99% of Formula (I) in the composition is Form B.

[0010] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: TIFF2025540598000006.tif22128 or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form C characterized by an X-ray powder diffraction pattern substantially as depicted in Panel C of Figure 1. In some embodiments, at least 80% of Formula (I) in the composition is Form C, at least 85% of Formula (I) in the composition is Form C, at least 90% of Formula (I) in the composition is Form C, at least 95% of Formula (I) in the composition is Form C, at least 98% of Formula (I) in the composition is Form C, or at least 99% of Formula (I) in the composition is Form C.

[0011] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: TIFF2025540598000007.tif22128 or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form E characterized by an X-ray powder diffraction pattern substantially as depicted in Panel E of Figure 1. In some embodiments, at least 80% of Formula (I) in the composition is Form E, at least 85% of Formula (I) in the composition is Form E, at least 90% of Formula (I) in the composition is Form E, at least 95% of Formula (I) in the composition is Form E, at least 98% of Formula (I) in the composition is Form E, or at least 99% of Formula (I) in the composition is Form E.

[0012] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: TIFF2025540598000008.tif22128 or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form F characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1, Panel F. In some embodiments, at least 80% of Formula (I) in the composition is Form F, at least 85% of Formula (I) in the composition is Form F, at least 90% of Formula (I) in the composition is Form F, at least 95% of Formula (I) in the composition is Form F, at least 98% of Formula (I) in the composition is Form F, or at least 99% of Formula (I) in the composition is Form F.

[0013] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: TIFF2025540598000009.tif22128 or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form G characterized by an X-ray powder diffraction pattern substantially as depicted in Panel G of Figure 1. In some embodiments, at least 80% of Formula (I) in the composition is Form G, at least 85% of Formula (I) in the composition is Form G, at least 90% of Formula (I) in the composition is Form G, at least 95% of Formula (I) in the composition is Form G, at least 98% of Formula (I) in the composition is Form G, or at least 99% of Formula (I) in the composition is Form G.

[0014] Crystalline form of formula (I): TIFF2025540598000010.tif22128 or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form H characterized by an X-ray powder diffraction pattern substantially as depicted in Panel H of Figure 1. In some embodiments, at least 80% of Formula (I) in the composition is Form H, at least 85% of Formula (I) in the composition is Form H, at least 90% of Formula (I) in the composition is Form H, at least 95% of Formula (I) in the composition is Form H, at least 98% of Formula (I) in the composition is Form H, or at least 99% of Formula (I) in the composition is Form H.

[0015] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: TIFF2025540598000011.tif22128 or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form I characterized by an X-ray powder diffraction pattern substantially as depicted in Panel I of Figure 1. In some embodiments, at least 80% of Formula (I) in the composition is Form I, at least 85% of Formula (I) in the composition is Form I, at least 90% of Formula (I) in the composition is Form I, at least 95% of Formula (I) in the composition is Form I, at least 98% of Formula (I) in the composition is Form I, or at least 99% of Formula (I) in the composition is Form I.

[0016] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: TIFF2025540598000012.tif22128 or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) includes Form J characterized by an X-ray powder diffraction pattern substantially as set forth in Panel J of Figure 1. In some embodiments, at least 80% of Formula (I) in the composition is Form J, at least 85% of Formula (I) in the composition is Form J, at least 90% of Formula (I) in the composition is Form J, at least 95% of Formula (I) in the composition is Form J, at least 98% of Formula (I) in the composition is Form J, or at least 99% of Formula (I) in the composition is Form J.

[0017] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: TIFF2025540598000013.tif22128 or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) includes Form K characterized by an X-ray powder diffraction pattern substantially as depicted in Panel K of Figure 1. In some embodiments, at least 80% of Formula (I) in the composition is Form K, at least 85% of Formula (I) in the composition is Form K, at least 90% of Formula (I) in the composition is Form K, at least 95% of Formula (I) in the composition is Form K, at least 98% of Formula (I) in the composition is Form K, or at least 99% of Formula (I) in the composition is Form K.

[0018] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: TIFF2025540598000014.tif22128 or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form L characterized by an X-ray powder diffraction pattern substantially as depicted in Panel L of Figure 1. In some embodiments, at least 80% of Formula (I) in the composition is Form L, at least 85% of Formula (I) in the composition is Form L, at least 90% of Formula (I) in the composition is Form L, at least 95% of Formula (I) in the composition is Form L, at least 98% of Formula (I) in the composition is Form L, or at least 99% of Formula (I) in the composition is Form L.

[0019] In some embodiments, the crystalline form of Formula (I) comprises at least 98% by weight of Formula (I). In some embodiments, the crystalline form of Formula (I) comprises at least 99% by weight of Formula (I). In some embodiments, the crystalline form of Formula (I) has an average particle size of about 10 to about 100 microns. In some embodiments, the crystalline form of Formula (I) has an average particle size of about 2 to about 12 microns. In some embodiments, the crystalline form of Formula (I) has a melting point of 140°C to 145°C. In some embodiments, the crystalline form of Formula (I) has a melting point of 145°C to 150°C. In some embodiments, the crystalline form of Formula (I) has a heat of fusion of at least 25 J / g. In some embodiments, the crystalline form of Formula (I) has a heat of fusion of at least 50 J / g. In some embodiments, the crystalline form of Formula (I) has a heat of fusion of at least 55 J / g. In some embodiments, the crystalline form of Formula (I) has less than 10% by weight of solvent. In some embodiments, the crystalline form of Formula (I) has less than 5% by weight of solvent. In some embodiments, the crystalline form of Formula (I) is stable at 25° C. and 0% humidity for at least 28 days. In some embodiments, the crystalline form of Formula (I) is stable at 25° C. and 0% humidity for at least 180 days.

[0020] An aspect of the present disclosure provides 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, isopropyl alcohol, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ether, n-butyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or a combination thereof, in the solvent system at a temperature of 35°C to 80°C, and cooling the solvent system to a temperature of 0°C to 30°C. In some embodiments, the dissolving is carried out at a temperature of 50°C to 75°C. In some embodiments, the cooling brings the solvent to a temperature of 27°C to -20°C. In some embodiments, the cooling brings the solvent system to a temperature of 10°C to -20°C. In some embodiments, the cooling is at a rate of 0.1°C / hr to 600°C / hr. In some embodiments, the solvent system comprises a secondary solvent in which Formula (I) has a solubility of at most 5 mg / mL. In some embodiments, the secondary solvent is water or a C5-C6 olefin. 12 In some embodiments, the secondary solvent is an alkane. In some embodiments, the secondary solvent is hexane or heptane. In some embodiments, the secondary solvent is c-hexane or n-heptane. In some embodiments, the method further comprises seeding the solvent system with solid Formula (I) after dissolution. In some embodiments, the solid Formula (I) is in any one of Forms A-L. In some embodiments, the method further comprises adding an additional volume of the secondary solvent during or after cooling.

[0021] An embodiment of the present disclosure provides 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% methanol or at least 90% toluene and cooling the solvent system to a temperature of -20°C to 30°C at a rate of 60°C / hr to 600°C / hr; (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 of 0°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; (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 of 0°C to 30°C at a rate of 60°C / hr to 600°C / hr; (iv) incubating Form C of Formula (I) at a temperature of 40°C to 90°C for at least 1 hour; or (v) a combination thereof. In some embodiments, (i) and (iii) comprise cooling the solvent system at a rate of 60°C / hr to 150°C / hr to a temperature of -20°C to 30°C. In some embodiments, (ii) comprises cooling the solvent system at a rate of 1°C / hr to 30°C / hr to a temperature of 0°C to 30°C. In some embodiments, the solvent system in (ii) comprises a ratio of water to a solvent selected from the group consisting of acetonitrile and acetone that is 5:1 to 1:5. In some embodiments, the solvent system in (ii) comprises a ratio of water to a solvent selected from the group consisting of acetonitrile and acetone that is 2:1 to 1:2. 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.

[0022] An embodiment of the present disclosure is 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% isopropyl alcohol, or at least 90% n-butanol, and cooling the solvent system to a temperature of -20°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; (ii) dissolving Formula (I) in a solvent system comprising at least 90% ethanol, at least 90% isopropyl alcohol, or at least 90% n-butanol, and cooling the solvent system to a temperature of -20°C to 30°C at a rate of 60°C / hr to 600°C / hr. (iii) dissolving Formula (I) in a solvent system comprising water and n-propanol and cooling the solvent system to a temperature of 0°C to 30°C at a rate of 60°C / hr to 600°C / hr; (iv) dissolving Formula (I) in a solvent system comprising hexane and dioxane and cooling to a temperature of 12°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; (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 of -20°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; or a combination thereof. In some embodiments, (i) and (v) comprise cooling the solvent system to a temperature of 0°C to 30°C at a rate of 1°C / hr to 30°C. 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 / hr and 150°C / hr. In some embodiments, the solvent system in (iii) comprises a volume ratio of water to n-propanol between 5:1 and 1:5. In some embodiments, the solvent system in (iv) comprises a volume ratio of hexane to dioxane between 5:1 and 1:5. In some embodiments, the solvent system in (v) comprises a volume ratio of hexane to acetonitrile between 10:1 and 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.

[0023] An aspect of the present disclosure provides 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 of 0°C to 30°C at a rate of 60°C / hr to 600°C / hr; (ii) incubating Formula (I) in water for at least 1 hour; (iii) incubating Formula (I) in a polyethylene glycol (PEG)-water mixture comprising at least 50% water by volume for at least 1 hour; or (iv) a combination thereof. In some embodiments, (i) comprises cooling the solvent system to a temperature of 0°C to 15°C at a rate of 60°C / hr to 150°C / hr. In some embodiments, (ii) comprises incubating Formula (I) in water for at least 1 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 1 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.

[0024] An embodiment of the present disclosure is 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 of -20°C to 30°C at a rate of 0.1°C / hr to 600°C / hr; (ii) dissolving Formula (I) to a concentration of up to 0.25 mg / ml in a solvent system comprising water and dimethylformamide, and cooling to a temperature of 0°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; (iii) dissolving Formula (I) in a solvent system comprising heptane and a solvent selected from the group consisting of ethanol, isopropyl alcohol, and ethyl acetate, and cooling to a temperature of -20°C to 30°C at a rate of 0.1°C / hr to 40°C / hr. (iv) dissolving Formula (I) in a solvent system comprising hexane and dimethyl sulfoxide and cooling to a temperature of -20°C to 30°C at a rate of 0.1°C / hr to 40°C / hr, (v) dissolving Formula (I) in a solvent system comprising heptane and isopropyl alcohol to a concentration of at least about 0.4 mg / ml and cooling the solvent system to a temperature of -20°C to 30°C at a rate of 0.1°C / hr to 40°C / hr, (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) a combination thereof. In some embodiments, (i) comprises cooling the solvent system to a temperature of -10°C to 15°C at a rate of 60°C / hr to 150°C / hr. In some embodiments, (ii)-(v) comprise cooling the solvent system to a temperature of 10°C to 30°C at a rate of 1°C / hr to 30°C / hr. In some embodiments, the solvent system of (i) comprises a ratio of heptane to a solvent selected from the group consisting of dimethyl sulfoxide and n-methyl-2-pyrrolidone of 10:1 to 200:1. In some embodiments, the solvent system of (ii) comprises a ratio of water to dimethylformamide of 5:1 to 1:5.In some embodiments, the solvent system (iii) comprises a ratio of heptane to a solvent selected from the group consisting of ethanol, isopropyl alcohol, and ethyl acetate that is between 5:1 and 1:5. In some embodiments, the solvent system (iv) comprises a ratio of hexane to dimethyl sulfoxide that is between 10:1 and 200:1. In some embodiments, the solvent system (v) comprises a ratio of heptane to isopropyl alcohol that is between 3:1 and 40:1. In some embodiments, the crystalline form is at least 80% Form D, 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.

[0025] An embodiment of the present disclosure provides 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 methanol, ethanol, acetonitrile, isopropyl alcohol, acetone, and n-propanol, and cooling the solvent system to a temperature of −20° C. to 30° C. at a rate of 60° C. / hr to 600° C. / hr; (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 to a temperature of −20° C. to 30° C. at a rate of 0.1° C. / hr to 40° C. / hr; (iii) dissolving Formula (I) in a solvent system comprising heptane and methyl ethyl ketone at a rate of 0.1° C. / hr to 40° C. / hr; (iv) dissolving Formula (I) in a solvent system comprising heptane and isopropyl alcohol to a concentration of up to 0.25 mg / ml and cooling the solvent system at a rate of 0.1° C. / hr to 40° C. / hr to a temperature of −20° C. to 30° C., (v) dissolving Formula (I) in a solvent system comprising hexane and methanol and cooling the solvent system at a rate of 0.1° C. / hr to 40° C. / hr to a temperature of −20° C. to 30° C., (vi) incubating Formula (I) in heptane for less than 1 day, or (vii) a combination thereof. In some embodiments, (i) comprises cooling the solvent system at a rate of 60° C. / hr to 150° C. / hr to a temperature of −10° C. to 15° C. In some embodiments, (ii)-(v) comprise cooling the solvent system to a temperature of 10°C to 30°C at a rate of 1°C / hr to 30°C / hr. In some embodiments, the solvent system of (i) comprises a ratio of heptane to methanol, ethanol, acetonitrile, isopropyl alcohol, or n-propanol of 5:1 to 200:1. In some embodiments, the solvent system of (i) comprises a ratio of heptane to acetone of 1:1 to 15:1. In some embodiments, the solvent system of (ii) comprises a ratio of heptane to methanol, ethanol, acetonitrile, or n-propanol of 5:1 to 200:1.In some embodiments, the solvent system in (iii) comprises a ratio of heptane to methyl ethyl ketone of 1:1 to 15:1. In some embodiments, the solvent system in (iv) comprises a ratio of heptane to isopropyl alcohol of 5:1 to 100:1. In some embodiments, the solvent system in (v) comprises a ratio of hexane to methanol of 10:1 to 200:1. In some embodiments, (vi) comprises incubating solid Formula (I) in heptane for less than 1 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.

[0026] An embodiment of the present disclosure provides a method for producing a crystalline form of Formula (I), comprising: (i) dissolving Formula (I) in a solvent system comprising water and a solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, tetrahydrofuran, acetone, dimethyl sulfoxide, dimethylformamide, and N-methyl-2-pyrrolidone (NMP), and cooling the solvent system to a temperature between 0°C and 30°C at a rate of 60°C / hr to 600°C / hr; (ii) dissolving Formula (I) in a solvent system comprising water and acetonitrile at a concentration of up to 0.25 mg / ml. (iii) dissolving formula (I) in a solvent system comprising heptane and dimethylformamide, and cooling the solvent system to a temperature of -20°C to 30°C at a rate of 60°C / hr to 600°C / hr; (iv) dissolving 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 of 0°C to 30°C at a rate of 60°C / hr to 600°C / hr. (v) dissolving Formula (I) in a solvent system comprising hexane and dioxane, and cooling the solvent system to a temperature of 4°C to 30°C at a rate of 60°C / hr to 600°C / hr; (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 of 0°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; (vii) dissolving Formula (I) in a solvent system comprising heptane and dimethylformamide, and cooling the solvent system to a temperature of 0°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; (viii) dissolving Formula (I) in a solvent system comprising hexane and a solvent selected from the group consisting of methanol, isopropyl alcohol, dimethylformamide, and n-propanol, and cooling the solvent system to a temperature of -20°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; or (ix) a combination thereof. In some embodiments, (i)-(iv) comprise cooling the solvent system to a temperature of 0°C to 15°C at a rate of 60°C / hr to 150°C / hr.In some embodiments, (v) comprises cooling the solvent system at a rate of 60°C / hr to 150°C / hr to a temperature of 4°C to 15°C. In some embodiments, (vi) to (viii) comprise cooling the solvent system at a rate of 1°C / hr to 30°C / hr to a temperature of 10°C to 30°C. In some embodiments, the solvent system in (i) comprises a ratio of water to methanol, ethanol, isopropyl alcohol, tetrahydrofuran, acetone, dimethyl sulfoxide, dimethylformamide, or NMP of 5:1 to 1:5. In some embodiments, the solvent system in (ii) comprises a ratio of water to acetonitrile of 5:1 to 1:5. In some embodiments, the solvent system in (iii) comprises a ratio of heptane to dimethylformamide of 10:1 to 200:1. In some embodiments, the solvent system in (iv) comprises a ratio of hexane to ethanol, NMP, or n-propanol of 5:1 to 100:1. In some embodiments, the solvent system (v) comprises a ratio of hexane to dioxane of 5:1 to 1:5. In some embodiments, the solvent system (vi) comprises a ratio of water to ethanol, tetrahydrofuran, dimethylformamide, or n-propanol of 5:1 to 1:5. In some embodiments, the solvent system (vii) comprises a ratio of heptane to dimethyl sulfoxide of 10:1 to 200:1. In some embodiments, the solvent system (viii) comprises a ratio of hexane to methanol, isopropyl alcohol, dimethylformamide, or n-propanol of 10:1 to 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.

[0027] An embodiment of the present disclosure is a method 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 of -20°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; (ii) dissolving Formula (I) in a solvent system comprising at least 90% dioxane, and cooling the solvent system to a temperature of 12°C to 30°C at a rate of 0.1°C / hr to 600°C / hr. (iii) dissolving Formula (I) in a solvent system comprising at least 90% tetrahydrofuran and cooling the solvent system to a temperature of -20°C to 30°C at a rate of 60°C / hr to 600°C / hr; (iv) dissolving Formula (I) in a solvent system comprising water and dioxane and cooling the solvent system to a temperature of 12°C to 30°C at a rate of 0.1°C / hr to 600°C / hr; (v) dissolving Formula (I) in a solvent system comprising heptane and dioxane and cooling the solvent system to a temperature of 0.1°C / hr to 600°C / hr; (vi) dissolving Formula (I) in a solvent system comprising heptane and tetrahydrofuran and cooling the solvent system to a temperature of -20°C to 30°C at a rate of 60°C / hr to 600°C / hr; (vii) dissolving Formula (I) in a solvent system comprising hexane and acetone to a concentration of up to 0.25 mg / ml and cooling the solvent system to a temperature of -20°C to 30°C at a rate of 60°C / hr to 600°C / hr. (viii) dissolving Formula (I) in a solvent system comprising hexane and tetrahydrofuran and cooling the solvent system to a temperature of -20°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; (ix) dissolving Formula (I) in a solvent system comprising hexane and dioxane to a concentration of at least about 0.4 mg / ml and cooling the solvent system to a temperature of 12°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; or (x) a combination thereof. In some embodiments, (i) comprises cooling the solvent system to a temperature of 0°C to 30°C at a rate of 1°C / hr to 30°C. In some embodiments, (iv) comprises a ratio of water to dioxane of 5:1 to 1:5.In some embodiments, (v) comprises a ratio of heptane to dioxane of 3:1 to 60:1. In some embodiments, (vi) comprises a ratio of heptane to tetrahydrofuran of 5:1 to 1:5. In some embodiments, (viii) comprises a ratio of hexane to tetrahydrofuran of 5:1 to 1:5. In some embodiments, (ix) comprises a ratio of hexane to dioxane of 5:1 to 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.

[0028] An embodiment of the present disclosure is a method 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 to a temperature of −20° C. to 30° C. at a rate of 0.1° C. / hr to 600° C. / hr; (ii) dissolving Formula (I) in a solvent system comprising at least 90% methyl isobutyl ketone and cooling the solvent system to a temperature of −20° C. to 30° C. at a rate of 0.1° C. / hr to 40° C. / hr; (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 to a temperature of −20° C. to 30° C. at a rate of 60° C. / hr to 600° C. / hr. (iv) dissolving Formula (I) in a solvent system comprising hexane and acetone to a concentration of at least about 0.4 mg / ml and cooling the solvent system to a temperature of −20° C. to 30° C. at a rate of 60° C. / hr to 600° C. / hr; (v) dissolving Formula (I) in a solvent system comprising hexane and acetone and cooling the solvent system to a temperature of −20° C. to 30° C. at a rate of 0.1° C. / hr to 40° C. / hr; (vi) dissolving Formula (I) in a solvent system comprising hexane and acetonitrile to a concentration of at least about 0.5 mg / ml and cooling the solvent system to a temperature of −20° C. to 30° C. at a rate of 0.1° C. / hr to 40° C. / hr; or (vii) a combination thereof. In some embodiments, (i), (ii), (v), and (vi) comprise cooling the solvent system to a temperature of 0° C. to 30° C. at a rate of 1° C. / hr to 30° C. / hr. In some embodiments, (i), (iii), and (iv) comprise cooling the solvent system at a rate of 60°C / hr to 150°C / hr to a temperature of 0°C to 30°C. In some embodiments, (iii) or (vi) comprises a ratio of hexane to acetonitrile of 5:1 to 100:1. In some embodiments, (iii) comprises a ratio of hexane to tetrahydrofuran of 5:1 to 1:5. In some embodiments, (iv) or (v) comprises a ratio of hexane to acetone of 5:1 to 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.

[0029] Aspects of the present disclosure provide methods for producing a crystalline form of Formula (I), the methods comprising: (i) dissolving Formula (I) in a solvent system comprising at least 90% dichloromethane and cooling the solvent system to a temperature of −20° C. to 30° C. at a rate of 0.1° C. / hr to 600° C. / hr; (ii) dissolving Formula (I) to a concentration of up to 0.25 mg / ml in a solvent system comprising at least 90% acetonitrile and cooling the solvent system to a temperature of −20° C. to 30° C. at a rate of 60° C. / hr to 600° C. / hr; or (iii) a combination thereof. In some embodiments, (i) and (ii) comprise cooling the solvent system to a temperature of 0° C. to 30° C. at a rate of 60° C. / hr to 150° C. / hr. 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.

[0030] Aspects of the present disclosure provide methods for producing a crystalline form of Formula (I), the method comprising dissolving Formula (I) in a solvent system comprising at least 90% toluene and cooling the solvent system to a temperature of between -20°C and 30°C at a rate of between 0.1°C / hr and 40°C / hr. In some embodiments, the method comprises cooling the solvent system to a temperature of between 0°C and 30°C at a rate of between 1°C / hr and 30°C / hr. 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.

[0031] Aspects of the present disclosure provide methods for producing a crystalline form of Formula (I), the method 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 of −20° C. to 30° C. at a rate of 0.1° C. / hr to 600° C. / hr; (ii) incubating Formula (I) in methyl tert-butyl ether for at least 1 hour; or (iii) a combination thereof. In some embodiments, the method comprises cooling the solvent system to a temperature of 0° C. to 30° C. at a rate of 1° C. / hr to 150° C. / hr. 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.

[0032] Aspects of the present disclosure provide methods for producing a crystalline form of Formula (I), the methods comprising: (i) dissolving Formula (I) in a solvent system comprising water and isopropyl alcohol to a concentration of at least about 0.4 mg / ml and cooling the solvent system to a temperature of 0°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; (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 of -20°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; (iii) dissolving Formula (I) in a solvent system comprising heptane and tetrahydrofuran and cooling the solvent system to a temperature of -20°C to 30°C at a rate of 60°C / hr to 600°C / hr; or (iv) a combination thereof. In some embodiments, (i) and (ii) comprise cooling the solvent system to a temperature of 10°C to 30°C at a rate of 1°C / hr to 40°C / hr. In some embodiments, (iii) comprises cooling the solvent system at a rate of 60°C / hr to 150°C / hr to a temperature of 0°C to 30°C. In some embodiments, (i) comprises a ratio of water to isopropyl alcohol of 5:1 to 1:5. In some embodiments, (ii) comprises a ratio of hexane to acetonitrile of 5:1 to 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.

[0033] Aspects of the present disclosure provide methods of treating a soluble epoxide hydrolase (sEH)-mediated disorder or disease in a subject, comprising administering a 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, seizure disorders, 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, seizure disorders, 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 due to diabetes or other disease. In some embodiments, the pain is diabetic neuropathic pain. In some embodiments, the pain is inflammatory pain. In some embodiments, the seizure disorder is epilepsy.

[0034] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form A, 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 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 21.7±0.3°2θ, 10.6±0.3°2θ, and 21.6±0.3°2θ.

[0035] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form B, characterized by an X-ray powder diffraction pattern comprising peaks at 12.2±0.3 degrees 2θ, 3.5±0.3 degrees 2θ, and 17.2±0.3 degrees 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 19.6±0.3 degrees 2θ, 13.1±0.3 degrees 2θ, and 18.0±0.3 degrees 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 20.2±0.3 degrees 2θ, 14.1±0.3 degrees 2θ, 17.6±0.3 degrees 2θ, and 14.8±0.3 degrees 2θ.

[0036] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form C 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 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 16.5±0.3°2θ, 21.4±0.3°2θ, and 10.7±0.3°2θ.

[0037] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form D, 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.

[0038] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form E, 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 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 14.9±0.3°2θ, 18.4±0.3°2θ, and 16.8±0.3°2θ.

[0039] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form F, 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 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 17.6±0.3°2θ, 19.2±0.3°2θ, and 17.3±0.3°2θ.

[0040] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form G, 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 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 or at least two peaks selected from 10.6±0.3°2θ and 21.7±0.3°2θ.

[0041] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form H, 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 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 14.8±0.3°2θ, 12.8±0.3°2θ, and 21.2±0.3°2θ.

[0042] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form I, 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 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 18.6±0.3°2θ, 24.8±0.3°2θ, and 19.1±0.3°2θ.

[0043] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form J, 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.

[0044] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form K, 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 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.

[0045] An embodiment of the present disclosure is a compound of formula (I) in crystalline form: or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form L, characterized by an X-ray powder diffraction pattern comprising peaks at 8.9±0.3 degrees 2θ, 3.4±0.3 degrees 2θ, and 18.3±0.3 degrees 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 degrees 2θ, 21.9±0.3 degrees 2θ, and 18.0±0.3 degrees 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 degrees 2θ, 13.2±0.3 degrees 2θ, 20.0±0.3 degrees 2θ, 19.3±0.3 degrees 2θ, and 14.9±0.3 degrees 2θ.

[0046] An embodiment of the present disclosure provides a compound of formula (I) in amorphous form: TIFF2025540598000027.tif22128 or a pharmaceutically acceptable salt thereof.

[0047] An embodiment of the present disclosure provides a compound of formula (I) in amorphous form: TIFF2025540598000028.tif22128, the method comprising converting a non-amorphous form of Formula (I) to an amorphous form of Formula (I). In some embodiments, the converting comprises an amorphous solid dispersion method. In some embodiments, the amorphous solid dispersion method comprises hot melt extrusion or spray drying. In some embodiments, the non-amorphous form of Formula (I) comprises 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.

[0048] 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, up to about 50%, up to about 45%, up to about 40%, up to about 35%, up to about 30%, up to about 25%, up to about 20%, up to about 15%, up to about 10%, up to about 5%, up to about 4%, up to about 3%, up to about 2%, up to about 1%, or up to about 0.5% of Formula (I) is amorphous.

[0049] Incorporation by Reference 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 explanation of the drawings]

[0050] The novel features of the 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 that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0051] [Figure 1]Panel A of Figure 1 provides a representative X-ray powder diffraction spectrum (XRD) of Form A of Formula (I). Panel B of Figure 1 provides a representative XRD of Form B of Formula (I). Panel C of Figure 1 provides a representative XRD of Form C of Formula (I). Panel D of Figure 1 provides a representative XRD of Form D of Formula (I). Panel E of Figure 1 provides a representative XRD of Form E of Formula (I). Panel F of Figure 1 provides a representative XRD of Form F of Formula (I). Panel G of Figure 1 provides a representative XRD of Form G of Formula (I). Panel H of Figure 1 provides a representative XRD of Form H of Formula (I). Panel I of Figure 1 provides a representative XRD of Form I of Formula (I). Panel J of Figure 1 provides a representative XRD of Form J of Formula (I). Panel K of Figure 1 provides a representative XRD of Form K of Formula (I). Panel L of Figure 1 provides a representative XRD of Form L of Formula (I).

[0052] [Figure 2] 1 provides a representative differential scanning calorimetry (DSC) thermogram of Form A of Formula (I).

[0053] [Figure 3] 1 provides a representative DSC thermogram of Form B of Formula (I).

[0054] [Figure 4] 1 provides a representative DSC thermogram of Form C of Formula (I).

[0055] [Figure 5] 1 provides a representative DSC thermogram of Form D of Formula (I).

[0056] [Figure 6] 1 provides a representative DSC thermogram of Form E of Formula (I).

[0057] [Figure 7] 1 provides a representative DSC thermogram of Form F of Formula (I).

[0058] [Figure 8] 1 provides a representative DSC thermogram of Form G of Formula (I).

[0059] [Figure 9] 1 provides a representative DSC thermogram of Form H of Formula (I).

[0060] [Figure 10] 1 provides a representative DSC thermogram of Form I of Formula (I).

[0061] [Figure 11] 1 provides a representative DSC thermogram of Form J of Formula (I).

[0062] [Figure 12] 1 provides a representative DSC thermogram of Form K of Formula (I).

[0063] [Figure 13] 1 provides a representative DSC thermogram of Form L of Formula (I).

[0064] [Figure 14] 1 provides a representative thermogravimetric analysis (TGA) thermogram of Form A of Formula (I).

[0065] [Figure 15] 1 provides a representative TGA thermogram of Form B of Formula (I).

[0066] [Figure 16] 1 provides a representative TGA thermogram of Form C of Formula (I).

[0067] [Figure 17] 1 provides a representative TGA thermogram of Form D of Formula (I).

[0068] [Figure 18] 1 provides a representative TGA thermogram of Form E of Formula (I).

[0069] [Figure 19] 1 provides a representative TGA thermogram of Form F of Formula (I).

[0070] [Figure 20] 1 provides a representative TGA thermogram of Form G of Formula (I).

[0071] [Figure 21] 1 provides a representative TGA thermogram of Form H of Formula (I).

[0072] [Figure 22] 1 provides a representative TGA thermogram of Form I of Formula (I).

[0073] [Figure 23] 1 provides a representative TGA thermogram of Form J of Formula (I).

[0074] [Figure 24] 1 provides a representative TGA thermogram of Form K of Formula (I).

[0075] [Figure 25] 1 provides a representative TGA thermogram of Form L of Formula (I).

[0076] [Figure 26] 1 provides a representative nuclear magnetic resonance (NMR) spectrum of Form A of Formula (I).

[0077] [Figure 27] 1 provides a representative NMR spectrum of Form B of Formula (I).

[0078] [Figure 28] 1 provides a representative NMR spectrum of Form C of Formula (I).

[0079] [Figure 29]1 provides a representative NMR spectrum of Form D of Formula (I).

[0080] [Figure 30] 1 provides a representative NMR spectrum of Form E of Formula (I).

[0081] [Figure 31] 1 provides a representative NMR spectrum of Form F of Formula (I).

[0082] [Figure 32] 1 provides a representative NMR spectrum of Form G of Formula (I).

[0083] [Figure 33] 1 provides a representative NMR spectrum of Form H of Formula (I).

[0084] [Figure 34] 1 provides a representative NMR spectrum of Form I of Formula (I).

[0085] [Figure 35] 1 provides a representative NMR spectrum of Form J of Formula (I).

[0086] [Figure 36] 1 provides a representative NMR spectrum of Form K of Formula (I).

[0087] [Figure 37] 1 provides a representative NMR spectrum of Form L of Formula (I).

[0088] [Figure 38] A calibration curve at 254 nm is provided for polarized light microscopy analysis.

[0089] [Figure 39] 1 shows the XRD spectra of Form B of Formula (I) from a 10 milligram scale crystallization (top) and a 100 milligram scale crystallization (bottom).

[0090] [Figure 40] 1 shows the XRD spectra of Form A of Formula (I) from a 10 milligram scale crystallization (top) and a 100 milligram scale crystallization (bottom).

[0091] [Figure 41] 1 shows the XRD spectra of Form L of Formula (I) from a 10 milligram scale crystallization (top) and a 100 milligram scale crystallization (bottom).

[0092] [Figure 42] 1 shows the XRD spectra of Form A of Formula (I) from a 10 milligram scale crystallization (top) and a 100 milligram scale crystallization (bottom).

[0093] [Figure 43] 1 shows the XRD spectra of Form D of Formula (I) from a 10 milligram scale crystallization (top) and a 100 milligram scale crystallization (bottom).

[0094] [Figure 44] 1 shows the XRD spectra of Form H of Formula (I) from a 10 milligram scale crystallization (top) and a 100 milligram scale crystallization (bottom).

[0095] [Figure 45] 1 shows the XRD spectra of Form L of Formula (I) from a 10 milligram scale crystallization (top) and a 100 milligram scale crystallization (bottom).

[0096] [Figure 46] 1 provides a DSC thermogram of Form B of Formula (I).

[0097] [Figure 47] 1 provides a DSC thermogram of Form A of Formula (I).

[0098] [Figure 48]1 provides a DSC thermogram of Form L of Formula (I).

[0099] [Figure 49] 1 provides a DSC thermogram of Form A of Formula (I).

[0100] [Figure 50] 1 provides a DSC thermogram of Form D of Formula (I).

[0101] [Figure 51] 1 provides a DSC thermogram of Form H of Formula (I).

[0102] [Figure 52] 1 provides a DSC thermogram of Form L of Formula (I).

[0103] [Figure 53] 1 provides a DSC thermogram of Form B of Formula (I).

[0104] [Figure 54] 1 provides a DSC thermogram of Form A of Formula (I).

[0105] [Figure 55] 1 provides a DSC thermogram of Form L of Formula (I).

[0106] [Figure 56] 1 provides a DSC thermogram of Form A of Formula (I).

[0107] [Figure 57] 1 provides a DSC thermogram of Form D of Formula (I).

[0108] [Figure 58] 1 provides a DSC thermogram of Form H of Formula (I).

[0109] [Figure 59]1 provides a DSC thermogram of Form L of Formula (I).

[0110] [Figure 60] 1 provides an XRD spectrum of Form I of Formula (I).

[0111] [Figure 61] 1 provides an XRD spectrum of Form G of Formula (I).

[0112] [Figure 62] 1 provides an XRD spectrum of Form F of Formula (I).

[0113] [Figure 63] 1 provides an XRD spectrum of Form E of Formula (I).

[0114] [Figure 64] 1 provides representative XRD spectra of Form C of Formula (I) (top), Formula (I) after 1 day of incubation in water (middle), and Formula (I) after 7 days of incubation in water (bottom).

[0115] [Figure 65] 1 provides representative XRD spectra of Form K of Formula (I) (top), Formula (I) after 1 day of incubation in MTBE (center), and Formula (I) after 7 days of incubation in MTBE (bottom).

[0116] [Figure 66] 1 provides representative XRD spectra of Form D of Formula (I) (top), Form E of Formula (I) (second from the top), Formula (I) after incubation in n-heptane for 1 day (second from the bottom), and Formula (I) after incubation in n-heptane for 7 days (bottom).

[0117] [Figure 67]1 provides representative XRD spectra of Form A of Formula (I) (top), Form D of Formula (I) (second from the top), Formula (I) after incubation in n-heptane at 70° C. for 1 day (second from the bottom), and Formula (I) after incubation in n-heptane at 70° C. for 7 days (bottom).

[0118] [Figure 68] 1 provides representative XRD spectra of Form D of Formula (I) (top), Form E of Formula (I) (second from the top), Formula (I) after incubation in n-heptane at 70° C. for 1 day (second from the bottom), and Formula (I) after incubation in n-heptane at 70° C. for 7 days (bottom).

[0119] [Figure 69] 1 provides representative XRD spectra of Form A of Formula (I) (top), Form E of Formula (I) (second from the top), Formula (I) after incubation in n-heptane for 1 day (second from the bottom), and Formula (I) after incubation in n-heptane for 7 days (bottom).

[0120] [Figure 70] 1 provides representative XRD spectra of Form D of Formula (I) (top), Formula (I) after 1 day of incubation in n-heptane (center), and Formula (I) after 7 days of incubation in n-heptane (bottom).

[0121] [Figure 71] 1 provides representative XRD spectra of Form E of Formula (I) (top), Formula (I) after 1 day of incubation in n-heptane (center), and Formula (I) after 7 days of incubation in n-heptane (bottom).

[0122] [Figure 72] 1 provides representative XRD spectra of Form C of Formula (I) (top), Form E of Formula (I) (second from the top), Formula (I) after incubation in n-heptane for 1 day (second from the bottom), and Formula (I) after incubation in n-heptane for 7 days (bottom).

[0123] [Figure 73] 1 provides representative XRD spectra of Form A of Formula (I) (top), Form A of Formula (I) after incubation at 60° C. for 1 day (center), and Form A of Formula (I) after incubation at 60° C. for 7 days (bottom).

[0124] [Figure 74] 1 provides representative XRD spectra of 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. for 1 day (second from the bottom), and Form D of Formula (I) after incubation at 60° C. for 7 days (bottom).

[0125] [Figure 75] 1 provides representative XRD spectra of Form D of Formula (I) (top), Form D of Formula (I) after incubation at 60° C. for 1 day (center), and Form D of Formula (I) after incubation at 60° C. for 7 days (bottom).

[0126] [Figure 76] 1 provides representative XRD spectra of Form E of Formula (I) (top), Form E of Formula (I) after incubation at 60° C. for 1 day (center), and Form E of Formula (I) after incubation at 60° C. for 7 days (bottom).

[0127] [Figure 77] 1 provides representative XRD spectra of Form F of Formula (I) (top), Form F of Formula (I) after incubation at 60° C. for 1 day (center), and Form F of Formula (I) after incubation at 60° C. for 7 days (bottom).

[0128] [Figure 78] 1 provides 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. for 1 day (center), and Form G of Formula (I) after incubation at 60° C. for 7 days (bottom).

[0129] [Figure 79] 1 provides representative XRD spectra of Form I of Formula (I) (top), Form I of Formula (I) after incubation at 60° C. for 1 day (center), and Form I of Formula (I) after incubation at 60° C. for 7 days (bottom).

[0130] [Figure 80] 1 provides representative XRD spectra of Form A of Formula (I) (top), Form C of Formula (I) (second from the top), Form A of Formula (I) at the start (middle), Form A of Formula (I) after 1 day of incubation at 60° C. (second from the bottom), and Form A of Formula (I) after 7 days of incubation at 60° C. (bottom).

[0131] [Figure 81] 1 provides an HPLC chromatogram of Form D of Formula (I) before high temperature incubation.

[0132] [Figure 82] FIG. 1 provides an HPLC chromatogram of Form D of Formula (I) after incubation at 60° C. for 1 day.

[0133] [Figure 83] FIG. 1 provides an HPLC chromatogram of Form D of Formula (I) after incubation at 60° C. for 7 days.

[0134] [Figure 84] 1 provides XRD spectra of Form D of Formula (I), where 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.

[0135] [Figure 85]Provides XRD spectra of Form C of Formula (I) (top), Form D of Formula (I) (second from top), a mixture of Forms C and D after incubation in PEG300 containing 75% water (third from top), a mixture of Forms C and D after incubation in PEG300 containing 50% water (middle), a mixture of Forms C and D after incubation in PEG300 containing 25% water (third from bottom), a mixture of Forms C and D after incubation in PEG300 containing 10% water (second from bottom), and a mixture of Forms C and D after incubation in PEG300 containing 5% water (bottom).

[0136] [Figure 86] 1 provides a representative HPLC chromatogram of Formula (I) after incubation in diethylene glycol monoethyl ether.

[0137] [Figure 87] 1 provides representative XRD spectra of Form A of Formula (I) (top), Form C of Formula (I) (second from the top), and three batches of Formula (I) (bottom three spectra).

[0138] [Figure 88] 1 provides a DSC thermogram of formula (I).

[0139] [Figure 89] 1 provides a TGA thermogram of formula (I).

[0140] [Figure 90] 1 provides a modulated DSC thermogram of formula (I).

[0141] [Figure 91] 1 provides two polarized microscope images of formula (I).

[0142] [Figure 92] 1 provides a dynamic vapor sorption plot of formula (I).

[0143] [Figure 93] 1 provides a DSC thermogram of formula (I).

[0144] [Figure 94] 1 provides a TGA thermogram of formula (I).

[0145] [Figure 95] 1 provides two polarized microscope images of formula (I).

[0146] [Figure 96] 1 provides a dynamic vapor sorption plot of formula (I).

[0147] [Figure 97] 1 provides a DSC thermogram of formula (I).

[0148] [Figure 98] 1 provides XRD spectra of Form D of Formula (I) (top) and three separate preparations of Formula (I) (bottom three spectra).

[0149] [Figure 99] 1 provides XRD spectra of several polymorphs of Formula (I).

[0150] [Figure 100] 1 provides XRD spectra of Form D of Formula (I) (top) and a sample of Formula (I) generated from a crystal seeding experiment.

[0151] [Figure 101] Provided are XRD spectra of Formula (I) in which Form D is blended with 2.5% (top), 5% (second from top), 7.5% (third from top), 10% (middle), and 15% (second from bottom) of Form C, along with representative spectra of Form D (second from bottom) and Form C (bottom).

[0152] [Figure 102] 10 provides an expanded view of the XRD spectrum from FIG. 101.

[0153] [Figure 103] 1 provides XRD data for unmilled Form D of Formula (I) (top and center) and milled Form D of Formula (I) (bottom).

[0154] [Figure 104] 1 provides a DSC thermogram of milled Form D of Formula (I).

[0155] [Figure 105] 1 provides thermograms of Formula (I) Form D in micronized form (top), Formula (I) Form D after 5 minutes of milling (second from top), Formula (I) Form D after 10 minutes of milling (second from bottom), and Formula (I) Form D after 15 minutes of milling (bottom).

[0156] [Figure 106] 1 provides an optical microscope image of unmilled Form D of Formula (I).

[0157] [Figure 107] 1 provides an optical microscope image of milled Form D of Formula (I).

[0158] [Figure 108] Figure 1 provides particle size data for unmilled Form D of formula (I) using a pressure of 2.5 bar.

[0159] [Figure 109] 1 provides particle size data for unmilled Form D of Formula (I) using a pressure of 3.0 bar.

[0160] [Figure 110] Figure 1 provides particle size data for unmilled Form D of formula (I) using a pressure of 3.5 bar.

[0161] [Figure 111] 1 provides particle size data for milled Form D of formula (I) using a pressure of 2.5 bar.

[0162] [Figure 112] 1 provides particle size data for milled Form D of Formula (I) using a pressure of 3.0 bar.

[0163] [Figure 113] 1 provides particle size data for milled Form D of formula (I) using a pressure of 3.5 bar. [Figure 114] Figure 1 provides particle size data for unmilled Form D of formula (I) utilizing a pressure of 2.5 bar and a high energy venturi.

[0164] [Figure 115] 1 provides particle size data for unmilled Form D of Formula (I) utilizing a pressure of 3.0 bar and a high energy venturi.

[0165] [Figure 116] Figure 1 provides particle size data for unmilled Form D of formula (I) utilizing a pressure of 3.5 bar and a high energy venturi.

[0166] [Figure 117] 1 provides particle size data for milled Form D of formula (I) utilizing a pressure of 2.5 bar and a high energy venturi.

[0167] [Figure 118] 1 provides particle size data for milled Form D of Formula (I) utilizing a pressure of 3.0 bar and a high energy venturi.

[0168] [Figure 119] 1 provides particle size data for milled Form D of formula (I) utilizing a pressure of 3.5 bar and a high energy venturi.

[0169] [Figure 120] 1 provides XRD spectra of Form C of Formula (I) (top) and amorphous of Formula (I) (bottom).

[0170] [Figure 121] 1 provides a DSC thermogram of amorphous Formula (I).

[0171] [Figure 122] Dynamic solubility data for sodium lauryl sulfate (SLS) of formula (I) is compiled over a 180 minute period. [Figure 123] Dynamic solubility data for sodium lauryl sulfate (SLS) of formula (I) is compiled over a 90 minute period.

[0172] [Figure 124] 1 provides 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.

[0173] [Figure 125] 1 provides 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.

[0174] [Figure 126]1 provides XRD spectra of Form C of Formula (I) (top), Form D of Formula (I) (second from the top), amorphous Formula (I) after 5 minutes of incubation in SLS (third from the top), amorphous Formula (I) after 60 minutes of incubation in SLS (third from the bottom), amorphous Formula (I) after 90 minutes of incubation in SLS (second from the bottom), and amorphous Formula (I) after 180 minutes of incubation in SLS.

[0175] [Figure 127] 1 provides a DSC thermogram of formula (I).

[0176] [Figure 128] 1 provides the 1H NMR spectrum of formula (I).

[0177] [Figure 129] 1 provides the 13C NMR spectrum of formula (I).

[0178] [Figure 130] 1 provides the 19F NMR spectrum of formula (I).

[0179] [Figure 131A] Figures 131A-L provide representative X-ray powder diffraction spectra of various polymorphs of Formula (I). Figure 131A provides a representative X-ray powder diffraction spectrum (XRD) of Form A of Formula (I). [Figure 131B] FIG. 131B provides a representative XRD of Form B of Formula (I). [Figure 131C] Figure 131C provides a representative XRD of Form C of Formula (I). [Figure 131D] Figure 131D provides a representative XRD of Form D of Formula (I). [Figure 131E] Figure 131E provides a representative XRD of Form E of Formula (I). [Figure 131F] Figure 131F provides a representative XRD of Form F of Formula (I). [Figure 131G]Figure 131G provides a representative XRD of Form G of Formula (I). [Figure 131H] Figure 131H provides a representative XRD of Form H of Formula (I). [Figure 131I] Figure 131I provides a representative XRD of Form I of Formula (I). [Figure 131J] Figure 131J provides a representative XRD of Form J of Formula (I). [Figure 131K] Figure 131K provides a representative XRD of Form K of Formula (I). [Figure 131L] Figure 131L provides a representative XRD of Form L of Formula (I). DETAILED DESCRIPTION OF THE INVENTION

[0180] Detailed Description Soluble epoxide hydrolase (sEH) is central to many forms of lipid metabolism and may be involved in the degradation of cytochrome P450-oxidized xenobiotics. Although the sEH active site is selective for hydrophobic species (often mimics of its natural lipid substrates), sEH is primarily localized within the cytosol and peroxisomal compartments of the cytosol and therefore often can only be targeted by aqueous species. Therefore, sEH inhibitor delivery is often a major barrier to sEH modulation. To address this challenge, the present disclosure provides a range of polymorphic forms of sEH inhibitors (Formula (I)) with physical properties well suited for formulation and therapeutic use.

[0181] 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.

[0182] As used herein, the terms "a," "an," and "the" include plural references unless the context dictates otherwise.

[0183] As used in this specification and claims, the terms "comprising," "containing," and "including" are inclusive and open-ended and do not exclude additional, unrecited elements, compositional components, or method steps. Thus, the terms "comprising" and "including" encompass the relatively more restrictive terms "consisting of" and "consisting essentially of."

[0184] As used herein, "soluble epoxide hydrolase" ("sEH") refers to an enzyme that converts EETs to dihydroxy derivatives called dihydroxyeicosatrienoic acids ("DHETs") in endothelial, smooth muscle, and other cell types. The cloning and sequence of mouse sEH are described in Grant et al., J. Biol. Chem. 268(23):17628-17633 (1993). The cloning, sequence, and accession number of the human sEH sequence are described in Beetham et al., Arch. Biochem. Biophys. 305(1):197-201 (1993). The amino acid sequence of human sEH is also set forth as SEQ ID NO:2 in U.S. Pat. No. 5,445,956, and the nucleic acid sequence encoding human sEH is set forth as nucleotides 42-1703 of SEQ ID NO:1 of that patent. Gene evolution and nomenclature are discussed in Beetham et al., DNA Cell Biol. 14(1):61-71 (1995). Soluble epoxide hydrolases represent a single, highly conserved gene product with over 90% homology between rodents and humans (Arand et al., FEBS Lett., 338:251-256 (1994)).

[0185] As used herein, the terms "active pharmaceutical ingredient," "active ingredient," "API," "drug," "active," "actives," and "therapeutic agent" may be used interchangeably to refer to the pharmaceutically active compound(s) in a pharmaceutical composition. This may be in contrast to other components in the composition, such as excipients, which are substantially or completely pharmaceutically inactive. Suitable APIs according to the present disclosure include APIs for which patient compliance issues exist or are likely to exist for treating a particular disease, condition, or disorder. As used herein, therapeutic agents include active compounds and their salts, prodrugs, and metabolites.

[0186] 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.

[0187] As used herein, the term "subject" refers to 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.

[0188] As used herein, the terms "treat," "treating," and "treatment" can refer to a method of alleviating or inhibiting a disease or its attendant symptoms.

[0189] References to "a compound" or "compounds" throughout this application, such as compounds of Formula (I), Formula (II), Formula (III), and Formula (IV), include polymorphic, amorphous, salt, free base, acid salt, co-crystal, and solvate forms of those formulas and / or compounds, unless further specified. Thus, appearances of phrases such as "compound," "a compound of Formula (I)," "compounds of Formula (I)," and the like, include polymorphic forms of compound of Formula (I), such as Forms A-L of compound of Formula (I), which are further disclosed herein.

[0190] "Crystalline form" and "polymorph" may be used interchangeably herein and are meant to include all crystalline forms of a compound, including, for example, polymorphs and pseudopolymorphs.

[0191] The term "form" can be interpreted to encompass the terms "crystalline form" and "polymorph," as well as other descriptions of physical states (e.g., "solvated," "amorphous," etc.). The term "form" can refer to salts, solvates, hydrates, non-solvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular form or physical characteristic is otherwise specified.

[0192] For example, when referring to an X-ray powder diffraction (XRPD) pattern, the term "substantially as shown in" includes patterns that are not necessarily identical to those shown herein, but that fall within the limits of experimental error or variation as considered by one of ordinary skill in the art.

[0193] The relative intensities of XRPD peaks can vary depending on particle size, sample preparation technique, sample mounting procedure, and the particular instrument used.

[0194] Additionally, instrument variation and other factors can affect two-theta (2θ) values.

[0195] Thus, where a specified 2 theta angle is provided, it should be understood that the specified 2 theta angle may vary from the specified value by 0.50, e.g., 0.40, 0.30, 0.20, or 0.10.

[0196] As used herein, the term "major peak" refers to an XRPD peak having a relative intensity of greater than 30%, for example, greater than 35%, where the 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.

[0197] The compounds of the present disclosure include crystalline and amorphous forms of these compounds, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, non-solvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0198] It is further understood that all compounds disclosed herein include all possible isotopes of atoms present in the compounds. Isotopes include 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 Contains C.

[0199] As used herein, the term "dosage form" can refer to the form in which a compound or composition of the present disclosure is delivered to a patient, including the physical form (e.g., microcrystalline, micelle, etc.) and characteristics (e.g., a powder compressed into a pill form).

[0200] As used herein, the term "combination therapy" can 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). The two or more compounds, compositions, therapies, or combinations thereof can be co-administered or can be provided on different dosing schedules and / or dosage forms.

[0201] As used herein, the term "pharmaceutical composition" can refer to a combination of an active agent and a pharmaceutically acceptable excipient (e.g., a carrier), which can make the composition suitable or enhance its suitability for in vitro, in vivo, and / or ex vivo diagnostic or therapeutic use.

[0202] As used herein, the term "compound" is intended to encompass not only the specified molecular entity but also pharmaceutically acceptable and pharmacologically active derivatives thereof, including, but not limited to, salts, prodrug conjugates such as esters and amides, metabolites, and the like.

[0203] As used herein, the term "composition" includes a product containing the specified ingredients in the specified amounts, and any product resulting directly or indirectly from a combination of the specified ingredients in the specified amounts.

[0204] As used herein, "pharmaceutically acceptable" indicates the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0205] As used herein, the term "alkyl" refers to a saturated hydrocarbon group (e.g., ethyl, isopropyl, t-amyl, or 2,5-dimethylhexyl) that may be straight or branched. This definition applies both when the term is used alone and when used as part of a compound term, such as "aralkyl," "alkylamino," and similar terms. In some embodiments, alkyl groups contain 1 to 24 carbon atoms. All numerical ranges in the specification and claims are intended to be inclusive. Lower alkyl refers to those alkyl groups having 1 to 4 carbon atoms. In addition, alkyl and heteroalkyl groups can be attached to other moieties at any position on the alkyl or heteroalkyl group that would otherwise be occupied by a hydrogen atom (e.g., 2-pentyl, 2-methylpent-1-yl, and 2-propyloxy). Divalent alkyl groups may also be referred to as "alkylene," and divalent heteroalkyl groups may also be referred to as "heteroalkylene," such as groups used as linkers 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, hydroxyl, alkoxy, aryloxy, and the like.

[0206] As used herein, the terms "cycloalkyl" and "cycloalkenyl" refer to saturated hydrocarbon rings, including bicyclic and polycyclic rings. Similarly, cycloalkyl and cycloalkenyl groups having heteroatoms (e.g., N, O, or S) in place of carbon ring atoms may be referred to as "heterocycloalkyl" and "heterocycloalkylene," respectively. Examples of cycloalkyl and heteroaryl groups include, for example, cyclohexyl, norbornyl, adamantyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, and the like. The cycloalkyl and heterocycloalkyl moieties may also be optionally substituted with halogen atoms or other groups such as nitro, alkyl, alkylamino, carboxyl, alkoxy, and aryloxy. In some embodiments, the cycloalkyl and cycloalkenyl moieties have 3 to 12 carbon atoms in the ring (e.g., cyclohexyl, cyclooctyl, norbornyl, adamantyl, and the like). In some embodiments, heterocycloalkyl and heterocycloalkylene moieties have 1 to 3 heteroatoms in the ring (e.g., morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, piperidinyl, etc.). Additionally, the term "(cycloalkyl)alkyl" refers to a group having a cycloalkyl moiety bound to an alkyl moiety. Examples are cyclohexylmethyl, cyclohexylethyl, and cyclopentylpropyl.

[0207] As used herein, the term "alkenyl" refers to an alkyl group as described above that contains one or more sites of unsaturation that are double bonds. Similarly, as used herein, the term "alkynyl" refers to an alkyl group as described above that contains one or more sites of unsaturation that are triple bonds.

[0208] As used herein, the term "alkoxy" refers to an alkyl group as defined above that also bears an oxygen substituent that can be covalently linked to another hydrocarbon group, such as, for example, methoxy, ethoxy, aryloxy, and t-butoxy.

[0209] As used herein, the term "aryl" refers to an aromatic carbocyclic substituent, which may be a single ring or multiple rings fused together, covalently bonded, or linked to a common group, such as an ethylene or methylene moiety. Similarly, aryl groups having heteroatoms (e.g., N, O, or S) in place of carbon ring atoms are referred to as "heteroaryl." Examples of aryl and heteroaryl groups are, for example, phenyl, naphthyl, biphenyl, diphenylmethyl, 2,2-diphenyl-1-ethyl, thienyl, pyridyl, and quinoxalyl. The aryl and heteroaryl moieties may also be optionally substituted with halogen atoms or other groups such as nitro, alkyl, alkylamino, carboxyl, alkoxy, and phenoxy. In addition, aryl and heteroaryl groups may be attached to other moieties at any position on the aryl or heteroaryl radical that would otherwise be occupied by a hydrogen atom (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, are referred to as "heteroarylene."

[0210] As used herein, the terms "arylalkyl," "arylalkenyl," and "aryloxyalkyl" refer to an aryl group directly bonded to an alkyl group, an alkenyl group, or an oxygen bonded to an alkyl group, respectively. For brevity, aryl as part of the above combined terms is meant to also include heteroaryl.

[0211] As used herein, the terms "halo" and "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, 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 meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0212] As used herein, the term "hetero" as used in "heteroatom" refers to any atom other than carbon or hydrogen, for example, nitrogen, oxygen, sulfur, phosphorus, or silicon.

[0213] As used herein, the term "hetero," as used in "heteroatom-containing alkyl group" ("heteroalkyl" group) or "heteroatom-containing aryl group" ("heteroaryl" group), refers to a molecule, bond, or substituent in which one or more carbon atoms have been replaced with an atom other than carbon, such as nitrogen, oxygen, sulfur, phosphorus, or silicon, typically nitrogen, oxygen, or sulfur, or more than zero non-carbon atoms (e.g., sulfonamide). Similarly, the term "heteroalkyl" refers to a heteroatom-containing alkyl substituent, the term "heterocyclic" refers to a heteroatom-containing cyclic substituent, and the terms "heteroaryl" and "heteroaromatic" refer to heteroatom-containing "aryl" and "aromatic" substituents, respectively. Examples of heteroalkyl groups include alkoxyaryl, alkylsulfanyl-substituted alkyl, 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; examples of heteroatom-containing alicyclic groups are pyrrolidino, morpholino, piperazino, piperidino, and the like.

[0214] 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, a hydrophobic group is a group containing at least 3 carbon atoms.

[0215] As used herein, the term "carboxylic acid analog" refers to a variety of groups having an acidic moiety that can mimic a carboxylic acid residue. Examples of such groups are sulfonic acids, sulfinic acids, phosphoric acids, phosphonic acids, phosphinic acids, sulfonamides, and heterocyclic moieties such as, for example, imidazole, triazole, and tetrazole.

[0216] As used herein, the term "substituted" refers to an atom or group of atoms of a compound being replaced with another atom or group of atoms. For example, an atom or group of atoms may be substituted with one or more of the following substitutions or groups: Halo, cyano, nitro, alkyl, alkylamino, hydroxyalkyl, haloalkyl, carboxyl, hydroxyl, alkoxy, alkoxyalkoxy, haloalkoxy, thioalkyl, aryl, aryloxy, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl optionally substituted with one 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 group, halo, cyano, hydroxy, haloalkyl and polyhaloalkyl, preferably halo lower alkyl, in particular trifluoromethyl, formyl group, alkylcarbonyl, arylcarbonyl optionally substituted with one or more, preferably 1 to 3, substituents selected from halo, haloalkyl and alkyl, heteroarylcarbonyl, carboxy, alkoxycarbonyl, aryl Oxycarbonyl, 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, mercapto, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfmyl, alkylsulfonyl, arylsulfmyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl and arylaminosulfonyl.When the term "substituted" appears before a list of possible substituents, it is intended that the term apply to every member of that group.

[0217] The term "unsubstituted" refers to naturally occurring compounds that lack substitution of an atom or group of atoms.

[0218] Soluble Epoxide Hydrolase Inhibitors The present disclosure provides soluble epoxide hydrolase inhibitors (sEH) of formula (I) that are effective in treating sEH-mediated diseases and disorders. Formula (I) TIFF2025540598000029.tif30128

[0219] 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 bis-tyrosine substrate hydrogen-bonding motif and an aspartate-histidine-aspartate bridge. Formula (I) has sufficient hydrophobicity to effectively bind to these hydrophobic and hydrophilic regions and reach these regions by traversing the hydrophobic sEH substrate access channel. Illustrating these characteristics, Formula (I) exhibits an sEH inhibitor constant (Ki) of less than 50 pM and a t of sEH inhibition of 22 minutes. 1 / 2 Shows.

[0220] Formula (I) also has a relatively low water solubility of 11 μg / mL, which can make formulation challenging for cellular uptake and sEH colocalization. Because sEH is primarily peroxisomal and cytosolic, effective delivery of Formula (I) may require a formulation that facilitates aqueous localization. To overcome this barrier, Formula (I) can be formulated and crystallized to enhance its activity and solubility.

[0221] Polymorphic forms of formula (I) A surprising discovery disclosed herein is that Formula (I) can be prepared in multiple crystalline forms (hereinafter "forms" or "polymorphs"), each with its own unique solubility and stability and thus useful for tailoring formulations for specific treatments and delivery means. Among the embodiments 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 unique physical structures and properties, including different solubilities and stabilities in various conditions and solvents. Forms A-L each differ from amorphous Formula (I) (e.g., as outlined in Examples 4-6), thereby expanding the options for formulating Formula (I) beyond those previously available.

[0222] The composition may comprise a single 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-L. The composition may comprise a mixture of non-amorphous forms of Formula (I), for example, 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-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% by weight of amorphous Formula (I).

[0223] Form C is a hydrate and differs from Forms A, B, and D-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) (either a single form or a mixture of forms) contains 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.

[0224] In certain embodiments, the present disclosure provides Form A of Formula (I) (hereinafter "Form A") characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1, panel A or Figure 131A. In certain embodiments, the present disclosure provides Form A of Formula (I) 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 cases, the relative intensities of the peaks at 3.3±0.3°2θ, 30.3±0.3°2θ, and 20.0±0.3°2θ differ by 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 measured by Gaussian or Lorentzian fitting peaks in the 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 have intensities that are 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, respectively, of the fourth most intense 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 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 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. 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% by weight of Form A.

[0225] Form A of Formula (I) may exhibit the X-ray powder diffraction pattern shown in Figure 131A, with Peaks 1-28 corresponding to the peak numbers in Table 27. The peaks in Figure 131A (numbered 1 to 28 in left-to-right order) and Table 27 are provided as relative intensities (Rel. Int. %) normalized to Peak 1 (the peak with the greatest intensity). (Table 27) TIFF2025540598000030.tif155167

[0226] In certain embodiments, the present disclosure provides Form B of Formula (I) (hereinafter "Form B") characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1, panel B or Figure 131B. In certain embodiments, the present disclosure provides Form B of Formula (I) 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 cases, the relative intensities of the peaks at 12.2±0.3°2θ and 3.5±0.3°2θ are within 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 that is 4% to 30% greater, 5% to 25% greater, 6% to 15% greater, or 7.5% to 12.5% ​​greater than the peak at 17.2±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 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 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% by weight of Form B.

[0227] Form B of Formula (I) may exhibit the X-ray powder diffraction pattern shown in Figure 131B, with peaks 1-29 corresponding to the peak numbers in Table 28. The peaks in Figure 131B (numbered 1 to 29 in left-to-right order) and Table 28 are provided as relative intensities (Rel. Int. %) normalized to peak 5 (the peak with the greatest intensity). (Table 28) TIFF2025540598000031.tif161167

[0228] In certain embodiments, the present disclosure provides Form C of Formula (I) (hereinafter "Form C"), characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1, panel C or Figure 131C. In certain embodiments, the present disclosure provides Form C of Formula (I), 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 cases, the relative intensities of the peaks at 16.3±0.3°2θ, 16.1±0.3°2θ, and 3.2±0.3°2θ are within 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 peaks at 16.3±0.3°2θ, 16.1±0.3°2θ, and 3.2±0.3°2θ are at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% more intense than the next most intense 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% by weight of Form C.

[0229] Form C of Formula (I) may exhibit the X-ray powder diffraction pattern shown in Figure 131C, with peaks 1-35 corresponding to the peak numbers in Table 29. The peaks in Figure 131C (numbered 1 to 35 in left-to-right order) and Table 29 are provided as relative intensities (Rel. Int. %) normalized to peak 12 (the peak with the greatest intensity). (Table 29) TIFF2025540598000032.tif192167

[0230] In certain embodiments, the present disclosure provides Form D of Formula (I) (hereinafter "Form D"), characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1, panel D or Figure 131D. In certain embodiments, the present disclosure provides Form D of Formula (I), 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 cases, the relative intensities of the peaks at 20.1±0.3°2θ, 18.3±0.3°2θ, and 18.1±0.3°2θ are within 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 comprises at least one or at least two peaks selected from 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% by weight of Form D.

[0231] Form D of Formula (I) may exhibit the X-ray powder diffraction pattern shown in Figure 131D, with peaks 1-45 corresponding to the peak numbers in Table 30. The peaks in Figure 131D (numbered 1 to 45 in left-to-right order) and Table 30 are provided as relative intensities (Rel. Int. %) normalized to peak 14 (the peak with the greatest intensity). (Table 30) TIFF2025540598000033.tif245167

[0232] In certain embodiments, the present disclosure provides Form E of Formula (I) (hereinafter "Form E"), characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1, panel E or Figure 131E. In certain embodiments, the present disclosure provides Form E of Formula (I), 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 cases, the peaks at 13.4±0.3°2θ, 11.2±0.3°2θ, and 3.1±0.3°2θ have relative intensities within 20%, within 18%, within 16%, within 14%, within 12%, or within 10%. In some cases, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from 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% by weight of Form E.

[0233] Form E of Formula (I) may exhibit the X-ray powder diffraction pattern shown in Figure 131E, with peaks 1-42 corresponding to the peak numbers in Table 31. The peaks in Figure 131E (numbered 1 to 42 in left-to-right order) and Table 31 are provided as relative intensities (Rel. Int. %) normalized to peak 8 (the peak with the greatest intensity). (Table 31) TIFF2025540598000034.tif229167

[0234] In certain embodiments, the present disclosure provides Form F of Formula (I) (hereinafter "Form F") characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 1, panel F or FIG. 131F. In certain embodiments, the present disclosure provides Form F of Formula (I), 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 cases, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from 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 comprises at least one, at least two, or at least three peaks selected from 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% by weight of Form F.

[0235] Form F of Formula (I) may exhibit the X-ray powder diffraction pattern shown in Figure 131F, with peaks 1-42 corresponding to the peak numbers in Table 32. The peaks in Figure 131F (numbered 1 to 42 in left-to-right order) and Table 32 are provided as relative intensities (Rel. Int. %) normalized to peak 10 (the peak with the greatest intensity). (Table 32) TIFF2025540598000035.tif229167

[0236] In certain embodiments, the present disclosure provides Form G of Formula (I) (hereinafter "Form G"), characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1, panel G or Figure 131G. In certain embodiments, the present disclosure provides Form G of Formula (I), 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 cases, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from 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 comprises at least one or at least two peaks selected from 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% by weight of Form G.

[0237] Form G of Formula (I) may exhibit the X-ray powder diffraction pattern shown in Figure 131G, with Peaks 1-50 corresponding to the peak numbers in Table 33. The peaks in Figure 131G (numbered 1 to 50 in left-to-right order) and Table 33 are provided as relative intensities (Rel. Int. %) normalized to Peak 24 (the peak with the greatest intensity). (Table 33) TIFF2025540598000036.tif240167TIFF2025540598000037.tif33167

[0238] In certain embodiments, the present disclosure provides Form H of Formula (I) (hereinafter "Form H"), characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1, panel H or Figure 131H. In certain embodiments, the present disclosure provides Form H of Formula (I), 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 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 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 comprises at least one, at least two, or at least three peaks selected from 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% by weight Form H.

[0239] Form H of Formula (I) may exhibit the X-ray powder diffraction pattern shown in Figure 131H, with Peaks 1-45 corresponding to the peak numbers in Table 34. The peaks in Figure 131H (numbered 1 to 45 in left-to-right order) and Table 34 are provided as relative intensities (Rel. Int. %) normalized to Peak 5 (the peak with the greatest intensity). (Table 34) TIFF2025540598000038.tif245167

[0240] In certain embodiments, the present disclosure provides Form I of Formula (I) (hereinafter "Form I"), characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1, panel I or Figure 131I. In certain embodiments, the present disclosure provides Form I of Formula (I), 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 cases, the peaks at 12.0±0.3°2θ, 12.3±0.3°2θ, and 3.2±0.3°2θ are at least 1.5 times, at least 1.6 times, at least 1.7 times, at least 1.8 times, at least 1.9 times, or at least 2 times more intense than the next most intense peak. In some cases, the X-ray powder diffraction pattern further comprises at least one, at least two, or at least three peaks selected from 14.5±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% by weight of Form I.

[0241] Form I of Formula (I) may exhibit the X-ray powder diffraction pattern shown in Figure 131I, with Peaks 1-41 corresponding to the peak numbers in Table 35. The peaks in Figure 131I (numbered 1 to 41 in left-to-right order) and Table 35 are provided as relative intensities (Rel. Int. %) normalized to Peak 5 (the peak with the greatest intensity). (Table 35) TIFF2025540598000039.tif224167

[0242] In certain embodiments, the present disclosure provides Form J of Formula (I) (hereinafter "Form J"), characterized by an X-ray powder diffraction pattern substantially as shown in Panel J of Figure 1 or Figure 131J. In certain embodiments, the present disclosure provides Form J of Formula (I), 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 cases, 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 cases, 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. 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% by weight of Form J.

[0243] Form J of Formula (I) may exhibit the X-ray powder diffraction pattern shown in Figure 131J, with Peaks 1-44 corresponding to the peak numbers in Table 36. The peaks in Figure 131J (numbered 1 to 44 in left-to-right order) and Table 36 are provided as relative intensities (Rel. Int. %) normalized to Peak 11 (the peak with the greatest intensity). (Table 36) TIFF2025540598000040.tif240167

[0244] In certain embodiments, the present disclosure provides Form K of Formula (I) (hereinafter "Form K") characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1, panel K or Figure 131K. In certain embodiments, the present disclosure provides Form K of Formula (I), 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 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 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 comprises a peak at 17.4±0.3°2θ. In some cases, the relative intensity of the peak at 17.4±0.3 degrees 2θ is between 30% and 80%, 35% and 75%, 40% and 70%, 45% and 65%, or 50% and 60% of the intensity of the peak at 5.3±0.3 degrees 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% by weight Form K.

[0245] Form K of Formula (I) may exhibit the X-ray powder diffraction pattern shown in Figure 131K, with Peaks 1-36 corresponding to the peak numbers in Table 37. The peaks in Figure 131K (numbered 1 to 36 in left-to-right order) and Table 37 are provided as relative intensities (Rel.Int.%) normalized to Peak 2 (the peak with the greatest intensity). (Table 37) TIFF2025540598000041.tif198167

[0246] In certain embodiments, the present disclosure provides Form L of Formula (I) (hereinafter "Form L"), characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1, panel L or Figure 131L. In certain embodiments, the present disclosure provides Form L of Formula (I), characterized by an X-ray powder diffraction pattern comprising peaks at 8.9±0.3 degrees 2θ, 3.4±0.3 degrees 2θ, and 18.3±0.3 degrees 2θ. In some cases, the peak at 8.9±0.3 degrees 2θ is about 10% to 45%, about 15% to 40%, about 20% to 35%, or about 23% to 31% greater in intensity than the peak at 18.3±0.3 degrees 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 14.4±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% by weight of Form L.

[0247] Form L of Formula (I) may exhibit the X-ray powder diffraction pattern shown in Figure 131L, with Peaks 1-36 corresponding to the peak numbers in Table 38. The peaks in Figure 131L (numbered 1 to 36 in left-to-right order) and Table 38 are provided as relative intensities (Rel. Int. %) normalized to Peak 4 (the peak with the greatest intensity). (Table 38) TIFF2025540598000042.tif198167

[0248] Synthesis method An embodiment of the present disclosure provides a synthetic method for preparing (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 1-2 described below and in Examples 1-3.

[0249] Synthetic Route 1 As disclosed herein, formula (I) can be produced using one, two, three, or all four of steps 1-4 of Scheme 1. Scheme 1 TIFF2025540598000043.tif65169

[0250] Step 1 - Activation of the Isocyanate The synthesis of Formula (I) can involve the activation of 3-fluoro-4-(trifluoromethoxy)aniline to form the reactive isocyanide 2-fluoro-4-isocyanato-1-(trifluoromethoxy)benzene. In this step, 3-fluoro-4-(trifluoromethoxy)aniline and 1-triethylamine can be dissolved in CHCl and stirred at -78°C. Triphosgene can then be dissolved in CHCl and added dropwise. The reaction can be warmed to room temperature, stirred for 30 minutes, and then cooled to 0°C. The resulting isocyanato product can be used directly in subsequent synthetic steps.

[0251] Step 2 - Urea formation The synthesis of Formula (I) can involve urea formation between 2-fluoro-4-isocyanato-1-(trifluoromethoxy)benzene and tert-butyl-4-aminopiperidine-1-carboxylate (a Boc-protected diamine) by combining these species with triethylamine in CHCl (e.g., in a ratio of about 2:3:3) and stirring at room temperature for 12 hours. The reaction can be quenched by the addition of acid (e.g., 2 M HCl). The intermediate compound tert-butyl 4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)piperidine-1-carboxylate (Compound S1) can be recovered from the organic layer and further extracted from the aqueous layer, and optionally dried and concentrated (e.g., under high vacuum) for further use.

[0252] Step 3 - Deprotection The synthesis of formula (I) can include the removal of the Boc protecting group from compound S1 by refluxing in acid. In this step, compound S1 can be dissolved in 2M HCl in MeOH (e.g., to a concentration of about 186 mM) and refluxed for 2 hours to form 1-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-(piperidin-4-yl)urea (compound S2). The solvent can optionally be removed (e.g., under high vacuum), and the pH of the crude reaction product can be increased (e.g., to pH 12 using NaOH). The precipitate can be filtered, dried, and collected.

[0253] Step 4 - Functionalization of Piperidine The synthesis of Formula (I) can involve functionalization of the piperidinylamine in Compound S2 or its analog. This step can involve activation of (S)-2-methylbutanoic acid with (S)-2-methylbutanoic acid (EDCI) and 4-dimethylaminopyridine (DMAP) in the presence of Compound S2 in CHCl. ​​The reaction mixture can be stirred overnight at room temperature and then quenched by the addition of acid (e.g., 1 M HCl). The resulting Formula (I) can be collected from the organic layer and extracted from the aqueous layer, and optionally further purified.

[0254] Synthetic Route 2 As disclosed herein, formula (I) can be produced using one or both of steps 1-2 of Scheme 2. Scheme 2 TIFF2025540598000044.tif29164

[0255] Step 1 - Activation of the Isocyanate The synthesis of Formula (I) can involve the activation of 3-fluoro-4-(trifluoromethoxy)aniline to form a reactive isocyanate, as outlined above in 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.

[0256] Step 2 - Urea formation The synthesis of Formula (I) can involve urea formation between 2-fluoro-4-isocyanato-1-(trifluoromethoxy)benzene and (S)-1-(4-aminopiperidin-1-yl)-2-methylbutan-1-one. This step can involve combining these species with triethylamine (in CHCl) and stirring at room temperature. The reaction can be quenched by the addition of acid (e.g., 2 M HCl). The product species of Formula (I) can be collected from the organic layer and further extracted from the aqueous layer, optionally dried, concentrated, and further purified.

[0257] Methods for Making Polymorphs A surprising discovery disclosed herein is that Formula (I) can be prepared in a variety of polymorphic forms, each with its own unique solubility and physical properties. Among the determinants of the form of Formula (I), the solvent system, temperature, cooling rate, and evaporation rate can affect the form of Formula (I) produced from the crystallization procedure. In many cases, the crystallization disclosed herein produces a single form of Formula (I), e.g., at least 90%, at least 95%, at least 98%, at least 99%, or at least 99.5% by weight of that single form. In some cases, the crystallization produces only a small amount of amorphous Formula (I), e.g., less than 5%, less than 2%, less than 1%, or less than 0.5% by weight. In some cases, non-target forms of Formula (I) are selectively removed after crystallization, for example, by triturating soluble impurities.

[0258] Formula (I) is soluble in a variety of solvents, but the type of solvent can strongly influence the form and purity of 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 protic organic solvent. In other cases, the organic solvent is aprotic. In some cases, the organic solvent is acetone, acetonitrile, dichloromethane, dioxane, isopropyl alcohol, isopropyl acetate, methanol, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ether, n-butyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or a combination thereof. In some cases, Formula (I) comprises a solubility in the primary solvent of at least about 5 mg / mL, at least about 10 mg / mL, at least about 20 mg / mL, at least about 30 mg / mL, at least about 40 mg / mL, or at least about 50 mg / mL (e.g., as outlined in Table 4 for Form A).

[0259] Crystallization of Formula (I) can utilize a single solvent or a mixture of solvents. In many cases, crystallization of Formula (I) utilizes a solvent system having at least two solvents. In some cases, the two solvents used in crystallization, such as methanol and water, are miscible. In some cases, Formula (I) has a solubility of at least 5 mg / mL in a secondary solvent. However, in many cases, crystallization of Formula (I) utilizes a primary solvent in which Formula (I) has a high solubility and an anti-solvent in which Formula (I) has a low solubility. As used herein, the term "anti-solvent" can refer to a solvent in which the analyte (e.g., Formula (I)) has an even lower solubility. In some cases, Formula (I) has a solubility in the secondary solvent of at most 5 mg / mL, at most 3 mg / mL, at most 2 mg / mL, or at most 1 mg / mL. In some cases, the secondary solvent is water or hexane. In some cases, the solvent system used to crystallize Formula (I) contains only solvents in which Formula (I) has a solubility of at least 5 mg / ml, 10 mg / ml, or 20 mg / ml. In some cases, the solvent system used to crystallize Formula (I) contains a first solvent in which Formula (I) has a solubility of at least 10 mg / ml at room temperature and a second solvent in which Formula (I) has a solubility of at most 5 mg / ml. In some cases, the solvent system used to crystallize Formula (I) contains a first solvent in which Formula (I) has a solubility of at least 20 mg / ml at room temperature and a second solvent in which Formula (I) has a solubility of at most 2 mg / ml.

[0260] In some cases, the crystallization of Formula (I) utilizes a multi-solvent 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-propanol, 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-propanol, and dioxane. In some cases, the ratio of water to organic solvent is 10:1 to 1:10, 10:1 to 1:1, 5:1 to 1:5, 5:2 to 2:5, 3:2 to 2:3, or 1:1 to 1:10.

[0261] In some cases, the crystallization of Formula (I) includes heptane and an additional organic solvent. In some cases, the heptane is n-heptane. 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-propanol, and dioxane. In some cases, the ratio of heptane to methanol, ethanol, acetonitrile, isopropyl alcohol, dimethyl sulfoxide, NMP, n-propanol, or dioxane is 5:1 to 200:1, 10:1 to 200:1, 5:1 to 100:1, or 10:1 to 300:1. In some cases, the ratio of heptane to tetrahydrofuran or acetone is 20:1 to 1:1, 10:1 to 1:1, 5:1 to 1:5, or 5:1 to 1:1.

[0262] In some cases, the crystallization of Formula (I) includes hexane and an additional organic solvent. In some cases, the hexane is c-hexane. 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-propanol, and dioxane. In some cases, the ratio of hexane to methanol, ethanol, acetonitrile, isopropyl alcohol, dimethyl sulfoxide, NMP, or n-propanol is 5:1 to 200:1, 10:1 to 200:1, 5:1 to 100:1, or 10:1 to 300:1. In some cases, the ratio of hexane to tetrahydrofuran, acetone, or dioxane is 20:1 to 1:1, 10:1 to 1:1, 5:1 to 1:5, or 5:1 to 1:1.

[0263] 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 of about 30°C to 90°C, about 40°C to 80°C, or about 50°C to 75°C and then cooled for crystallization.

[0264] The rate at which a solution of Formula (I) is cooled after dissolution in a solvent system can affect the polymorph(s) produced during crystallization. Cooling can be slow, for example, at most about 0.1°C / hr, at most about 1°C / hr, at most about 2°C / hr, at most about 4°C / hr, at most about 8°C / hr, at most about 12°C / hr, at most about 15°C / hr, at most about 20°C / hr, at most about 25°C / hr, at most about 30°C / hr, or at most about 40°C / hr. The cooling rate can be between about 0.1°C / hr and 40°C / hr, between about 1°C / hr and about 40°C / hr, between about 4°C / hr and 20°C / hr, between about 4°C / hr and 30°C / hr, between about 8°C / hr and 25°C / hr, or between about 15°C / hr and 40°C / hr. The cooling rate can also be fast, for example, between 60°C / hr and 600°C / hr, greater than about 60°C / hr, greater than about 100°C / hr, or greater than about 200°C / hr. 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.

[0265] In some cases, Formula (I) is added to the solvent system at a first temperature and then cooled to a second temperature at which Formula (I) has lower solubility in the solvent system. In some cases, the solvent system is saturated with Formula (I) at the first temperature. In some cases, Formula (I) is added to the solvent system at about 60-90% saturation at the first temperature. In some cases, Formula (I) is added to the solvent system at about 40-80% saturation at the first temperature. In some cases, Formula (I) is added to the solvent system at about 30-60% saturation at the first temperature. In some cases, Formula (I) is added to the solvent system at about 75% to greater than 100% saturation at the first temperature.

[0266] After dissolution, the solvent system containing Formula (I) can be seeded with solid Formula (I). In some cases, Formula (I) is a single polymorphic form. In some cases, Formula (I) is of Form A, B, C, D, E, F, G, H, I, J, K, or L. In some cases, Formula (I) is added on a milligram scale, for example, 1 to 5 mg.

[0267] Crystallization can also include the addition of a low Formula (I) solubility solvent (e.g., an anti-solvent). The added solvent may have a lower Formula (I) solubility than the primary solvent used for crystallization, thereby reducing the solubility of Formula (I) within the solvent system. In many cases, crystallization methods can include gradually adding an anti-solvent (e.g., water) to a solvent system containing a primary solvent in which Formula (I) has a high solubility. For example, certain crystallization methods disclosed herein include the addition of water, n-heptane, c-heptane, or another solvent in which Formula (I) has a solubility of less than about 5 mg / ml under the conditions used for crystallization.

[0268] 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 about 60-90% saturation before adding the anti-solvent. In some cases, Formula (I) is added to the solvent system to about 40-80% saturation before adding the anti-solvent. In some cases, Formula (I) is added to the solvent system to about 30-60% saturation before adding the anti-solvent. In some cases, Formula (I) is added to the solvent system to about 75% to over 100% saturation before adding the anti-solvent.

[0269] (i) Method for Making Form A In some cases, Form A is formed during fast 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 the primary solvent. In some cases, the solvent is methanol or toluene.

[0270] 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 the specified solvent). In some cases, the solvent system comprises water and a solvent selected from the group consisting of acetonitrile and acetone.

[0271] In some cases, Form A is formed during fast 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 a multi-solvent system.

[0272] In some cases, Form A is formed by heating Form C. As shown in Table 15, Form C completes 100% conversion to Form A in less than one day when incubated at 60° C. Methods for making Form A can include 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 carried out under low humidity or strictly anhydrous conditions.

[0273] (ii) Method for Making Form B In some cases, Form B is formed during slow cooling in a single solvent or substantially single solvent system. In some cases, the single solvent is methanol, ethanol, isopropyl alcohol, or n-butanol.

[0274] In some cases, Form B is formed during fast cooling in a single solvent or substantially single solvent system. In some cases, the solvent is ethanol, isopropyl alcohol, or n-butanol.

[0275] In some cases, Form B is formed during fast cooling in a multi-solvent system. In some cases, the solvent system comprises water and n-propanol.

[0276] In some cases, Form B is formed during slow cooling in a multi-solvent system. In some cases, the multi-solvent system includes 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 includes 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 includes c-hexane and dioxane. In some cases, the multi-solvent system includes c-hexane and acetonitrile, and the crystallization utilizes up to about 0.1 mg / ml of Formula (I).

[0277] (iii) Method for Making Form C In some cases, Form C is formed during fast cooling in a multi-solvent system. In some cases, the solvent system comprises water and methanol.

[0278] In some cases, Form C is formed by incubating the polymorph of Formula (I) in water. In some cases, the polymorph of Formula (I) is one or more of Forms A-L. In some cases, the incubation is at or near room temperature (e.g., 15°C to 35°C). 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 amorphous polymorph.

[0279] In some cases, Form C is formed by incubating the 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 amorphous polymorph.

[0280] In some cases, Form C is formed by incubating another form of Formula (I) in a micellar system. In some cases, the micellar system includes a non-ionic surfactant. In some cases, the non-ionic surfactant is polysorbate 80 ("Tween 80") or sodium lauryl sulfate. In some cases, the micellar system has a critical micelle concentration of about 0.1 to 150, or about 1 to 100.

[0281] (iv) Methods for Making Form D 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.

[0282] In some cases, Form D is formed during slow cooling in a multi-solvent system. In some cases, the solvent system includes water and dimethylformamide, and the crystallization utilizes up to about 0.25 mg / ml of Formula (I). In some cases, the solvent system includes 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 includes n-heptane and a solvent selected from the group consisting of dimethylformamide and NMP. In some cases, the solvent system includes n-heptane, isopropyl alcohol, and utilizes at least about 0.4 mg / ml of Formula (I) for crystallization. In some cases, the solvent system includes n-heptane and a solvent selected from the group consisting of ethanol, isopropyl alcohol, and ethyl acetate, and the crystallization includes seeding with crystals of Form D. In some cases, the solvent system includes c-hexane and dimethyl sulfoxide.

[0283] 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 through L. In some cases, the incubation is at or near room temperature (e.g., 15°C to 35°C). In some cases, the incubation is for more than one day.

[0284] In some cases, form D is formed by heating form B. For example, as outlined in Table 15, form B converts rapidly to form D at 60° C., with 100% conversion occurring after one day of incubation. Following this observation, methods for making form D can include 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.

[0285] 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.

[0286] (v) Methods for Making Form E 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, isopropyl alcohol, 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.

[0287] In some cases, Form E is formed during slow cooling in a multi-solvent system. In some cases, the solvent system includes 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 includes n-heptane and a solvent selected from the group consisting of methanol, ethanol, acetonitrile, and n-propanol. In some cases, the solvent system includes n-heptane and methyl ethyl ketone, and the crystallization includes seeding with crystals of Form E. In some cases, the solvent system includes c-hexane and methanol. In some cases, the solvent system includes n-heptane and isopropyl alcohol, and the crystallization utilizes up to about 0.25 mg / ml of Formula (I).

[0288] For many slurry-based conversions disclosed herein, non-form D is first converted to form E, and then subsequently 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-C or E-L. In some cases, incubation is at or near room temperature (e.g., 15°C to 35°C). In some cases, incubation is for up to one day.

[0289] (vi) Methods for Making Form F In some cases, Form F is formed during rapid cooling in a multi-solvent system. In some cases, the solvent system includes water and a solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, tetrahydrofuran, acetone, dimethyl sulfoxide, dimethylformamide, and N-methyl-2-pyrrolidone (NMP). In some cases, the solvent system includes water and acetonitrile, and the crystallization utilizes up to about 0.25 mg / ml of Formula (I). In some cases, the solvent system includes 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 includes n-heptane and dimethylformamide. In some cases, the solvent system includes c-hexane and a solvent selected from the group consisting of ethanol, NMP, n-propanol, and dioxane.

[0290] In some cases, Form F is formed during slow cooling in a multi-solvent system. In some cases, the solvent system includes water and a solvent selected from the group consisting of ethanol, tetrahydrofuran, dimethylformamide, and n-propanol. In some cases, the solvent system includes 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 includes n-heptane and dimethyl sulfoxide. In some cases, the solvent system includes c-hexane and a solvent selected from the group consisting of methanol, isopropyl alcohol, dimethylformamide, and n-propanol.

[0291] (vii) Methods for Making Form G In some cases, Form G is formed 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.

[0292] In some cases, Form G is formed during fast cooling in a single solvent or substantially single solvent system. In some cases, the solvent is tetrahydrofuran or dioxane.

[0293] In some cases, Form G is formed during rapid cooling in a multi-solvent system. In some cases, the solvent system includes water and dioxane. In some cases, the solvent system includes 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 includes n-heptane and a solvent selected from the group consisting of tetrahydrofuran and dioxane. In some cases, the solvent system includes c-hexane and acetone, and crystallization utilizes up to about 0.25 mg / ml of Formula (I).

[0294] In some cases, Form G is formed during slow cooling in a multi-solvent system. In some cases, the solvent system includes water and dioxane. In some cases, the solvent system includes 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 includes n-heptane and dioxane. In some cases, the solvent system includes c-hexane and tetrahydrofuran. In some cases, the solvent system includes c-hexane, dioxane, and at least 0.4 mg / ml of Formula (I) in the solvent system.

[0295] (viii) Methods for Making Form H In some cases, Form H is formed 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).

[0296] In some cases, Form H is formed during fast cooling in a single solvent or substantially single solvent system. In some cases, the solvent is isopropyl acetate or 2-methyltetrahydrofuran.

[0297] 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 c-hexane and a solvent selected from the group consisting of acetonitrile and tetrahydrofuran. In some cases, the solvent system comprises c-hexane and acetone, and at least 0.4 mg / ml of Formula (I) in the solvent system.

[0298] In some cases, Form H is formed during slow cooling in a multi-solvent system. In some cases, the multi-solvent system includes 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 includes c-hexane and acetone. In some cases, the multi-solvent system includes c-hexane and acetonitrile, and at least 0.4 mg / ml of Formula (I) is in the solvent system.

[0299] (ix) Methods for Making Form I In some cases, Form I is formed during slow cooling in a single solvent or substantially single solvent system. In some cases, the single solvent is dichloromethane.

[0300] 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).

[0301] (x) Method for Making Form J In some cases, Form J is formed during slow cooling in a single solvent or substantially single solvent system. In some cases, the single solvent is toluene.

[0302] (xi) Method for making Form K In some cases, Form K is formed during slow cooling in a single solvent or substantially single solvent system. In some cases, the single solvent is methyl tert-butyl ether (MTBE).

[0303] In some cases, Form K is formed during fast cooling in a single solvent or substantially single solvent system. In some cases, the single solvent is methyl tert-butyl ether (MTBE).

[0304] 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-L. In some cases, the incubation is at or near room temperature (e.g., 15°C to 35°C). In some cases, the incubation is for at least one day.

[0305] (xii) Methods for making Form L In some cases, Form L is formed during slow cooling in a multi-solvent system. In some cases, the multi-solvent system includes water and isopropyl alcohol, and at least about 0.4 mg / mL of Formula (I) is utilized for crystallization. In some cases, the multi-solvent system includes c-hexane and acetonitrile, and at least about 0.2 mg / mL of Formula (I) is utilized for crystallization.

[0306] 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.

[0307] formulation 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 cutaneous, buccal, sublingual, and ocular) administration. As disclosed herein, Formula (I) can be prepared in numerous polymorphic forms, each with its own unique solubility, stability, and activity. Following these discoveries, formulations of Formula (I) can be tailored not only for specific delivery routes, but also to optimize compatibility of the Formula (I) form with specific delivery systems. For example, as outlined in Example 17, solubility and stability in PEG-water mixtures can be improved by appropriate selection of the polymorphic form of Formula (I). Therefore, an optimal formulation will include not only the delivery form (e.g., solid pill or micellar suspension), but also the selected Formula (I) polymorph for the delivery form and desired activity level.

[0308] Formula (I) can be formulated as a raw material or as a component of a pharmaceutical preparation. In many cases, the formulation of Formula (I) includes one or more pharmaceutically acceptable carriers. As used herein, a pharmaceutically acceptable carrier can refer to a non-therapeutic active ingredient that is compatible with other ingredients of a pharmaceutical preparation. The pharmaceutical compositions disclosed herein can be prepared in any manner known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, encapsulating, or compressing processes. The pharmaceutically acceptable carrier can be a solid, liquid, emulsifier, or a combination thereof. In some cases, the formulation of Formula (I) includes 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, plurol oleique, pecceol, labrasol, labrafil M1944CS, Felucire 44 / 14, Captex 355, Plurol Oleique CC 497, triacetin, transcutol HP, glycerol, Intralipid, or a combination thereof. In some cases, the formulation of Formula (I) includes a surfactant. In some cases, the surfactant is an ionic surfactant. In some cases, the surfactant is a non-ionic surfactant.

[0309] The size of Formula (I) can be an important determinant of its properties (e.g., dissolution rate in a particular solvent). Within a formulation, Formula (I) can be uniform in size or polydisperse. In some cases, the standard deviation of particle size (e.g., crystal diameter) of Formula (I) is about 0.1 times the average particle size, about 0.2 times the average particle size, about 0.4 times the average particle size, about 0.75 times the average particle size, approximately the same as the average particle size, or greater than the average particle size. For some formulations disclosed herein, Formula (I) has an average particle size (e.g., the average diameter of individual crystals) of about 0.1 to 500 microns. In some cases, Formula (I) has an average particle size of about 10 to 50 microns, about 10 to 100 microns, about 10 to 200 microns, about 20 to 100 microns, about 50 to 100 microns, about 50 to 250 microns, or about 100 to about 500 microns. In some cases, Formula (I) has an average particle size of about 0.1 to 25 microns, about 0.1 to 0.5 microns, about 0.1 to 1 micron, about 0.1 to 2 microns, about 0.25 to 1 micron, about 0.25 to 2 microns, about 0.25 to 4 microns, about 0.5 to 2 microns, about 0.5 to 5 microns, about 1 to 5 microns, about 2 to 6 microns, about 2 to 9 microns, about 2 to 12 microns, about 4 to 12 microns, about 4 to 20 microns, about 6 to 12 microns, about 6 to 20 microns, about 8 to 25 microns, or about 10 to 30 microns.

[0310] The most suitable route can depend, for example, on the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods known in the art of pharmaceutical formulation. Typically, these methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof (the "active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0311] Formulations of the compounds disclosed herein suitable for oral administration can each be presented as discrete units (e.g., capsules, cachets, or tablets containing a predetermined amount of the active ingredient), as a powder or granules, as a solution or suspension in an aqueous liquid or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient can also be presented as a bolus, electuary, or paste.

[0312] Orally available pharmaceutical preparations 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 made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricating surfactant or dispersant. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets can optionally be coated or scored and can be formulated to provide sustained or controlled release of the active ingredient therein. All formulations for oral administration should be in a dosage suitable for such administration. Push-fit capsules can contain the active ingredient in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. The sugar-coated core is coated with a suitable coating. For this purpose, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and concentrated sugar solutions, which may optionally contain suitable organic solvents or solvent mixtures, can be used. Dyes or pigments can be added to the tablets or drug coatings for identification or to characterize different combinations of active compound doses.

[0313] The compounds can be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion. Formulations for injection can be provided in unit dosage form, for example, in ampoules or multi-dose containers, together with added preservatives. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. The formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in powder form or in a lyophilized state requiring only the addition of a sterile liquid carrier (e.g., physiological saline or sterile pyrogen-free water) immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the type described above.

[0314] 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 render the formulation isotonic with the blood of the intended recipient, as well as 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, allowing for the preparation of highly concentrated solutions.

[0315] In addition to the above-mentioned formulations, the compound can also be formulated as a depot preparation.Such long-acting preparations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.Thus, for example, the compound can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as a sparingly soluble derivative, for example, as a sparingly soluble salt.

[0316] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastes, or gels formulated in a conventional manner. Such compositions may comprise the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

[0317] 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.

[0318] Formula (I) can be formulated for topical administration, i.e., non-systemic administration. This includes applying the compounds disclosed herein externally to the epidermis or oral cavity and administering drops of such compounds to the ears, eyes, and nose so that such compounds do not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for passing through the skin to the site of inflammation, such as gels, ointments, lotions, creams, ointments, or pastes, as well as drops suitable for administration to the eyes, ears, or nose. The active ingredient for topical administration may comprise, for example, 0.001% to 10% w / w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise up to 10% w / w. In other embodiments, it may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise 2% w / w to 5% w / w. In other embodiments, it may comprise 0.1% to 1% w / w of the formulation.

[0319] The topical ophthalmic, otic, and nasal formulations of the present invention may 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 can 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 0.5-5% non-toxic water-soluble polymers, natural products such as alginates, pectin, tragacanth, karaya gum, guar gum, xanthan gum, carrageenan, agar, and acacia, starch derivatives such as starch acetate and hydroxypropyl starch, and other synthetic products such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably mixtures with cross-linked polyacrylic acid, and mixtures of these products. The concentration of the excipient is typically 1-100,000 times the concentration of the active ingredient. In preferred embodiments, the excipients included in the formulation are typically selected based on their inertness toward the active ingredient components of the formulation.

[0320] For ophthalmic, otic, and nasal formulations, suitable tonicity adjusting agents include, but are not limited to, mannitol, sodium chloride, glycerin, sorbitol, etc. Suitable buffering agents include, but are not limited to, phosphates, borates, acetates, etc. Suitable surfactants include, but are not limited to, ionic and non-ionic surfactants (although non-ionic surfactants are preferred), RLM 100, POE 20 cetyl stearyl ether, e.g., Procol® CS20, and poloxamers, e.g., Pluronic® F68.

[0321] The formulations described herein may contain one or more preservatives. Examples of such preservatives include p-hydroxybenzoic acid esters, sodium perborate, sodium chlorite, alcohols such as chlorobutanol, benzyl alcohol or phenylethanol, 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, eliminating the need for preservatives.

[0322] For ophthalmic, otic, or nasal administration, the formulation may be a solution, suspension, or gel. In a preferred embodiment, the formulation is for topical application to the eye, nose, or ear of an aqueous solution in the form of drops. The term "aqueous" typically refers to an aqueous formulation, where the formulation contains more than 50% by weight, more preferably more than 75% by weight, and especially more than 90% by weight, of water. These drops may preferably be delivered from a single-dose ampoule, which may be sterile and thus obviate the need for a bacteriostatic component of the formulation. Alternatively, the drops may preferably be delivered from a multi-dose bottle, which may include a device that extracts any preservatives from the formulation as it is delivered, such devices being known in the art.

[0159] For ocular disorders, the components of the present invention may be delivered to the eye as a concentrated gel or similar vehicle, or as a dissolvable insert placed under the eyelid.

[0323] Formulations of the present invention suitable for topical administration to the eye are preferably isotonic or slightly hypotonic to combat any hypertonicity of tears caused by evaporation and / or disease. This may require a tonicity agent to bring the osmolality of the formulation to levels at or near 210-320 milliosmoles per kilogram (mOsm / kg). Formulations of the present invention generally have an osmolality in the range of 220-320 mOsm / kg, preferably 235-300 mOsm / kg. Ophthalmic formulations are generally formulated as sterile aqueous solutions.

[0324] In certain ophthalmic embodiments, the compositions of the present invention are formulated with one or more tear substitutes. Various tear substitutes are known in the art, including, but not limited to: monomeric polyols such as glycerol, propylene glycol, and ethylene glycol; polymeric polyols such as polyethylene glycol; cellulose esters such as hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and hydroxypropylcellulose; dextrans 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 about 8. The most preferred formulation pH is between 6 and 8.

[0325] Gels for topical or transdermal administration generally may comprise a mixture of a volatile solvent, a non-volatile solvent, and water. In certain embodiments, the volatile solvent component of the buffer solvent system may comprise a lower (Ci-C6) alkyl alcohol, a lower alkyl glycol, and a lower glycol polymer. In further embodiments, the volatile solvent is ethanol. The volatile solvent component is believed to act as a penetration enhancer while also providing a cooling effect on the skin as it evaporates. The non-volatile solvent portion of the buffer 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 buffer solvent system. The amount of this non-volatile solvent component, as well as the volatile solvent, is determined by the pharmaceutical compound or drug used. If there is too little non-volatile solvent in the system, the pharmaceutical compound may crystallize due to evaporation of the volatile solvent, while an excess may cause a lack of bioavailability due to insufficient release of the drug from the solvent mixture. The buffer component of the buffer solvent system may be selected from any buffer commonly used in the art. In certain embodiments, water is used. The typical 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 include, but are not limited to, chelating agents and gelling agents. Suitable gelling agents may include, but are not limited to, semi-synthetic cellulose derivatives (such as hydroxypropylmethylcellulose), synthetic polymers, galactomannan polymers (such as guar and its derivatives), and cosmetic agents.

[0326] 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 for preparing drops. Lotions or ointments for application to the skin may also contain agents that promote drying and cooling of the skin, for example, alcohol or acetone, and / or moisturizing agents such as glycerol or oils such as castor oil or peanut oil.

[0327] Creams, ointments, or pastes are semisolid preparations of the active ingredient for external application. They can be prepared by mixing the active ingredient in finely divided or powdered form with an oily or non-oily base, either alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of a suitable machine. The base may include hydrocarbons such as hard, soft, or liquid paraffin, glycerol, beeswax, or metal soaps; mucilage; natural oils such as almond, corn, peanut, castor, or olive oil; wool fat or its derivatives; or fatty acids such as steric or oleic acid, together with alcohols such as propylene glycol or macrogels. The formulations may incorporate any suitable surface-active agent, such as anionic, cationic, or nonionic surfactants, such as sorbitan esters or their polyoxyethylene derivatives. Suspending agents such as natural gums, cellulose derivatives, or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.

[0328] The drops may comprise a sterile aqueous or oily solution or suspension and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericide and / or fungicide and / or any other suitable preservative, and in certain embodiments, a surfactant. The resulting solution can then be clarified by filtration, transferred to a suitable container, which can then be sealed and sterilized by autoclaving or maintaining at 98°C-100°C for 30 minutes. Alternatively, the solution can be sterilized by filtration and transferred to a container using aseptic techniques. Examples of bactericides and fungicides suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%), and chlorhexidine acetate (0.01%). Suitable solvents for preparing oily solutions include glycerol, diluted alcohol, and propylene glycol. Formulations for topical administration in the mouth (e.g., buccal or sublingual administration) include, for example, lozenges (active ingredient in a flavored base such as sucrose or acacia or tragacanth) and pastilles (active ingredient in a base such as gelatin and glycerin or sucrose and acacia).

[0329] For administration by inhalation, the compound can be conveniently delivered from an insufflator, a nebulizer pressurized pack, or other convenient means for delivering an aerosol spray.Pressurized packs can contain 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 be in the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base, such as lactose or starch.The powder composition can be presented in unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs, from which the powder can be administered using an inhaler or insufflator.

[0330] In some cases, the formulation of Formula (I) contains one or more additional therapeutic components. By way of example only, if hypertension is one of the side effects experienced by a patient when receiving one of the compounds herein, it may be appropriate to administer an antihypertensive drug in combination with the first therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by the administration of an adjuvant (i.e., the adjuvant itself may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (including a treatment regimen) that has a therapeutic benefit. By way of example only, in the treatment of diabetic neuropathic pain with the administration of one of the compounds described herein, providing the patient with another diabetes therapeutic agent may result in an increased therapeutic benefit. In either case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may simply be the sum of the two therapeutic agents, or the patient may experience a synergistic benefit. The multiple therapeutic agents (at least one of which is a compound disclosed herein) may be administered in any order or simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, integrated 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 may be administered in multiple doses. If not simultaneously, the timing between the multiple administrations may be any period ranging from a few minutes to four weeks.

[0331] How to use Formula (I) (e.g., a single polymorph or a mixture of Forms A-L) is effective as a soluble epoxide hydrolase inhibitor. The present disclosure provides methods for inhibiting soluble epoxide hydrolase with Formula (I). Often, such methods include using one or more of Forms A-L to inhibit soluble epoxide hydrolase.

[0332] Among other uses, Formula (I) can be administered to mediate a disorder or disease in which modulation of sEH results in some effect on the underlying condition or disease (e.g., an sEH inhibitor or antagonist results in some improvement in patient well-being in at least some patients). Such disorders and diseases may include epilepsy, nephropathy, cardiomyopathy, hypertension, pain, inflammation, inflammatory pain, post-operative pain, neuropathic pain, diabetic neuropathic pain, tissue wound or pain therefrom, acute inflammation, inflammation from sepsis, pancreatitis, multiple trauma such as brain injury, and tissue injury such as laceration of muscle tissue, brain surgery, hemorrhagic shock, and immune-mediated organ injury, adult respiratory distress syndrome, emphysema, chronic bronchitis, obstructive pulmonary disease, chronic obstructive pulmonary disease (COPC), small airway disease, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, skin disorders such as dermatitis, chemical burns, thermal burns, redness of the skin, and chemically induced lesions near the surface of the skin, seizure disorders such as neuralgia, pain caused by trauma or irritation of nerves surrounding the skin.

[0333] In many cases, Formula (I) inhibits microsomal epoxide hydrolase (sEH), which is important for sodium transport and xenobiotic degradation, while absent or negligible inhibition of mEH. The favorable solubility of Forms A-L can facilitate formulation for cytosolic and peroxisomal delivery (where sEH is typically localized), minimizing delivery to mEH, which is primarily anchored in the plasma membrane.

[0334] In certain embodiments, the formulations of the present invention are administered once daily. However, the formulations may also be formulated for administration at any dosing frequency, including once a week, once every five days, once every three days, once every two days, twice a day, three times a day, four times a day, five times a day, six times a day, eight times a day, hourly, or any greater frequency. Such dosing frequencies may also be maintained for various durations depending on the treatment regimen. The duration of a particular treatment regimen may vary from a single administration to regimens extending for several months or years. The formulations are administered in various dosage amounts, with a typical dosage being one to two drops or an equivalent amount of gel or other formulation at each administration. Those skilled in the art will be familiar with determining a treatment regimen for a particular indication.

[0335] Formula (I) may be administered orally, topically, or by injection at a dose of 0.1 to 500 mg / kg per day. The dose range for adult humans is generally 5 mg to 2 g per day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds effective in such a dose or as a multiple thereof, for example, a unit containing 5 mg to 500 mg, usually about 10 mg to 200 mg. [Example]

[0336] The following examples are provided to further illustrate embodiments of the present invention, but are not intended to limit the scope of the invention. While they are typical of those that might be used, other procedures, methods, or techniques known to those skilled in the art may alternatively be used.

[0337] Experimental Method Differential scanning calorimetry (DSC) Differential scanning calorimetry analysis was performed on each sample "as is." Unless otherwise specified, samples were weighed into aluminum pans, covered with pierced lids, then crimped and analyzed at a 10°C / min ramp from 30°C to 300°C.

[0338] Thermogravimetric analysis (TGA) Thermogravimetric analysis was performed on each sample "as is." Unless otherwise stated, samples were weighed in alumina crucibles and analyzed from 30°C to 350°C at 10°C / min.

[0339] X-ray powder diffraction (XRD) X-ray powder diffraction was performed "as is" on each sample. Samples were placed on a Si zero-return ultra-micro specimen holder and analyzed using a 10 mm beam width and the parameters outlined in Table 1. Following analysis, the data were converted from adjustable to fixed slit using X'Pert HighScore Plus software, using a fixed divergence slit size of 1.00°, a crossover point of 1.59 mm, and 44.3° omega. (Table 1) TIFF2025540598000045.tif66167

[0340] Moisture absorption analysis (DVS) Gravimetric moisture sorption experiments were performed on all materials by first holding the samples at 40% RH and 25 °C until equilibrium weight was reached, or for a maximum of 4 hours. The samples were then subjected to isothermal (25 °C) sorption scans from 40% to 90% RH in 10% RH steps. The samples were allowed to equilibrate to asymptotic weight for a maximum of 4 hours at each point. After sorption, desorption scans from 90% to 0% RH (at 25 °C) were performed in -10% RH steps, allowing a maximum of 4 hours to equilibrate to asymptotic weight. Adsorption scans were then performed from 0% RH to 40% RH in +10% RH steps. The samples were then dried at 60 °C and 0% RH for at least 2 hours, and the resulting solids were analyzed by XRD.

[0341] Nuclear magnetic resonance Samples were dissolved in DMSO-d6. H NMR spectra were acquired at 300 MHz or 500 MHz using a 5 mm broadband (H-X) Z gradient probe. Spectra were acquired using a 30-degree pulse with a spectral width of 20 ppm, a 1.0 second repetition rate, and 32 transients.

[0342] Polarized optical microscope analysis The samples were examined using a polarized light microscope combined with a digital camera (1600 x 1200 resolution). A small amount of sample was dispersed on a glass slide with a minimal amount of mineral oil at 100x or 200x magnification. The parameters for the polarized light microscope measurements are provided in Table 2. A calibration curve at 254 nm is provided in Figure 38. (Table 2) TIFF2025540598000046.tif89167

[0343] Example 1 Synthesis of tert-butyl 4-(3-(3-fluoro-4-(trifluoromethoxy)phenyl)ureido)piperidine-1-carboxylate (Compound S1) TIFF2025540598000047.tif25164 Meta-fluoro-4-(trifluoromethoxy)aniline (500 mg, 2.56 mmol) and triethylamine (388 mg, 3.84 mmol) were dissolved in CHCl (4 mL) and added dropwise to a solution of triphosgene (341 mg, 1.15 mmol) dissolved in CHCl (5 mL) at −78 °C. The reaction mixture was stirred at 0 °C for 1 h and then cooled to −78 °C. 4-Amino-l-Boc-piperidine (769 mg, 3.84 mmol) and triethylamine (388 mg, 3.84 mmol) were dissolved in CHCl (4 mL), and the suspension was added dropwise to the reaction mixture at −78 °C. The reaction mixture was stirred at room temperature (RT) for 2 h. The reaction was quenched by adding water. The organic layer was isolated and washed four more times with HCl solution (1 M). The organic layer was dried over anhydrous magnesium sulfate and concentrated under high vacuum 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).

[0344] 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).

[0345] Example 2 Synthesis of 1-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-(piperidin-4-yl)urea (Compound S2) TIFF2025540598000048.tif22150 Compound S1 (186 mM) was dissolved in HCl solution (2 M, MeOH) to form a reaction mixture. The resulting solution was refluxed for 2 hours. The solvent was removed under high vacuum, and the crude reaction product was adjusted to pH 12 with NaOH. The precipitated product S2 was filtered and dried under very high vacuum.

[0346] Example 3 Synthesis of (S)-1-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-(1-(2-methylbutanoyl)piperidin-4-yl)urea (formula (I)) TIFF2025540598000049.tif22154 (S)-2-Methylbutanoic acid (14 mg, 140 μmol) was activated with molar equivalents of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and 4-dimethylaminopyridine (DMAP) in CHCl and then combined with compound S2 (30 mg, 93.4 μmol). The reaction was stirred at room temperature for 12 hours and then quenched by the addition of 1 M HCl. The organic layer was collected, and the aqueous layer was extracted four times with EtOAc. The organic layer and EtOAc were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The product was purified by flash chromatography and eluted with ethyl acetate. The collected fractions were dried under high vacuum to give formula (I) as a white solid. The product was further purified by recrystallization using methanol and water (30 mg, 83.9 μmol, 79.2% yield, purity (H-NMR): >95%).

[0347] MP:147-147.8℃.1H NMR(de-DMSO,600Mhz):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).

[0348] Example 4 Evaluation of multiple crystallization conditions This example addresses the crystallization of Formula (I) in multiple solvent systems. Solvents were selected to span a range of polarity, functionality, and classification according to the International Conference on Harmonization (ICH), with preference given to Class II and Class III solvents. The solvents also varied with respect to Formula (I) solubility. For these analyses, approximately 4-6 mg of Formula (I) was dispensed into a 7 mL glass vial, and the selected solvent was added in 100 μL aliquots to allow complete dissolution at room temperature. After each solvent addition, the vial was shaken and visually inspected for residual solids. If necessary, the solution was heated to 50 °C or to reflux for approximately 2 minutes (for low-boiling solvents) to ensure complete dissolution. If residual solids remained, an additional solvent aliquot was added. Solvent addition was discontinued when complete dissolution was achieved.

[0349] Table 3 summarizes the solvents used for crystallization and the corresponding solubilities of Formula (I) at room temperature (RT) and 50 °C. Based on these solubility data, the following 16 solvents were selected as primary solvents: methanol (MeOH), ethanol (EtOH), isopropanol (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 c-hexane, were selected as antisolvents for crystallization. A total of 12 unique XRD patterns were identified from the single-solvent and binary-solvent crystallizations, as provided in Figure 1, panels A–L. Table 3: Summary of solubility screening for formula (I) TIFF2025540598000050.tif155167

[0350] The crystallization of Formula (I) was first analyzed in a single solvent system without an antisolvent. For these analyses, approximately 30–70 mg of Formula (I) was weighed into a 7 mL clear glass vial equipped with a stir bar and dissolved in the minimum amount of solvent required for dissolution (minimum 0.1 mL). Rapid cooling was achieved by placing the vial in a 4°C refrigerator for 24 hours, while slow cooling was achieved by decreasing the vial's temperature at 20°C / hour while stirring. The resulting solid was isolated by centrifugal filtration through a 0.45 μm centrifugal filter. If no solid was produced, the solution was evaporated under nitrogen in an additional attempt to obtain a solid. All resulting solids were analyzed by XRD to determine the solid pattern. For each recrystallization, Formula (I) was dissolved in a solvent and recrystallized from either 40°C, 50°C, or 70°C, depending on the boiling point of the primary solvent. In total, eight unique XRD patterns were observed for the crystals produced from the crystallization, and the results are summarized in Table 4 for the slow and fast cooling experiments, respectively. (Table 4) TIFF2025540598000051.tif208167

[0351] The recrystallization of Formula (I) was then tested using binary solvent systems containing water, n-heptane, or c-hexane as the anti-solvent. For these analyses, approximately 30–40 mg of Formula (I) was weighed into a 7 mL clear glass vial equipped with a stir bar and dissolved in the minimum amount of each primary solvent required for dissolution (minimum 0.1 mL). Anti-solvent was added dropwise at the same temperature until a precipitate was observed or the vial volume was reached (approximately 7 mL). The vial was either rapidly cooled to 4 °C, as in the single-solvent recrystallization, or slowly cooled at 20 °C / h. The resulting solid was isolated by centrifugal filtration. Precipitate-free samples were evaporated to dryness under a gentle stream of nitrogen gas in a further attempt to obtain a solid. All resulting solids were analyzed by XRD to determine their solid form. The choice of 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 either 50 °C or 70 °C. Ten unique XRD patterns were identified from the resulting crystals and are summarized in Tables 5-7 below. (Table 5) TIFF2025540598000052.tif161167 (Table 6) TIFF2025540598000053.tif161167 (Table 7) TIFF2025540598000054.tif161167

[0352] Example 5 Polymorph characterization This example addresses the characterization of the 12 polymorphs identified in Example 4. Each polymorph was analyzed by XRD (Figure 1, panels A-L), differential scanning calorimetry (Figures 2-13), thermogravimetric analysis for polymorph and pseudopolymorph identification (Figures 14-25), and nuclear magnetic resonance (Figures 26-37) for confirmation of chemical integrity and residual solvent. Exemplary conditions and physical characteristics for producing each of the 12 polymorphs are summarized in Table 8.

[0353] DSC results for each of Forms A-L are provided in Figures 2-13, respectively. Each sample exemplified a single polymorph, although some samples showed evidence of traces of additional forms. In particular, DSC showed 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 did not exhibit any other polymorphs detected by DSC.

[0354] The results of thermogravimetric analysis for Forms A-L are provided in Figures 14-25, respectively. All forms exhibited weight loss above 150°C, corresponding to the elimination of Formula (I). Only Forms C, E, H, J, K, and L exhibited weight changes below 150°C, indicating loss of solvent. The weight loss of Form C between 39-50°C likely reflected the loss of methanol. Forms E, H, J, K, and L exhibited weight loss at approximately 120°C, corresponding to the loss of organic solvent.

[0355] 26-37 provide the NMR spectra of Forms A-L, respectively. In addition to Formula (I), NMR identified about 2.5% methanol in Form C, about 0.9% isopropyl alcohol in Form E, about 0.04% acetone in Form G, about 7.1% c-hexane in Form H, about 8.8% toluene in Form J, about 8.8% MTBE in Form K, and about 0.2% THF in Form L. (Table 8) TIFF2025540598000055.tif227167TIFF2025540598000056.tif231167TIFF2025540598000057.tif63167

[0356] Example 6 Scale-up method for polymorph production 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 1-3 and then recrystallized using the solvent system and conditions outlined in Example 5. The parameters for the scaled-up recrystallization are outlined in Table 9. Briefly, the scaled-up recrystallization utilized approximately 330-450 mg of Formula (I), which is approximately 10 times greater than the amount used in the recrystallization of Example 4. (Table 9) TIFF2025540598000058.tif79167

[0357] X-ray powder diffraction data for the resulting polymorphs are presented in Figures 39-45. In each figure, the top spectrum corresponds to the previously produced polymorph with a similar XRD pattern, and the bottom spectrum corresponds to the XRD of the polymorph produced from the scale-up experiment. DSC and TGA of the polymorphs produced in the scale-up recrystallization are shown in Figures 46-52 and Figures 53-59, respectively.

[0358] DSC data was used to determine the heats of fusion for Forms A, B, D, and F based on the heat of fusion measured during conversion from Form C. As outlined in Table 10, each of Forms A, B, D, and F is thermodynamically stable, with Form D having the greatest stability of these four forms. (Table 10) TIFF2025540598000059.tif31128

[0359] Because patterns E, F, G, and I were not obtained, materials from the initial screening experiment were combined for use. Data for the combined materials are summarized in Table 11. XRDs of these crystallizations (to obtain I, G, F, and E, respectively) are shown in Figures 60-63, with standard XRDs of the target spectra provided as the top spectra in each figure and the resulting spectra shown below each figure. (Table 11) TIFF2025540598000060.tif60167

[0360] Example 7 Competitive Slurry Experiment The stability and interconversion of polymorphs were analyzed in competitive slurry experiments. Competitive slurry (solvent-mediated conversion) experiments were performed on Forms A, B, D, E, F, G, and I produced by scaled-up crystallization (summarized in Table 11). Competitive slurry experiments were performed using water, MTBE, and n-heptane, which were chosen due to their low solubility in Formula (I). Briefly, competitive slurry experiments were performed by suspending one or more forms of Formula (I) in 1.0 mL of solvent and incubating at room temperature with stirring. The suspension was aliquoted on days 1 and 7 and filtered to isolate the solids. The residual solids were analyzed by XRD without drying.

[0361] XRD data for the polymorphs in these solvents (water, MTBE, and n-heptane, respectively) are shown in Figures 64-66, respectively. The top spectra in Figures 64-66 correspond to Form C (Figure 64), Form K (Figure 65), and Forms D and E (Figure 66), respectively, while the bottom and penultimate spectra in each figure correspond to Formula (I) in each solvent system shown after 1 and 7 days at room temperature. In Figure 66, the penultimate spectrum corresponds to Form E. These XRD data confirmed that patterns C, K, and D were obtained in these solvents. The data are summarized in Table 12. (Table 12) TIFF2025540598000061.tif124167

[0362] Competitive slurry experiments indicated that pattern C (formed in water) is an unstable hydrate. Pattern K from MTBE slurry was only produced in single-solvent crystallizations using MTBE as the solvent by slow and fast cooling processes, and residual MTBE was detected by NMR, suggesting it is an MTBE solvate. Conversion of the polymorph mixture in n-heptane to single pattern D (anhydrous form of Formula (I)) suggested that pattern D is the most stable form at RT.

[0363] To further confirm the stability order ranking of selected forms and extend the temperature range of the stability relationships to 70°C to encompass potential API process conditions, binary form slurries were performed using a starting mixture 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 results of the analyses are shown in Figures 67-68 and summarized in Table 13. Pattern D was prominent in the binary mixture slurries of both A and D and D and E after 7 days of stirring at elevated temperature. Therefore, it can be concluded that Form D was the most thermodynamically stable from room temperature to 70°C. (Table 13) TIFF2025540598000062.tif35167

[0364] Additional monomorph slurry experiments were performed on Forms A, D, and E in either 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 69-72. In Figure 69, the top two spectra correspond to the starting material of Formula (I) (Form A) and the product Form E, respectively, and the bottom two spectra correspond to the XRD spectra of Formula (I) after 1 and 7 days in n-heptane, respectively. In Figure 70, the top spectrum corresponds to the starting material of Formula (I) (Form A), the middle spectrum corresponds to Formula (I) after 1 day in n-heptane, and the bottom spectrum corresponds to Formula (I) after 7 days in n-heptane. In Figure 71, the top spectrum corresponds to the starting material of Formula (I) (Form E), the middle spectrum corresponds to Formula (I) after 1 day in n-heptane, and the bottom spectrum corresponds to Formula (I) after 7 days in n-heptane. In Figure 72, the top spectrum corresponds to the XRD pattern of the product (Form C), the second spectrum from the top corresponds to the starting material of Formula (I) (Form E), the second spectrum from the bottom corresponds to Formula (I) after 1 day in n-heptane, and the bottom spectrum corresponds to Formula (I) after 7 days in n-heptane. The competitive slurry experiments and the resulting polymorphs are summarized in Table 14. Consistent with previous competitive slurry experiments, Form D was stable in n-heptane at room temperature. Pattern E was obtained from a slurry starting from Forms A and E in n-heptane. As expected, Form C was formed from a slurry of Pattern E in water. (Table 14) TIFF2025540598000063.tif57167

[0365] Example 8 thermal stress research This example addresses the thermal stability of multiple polymorphs of Formula (I). Seven forms of Formula (I) were incubated at elevated temperatures to investigate polymorphic stability and thermally mediated polymorphic transformation. 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 at 60°C and ambient pressure. After 1 and 7 days of incubation, the solids were collected for XRD analysis.

[0366] The results of the thermal stress analysis are summarized in Table 15. XRD data for the polymorphs before and after thermal stress are shown in Figures 73-80, where the top spectrum in each figure corresponds to the XRD before thermal stress, the middle spectrum in each figure provides the XRD after 1 day of thermal stress, and the bottom spectrum in each figure provides the XRD after 7 days of thermal stress at the temperatures shown in Table 15, with Figures 73-80 providing the progression of thermal stress for Forms A, D, D, E, F, G, I, and A of Formula (I) at the start, respectively. As shown in these figures, Forms B and C converted to Forms D and A, respectively, while the other forms remained unchanged. (Table 15) TIFF2025540598000064.tif54167

[0367] The starting material, intermediates (1 day heat stress), and product (7 day heat stress) were analyzed by HPLC. Representative chromatograms from the heat stress analysis of Form D are shown in Figures 81-83 (starting material, day 1, and day 7 samples, respectively). These data suggest that no impurities were observed for all samples during the 7 day heat stress at 60°C.

[0368] Example 9 Hygroscopic analysis 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 summarizes the XRD analysis used to monitor the polymorphism over the 14-day experiment. 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 show that Form D remained unchanged after 4 days and 14 days of equilibration, suggesting that Form D has extended air and humidity stability.

[0369] Example 10 PEG stability analysis Because Formula (I) can be formulated in PEG (e.g., as a suspension or solution), the stability of various Formula (I) forms was evaluated in PEG300. Of particular interest was whether Form D would convert to a hydrate (e.g., Form C) in the presence of water. A series of experiments (summarized in Table 16) was designed to investigate the critical water concentration for phase conversion between Forms C and D. 1:1 mixtures of Forms C and D were prepared and slurried in PEG300 at different levels of water concentration. The phase conversion was monitored by XRD and is summarized in Figure 85, which provides XRD data for (from top to bottom) Form C, Form D, mixtures after incubation in PEG300 containing 75% water, mixtures after incubation in PEG300 containing 50% water, mixtures after incubation in PEG300 containing 25% water, mixtures after incubation in PEG300 containing 10% water, and mixtures after incubation in PEG300 containing 5% water. The data indicated a critical water concentration at 50%. Form D is a stable form in PEG300 with less than 50% water. However, in PEG300 solutions with a water content of 50% or more, Form C becomes more stable and conversion to Form C was observed, resulting in either a mixture of Form C and Form D or pure Form C. (Table 16) TIFF2025540598000065.tif40167

[0370] Example 11 Chemical stability analysis Chemical stability studies of Form D of Formula (I) were conducted in various pH media and selected excipients at both RT and 50°C for up to 1 week. For pH stability analysis, approximately 2-3 mg of Form D was incubated in 1.0 mL of pH 1.0 aqueous solution (0.1 M HCl), pH 6.8 (water adjusted using 0.1 M NaOH and 0.1 M HCl), and pH 10.0 solution. No impurities could be detected after 4 or 7 days of incubation at room temperature or 50°C at any of the tested pHs.

[0371] For excipient stability analysis, approximately 10-20 mg of Form D was incubated in PEG 400, propylene glycol, D-α-tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS), Gelucire® 44 / 14, hydrogenated castor oil, glyceryl caprylate / caprate (Capmul® MCM), ethoxylated solubilizers (Kolliphor® HS 15, Kolliphor® EL), non-ionic surfactants (Labrasol®), and diethylene glycol monoethyl ether (Transcutol® HP). Impurities resulting from the incubation were monitored by HPLC chromatography and are summarized in Tables 17-18. Representative HPLC chromatograms are shown in Figure 86. No impurities were observed after incubation at room temperature or 50°C for 4 or 7 days. These data suggest that Form D of Formula (I) is chemically compatible with a wide range of pH media and pharmaceutically acceptable excipients. (Table 17) TIFF2025540598000066.tif48167 (Table 18) TIFF2025540598000067.tif142167TIFF2025540598000068.tif130167

[0372] Example 12 Characteristics of the starting material of formula (I) Three batches of Formula (I) were analyzed for purity prior to crystallization and polymorph analysis as shown in the previous example. Each batch contained either Form A or Form C. Baseline characterization of the batches included DSC, TGA, microscopy, and vapor sorption, and the results are summarized in Table 19. Figure 87 provides XRDs of representative Form A and Form C lots (top and second from the top, respectively) over the XRDs of the three batches of Formula (I). Lot 1 contained primarily Form A, and Lots 2 and 3 contained primarily Form C.

[0373] Figures 88-92 provide physical analyses of Lot 1. Briefly, Figure 88 is a DSC thermogram of Lot 1, including peaks corresponding to Forms A and B. Figure 89 provides a TGA thermogram of Lot 1, with 0% weight change below 100°C and 99% weight change at 233°C, indicating high purity and low water content. Figure 90 provides a modulated DSC thermogram of Lot 1, identifying the midpoint of the glass transition temperature at approximately 48.5°C. Figure 91 provides two polarized light microscope images of Lot 1, showing that Formula (I) is primarily microcrystalline with crystals of approximately 1-50 μm. Figure 92 provides a dynamic vapor sorption plot of Lot 1, 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.

[0374] Figures 93-96 provide physical analyses of Lot B. Figure 93 provides a DSC thermogram of Lot 2, showing a low-temperature peak (from Form C) corresponding to the desorption of bound water, and a higher-temperature peak corresponding to the melting of Forms A and B. Figure 94 provides a TGA thermogram of Lot 2, showing a 2.9% weight change below 100°C corresponding to the desorption of water, 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 provides a polarized light microscope image of Lot 2 at 200x magnification, showing the 50 μm and 100 μm scales. The image shows that Lot 2 contained a mixture of crystallites ranging in size from a few microns to hundreds of microns. Figure 96 provides a dynamic vapor sorption plot of Lot 2, 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.

[0375] Figure 97 provides a DSC thermogram of Lot 3, which contains a large endothermic peak at 84°C corresponding to the desorption of water, as well as melting and crystallization peaks for Forms A and B, indicating that Lot 3 contains a mixture of Forms A, B, and C. (Table 19) TIFF2025540598000069.tif118167

[0376] Example 13 Characteristics of the starting material of formula (I) This example addresses the thermal conversion of Form B to Form D as a scalable route for the production of 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 study outlined in Example 8 suggested that Form D could be obtained by solid-solid conversion from Form B by incubation at elevated temperatures.

[0377] Several scaled crystallization conditions are summarized in Table 20, each utilizing Form C as the starting material. In one crystallization, Form B was obtained by fast-cooling crystallization in ACN. Therefore, the preparation of Form B was further attempted in fast-cooling ACN. However, as shown in Table 20, fast-cooling crystallization in ACN directly afforded Form D. (Table 20) TIFF2025540598000070.tif48167

[0378] Because fast cooling can be difficult to achieve on a large scale, crystallization in ACN was optimized using slow cooling. The results of multiple ACN crystallizations are summarized in Table 24 and the XRD spectra in Figure 98 (showing, from top to bottom, the XRD spectra of Form D, Preparation 4 in Table 20, Preparation 5 in Table 20, and Preparation 6 in Table 20), demonstrating that Form D can be produced from ACN solvent crystallization by both fast and slow cooling. However, from a process development perspective, the ACN process had two drawbacks. First, the volume ratio of solvent to API was often low, which can lead to a highly concentrated process and poor material transfer and recovery. Second, ACN is an ICH Class II solvent with a low residual solvent limit. Therefore, in some pharmaceutical formulations, it may be preferable to use an ICH Class III solvent instead of ACN.

[0379] Several additional crystallization conditions using seeded and binary solvent systems were tested. As summarized in Table 21, these crystallizations utilized ethanol, isopropyl alcohol, methyl ethyl ketone, and ethyl acetate as the primary solvents, n-heptane as the antisolvent, an initial temperature of 70 °C, and a cooling rate of 20 °C / hr. Each condition was performed in duplicate. XRDs of the resulting polymorphs are shown in Figure 99, which provides, from top to bottom, the XRDs of Form D, Form E, two replicates of ethanol recrystallization, two replicates of isopropyl alcohol recrystallization, two replicates of methyl ethyl ketone recrystallization, and two replicates of ethyl acetate recrystallization, respectively. Form D solids were successfully produced from a system using EtOH, IPA, and EtOAc as the primary solvent and n-heptane as the antisolvent. Form E was produced using methyl ethyl ketone as the primary solvent and n-heptane as the secondary solvent. (Table 21) TIFF2025540598000071.tif42167

[0380] 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. In the cases of isopropyl alcohol, methyl ethyl ketone, and ethyl acetate, the solubility of Formula (I) increased with increasing n-heptane solvent content. (Table 22) TIFF2025540598000072.tif46167

[0381] Example 14 Stallization of polymorphs on the gram scale To obtain a sufficient amount of Form D for solubility testing and micronization, seeded crystallization was performed on a gram scale. Specifically, 27 g of Form C was dissolved in 15 mL of EtOH at 70 °C in a 500 mL flask equipped with a stir bar. n-Heptane was added in 20 mL aliquots until the solution became slightly cloudy (a total of 220 mL of n-heptane was added). The mixture was stirred at 70 °C to form a clear solution. The batch was cooled to room temperature at 20 °C per hour, with a final temperature of 40 °C. Simultaneously, 2–3 milligrams of Form D seed crystals were added at 5-minute intervals until precipitation was observed. The solid was isolated by filtration and dried in a high-vacuum oven at RT, yielding 18.17 g of solid (67% yield). Figure 100 provides the XRD of Form D (top) and the crystals obtained from the scaled-up seeded crystallization (bottom). As shown in this figure, the XRD of the resulting crystals was consistent with Form D.

[0382] Example 15 X-ray powder diffraction detection limit The detection limit for Form C in Form D using XRD was evaluated to determine the minimum purity of Form D produced in a scaled-up crystallization. To perform these analyses, a series of blends containing varying levels of Form C, ranging from 2.5% to 15%, were analyzed by XRD. The characteristic peak of Form C at 22.2 degrees 2-theta was used to quantify Form C in each blend. XRDs of Form C and Form D blends are provided in Figures 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 provides an expanded view of the XRD spectrum provided in Figure 101. Because the 22.2 degree 2-theta peak (corresponding to Form C) is distinguishable from mixtures containing 7.5% or more of Form C, additional physical characterization techniques (e.g., detection of low temperature water desorption in differential scanning calorimetry) may be required to quantify low levels of Form C in preparations of Form D.

[0383] Example 16 Solubility improvement screening This example deals with the solubility of polymorphs of Formula (I) in various solvent systems. Because Formula (I) often has limited water solubility, strategies to increase its solubility can be used to enhance its dissolution and bioavailability upon administration. Based on this, several experiments were conducted, including particle size reduction and amorphous formulation, to evaluate various solubility enhancement approaches for optimized drug delivery.

[0384] Equilibrium solubility screening The equilibrium solubility of Formula (I) was tested in various solvent and excipient systems. For these analyses, Form D or Form C was mixed with 0.5 or 1.0 mL of solvent and allowed to equilibrate for approximately 24 hours. The mixture was filtered through a 0.45 μm centrifugal filter. The solid Formula (I) collected during filtration was analyzed by XRD to determine the remaining solid polymorphic form, while the filtrate was collected for analysis by HPLC to determine the solubility in each solvent.

[0385] Equilibrium solubility data are summarized in Table 23. As expected, the compounds did not readily ionize at physiologically relevant pH. Nevertheless, several excipients were identified with solubilities of Formula (I) greater than 20 mg / mL, 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 contained surfactants, cosolvents, and lipids that could be modified for use in self-emulsifying drug delivery systems (SEDDS). The XRD patterns of the starting materials were maintained for each sample after equilibration. (Table 23) TIFF2025540598000073.tif221167TIFF2025540598000074.tif108167

[0386] Supersaturation monitoring in PEG300 Supersaturated solubility and Pattern C of Form D of Formula (I) were prepared at 100 mg / mL and 200 mg / mL in PEG300, a selective solvent in which Formula (I) exhibited high solubility. Experimental details and results of these analyses are summarized in Table 24. Formula (I) at 100 mg / mL was stable in PEG300, showing no visible precipitation at room temperature for up to 9 days of incubation, indicating long-term stability under these conditions. When prepared at 200 mg / mL in PEG300, Formula (I) readily precipitated overnight, suggesting that Formula (I) is not stable at this higher concentration in PEG300. (Table 24) TIFF2025540598000075.tif172167

[0387] Particle size analysis To facilitate formulation development, the solubility of Form D of Formula (I) was tested after milling to a smaller particle size to determine the effect of particle size reduction of Formula (I) on apparent solubility / dissolution. Prior to milling, Form D was sieved through a 30 micron mesh sieve. Form D was then micronized using a 2-inch jet mill, 70 psig feed pressure, 40 psig milling pressure, and a powder feed rate of 4.3 g / min. The micronization process provided a 69% yield and 95.6% crystallinity compared to the unmilled material. The bulk and tapped densities of Form D (including unmilled and milled) were measured before and after tapping with a tap density tester, demonstrating a decrease in density upon micronization. The unmilled form exhibited a bulk density of 0.54 g / mL and a tapped density of 0.61 g / mL, while the micronized form exhibited a bulk density of 0.20 g / mL and a tapped density of 0.22 g / mL.

[0388] To confirm that the compound was unchanged during micronization, XRD and DSC were performed on the micronized Formula (I). Figure 103 provides the results of the XRD analysis, 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 provides the DSC thermogram of the micronized material. No changes were detected from either the XRD or DSC after micronization.

[0389] However, small amounts of two new endotherms (at 147°C and 150°C) were detected by DSC in the micronized material. The appearance of the two endotherms was likely due to melting of the crystalline phase during the DSC scan. To test the hypothesis of amorphous content transformation (conversion to two endotherms) during DSC, Form D material was ground to various degrees using a mortar and pestle to produce different levels of amorphous content, which were then analyzed by DSC. Figure 105 provides the results of these analyses, with the top thermogram corresponding to micronized Form D, the second thermogram from the top corresponding to Form D ground for 5 minutes (with a mortar and pestle), the second thermogram from the bottom corresponding to Form D ground for 10 minutes, and the bottom thermogram corresponding to Form D ground for 15 minutes. The DSC endotherm of milled Form D showed a similar endotherm at 150°C. The intensity of this endotherm correlated with the milling time, supporting its assignment as a melted crystalline phase.

[0390] First, particle size was analyzed by optical microscopy. Representative optical microscopy images with 200x magnification are shown in Figure 106 for unmilled Form D and Figure 107 for micronized Form D. As can be seen from these images, micronization effectively reduced the particle size within the samples.

[0391] Particle size was also analyzed dry using a Malvern 300 particle sizer equipped with a standard energy venturi and utilizing air pressures of 2.5 bar, 3.0 bar, and 3.5 bar. The results of these analyses are provided in Figures 108-113. Figures 108-110 provide the results obtained at 2.5 bar, 3.0 bar, and 3.5 bar, respectively, for unmilled Form D, while Figures 111-113 provide the results obtained at 2.5 bar, 3.0 bar, and 3.5 bar, respectively, for micronized Form D. The 10th, 50th, and 90th percentile particle sizes (D, respectively) measured at each pressure are shown. 10 , D 50 , and D 90 ) are summarized in Table 25 for unmilled Form D and micronized Form D. Notably, the sizing data obtained by the particle sizer did not agree with the particle sizes measured by optical microscopy. One possible explanation is that insufficient energy was provided to break up particle agglomerations. D for micronized Form D from the three pneumatic titrations 90 The significant variation in size, as well as the bimodal profile of the particle size results, supports this model and suggests that Form D particles form relatively strong clusters. (Table 25) TIFF2025540598000076.tif79167

[0392] Based on these findings, particle size analysis was repeated at 2.5 bar, 3.0 bar, and 3.5 bar using a higher energy venturi to ensure breakup of potential agglomerates. Detailed particle size data using the high energy venturi are summarized in Table 26 and Figures 114-119, where Figures 114-116 correspond to the analysis of unmilled Form D at 2.5 bar, 3.0 bar, and 3.5 bar, and Figures 117-119 correspond to the analysis of micronized Form D at 2.5 bar, 3.0 bar, and 3.5 bar, respectively. The data remained bimodal, indicating incomplete breakup of particle agglomerates, but the D of the micronized material 90was measured to be less than 6 μm, which was in close agreement with the optical analysis. (Table 26) TIFF2025540598000077.tif79167

[0393] Example 17 Amorphous phase transition analysis This example deals with the generation of amorphous form of Formula (I) under various temperatures and conditions. As previously shown, the glass transition temperature (Tg) of in situ generated amorphous Formula (I) in DSC is 48°C (Figure 90 and Table 19), suggesting that thermal generation of amorphous Formula (I) is possible.

[0394] As an alternative approach to the preparation of amorphous Formula (I), bulk amorphous material was reformed by spray drying. 2% Form C (solids concentration) in ethanol was spray dried at an inlet temperature of 115-120°C, an outlet temperature of 39-35°C, an aspirator speed of 90-95%, and a pump speed of 50-54%. The XRD of the resulting material is shown in Figure 120. The top spectrum corresponds primarily to Form C starting material, while the bottom spectrum corresponds to powder-dried material. The bottom spectrum has no peaks, indicating that the powder-dried material is in an amorphous state. DSC of the spray-dried material (Figure 121) showed a glass transition temperature (Tg) of approximately 43°C, which was comparable to the Tg of the amorphous material produced in situ in the DSC.

[0395] Example 18 Dynamic solubility analysis The dynamic solubility of Formula (I) provided as unmilled Form D, micronized Form D, and amorphous form was measured in 60 mM (7× critical micelle concentration) sodium dodecyl sulfate (SLS) at a nominal concentration of approximately 4 mg / mL (see Table 23 for unimmersed conditions, SLS solubility of Formula (I)). The mixture was stirred at room temperature using a stir bar. Samples (n=3) were collected and centrifuged at each predetermined time point (5, 10, 15, 20, 30, 60, 90, 120, and 180 minutes). The filtrate was analyzed by HPLC to determine solubility, and the remaining solid was analyzed by XRD as needed. Triplicates were run for each condition.

[0396] Figures 122-123 summarize the SLS dynamic solubility data over 180 and 90 minutes, with each trace corresponding to the average of three replicates. Milled Formula (I), unmilled Formula (I), and amorphous Formula (I) exhibited similar dynamic solubilities in SLS. The benefits of achieving higher supersaturation from the milled material (by providing a larger surface area) and the amorphous material (by providing higher solubility) were offset by the phase transformation from Form D to Pattern C (i.e., the hydrate form).

[0397] The conversion of Form D and amorphous Formula (I) during dynamic solubility analysis was monitored by XRD. Figures 124-126 provide XRD spectra of unmilled Form D, milled Form D, and amorphous Formula (I), respectively, over 180 minutes of solubilization. In each figure, the top spectrum corresponds to pure Form C, the second figure corresponds to pure Form D, the third spectrum corresponds to solids collected after 5 minutes of solubilization, the fourth spectrum corresponds to solids collected after 60 minutes of solubilization, the fifth spectrum corresponds to solids collected after 90 minutes of solubilization, and the bottom spectrum corresponds to solids collected after 180 minutes of solubilization. As shown by these XRD data, the milled and amorphous materials converted to Form C within 5 minutes of exposure to the dissolution medium. Perhaps due to the relatively large particle size of the unmilled material, the unmilled material showed a slower conversion rate to Form C and completely transitioned to the hydrate form after 60 minutes of solubilization. This may explain the slightly longer maintenance of supersaturation from the unmilled material. As a mitigating formulation strategy, the amorphous material can be stabilized in the dissolution medium by solid dispersions, if necessary, in future formulation work. The advantages of the milled and amorphous approaches for reaching high supersaturation were offset by the phase transition to the hydrate form in the dynamic solubility study. In future studies, if the amorphous form is desired for solubility enhancement, the amorphous state can be maintained via amorphous solid dispersions by selecting the optimal polymer.

[0398] While the present invention has been described with reference to presently preferred embodiments, it should 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 scope of the following claims.

Claims

1. Anhydrous crystalline form of formula (I): or a pharmaceutically acceptable salt thereof.

2. 10. The composition of claim 1, wherein the anhydrous crystalline form of Formula (I) contains less than 2.9% water content.

3. 3. The composition of claim 1 or 2, wherein the anhydrous crystalline form of formula (I) contains less than 1.0% water content.

4. 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. 5. The composition of any one of claims 1 to 4, comprising less than 5 wt% decomposition products of formula (I), less than 3 wt% decomposition products of formula (I), less than 2 wt% decomposition products of formula (I), or less than 1 wt% decomposition products of formula (I).

6. 6. The composition of any one of claims 1 to 5, wherein the anhydrous crystalline form of formula (I) is characterized by an X-ray powder diffraction pattern substantially as set forth in any one of panels A to L of Figure 1.

7. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, A composition wherein said crystalline form of Formula (I) comprises Form D characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1, Panel D.

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

9. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, A composition wherein said crystalline form of Formula (I) comprises Form A characterized by an X-ray powder diffraction pattern substantially as depicted in Panel A of Figure 1.

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

11. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, A composition wherein said crystalline form of Formula (I) comprises Form B characterized by an X-ray powder diffraction pattern substantially as depicted in Panel B of Figure 1.

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

13. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, A composition wherein said crystalline form of Formula (I) comprises Form C characterized by an X-ray powder diffraction pattern substantially as depicted in Panel C of Figure 1.

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

15. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, A composition wherein said crystalline form of Formula (I) comprises Form E, characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1, Panel E.

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

17. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, 10. A composition wherein said crystalline form of Formula (I) comprises Form F, characterized by an X-ray powder diffraction pattern substantially as depicted in Panel F of FIG.

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

19. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, A composition wherein said crystalline form of Formula (I) comprises Form G, characterized by an X-ray powder diffraction pattern substantially as depicted in Panel G of Figure 1.

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

21. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, A composition wherein said crystalline form of Formula (I) comprises Form H, characterized by an X-ray powder diffraction pattern substantially as depicted in Figure 1, Panel H.

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

23. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, A composition wherein said crystalline form of Formula (I) comprises Form I characterized by an X-ray powder diffraction pattern substantially as depicted in Panel I of Figure 1.

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

25. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, The composition, wherein said crystalline form of Formula (I) comprises Form J characterized by an X-ray powder diffraction pattern substantially as depicted in Panel J of Figure 1.

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

27. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, A composition wherein said crystalline form of Formula (I) comprises Form K characterized by an X-ray powder diffraction pattern substantially as depicted in Panel K of Figure 1.

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

29. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, A composition wherein said crystalline form of Formula (I) comprises Form L characterized by an X-ray powder diffraction pattern substantially as depicted in Panel L of Figure 1.

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

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

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

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

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

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

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

37. 37. The composition of 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. 38. The composition of 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. 39. The composition of 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. 40. The composition of any one of claims 1 to 39, wherein the crystalline form of formula (I) has less than 10% by weight of solvent.

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

42. 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. 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 process for producing a crystalline form of formula (I), comprising: dissolving Formula (I) in a solvent system comprising acetone, acetonitrile, dichloromethane, dioxane, isopropyl alcohol, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ether, n-butyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or a combination thereof, in the solvent system at a temperature of 35° C. to 80° C.; cooling the solvent system to a temperature of between 0°C and 30°C; A method comprising:

45. 45. The method of claim 44, wherein the dissolving is carried out at a temperature of from 50°C to 75°C.

46. 46. ​​The method of claim 44 or 45, wherein the cooling brings the solvent to a temperature of 27°C to -20°C.

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

48. 48. The method of any one of claims 44 to 47, wherein the rate of cooling is from 0.1°C / hr to 600°C / hr.

49. the solvent system being A secondary solvent in which formula (I) has a solubility of up to 5 mg / mL 49. The method of any one of claims 44 to 48, comprising:

50. The secondary solvent is water or C ５ ~C １２ The method according to any one of claims 44 to 49, wherein the solvent is an alkane.

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

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

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

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

56. A process 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 at a rate of 60°C / hr to 600°C / hr to a temperature of -20°C to 30°C; (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 of 0°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; (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 at a rate of 60°C / hr to 600°C / hr to a temperature of 0°C to 30°C; (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 A method comprising:

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

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

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

5.

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

2.

61. 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 process 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% isopropyl alcohol, or at least 90% n-butanol, and cooling the solvent system to a temperature of -20°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; (ii) dissolving Formula (I) in a solvent system comprising at least 90% ethanol, at least 90% isopropyl alcohol, or at least 90% n-butanol, and cooling the solvent system at a rate of 60°C / hr to 600°C / hr to a temperature of -20°C to 30°C; (iii) dissolving Formula (I) in a solvent system comprising water and n-propanol, and cooling the solvent system at a rate of 60°C / hr to 600°C / hr to a temperature of 0°C to 30°C; (iv) dissolving Formula (I) in a solvent system comprising hexane and dioxane and cooling at a rate of 0.1°C / hr to 40°C / hr to a temperature of 12°C to 30°C; (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 of −20° C. to 30° C. at a rate of 0.1° C. / hr to 40° C. / hr; or (vi) combinations thereof A method comprising:

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

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

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

5.

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

5.

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

1.

68. 68. The method of any one of claims 62-67, 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 process 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 at a rate of 60°C / hr to 600°C / hr to a temperature of 0°C to 30°C; (ii) incubating formula (I) in water for at least 1 hour; (iii) incubating Formula (I) in a polyethylene glycol (PEG) water mixture containing at least 50% water by volume for at least 1 hour; or (iv) combinations thereof A method comprising:

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

71. 71. The method of claim 69 or 70, wherein (ii) comprises incubating formula (I) in water for at least 1 day.

72. 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 1 day.

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

74. 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 process 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 said formula (I) to a temperature of -20°C to 30°C at a rate of 0.1°C / hr to 600°C / hr; (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 of 0°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; (iii) dissolving Formula (I) in a solvent system comprising heptane and a solvent selected from the group consisting of ethanol, isopropyl alcohol, and ethyl acetate, and cooling to a temperature of −20° C. to 30° C. at a rate of 0.1° C. / hr to 40° C. / hr; (iv) dissolving formula (I) in a solvent system comprising hexane and dimethyl sulfoxide and cooling to a temperature of −20° C. to 30° C. at a rate of 0.1° C. / hr to 40° C. / hr; (v) dissolving Formula (I) in a solvent system comprising heptane and isopropyl alcohol to a concentration of at least about 0.4 mg / ml, and cooling the solvent system to a temperature of −20° C. to 30° C. at a rate of 0.1° C. / hr to 40° C. / hr; (vi) incubating formula (I) in heptane for at least 1 day; (vii) incubating Formula (I) in a polyethylene glycol:water mixture containing greater than 50% by volume of polyethylene glycol for at least 1 hour; or (viii) combinations thereof A method comprising:

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

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

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

1.

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

5.

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

5.

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

1.

82. 82. The method of any one of claims 75-81, wherein the solvent system in (v) comprises a ratio of heptane to isopropyl alcohol that is from 3:1 to 40:

1.

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

84. A process 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 methanol, ethanol, acetonitrile, isopropyl alcohol, acetone, and n-propanol, and cooling the solvent system to a temperature of −20° C. to 30° C. at a rate of 60° C. / hr to 600° C. / hr; (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 to a temperature of −20° C. to 30° C. at a rate of 0.1° C. / hr to 40° C. / hr; (iii) dissolving Formula (I) in a solvent system comprising heptane and methyl ethyl ketone, seeding said solvent system with Form E, and cooling said solvent system to a temperature of −20° C. to 30° C. at a rate of 0.1° C. / hr to 40° C. / hr; (iv) dissolving Formula (I) in a solvent system comprising heptane and isopropyl alcohol to a concentration of up to 0.25 mg / ml, and cooling the solvent system to a temperature of −20° C. to 30° C. at a rate of 0.1° C. / hr to 40° C. / hr; (v) dissolving Formula (I) in a solvent system comprising hexane and methanol, and cooling the solvent system to a temperature of −20° C. to 30° C. at a rate of 0.1° C. / hr to 40° C. / hr; (vi) incubating formula (I) in heptane for less than 1 day; or (vii) combinations thereof A method comprising:

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

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

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

1.

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

1.

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

1.

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

1.

91. 91. The method of any one of claims 84 to 90, wherein the solvent system in (iv) comprises a ratio of heptane to isopropyl alcohol that is from 5:1 to 100:

1.

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

1.

93. 93. The method of any one of claims 84-92, wherein (vi) comprises incubating solid Formula (I) in heptane for less than 1 day.

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

96. 96. The method of claim 95, wherein (i) through (iv) comprise cooling the solvent system to a temperature of from 0°C to 15°C at a rate of from 60°C / hr to 150°C / hr.

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

98. 98. The method of any one of claims 95-97, wherein (vi)-(viii) comprise cooling the solvent system at a rate of from 1°C / hr to 30°C / hr to a temperature of from 10°C to 30°C.

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

5.

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

5.

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

1.

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

1.

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

5.

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

5.

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

1.

106. 106. The method of any one of claims 95-105, wherein the solvent system in (viii) comprises a ratio of hexane to methanol, isopropyl alcohol, dimethylformamide, or n-propanol that is from 10:1 to 200:

1.

107. 107. The method of any one of claims 95-106, 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 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 of -20°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; (ii) dissolving Formula (I) in a solvent system comprising at least 90% dioxane, and cooling said solvent system at a rate of 0.1°C / hr to 600°C / hr to a temperature of 12°C to 30°C; (iii) dissolving Formula (I) in a solvent system comprising at least 90% tetrahydrofuran, and cooling said solvent system at a rate of 60°C / hr to 600°C / hr to a temperature of -20°C to 30°C; (iv) dissolving Formula (I) in a solvent system comprising water and dioxane, and cooling the solvent system at a rate of 0.1°C / hr to 600°C / hr to a temperature of 12°C to 30°C; (v) dissolving Formula (I) in a solvent system comprising heptane and dioxane, and cooling the solvent system to a temperature of 4°C to 30°C at a rate of 0.1°C / hr to 600°C / hr; (vi) dissolving Formula (I) in a solvent system comprising heptane and tetrahydrofuran, and cooling the solvent system to a temperature of −20° C. to 30° C. at a rate of 60° C. / hr to 600° C. / hr; (vii) dissolving formula (I) in a solvent system comprising hexane and acetone to a concentration of up to 0.25 mg / ml, and cooling the solvent system to a temperature of -20°C to 30°C at a rate of 60°C / hr to 600°C / hr; (viii) dissolving Formula (I) in a solvent system comprising hexane and tetrahydrofuran, and cooling the solvent system to a temperature of −20° C. to 30° C. at a rate of 0.1° C. / hr to 40° C. / hr; (ix) dissolving Formula (I) in a solvent system comprising hexane and dioxane to a concentration of at least about 0.4 mg / ml, and cooling the solvent system at a rate of 0.1°C / hr to 40°C / hr to a temperature of 12°C to 30°C; or (x) combinations thereof A method comprising:

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

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

5.

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

1.

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

5.

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

5.

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

5.

115. 115. The method of any one of claims 108 to 114, wherein (ix) comprises a ratio of hexane to dioxane of from 5:1 to 1:

5.

116. 116. The method of any one of claims 108-115, 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 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 to a temperature of from −20° C. to 30° C. at a rate of from 0.1° C. / hr to 600° C. / hr; (ii) dissolving Formula (I) in a solvent system comprising at least 90% methyl isobutyl ketone, and cooling the solvent system to a temperature of -20°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; (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 to a temperature of −20° C. to 30° C. at a rate of 60° C. / hr to 600° C. / hr; (iv) dissolving 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 at a rate of 60°C / hr to 600°C / hr to a temperature of -20°C to 30°C; (v) dissolving Formula (I) in a solvent system comprising hexane and acetone, and cooling the solvent system to a temperature of −20° C. to 30° C. at a rate of 0.1° C. / hr to 40° C. / hr; (vi) dissolving Formula (I) in a solvent system comprising hexane and acetonitrile to a concentration of at least about 0.5 mg / ml, and cooling the solvent system to a temperature of −20° C. to 30° C. at a rate of 0.1° C. / hr to 40° C. / hr; or (vii) combinations thereof A method comprising:

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

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

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

1.

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

5.

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

5.

123. 123. The method of any one of claims 117-122, 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 process for producing a crystalline form of formula (I), comprising: (i) dissolving Formula (I) in a solvent system comprising at least 90% dichloromethane, and cooling said solvent system to a temperature of -20°C to 30°C at a rate of 0.1°C / hr to 600°C / hr; (ii) dissolving 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 at a rate of 60°C / hr to 600°C / hr to a temperature of -20°C to 30°C; or (iii) combinations thereof A method comprising:

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

126. 126. The method of claim 124 or 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. 1. A process 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 to a temperature of -20°C to 30°C at a rate of 0.1°C / hr to 40°C / hr.

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

129. 129. The method of claim 127 or 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 process 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 of -20°C to 30°C at a rate of 0.1°C / hr to 600°C / hr; (ii) incubating formula (I) in methyl tert-butyl ether for at least 1 hour; or (iii) combinations thereof A method comprising:

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

132. 132. The method of claim 130 or 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 process for producing a crystalline form of formula (I), comprising: (i) dissolving Formula (I) in a solvent system comprising water and isopropyl alcohol to a concentration of at least 0.4 mg / ml, and cooling the solvent system to a temperature of 0°C to 30°C at a rate of 0.1°C / hr to 40°C / hr; (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 of −20° C. to 30° C. at a rate of 0.1° C. / hr to 40° C. / hr; (iii) dissolving Formula (I) in a solvent system comprising heptane and tetrahydrofuran, and cooling the solvent system to a temperature of −20° C. to 30° C. at a rate of 60° C. / hr to 600° C. / hr; or (iv) combinations thereof A method comprising:

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

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

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

5.

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

5.

138. 138. The method of any one of claims 133-137, 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. 44. A method of treating a soluble epoxide hydrolase (sEH)-mediated disorder or disease in a subject, comprising administering to the subject a composition of any one of claims 1 to 43, thereby treating the disorder or disease in the subject.

140. 140. The method of claim 139, wherein the sEH-mediated disorder or disease is selected from the group consisting of pain, seizure disorders, 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.

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

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

143. 143. The method of claim 142, wherein the nerve damage results from diabetes or other disease.

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

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

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

147. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form A 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. 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 12.1±0.3°2θ, 15.6±0.3°2θ, and 6.0±0.3°2θ.

149. 149. The composition of claim 147 or 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. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form B 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. 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 19.6±0.3°2θ, 13.1±0.3°2θ, and 18.0±0.3°2θ.

152. 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 20.2±0.3°2θ, 14.1±0.3°2θ, 17.6±0.3°2θ, and 14.8±0.3°2θ.

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

154. 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 21.6±0.3°2θ, 23.2±0.3°2θ, and 21.7±0.3°2θ.

155. 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 16.5±0.3°2θ, 21.4±0.3°2θ, and 10.7±0.3°2θ.

156. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form D, 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. 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 20.3±0.3°2θ and 17.1±0.3°2θ.

158. 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 3.4±0.3°2θ, 19.6±0.3°2θ, 23.4±0.3°2θ, and 25.1±0.3°2θ.

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

160. 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 9.0±0.3°2θ, 22.2±0.3°2θ, and 14.3±0.3°2θ.

161. 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 14.9±0.3°2θ, 18.4±0.3°2θ, and 16.8±0.3°2θ.

162. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form F, 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. 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 18.1±0.3°2θ, 20.2±0.3°2θ, and 16.7±0.3°2θ.

164. 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 17.6±0.3°2θ, 19.2±0.3°2θ, and 17.3±0.3°2θ.

165. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form G, 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. 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 10.8±0.3°2θ, 19.2±0.3°2θ, and 5.4±0.3°2θ.

167. 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 10.6±0.3°2θ and 21.7±0.3°2θ.

168. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form H, 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. 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 17.9±0.3°2θ, 14.5±0.3°2θ, 12.7±0.3°2θ, and 8.7±0.3°2θ.

170. 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 14.8±0.3°2θ, 12.8±0.3°2θ, and 21.2±0.3°2θ.

171. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form I 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. 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 14.5±0.3°2θ, 18.1±0.3°2θ, and 13.4±0.3°2θ.

173. 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 18.6±0.3°2θ, 24.8±0.3°2θ, and 19.1±0.3°2θ.

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

175. 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 15.1±0.3°2θ, 11.4±0.3°2θ, and 15.0±0.3°2θ.

176. 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 3.4±0.3°2θ, 20.2±0.3°2θ, and 21.0±0.3°2θ.

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

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

180. Crystalline form of formula (I): or a pharmaceutically acceptable salt thereof, wherein the crystalline form of Formula (I) comprises Form L 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. 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 14.4±0.3°2θ, 21.9±0.3°2θ, and 18.0±0.3°2θ.

182. 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 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. Amorphous form of formula (I): or a pharmaceutically acceptable salt thereof.

184. Amorphous form of formula (I):

10. A method for producing a compound of formula (I) comprising converting a non-amorphous form of formula (I) to said amorphous form of formula (I).

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

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

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

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

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

190. 184. The composition of any one of claims 1-43 or 147-183, 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. 184. The composition of any one of claims 1-43 or 147-183, wherein up to about 50%, up to about 45%, up to about 40%, up to about 35%, up to about 30%, up to about 25%, up to about 20%, up to about 15%, up to about 10%, up to about 5%, up to about 4%, up to about 3%, up to about 2%, up to about 1%, or up to about 0.5% of Formula (I) is amorphous.

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