Formulations of RBP4 inhibitors and methods of use

Abstract

Provided herein are pharmaceutical compositions comprising a RBPR inhibitor that are useful for the treatment of retinal binding protein (RBP4) related diseases.

Description

Attorney Docket No. 56350-744.601FORMULATIONS OF RBP4 INHIBITORS AND METHODS OF USECROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Application No. 63 / 790,471, filed April 17, 2025, which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] A need exists in the medicinal arts for the effective treatment of visual diseases and disorders associated with retinol-binding protein 4 (RBP4).BRIEF SUMMARY

[0003] In one aspect, provided herein is a method of manufacturing a crystalline compound comprising the steps:milling a crystalline compound,wherein the crystalline compound has the structure:wherein the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three characteristic peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 18.2, 23.5, 27.1, and / or 29.0; and sieving the crystalline compound.

[0004] In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least four peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 18.2, 23.5, 27.1, and / or 29.0. In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, and / or 17.2 at least one peak at 23.5, 27.1, and / or 29.0. In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) 6.7, 9.3, 14.1, and / or 17.2 at least two peaks at 23.5, 27.1, and / or 29.0.

[0005] In certain embodiments, the crystalline compound is micronized.

[0006] In certain embodiments, the crystalline compound comprises a particle size from about 100 nm to about 10 pm, about 1 pm to about 5 pm, about 1 pm to about 2.5 pm, about 1 pm toAttorney Docket No. 56350-744.601about 5 pm, or about 1 pm to about 10 pm. In certain embodiments, the crystalline compound comprises a particle size of less than 10 pm, less than 5 pm, or less than 2 pm. In certain embodiments, the crystalline compound comprises a particle size distribution of no more than 10 pm. In certain embodiments, the crystalline compound comprise a particle size distribution of no more than 5 pm. In certain embodiments, the crystalline compound comprises a particle size distribution of no more than 2 pm.

[0007] In certain embodiments, the crystalline compound has a solubility of about 0.001 mg / mL to about 0.005 mg / mL. In certain embodiments, the crystalline compound has a solubility of about 0.001 mg / mL after 60 min. In certain embodiments, the crystalline compound has a solubility of about 0.005 mg / mL after 180 min.

[0008] In certain embodiments, the method further comprises manufacturing the crystalline compound comprising the steps of:dissolving a compound in a solvent, the compound having the structure:N HNi\LCF3crystallizing the compound to obtain the crystalline compound.

[0009] In certain embodiments, the compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 4.8, 7.2, 9.8, 11.2, 14.5, 16.6, 21.9, 22.5, and 25.5. In certain embodiments, the compound exhibits an X-ray powder diffraction pattern (XRPD) having peaks at 21.9, and 22.5 and at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 4.8, 7.2, 9.8, 11.2, 14.5, 16.6, and 25.5.

[0010] In certain embodiments, the crystalline compound is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% pure. In certain embodiments, the crystalline compound comprises no more than 5% (w / w), no more than 2.5% (w / w), no more than 1% (w / w), no more than 0.5% (w / w), or no more than 0.1% (w / w) impurities.

[0011] In certain embodiments, the solvent comprises methanol, ethanol, acetone, acetonitrile, dichloromethane, dimethyl formamide, ethyl acetate, ethyl ether, isopropanol, tetrahydrofuran, water, or a combination thereof.Attorney Docket No. 56350-744.601

[0012] In certain embodiments, the compound is further formulated as a tablet. In certain embodiments, the method further comprises compressing the crystalline compound to provide the tablet. In certain embodiments, the tablet comprises from about 0.5 mg to about 50 mg of the compound. In certain embodiments, the tablet comprises about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, or about 50 mg of the compound.

[0013] In another aspect, provided herein is a method of manufacturing a tablet formulation of a crystalline form of a compound, the method comprising the steps:blending a crystalline compound having the structure:N HNN<CF3with one or more excipients to obtain a mixture, wherein the crystalline compound exhibits a X-ray powder diffraction pattern (XRPD) having at least three characteristic peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 18.2, 23.5, 27.1, and / or 29.0;roller compacting the mixture;milling the mixture;sieving the mixture to obtain one or more granules comprising a substantially uniform particle size; andcompressing the one or more granules into a tablet.

[0014] In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, and / or 14.1 at least one peak at 17.2, 23.5, 27.1, and / or 29.0.

[0015] In certain embodiments, the milling and sieving produces a particle distribution of no more than 10 pm. In certain embodiments, the milling and sieving produces a particle distribution of no more than 5 pm. In certain embodiments, the milling and sieving produces a particle distribution of no more than 2 pm. In certain embodiments, a D90 of the granules is about 5 pm to about 50 pm, about 5 pm to about 40 pm, about 5 pm to about 30 pm, about 5 pm to about 20 pm, or about 5 pm to about 10 pm. In certain embodiments, a D50 of the granules is about 3 pm to about 20 pm, about 3 pm to about 15 pm, about 3 pm to about 10 pm, or about 3 pm to about 5 pm. In certain embodiments, a Dio of the granules is about 0.5 pm to about 3 pm,Atorney Docket No. 56350-744.601about 0.5 pm to about 2 m, about 0.5 pm to about 1 pm, about 1 pm to about 2 pm, or about 1 pm to about 1.5 pm.

[0016] In certain embodiments, the tablet comprises from about 0.5 mg to about 50 mg of the crystalline compound. In certain embodiments, the tablet comprises about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, or about 50 mg of the crystalline compound. In certain embodiments, the tablet has an average weight of about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 100 mg, or about 100 mg to about 200 mg. In certain embodiments, the tablet has an average weight of about 100 mg.

[0017] In certain embodiments, the tablet has an average thickness of about 1 mm to about 10 mm, about 1 mm to about 9 mm, about 1 mm to about 8 mm, about 1 mm to about 7 mm, about 1 mm to about 6 mm, about 1 mm to about 5 mm, about 1 mm to about 4 mm, about 1 mm to about 3 mm, or about 1 mm to about 2 mm. In certain embodiments, the tablet has a thickness of about 3.3 mm. In certain embodiments, the tablet has an average hardness of about 2 kP to about 10 kP, about 2 kP to about 9 kP, about 2 kP to about 8 kP, about 2 kP to about 7 kP, about 2 kP to about 6 kP, about 2 kP to about 5 kP, about 5 kP to about 10 kP, about 5 kP to about 9 kP, or about 5 kP to about 8 kP. In certain embodiments, the tablet has an average hardness of about 7.1 kP. In certain embodiments, the tablet has a dissolution time of less than about 15 min.

[0018] In certain embodiments, the one or more excipients comprises a filler, a dispersion polymer, a disintegrant, a glidant, a lubricant, a solid carrier, or a combination thereof. In certain embodiments, the filler comprises lactose monohydrate, mannitol, sorbitol, cellulose, calcium phosphate, starch, sugar, cellulose, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, dibasic calcium phosphate, sucrose, lactose, com starch, potato starch, or a combination thereof. In certain embodiments, the dispersion polymer comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylenepolyoxypropylene block copolymers, or a combination thereof. In certain embodiments, the disintegrant comprises croscarmellose sodium (CCNa), microcrystalline cellulose (MCC), crospovidone, tapioca starch, or a combination thereof. In certain embodiments, the glidant comprises colloidal silicon dioxide, talc, corn starch, metal silicates, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, metal hydroxides, or combination thereof. InAtorney Docket No. 56350-744.601certain embodiments, the lubricant comprises magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate, or a combination thereof. In certain embodiments, the solid carrier comprises mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, or a combination thereof. In certain embodiments, the blending comprises blending the crystalline compound with a filler, a lubricant, a dispersion polymer, or a combination thereof.

[0019] In another aspect, provided herein is a method of providing a crystalline compound, the method comprising:contacting a compound with a solution having a pH of about 1.5 to about 6.0, thereby forming a crystalline compound,wherein the crystalline compound exhibits a X-ray powder diffraction pattern (XRPD) having at least three characteristic peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 18.2, 23.5, 27.1, and / or 29.0.

[0020] In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least four peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 18.2, 23.5, 27.1, and / or 29.0. In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, and / or 14.1 at least one peak at 17.2, 23.5, 27.1, and / or 29.0. In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, and / or 14.1 at least two peaks at 17.2, 23.5, 27.1, and / or 29.0. In certain embodiments, the compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 9.7, 11.1, 14.5, 16.7, 21.8, 22.3, and 25.5. In certain embodiments, the compound exhibits an X-ray powder diffraction pattern (XRPD) having peaks at 21.9, and 22.5 and at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 9.7, 11.1, 14.5, 16.7, 21.8, 22.3 and 25.5.

[0021] In certain embodiments, the solution comprises a surfactant, a phospholipid, a salt, an enzyme, a buffer, or a combination thereof. In certain embodiments, the surfactant comprises sodium lauryl sulfate, sodium dodecyl sulfate, or both. In certain embodiments, the phospholipid comprises lecithin, phosphatidylcholine, or a combination thereof. In certain embodiments, the salt comprises sodium chloride, calcium chloride, potassium chloride, sodium taurocholate, sodium glycocholate, sodium taurochenodeoxycholate, sodium glycochenodeoxycholate, sodium deoxycholate, sodium lithocholate, or a combination thereof. In certain embodiments,Attorney Docket No. 56350-744.601the enzyme comprises pepsin, chymotrypsin, trypsin, or a combination thereof. In certain embodiments, the buffer comprises acetate, Tris, phosphate, or a combination thereof.

[0022] In certain embodiments, the compound is micronized. In certain embodiments, the micronized compound has an average particle size of about 100 nm, about 200 nm, about 500 nm, about 1 pm, about 2 pm, about 3 pm, about 5 pm, about 10 pm, or about 20 pm. In certain embodiments, the solution has a pH of about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, or about 6.

[0023] In another aspect, provided herein is a pharmaceutical composition comprising:one or more granules comprising a compound having the structure:N HNi\LCF3wherein the granules are micronized and have an average particle size of about 0.5 pm to about 20 pm,wherein the compound is crystalline and has an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, and / or 14.1 at least one peak at 17.2, 23.5, 27.1, and / or 29.0 (Form C); andone or more pharmaceutically acceptable excipients.

[0024] In certain embodiments, the one or more excipients comprises a filler, a dispersion polymer, a disintegrant, a glidant, a lubricant, a solid carrier, an anti -adherent, a filler, a sweetener, a wetting agent, a binder, or a combination thereof. In certain embodiments, the filler comprises lactose monohydrate, mannitol, sorbitol, cellulose, calcium phosphate, starch, sugar, cellulose, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, dibasic calcium phosphate, sucrose, lactose, com starch, potato starch, or a combination thereof. In certain embodiments, the dispersion polymer comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene blockAtorney Docket No. 56350-744.601copolymers, or a combination thereof. In certain embodiments, the disintegrant comprises croscarmellose sodium (CCNa), microcrystalline cellulose (MCC), crospovidone, tapioca starch, or a combination thereof. In certain embodiments, the glidant comprises colloidal silicon dioxide, talc, com starch, metal silicates, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, metal hydroxides, or combination thereof. In certain embodiments, the lubricant comprises magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate, or a combination thereof. In certain embodiments, the solid carrier comprises mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, or a combination thereof. In certain embodiments, the antiadherent comprises microcrystalline cellulose, lactose monohydrate, hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate, or a combination thereof.INCORPORATION BY REFERENCE

[0025] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The novel features of the disclosure 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 disclosure are utilized, and the accompanying drawings of which:

[0027] FIG. 1 illustrates a schematic of a mechanism of action for dry (atrophic) macular degeneration and Stargardt disease. Without being bound by theory, RBP4 transports retinol (a precursor to cytotoxic A2E) into the retina by way of the visual cycle. RBP4 inhibitors, such as Compound 1, are in some instances used to treat RBP4-related visual diseases and disorders.

[0028] FIG. 2 illustrates a schematic of the tablet manufacturing process. The schematic describes the steps of pre-blending and blending, roller compaction, final blending and lastly tablet compression.

[0029] FIG. 3 shows an XRPD overlay of Form A after a two-step dissolution.

[0030] FIG. 4 shows an XRPD overlay of Form C after a two-step dissolution.

[0031] FIG. 5 shows an XRPD characterization of micronized Form A.

[0032] FIG. 6 shows a TGA and DSC characterization of micronized From A.

[0033] FIG. 7 shows the PLM / SEM characterization of micronized Form A.

[0034] FIG. 8 shows the PSD characterization of micronized Form A.Atorney Docket No. 56350-744.601

[0035] FIG. 9 shows an XRPD overlay of solubility test for Form A with larger particles.

[0036] FIG. 10 shows an XRPD overlay of solubility test for Form A with larger particles.

[0037] FIG. 11 shows an XRPD overlay of solubility test for Form A with larger particles.

[0038] FIG. 12 shows an XRPD overlay of solubility test for Form C with larger particles.

[0039] FIG. 13 shows an XRPD overlay of solubility test for Form C with larger particles.

[0040] FIG. 14 shows an XRPD characterization of recrystallized Form C.

[0041] FIG. 15 shows a TGA and DSC characterization of recrystallized Form C.

[0042] FIG. 16 shows the PSD and PLM characterization of recrystallized Form C after sieving. Agglomerated irregular particles range from about 2 pm to 210 pm.

[0043] FIG. 17 shows the PDS and PLM characterization of recrystallized Form C after sieving. The particle size shows agglomerated irregular particles ranging from 2 pm to 80 pm.

[0044] FIG. 18 shows the XRPD overlay of Form A before and after sieving.

[0045] FIG. 19 shows the PSD and PLM characterization of Form A after sieving. The particle size shows agglomerated irregular particles ranging from 2 pm to 210 pm.

[0046] FIG. 20 shows the PSD and PLM characterization of Form A after sieving. The particle size shows agglomerated irregular particles ranging from 2 pm to 80 pm

[0047] FIG. 21 shows the XRPD characterization of Form A.

[0048] FIG. 22 shows the TGA and DSC characterization of Form A.

[0049] FIG. 23 Shows the PLM / SEM characterization of Form A.

[0050] FIG. 24 shows the PSD characterization of Form A.

[0051] FIG. 25 shows XRPD pattern overlay of Compound 1 Form C, drug substance (DS), drug product (DP) and excipient mixture.

[0052] FIG. 26 shows the signature peaks for comparing polymorph mixtures of Form A and C.DETAILED DESCRIPTION

[0053] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0054] As used herein and in the appended claims, the term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thusAttomey Docket No. 56350-744.601the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of' or "consist essentially of' the described features.Definitions

[0055] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0056] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0057] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0058] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br,125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0059] In certain embodiments, the compounds disclosed herein have some or all of theJH atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0060] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of RadiolabeledAtorney Docket No. 56350-744.601Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0061] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium -containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0062] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeableJH hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0063] Throughout the specification, examples, and claims, various components are expressed as being present in ratios, e.g., 1:2, 1:3, 1:4, or 1:5 and the like. Unless otherwise specified, such ratios refer to the ratio of each component by weight.

[0064] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the heterocyclic RBP4 inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0065] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono-and dicarboxylic acids, phenyl -substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelicAtorney Docket No. 56350-744.601acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0066] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropyl amine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, / A-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, A -ethyl pi peri dine, polyamine resins and the like. See Berge et al., supra.

[0067] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered toAtorney Docket No. 56350-744.601a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0068] "Prodrug" is meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

[0069] A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0070] The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like

[0071] Throughout the specification and claims, x-ray powder diffraction (XRPD) peaks are described. XRPD peak values in the application refer to those obtained using a copper source with a wavelength of 1.5406 angstrom unless otherwise noted.

[0072] As used herein, the term “compound”, “Compound 1” or “CMPD-1” refers to Compound No. 1. Compound 1 has the structureOAttorney Docket No. 56350-744.601Compound 1 is also referred to by its full chemical name of l-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-l-carbonyl)-l,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)ethan-l-one.Methods of Polymorph Manufacture of Compound 1

[0073] Compound I can be readily prepared as various polymorphs, including Form C and Form A. Form C is a crystalline solid having high thermodynamic stability, making it well suited for pharmaceutical formulations of Compound 1.

[0074] In one aspect, provided herein is a crystalline form of Compound 1 having the structureN HNN<CF3wherein the crystalline compound exhibits a X-ray powder diffraction pattern (XRPD) having at least three characteristic peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 18.2, 23.5, 27.1, and / or 29.0 (Form C).

[0075] In one aspect, provided herein is a crystalline form of Compound 1 having the structureN HNN.CF3wherein the crystalline compound exhibits a X-ray powder diffraction pattern (XRPD) having at least three characteristic peaks expressed in degrees two theta (± 0.2 degree theta) at 9.7, 11.1, 14.5, 16.7, 21.8, 22.3, and 25.5 (Form A).

[0076] Form C and Form A of Compound 1 are described in more detail in PCT Publication No. W02021007172A1. FIG. 26 shows the signature peaks for comparing polymorph mixtures of Form A and C.

[0077] In one aspect, provided herein is a method of providing a crystalline compound, the method comprising:contacting a compound with a solution having a pH of about 1.5 to about 6.0, thereby forming a crystalline compound,Atorney Docket No. 56350-744.601wherein the crystalline compound exhibits a X-ray powder diffraction pattern (XRPD) having at least three characteristic peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0.

[0078] In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least four peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0. In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, and / or 14.1 at least one peak at 17.2, 23.5, 27.1, and / or 29.0. In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction patern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, and / or 14.1 at least two peaks at 17.2, 23.5, 27.1, and / or 29.0. In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having a peak expressed in degrees two theta (± 0.2 degree theta) at 9.3 and / or at least two peaks at 6.7, 14.1, 17.2, 18.2, 23.5, 27.1, and / or 29.0.

[0079] In certain embodiments, the compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 9.7, 11.1, 14.5, 16.7, 21.8, 22.3, and 25.5. In certain embodiments, the compound exhibits an X-ray powder diffraction pattern (XRPD) having peaks at 21.9, and 22.5 and at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 9.7, 11.1, 14.5, 16.7, 21.8, 22.3, and 25.5.

[0080] In certain embodiments, the solution comprises a surfactant, a phospholipid, a salt, an enzyme, a buffer, or a combination thereof. In certain embodiments, the solution comprises a surfactant. In certain embodiments, the solution comprises a phospholipid. In certain embodiments, the solution comprises a salt. In certain embodiments, the solution comprises an enzyme. In certain embodiments, the solution comprises a buffer.

[0081] In certain embodiments, the surfactant comprises sodium lauryl sulfate, sodium dodecyl sulfate, or both.

[0082] In certain embodiments, the phospholipid comprises lecithin, phosphatidylcholine, or a combination thereof.

[0083] In certain embodiments, the salt comprises sodium chloride, calcium chloride, potassium chloride, sodium taurocholate, sodium glycocholate, sodium taurochenodeoxycholate, sodium glycochenodeoxycholate, sodium deoxycholate, sodium lithocholate, or a combination thereof.

[0084] In certain embodiments, the enzyme comprises pepsin, chymotrypsin, trypsin, or a combination thereof.Atorney Docket No. 56350-744.601

[0085] In certain embodiments, the buffer comprises acetate, Tris, phosphate, or a combination thereof.

[0086] In certain embodiments, the compound is micronized.

[0087] In certain embodiments, the micronized compound has an average particle size of about 100 nm, about 200 nm, about 500 nm, about 1 pm, about 2 pm, about 3 pm, about 5 pm, about 10 pm, or about 20 pm. In certain embodiments, the micronized compound has an average particle size of about 100 nm. In certain embodiments, the micronized compound has an average particle size of about 200 nm. In certain embodiments, the micronized compound has an average particle size of about 500 nm. In certain embodiments, the micronized compound has an average particle size of about 1 pm. In certain embodiments, the micronized compound has an average particle size of about 2 pm. In certain embodiments, the micronized compound has an average particle size of about 3 pm. In certain embodiments, the micronized compound has an average particle size of about 5 pm. In certain embodiments, the micronized compound has an average particle size of about 10 pm. In certain embodiments, the micronized compound has an average particle size of about 20 pm.

[0088] In certain embodiments, the solution has a pH of about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, or about 6. In certain embodiments, the solution has a pH of about 1.5. In certain embodiments, the solution has a pH of about 2. In certain embodiments, the solution has a pH of about 2.5. In certain embodiments, the solution has a pH of about 3. In certain embodiments, the solution has a pH of about 3.5. In certain embodiments, the solution has a pH of about 4. In certain embodiments, the solution has a pH of about 4.5. In certain embodiments, the solution has a pH of about 5. In certain embodiments, the solution has a pH of about 5.5. In certain embodiments, the solution has a pH of about 6.

[0089] In another aspect, provided herein is a method of manufacturing a crystalline compound comprising the steps:milling a crystalline compound,wherein the crystalline compound has the structure:Attorney Docket No. 56350-744.601wherein the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three characteristic peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 18.2, 23.5, 27.1, and / or 29.0; and sieving the crystalline compound.

[0090] In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least four peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 18.2, 23.5, 27.1, and / or 29.0. In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, and / or 17.2 at least one peak at 23.5, 27.1, and / or 29.0. In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) 6.7, 9.3, 14.1, and / or 17.2 at least two peaks at 23.5, 27.1, and / or 29.0. In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having a peak expressed in degrees two theta (± 0.2 degree theta) at 9.3 and / or at least two peaks at 6.7, 14.1, 17.2, 18.2, 23.5, 27.1, and / or 29.0.

[0091] In certain embodiments, the crystalline compound is micronized.

[0092] In certain embodiments, the crystalline compound comprises a particle size from about 100 nM to about 10 pM, about 1 pM to about 5 pM, about 1 pM to about 2.5 pM, about 1 pM to about 5 pM, or about 1 pM to about 10 pM. In certain embodiments, the crystalline compound comprises a particle size from about 100 nM to about 10 pM. In certain embodiments, the crystalline compound comprises a particle size from about 1 pM to about 5 pM. In certain embodiments, the crystalline compound comprises a particle size from about 1 pM to about 2.5 pM. In certain embodiments, the crystalline compound comprises a particle size from about 1 pM to about 5 pM. In certain embodiments, the crystalline compound comprises a particle size from about 1 pm to about 10 pm.

[0093] In certain embodiments, the crystalline compound comprises a particle size of less than 10 pm, less than 5 pm, or less than 2 pm. In certain embodiments, the crystalline compound comprises a particle size of less than 10 pm. In certain embodiments, the crystalline compound comprises a particle size of less than 5 pm. In certain embodiments, the crystalline compound comprises a particle size of less than 2 pm.

[0094] In certain embodiments, the crystalline compound comprises a particle size distribution of no more than 10 pm. In certain embodiments, the crystalline compound comprise a particle size distribution of no more than 5 pm. In certain embodiments, the crystalline compound comprises a particle size distribution of no more than 2 pm.Atorney Docket No. 56350-744.601

[0095] In certain embodiments, the crystalline compound has a solubility of about 0.001 mg / mL to about 0.005 mg / mL. In certain embodiments, the crystalline compound has a solubility of about 0.001 mg / mL after 60 min. In certain embodiments, the crystalline compound has a solubility of about 0.005 mg / mL after 180 min.

[0096] In certain embodiments, the method further comprises manufacturing the crystalline compound comprising the steps of:dissolving a compound in a solvent, the compound having the structure:crystallizing the compound to obtain the crystalline compound.

[0097] In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 9.7, 11.1, 14.5, 16.7, 21.8, 22.3, and 25.5. In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having peaks at 21.8, and 22.3 and at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 9.7, 11.1, 14.5, 16.7, and 25.5.

[0098] In certain embodiments, the crystalline compound is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% pure. In certain embodiments, the crystalline compound is at least 90% pure. In certain embodiments, the crystalline compound is at least 95% pure. In certain embodiments, the crystalline compound is at least 96% pure. In certain embodiments, the crystalline compound is at least 97% pure. In certain embodiments, the crystalline compound is at least 98% pure. In certain embodiments, the crystalline compound is at least 99% pure.

[0099] In certain embodiments, the crystalline compound comprises no more than 5% (w / w), no more than 2.5% (w / w), no more than 1% (w / w), no more than 0.5% (w / w), or no more than 0.1% (w / w) impurities. In certain embodiments, the crystalline compound comprises no more than 5% (w / w) impurities. In certain embodiments, the crystalline compound comprises no more than 2.5% (w / w) impurities. In certain embodiments, the crystalline compound comprises no more than 1% (w / w) impurities. In certain embodiments, the crystalline compound comprises no more than 0.5% (w / w) impurities. In certain embodiments, the crystalline compound comprises no more than 0.1% (w / w) impurities.Attorney Docket No. 56350-744.601

[0100] In certain embodiments, the solvent comprises methanol, ethanol, acetone, acetonitrile, dichloromethane, dimethyl formamide, ethyl acetate, ethyl ether, isopropanol, tetrahydrofuran, water, or a combination thereof. In certain embodiments, the solvent comprises methanol. In certain embodiments, the solvent comprises ethanol. In certain embodiments, the solvent comprises acetone. In certain embodiments, the solvent comprises acetonitrile. In certain embodiments, the solvent comprises dichloromethane. In certain embodiments, the solvent comprises dimethyl formamide. In certain embodiments, the solvent comprises ethyl acetate. In certain embodiments, the solvent comprises ethyl ether. In certain embodiments, the solvent comprises isopropanol. In certain embodiments, the solvent comprises tetrahydrofuran. In certain embodiments, the solvent comprises water.

[0101] In certain embodiments, the crystalline compound is further formulated as a tablet.

[0102] In certain embodiments, the method further comprises compressing the crystalline compound to provide the tablet.

[0103] In certain embodiments, the tablet comprises from about 0.5 mg to about 50 mg of the crystalline compound. In certain embodiments, the tablet comprises about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, or about 50 mg of the crystalline compound. In certain embodiments, the tablet comprises about 0.5 mg of the crystalline compound. In certain embodiments, the tablet comprises about 1 mg of the crystalline compound. In certain embodiments, the tablet comprises about 5 mg of the crystalline compound. In certain embodiments, the tablet comprises about 10 mg of the crystalline compound. In certain embodiments, the tablet comprises about 25 mg of the crystalline compound. In certain embodiments, the tablet comprises about 50 mg of the crystalline compound.Manufacture of Tablet Formulations

[0104] In another aspect, provided herein is a method of manufacturing a tablet formulation of a crystalline form of a compound, the method comprising the steps:blending a crystalline compound having the structure:N HNi\LCF3with one or more excipients to obtain a mixture, wherein the crystalline compound exhibits a X-ray powder diffraction pattern (XRPD) having at least three characteristic peaksAtorney Docket No. 56350-744.601expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 18.2, 23.5, 27.1, and / or 29.0;roller compacting the mixture;milling the mixture;sieving the mixture to obtain one or more granules comprising a substantially uniform particle size; andcompressing the one or more granules into a tablet.

[0105] In certain embodiments, blending comprises combining the crystalline compound with one or more disintegrants, dispersion polymers, fillers, or lubricants, or a combination thereof. In certain embodiments blending comprises combining the crystalline compound with one or more disintegrants. In certain embodiments, the one or more disintegrants is comprises croscarmellose sodium (CCNa), microcrystalline cellulose (MCC), crospovidone, tapioca starch, or a combination thereof. In certain embodiments blending comprises combining the crystalline compound with one or more dispersion polymers. In certain embodiments, the one or more dispersion polymers comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers, or a combination thereof. In certain embodiments, the blending comprises combining the crystalline compound with one or more fillers. In certain embodiments, the one or more fillers comprises lactose monohydrate, mannitol, sorbitol, cellulose, calcium phosphate, starch, sugar, cellulose, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, dibasic calcium phosphate, sucrose, lactose, corn starch, potato starch, or a combination thereof. In certain embodiments, the blending comprises combining the crystalline compound with one or more lubricants. In certain embodiments, the one or more lubricants comprises magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate, or a combination thereof.

[0106] In certain embodiments, the blending comprises co-sifting the crystalline compound with one or more disintegrants, dispersion polymers, or fillers, or a combination thereof through a screen. In certain embodiments, the co-sifting of the crystalline compound and the one or more disintegrants, dispersion polymers, or fillers, is sequential. In certain embodiments, the screen is a 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100 mesh screen. In certain embodiments, theAtorney Docket No. 56350-744.601screen is a 20 mesh screen. In certain embodiments, the screen is a 30 mesh screen. In certain embodiments, the screen is a 40 mesh screen. In certain embodiments, the screen is a 50 mesh screen. In certain embodiments, the screen is a 60 mesh screen. In certain embodiments, the screen is a 70 mesh screen. In certain embodiments, the screen is a 80 mesh screen. In certain embodiments, the screen is a 90 mesh screen. In certain embodiments, the screen is a 100 mesh screen.

[0107] In certain embodiments, the blending comprises a V-blender between about 18 to about 25 RMP. In certain embodiments, the blending comprises a V-blender at 18 RPM. In certain embodiments, the blending comprises a V-blender at 25 RPM. In certain embodiments, the blending comprises a V-blender at 25 RMP for 3 min. In certain embodiments, the blending comprises a V-blender at 18 RPM for 4 min.

[0108] In certain embodiments, the blending comprises a pre-blending and a final blending.

[0109] In certain embodiments, the material resulting from the blending comprises a bulk uniformity of between about 90% to about 110%. In certain embodiments, the material resulting from the blending comprises a bulk uniformity of between about 90% to about 100%. In certain embodiments, the material resulting from the blending comprises a bulk uniformity of at least 90%. In certain embodiments, the material resulting from the blending comprises a bulk uniformity of at least 95%.

[0110] In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, and / or 14.1 at least one peak at 17.2, 23.5, 27.1, and / or 29.0. In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) 6.7, 9.3, 14.1, and / or 17.2 at least two peaks at 23.5, 27.1, and / or 29.0. In certain embodiments, the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having a peak expressed in degrees two theta (± 0.2 degree theta) at 9.3 and / or at least two peaks at 6.7, 14.1, 17.2, 18.2, 23.5, 27.1, and / or 29.0.

[0111] In certain embodiments, the roller compaction comprises a compression force of about 3.0 to about 5.0 kN / cm. In certain embodiments, the roller compaction comprises a compression force of about 3.0 kN / cm. In certain embodiments, the roller compaction comprises a compression force of about 3.5 kN / cm. In certain embodiments, the roller compaction comprises a compression force of about 4.0 kN / cm. In certain embodiments, the roller compaction comprises a compression force of about 4.5 kN / cm. In certain embodiments, the roller compaction comprises a compression force of about 5.0 kN / cm.Atorney Docket No. 56350-744.601

[0112] In certain embodiments, the roller compression comprises a compression force of about 3.0 to about 5.0 kN / cm, a press roller speed of about 1.0 to about 3.0 RPM, a roller gap width of about 4.0 to about 6.0 mm, and a granulator gap of about 1 mm.

[0113] In certain embodiments, the milling and sieving produces a particle distribution of no more than 10 pm. In certain embodiments, the milling and sieving produces a particle distribution of no more than 5 pm. In certain embodiments, the milling and sieving produces a particle distribution of no more than 2 pm.

[0114] In certain embodiments, a D90 of the granules is about 5 pm to about 50 pm, about 5 pm to about 40 pm, about 5 pm to about 30 pm, about 5 pm to about 20 pm, or about 5 pm to about 10 pm. In certain embodiments, a D90 of the granules is about 5 pm to about 50 pm. In certain embodiments, a D90 of the granules is about 5 pm to about 40 pm. In certain embodiments, a D90 of the granules is about 5 pm to about 30 pm. In certain embodiments, a D90 of the granules is about 5 pm to about 20 pm. In certain embodiments, a D90 of the granules is about 5 pm to about 10 pm.

[0115] In certain embodiments, a D50 of the granules is about 3 pm to about 20 pm, about 3 pm to about 15 pm, about 3 pm to about 10 pm, or about 3 pm to about 5 pm. In certain embodiments, a D50 of the granules is about 3 pm to about 20 pm. In certain embodiments, a D50 of the granules is about 3 pm to about 15 pm. In certain embodiments, a D50 of the granules is about 3 pm to about 10 pm. In certain embodiments, a D50 of the granules is about 3 pm to about 5 pm.

[0116] In certain embodiments, a Dio of the granules is about 0.5 pm to about 3 pm, about 0.5 pm to about 2 pm, about 0.5 pm to about 1 pm, about 1 pm to about 2 pm, or about 1 pm to about 1.5 pm. In certain embodiments, a Dio of the granules is about 0.5 pm to about 3 pm. In certain embodiments, a Dio of the granules is about 0.5 pm to about 2 pm. In certain embodiments, a Dio of the granules is about 0.5 pm to about 1 pm. In certain embodiments, a Dio of the granules is about 1 pm to about 2 pm. In certain embodiments, a Dio of the granules is about 1 pm to about 1.5 pm.

[0117] In certain embodiments, the tablet comprises from about 0.5 mg to about 50 mg of the compound. In certain embodiments, the tablet comprises about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, or about 50 mg of the compound. In certain embodiments, the tablet comprises about 0.5 mg of the compound. In certain embodiments, the tablet comprises about 1 mg of the compound. In certain embodiments, the tablet comprises about 5 mg of the compound. In certain embodiments, the tablet comprises about 10 mg of the compound. In certain embodiments, the tablet comprises about 25 mg of the compound. In certain embodiments, the tablet comprises about 50 mg of the compound.Atorney Docket No. 56350-744.601

[0118] In certain embodiments, the tablet has an average weight of about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300 mg, about 50 mg to about 200 mg, about 50 mg to about 100 mg, or about 100 mg to about 200 mg. In certain embodiments, the tablet has an average weight of about 50 mg. In certain embodiments, the tablet has an average weight of about 100 mg. In certain embodiments, the tablet has an average weight of about 150 mg. In certain embodiments, the tablet has an average weight of about 200 mg. In certain embodiments, the tablet has an average weight of about 250 mg. In certain embodiments, the tablet has an average weight of about 300 mg. In certain embodiments, the tablet has an average weight of about 350 mg. In certain embodiments, the tablet has an average weight of about 400 mg.

[0119] In certain embodiments, the tablet has an average thickness of about 1 mm to about 10 mm, about 1 mm to about 9 mm, about 1 mm to about 8 mm, about 1 mm to about 7 mm, about 1 mm to about 6 mm, about 1 mm to about 5 mm, about 1 mm to about 4 mm, about 1 mm to about 3 mm, or about 1 mm to about 2 mm. In certain embodiments, the tablet has a thickness of about 1 mm. In certain embodiments, the tablet has a thickness of about 2 mm. In certain embodiments, the tablet has a thickness of about 3 mm. In certain embodiments, the tablet has a thickness of about 3.3 mm. In certain embodiments, the tablet has a thickness of about 4 mm. In certain embodiments, the tablet has a thickness of about 5 mm. In certain embodiments, the tablet has a thickness of about 6 mm.

[0120] In certain embodiments, the tablet has an average hardness of about 2 kP to about 10 kP, about 2 kP to about 9 kP, about 2 kP to about 8 kP, about 2 kP to about 7 kP, about 2 kP to about 6 kP, about 2 kP to about 5 kP, about 5 kP to about 10 kP, about 5 kP to about 9 kP, or about 5 kP to about 8 kP. In certain embodiments, the tablet has an average hardness of about 2 kP. In certain embodiments, the tablet has an average hardness of about 3 kP. In certain embodiments, the tablet has an average hardness of about 4 kP. In certain embodiments, the tablet has an average hardness of about 5 kP. In certain embodiments, the tablet has an average hardness of about 6 kP. In certain embodiments, the tablet has an average hardness of about 7 kP. In certain embodiments, the tablet has an average hardness of about 7.1 kP. In certain embodiments, the tablet has an average hardness of about 7.2 kP. In certain embodiments, the tablet has an average hardness of about 7.3 kP. In certain embodiments, the tablet has an average hardness of about 7.4 kP. In certain embodiments, the tablet has an average hardness of about 7.5 kP. In certain embodiments, the tablet has an average hardness of about 7.6 kP. In certain embodiments, the tablet has an average hardness of about 7.7 kP. In certain embodiments, the tablet has an average hardness of about 7.8 kP. In certain embodiments, the tablet has an average hardness of about 7.9 kP. In certain embodiments, the tablet has an average hardness of about 8- 1 -Atorney Docket No. 56350-744.601kP. In certain embodiments, the tablet has an average hardness of about 8.2 kP. In certain embodiments, the tablet has an average hardness of about 8.3 kP. In certain embodiments, the tablet has an average hardness of about 8.4 kP. In certain embodiments, the tablet has an average hardness of about 8.5 kP. In certain embodiments, the tablet has an average hardness of about 8.6 kP. In certain embodiments, the tablet has an average hardness of about 8.7 kP. In certain embodiments, the tablet has an average hardness of about 8.8 kP. In certain embodiments, the tablet has an average hardness of about 8.9 kP. In certain embodiments, the tablet has an average hardness of about 9 kP. In certain embodiments, the tablet has an average hardness of about 9.1 kP. In certain embodiments, the tablet has an average hardness of about 9.2 kP. In certain embodiments, the tablet has an average hardness of about 9.3 kP. In certain embodiments, the tablet has an average hardness of about 9.4 kP. In certain embodiments, the tablet has an average hardness of about 9.5 kP. In certain embodiments, the tablet has an average hardness of about 9.6 kP. In certain embodiments, the tablet has an average hardness of about 9.7 kP. In certain embodiments, the tablet has an average hardness of about 9.8 kP. In certain embodiments, the tablet has an average hardness of about 9.9 kP. In certain embodiments, the tablet has an average hardness of about 10 kP.

[0121] In certain embodiments, the tablet has a dissolution time of less than about 10 min. In certain embodiments, the tablet has a dissolution time of less than about 15 min. In certain embodiments, the tablet has a dissolution time of less than about 20 min. In certain embodiments, the tablet has a dissolution time of less than about 25 min.

[0122] In certain embodiments, the one or more excipients comprises a filler, a dispersion polymer, a disintegrant, a glidant, a lubricant, a solid carrier, or a combination thereof.

[0123] In certain embodiments, the filler comprises lactose monohydrate, mannitol, sorbitol, cellulose, calcium phosphate, starch, sugar, cellulose, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, dibasic calcium phosphate, sucrose, lactose, corn starch, potato starch, or a combination thereof. In certain embodiments, the filler comprises lactose monohydrate or microcrystalline cellulose, or a combination thereof. In certain embodiments, the filler comprises lactose monohydrate. In certain embodiments, the filler comprises microcrystalline cellulose.

[0124] In certain embodiments, the dispersion polymer comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycol copolymers,Atorney Docket No. 56350-744.601polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylenepolyoxypropylene block copolymers, or a combination thereof. In certain embodiments, the dispersion polymer comprises hydroxypropyl cellulose (HPC).

[0125] In certain embodiments, the disintegrant comprises croscarmellose sodium (CCNa), microcrystalline cellulose (MCC), crospovidone, tapioca starch, or a combination thereof. In certain embodiments, the disintegrant comprises croscarmellose sodium (CCNa).

[0126] In certain embodiments, the glidant comprises colloidal silicon dioxide, talc, com starch, metal silicates, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, metal hydroxides, or combination thereof.

[0127] In certain embodiments, the lubricant comprises magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate, or a combination thereof.

[0128] In certain embodiments, the solid carrier comprises mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, or a combination thereof.

[0129] In certain embodiments, the blending comprises blending the crystalline compound with a filler, a lubricant, a dispersion polymer, or a combination thereof.Pharmaceutical Compositions

[0130] In another aspect, provided herein is a pharmaceutical composition comprising:one or more granules comprising a compound having the structure:HNi\LCF3N Owherein the granules are micronized and have an average particle size of about 0.5 pm to about 20 pm,wherein the compound is crystalline and has an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, and / or 14.1 at least one peak at 17.2, 23.5, 27.1, and / or 29.0; andone or more pharmaceutically acceptable excipients.Atorney Docket No. 56350-744.601

[0131] In certain embodiments, the one or more excipients comprises a filler, a dispersion polymer, a disintegrant, a glidant, a lubricant, a solid carrier, an anti -adherent, a filler, a sweetener, a wetting agent, a binder, or a combination thereof.

[0132] In certain embodiments, the filler comprises lactose monohydrate, mannitol, sorbitol, cellulose, calcium phosphate, starch, sugar, cellulose, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, dibasic calcium phosphate, sucrose, lactose, corn starch, potato starch, or a combination thereof. In certain embodiments, the filler comprises lactose monohydrate or microcrystalline cellulose, or a combination thereof. In certain embodiments, the filler comprises lactose monohydrate. In certain embodiments, the filler comprises microcrystalline cellulose.

[0133] In certain embodiments, the dispersion polymer comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylenepolyoxypropylene block copolymers, or a combination thereof.

[0134] In certain embodiments, the disintegrant comprises croscarmellose sodium (CCNa), microcrystalline cellulose (MCC), crospovidone, tapioca starch, or a combination thereof.

[0135] In certain embodiments, the glidant comprises colloidal silicon dioxide, talc, com starch, metal silicates, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, metal hydroxides, or combination thereof.

[0136] In certain embodiments, the lubricant comprises magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate, or a combination thereof.

[0137] In certain embodiments, the solid carrier comprises mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, or a combination thereof.

[0138] In certain embodiments, the anti-adherent comprises microcrystalline cellulose, lactose monohydrate, hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate, or a combination thereof.Additional Elements

[0139] In certain embodiments, the pharmaceutical composition further comprises a filler, a sweetener, a disintegrant, a wetting agent, a glidant, a lubricant, or a surfactant, or anyAtorney Docket No. 56350-744.601combinations thereof. In certain embodiments, the solid dispersion of the pharmaceutical composition further comprises a filler, a sweetener, a disintegrant, a wetting agent, a glidant, a lubricant, or a surfactant, or any combinations thereof.Fillers

[0140] In certain embodiments, the pharmaceutical composition further comprises a filler. In certain embodiments, the solid dispersion of the pharmaceutical composition further comprises a filler. Fillers may be any biocompatible substance that is unreactive with the compound of Formula (I) and the compound of Formula (I). Non-limiting examples of fillers include lactose monohydrate, mannitol, sorbitol, cellulose, calcium phosphate, starch, sugar, cellulose, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, dibasic calcium phosphate, sucrose, lactose, corn starch, potato starch, or any combination thereof.

[0141] In certain embodiments, the filler comprises about 1-99% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 10% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 20% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 30% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 40% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 50% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 60% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 70% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 80% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises about 90% by weight of the pharmaceutical composition.

[0142] In certain embodiments, the filler comprises up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises up to about 20% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises up to about 90% by weight of the pharmaceutical composition.Atorney Docket No. 56350-744.601

[0143] In certain embodiments, the filler comprises at least about 10% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises at least about 20% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises at least about 30% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises at least about 40% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises at least about 50% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises at least about 60% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises at least about 70% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises at least about 80% by weight of the pharmaceutical composition. In certain embodiments, the filler comprises at least about 90% by weight of the pharmaceutical composition.Sweeteners

[0144] In certain embodiments, the pharmaceutical composition comprising a compound of Formula (I) further comprises a sweetener. In certain embodiments, the solid dispersion of the pharmaceutical composition further comprises a sweetener. Non-limiting examples of sweeteners include water-soluble sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), high fructose corn syrup, maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, com syrup solids, and dihydrochalcones; water-soluble artificial sweeteners such as the soluble saccharin salts, i.e., sodium or calcium saccharin salts, cyclamate salts, the sodium, ammonium or calcium salt of 3,4-dihydro-6-methyl-l,2,3-oxathiazine-4-one-2, 2-dioxide, the potassium salt of 3,4-dihydro-6-methyl-l,2,3-oxathiazine-4-one-2,2-dioxide (acesulfame-K), the free acid form of saccharin and the like; dipeptide based sweeteners, such as L-aspartic acid derived sweeteners, such as L-aspartyl-L-phenylalanine methyl ester (aspartame), L-alpha-aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide hydrate, methyl esters of L-aspartyl-L-phenylglycerin and L-aspartyl-L-2, 5, dihydrophenylglycine, L-aspartyl-2,5-dihydro-L-phenylalanine, L-aspartyl-L-(l-cyclohexyen)-alanine, and the like; and water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, such as a chlorinated derivatives of ordinary sugar (sucrose), known, for example, as sucralose.

[0145] In certain embodiments, the sweetener comprises about 1-99% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 10% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 20% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 30% by weight of the pharmaceutical composition. In certain embodiments, theAtorney Docket No. 56350-744.601sweetener comprises about 40% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 50% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 60% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 70% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 80% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises about 90% by weight of the pharmaceutical composition.

[0146] In certain embodiments, the sweetener comprises up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises up to about 20% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises up to about 90% by weight of the pharmaceutical composition.

[0147] In certain embodiments, the sweetener comprises at least about 10% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises at least about 20% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises at least about 30% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises at least about 40% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises at least about 50% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises at least about 60% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises at least about 70% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises at least about 80% by weight of the pharmaceutical composition. In certain embodiments, the sweetener comprises at least about 90% by weight of the pharmaceutical composition.Disintegrants

[0148] In certain embodiments, the pharmaceutical composition comprising a compound of Formula (I) further comprises a disintegrant. In certain embodiments, the solid dispersion of the pharmaceutical composition further comprises a disintegrant. Non-limiting examples of disintegrants include agar-agar, algins, calcium carbonate, carboxymethylcellulose, cellulose,Atorney Docket No. 56350-744.601hydroxypropylcellulose, low substituted hydroxypropylcellulose, clays, croscarmellose sodium, crospovidone, gums, magnesium aluminum silicate, methylcellulose, polacrilin potassium, sodium alginate, sodium starch glycolate, maize starch, potato starch, tapioca starch, or any combination thereof.

[0149] In certain embodiments, the disintegrant comprises about 1-99% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 10% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 20% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 30% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 40% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 50% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 60% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 70% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 80% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises about 90% by weight of the pharmaceutical composition.

[0150] In certain embodiments, the disintegrant comprises up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises up to about 20% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises up to about 90% by weight of the pharmaceutical composition.

[0151] In certain embodiments, the disintegrant comprises at least about 10% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises at least about 20% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises at least about 30% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises at least about 40% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises at least about 50% by weight ofAttomey Docket No. 56350-744.601the pharmaceutical composition. In certain embodiments, the disintegrant comprises at least about 60% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises at least about 70% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises at least about 80% by weight of the pharmaceutical composition. In certain embodiments, the disintegrant comprises at least about 90% by weight of the pharmaceutical composition.Wetting Agents

[0152] In certain embodiments, the pharmaceutical composition comprising a compound of Formula (I) further comprises a wetting agent. In certain embodiments, the solid dispersion of the pharmaceutical composition further comprises a wetting agent. Non-limiting examples of wetting agents include sodium lauryl sulfate, cetostearyl alcohol, cetomacrogol emulsifying wax, gelatin, casein, docusate sodium, benzalkonium chloride, calcium stearate, polyethylene glycols, phosphates, polyoxyethylene sorbitan fatty acid esters, gum acacia, cholesterol, tragacanth, polyoxyethylene 20 stearyl ethers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, PEGylated hydrogenated castor oils, sorbitan esters of fatty acids, Vitamin E or tocopherol derivatives, vitamin E TPGS, tocopheryl esters, lecithin, phospholipids and their derivatives, poloxamers, stearic acid, oleic acid, oleic alcohol, cetyl alcohol, mono and diglycerides, propylene glycol esters of fatty acids, glycerol esters of fatty acids, ethylene glycol palmitostearate, polyoxylglycerides, propylene glycol monocaprylate, propylene glycol monolaurate, alkyl aryl polyether alcohols and polyglyceryl oleate or combinations thereof.

[0153] In certain embodiments, the wetting agent comprises about 1-99% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 10% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 20% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 30% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 40% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 50% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 60% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 70% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 80% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises about 90% by weight of the pharmaceutical composition.

[0154] In certain embodiments, the wetting agent comprises up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises up to aboutAtorney Docket No. 56350-744.60120% by weight of the pharmaceutical composition. In certain embodiments, the weting agent comprises up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises up to about 90% by weight of the pharmaceutical composition.

[0155] In certain embodiments, the wetting agent comprises at least about 10% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises at least about 20% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises at least about 30% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises at least about 40% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises at least about 50% by weight of the pharmaceutical composition. In certain embodiments, the weting agent comprises at least about 60% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises at least about 70% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises at least about 80% by weight of the pharmaceutical composition. In certain embodiments, the wetting agent comprises at least about 90% by weight of the pharmaceutical composition.Glidants

[0156] In certain embodiments, the pharmaceutical composition comprising a compound of Formula (I) further comprises a glidant. In certain embodiments, the solid dispersion of the pharmaceutical composition further comprises a glidant. Non -limiting examples of glidants include colloidal silicon dioxide, talk, com starch, metal silicates, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, and metal hydroxides or any combination thereof.

[0157] In certain embodiments, the glidant comprises about 1-99% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 10% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 20% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 30% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 40% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 50% by weight of the pharmaceutical composition. InAttomey Docket No. 56350-744.601certain embodiments, the glidant comprises about 60% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 70% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 80% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises about 90% by weight of the pharmaceutical composition.

[0158] In certain embodiments, the glidant comprises up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises up to about 20% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises up to about 90% by weight of the pharmaceutical composition.

[0159] In certain embodiments, the glidant comprises at least about 10% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises at least about 20% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises at least about 30% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises at least about 40% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises at least about 50% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises at least about 60% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises at least about 70% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises at least about 80% by weight of the pharmaceutical composition. In certain embodiments, the glidant comprises at least about 90% by weight of the pharmaceutical composition.Lubricants

[0160] In certain embodiments, the pharmaceutical composition comprising a compound of Formula (I) further comprises a lubricant. In certain embodiments, the solid dispersion of the pharmaceutical composition further comprises a lubricant. Non-limiting examples of lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate, or any combination thereof.Atorney Docket No. 56350-744.601

[0161] In certain embodiments, the lubricant comprises about 1-99% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 10% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 20% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 30% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 40% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 50% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 60% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 70% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 80% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises about 90% by weight of the pharmaceutical composition.

[0162] In certain embodiments, the lubricant comprises up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises up to about 20% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises up to about 90% by weight of the pharmaceutical composition.

[0163] In certain embodiments, the lubricant comprises at least about 10% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises at least about 20% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises at least about 30% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises at least about 40% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises at least about 50% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises at least about 60% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises at least about 70% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises at least about 80% by weight of the pharmaceutical composition. In certain embodiments, the lubricant comprises at least about 90% by weight of the pharmaceutical composition.Attomey Docket No. 56350-744.601Surfactant

[0164] In some embodiments of pharmaceutical composition comprising a compound of Formula (I), the pharmaceutical composition further comprises a surfactant. In certain embodiments, the solid dispersion of the pharmaceutical composition further comprises a surfactant. Non limiting examples of surfactants include sodium dodecyl sulfate (SDS), sodium laurel sulfate (SLS), macroglycerol ricinoleate (Kolliphor EL® or Cremophor EL®), caprylocaproyl polyoxyl-8 glyceride (Labrasol®), lauroyl polyoxyl-6 glycerides (Labrafil® M 2130 CS), lauroyl polyoxyl-32 glyceride (Gelucire® 44 / 14), polyethylene glycol monostearate (Gelucire® 48 / 16), polyoxyethylene hydrogenated castor oil 60 (HCO-60), polysorbate 80 (Tween®-80), polyethylene glycol sorbitan monolaurate (Tween®-20), polyoxyethylene sorbitan trioleate (Tween®-85), polyoxyethyelene glyceryl trioleate (tagot-TO), sorbitan monooleate (Span®-80), sorbitan monolaurate (Span®-20), or any combinations thereof.

[0165] In certain embodiments, the surfactant comprises about 1-99% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 10% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 20% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 30% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 40% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 50% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 60% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 70% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 80% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises about 90% by weight of the pharmaceutical composition.

[0166] In certain embodiments, the surfactant comprises up to about 10% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises up to about 20% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises up to about 30% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises up to about 40% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises up to about 50% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises up to about 60% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises up to about 70% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises up to about 80% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises up to about 90% by weight of the pharmaceutical composition.Atorney Docket No. 56350-744.601

[0167] In certain embodiments, the surfactant comprises at least about 10% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises at least about 20% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises at least about 30% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises at least about 40% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises at least about 50% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises at least about 60% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises at least about 70% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises at least about 80% by weight of the pharmaceutical composition. In certain embodiments, the surfactant comprises at least about 90% by weight of the pharmaceutical compositionPreparation of Compounds

[0168] The compounds used in the chemical reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pitsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0169] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modem Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure",Attomey Docket No. 56350-744.6014th Ed., Wiley -Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5;Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modem Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0170] Alternatively, specific and analogous reactants can be identified through the indices of known chemicals and reactions prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. formore details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the heterocyclic RBP4 inhibitory compound described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.Methods of Treatment

[0171] In some embodiments, the formulations disclosed herein is used to treat or ameliorate a disease associated with altered RBP4 pathways when administered to a subject in need thereof. In some cases, a compound disclosed herein is used to treat or ameliorate the effects of a disease associated with altered RBP4 pathway when administered to a subject in need thereof.Exemplary diseases associated with altered RBP4 include eye diseases. In some instances, the eye disease is characterized by excessive lipofuscin accumulation in the retina. In someAttomey Docket No. 56350-744.601instances, a compound disclosed herein is used to treat or ameliorate an eye disease when administered to a subject in need thereof. Exemplary eye disease include Age-Related Macular Degeneration, dry (atrophic) Age-Related Macular Degeneration, Juvenile Macular Degeneration (Stargardt Disease), Best disease, adult vitelliform maculopathy, Geographic Atrophy, Stargardt-like macular dystrophy, diabetic retinopathy, or an ABCA4 gene associated retinal disease.Age-related Macular degeneration

[0172] Age-related macular degeneration (AMD) is a common eye condition and a leading cause of vision loss among people age 50 and older. It causes damage to the macula, a small spot near the center of the retina and the part of the eye needed for sharp, central vision. As AMD progresses, a blurred area near the center of vision is a common symptom. Over time, the blurred area may grow larger and the subject may develop blank spots in his or her central vision.

[0173] Some embodiments provided herein describe the use of the compositions described herein for treating AMD in a subject in need thereof. In some embodiments, the compositions described herein inhibit AMD. In certain embodiments, the compositions described herein arrest development of AMD or its clinical symptoms. In certain embodiments, the compositions described herein reduce development of AMD or its clinical symptoms. In certain embodiments, the compositions described herein relieve the subject of AMD. In certain embodiments, the compositions described herein cause regression, reversal, or amelioration of AMD. In certain embodiments, the compositions described herein reduce the number, frequency, duration, or severity of AMD clinical symptoms.

[0174] In some embodiments, the compositions are used prophylactically. In certain embodiments, the compositions are used to prevent or reduce the risk of developing AMD. In certain embodiments, the compositions cause the clinical symptoms of AMD to not develop in a subject who may be predisposed to AMD but who does not yet experience or display symptoms of AMD.Dry (atrophic) Age-related Macular degeneration

[0175] Approximately 85% to 90% of the cases of macular degeneration are the “dry” (atrophic) type. It is estimated that 62.9 million individuals worldwide have this form of AMD; 8 million of them are Americans. Due to increasing life expectancy and current demographics this number is expected to triple by 2020. There is currently no FDA-approved treatment for dry AMD. Given the lack of treatment and high prevalence, development of drugs for dry AMD is of upmost importance. Clinically, atrophic AMD represents a slowly progressing neurodegenerative disorder in which specialized neurons (rod and cone photoreceptors) die inAtorney Docket No. 56350-744.601the central part of the retina called the macula. Histopathological and clinical imaging studies indicate that photoreceptor degeneration in dry AMD is triggered by abnormalities in the retinal pigment epithelium (RPE) that lies beneath photoreceptors and provides critical metabolic support to these light-sensing neuronal cells. Experimental and clinical data indicate that excessive accumulation of cytotoxic autofluorescent lipid-protein-retinoid aggregates (lipofuscin) in the RPE is a major trigger of dry AMD. The major cytotoxic component of RPE lipofuscin is pyridinium bisretinoid A2E (FIG. 1). Additional cytotoxic bisretinoids are isoA2E, atRAL di-PE, and A2-DHP-PE. Formation of A2E and other lipofuscin bisretinoids, such as A2-DHP-PE (A2-dihydropyridine-phosphatidylethanolamine) and atRALdi-PE (all-trans-retinal dimer-phosphatidylethanolamine), begins in photoreceptor cells in a non-enzymatic manner and can be considered as a by-product of the properly functioning visual cycle.

[0176] Some embodiments provided herein describe the use of the compositions described herein for treating dry (atrophic) AMD in a subject in need thereof. In some embodiments, the compositions inhibit dry (atrophic) AMD. In certain embodiments, the compositions arrest development of dry (atrophic) AMD or its clinical symptoms. In certain embodiments, the compositions reduce development of dry (atrophic) AMD or its clinical symptoms. In certain embodiments, the compositions relieve the subject of dry (atrophic) AMD. In certain embodiments, the compositions cause regression, reversal, or amelioration of dry (atrophic) AMD. In certain embodiments, the compositions reduce the number, frequency, duration, or severity of dry (atrophic) AMD clinical symptoms.

[0177] In some embodiments, the compositions described herein are used prophylactically. In certain embodiments, the compositions are used to prevent or reduce the risk of developing dry (atrophic) AMD. In certain embodiments, the compositions cause the clinical symptoms of dry (atrophic) AMD to not develop in a subject who may be predisposed to dry (atrophic) AMD but who does not yet experience or display symptoms of dry (atrophic) AMD.Juvenile Macular Degeneration (Stargardt Disease)

[0178] Stargardt Disease (STGD) is an inherited form of juvenile-onset macular degeneration. STGD is characterized by the dramatic accumulation of lipofuscin in the retina. STGD is linked to defects in the ABCA4 gene. Excessive production of lipofuscin bisretinoids is thought to be the sole biochemical trigger of monogenic STGD caused by recessive mutations in the ABCA4 gene. Symptoms include wavy vision, blind spots, blurriness, loss of depth perception, sensitivity to glare, impaired color vision, and difficulty adapting to dim lighting. Symptoms typically develop before age 20.

[0179] Some embodiments provided herein describe the use of the compositions described herein for treating STGD in a subject in need thereof. In some embodiments, the compositionsAttomey Docket No. 56350-744.601inhibit STGD. In certain embodiments, the compositions arrest development of STGD or its clinical symptoms. In certain embodiments, the compositions reduce development of STGD or its clinical symptoms. In certain embodiments, the compositions relieve the subject of STGD. In certain embodiments, the compositions cause regression, reversal, or amelioration of STGD. In certain embodiments, the compositions reduce the number, frequency, duration, or severity of STGD clinical symptoms.

[0180] In some embodiments, the compositions are used prophylactically. In certain embodiments, the compositions are used to prevent or reduce the risk of developing STGD. In certain embodiments, the compositions cause the clinical symptoms of STGD to not develop in a subject who may be predisposed to STGD but who does not yet experience or display symptoms of STGD.Best Disease

[0181] Vitelliform dystrophy, or Best disease, is a hereditary retinal dystrophy involving the retinal pigment epithelium (RPE), and leads to a characteristic bilateral yellow “egg-yolk” appearance of the macula. This disease tends to present itself in childhood or early adulthood. Best disease is caused by mutations in the BEST1 gene, which encodes the transmembrane protein bestrophin 1. The mutations lead to a buildup of lipofuscin between the outer retina and the retinal pigment epithelium.

[0182] Some embodiments provided herein describe the use of the compositions described herein for treating Best disease in a subject in need thereof. In some embodiments, the compositions inhibit Best disease. In certain embodiments, the compositions arrest development of Best disease or its clinical symptoms. In certain embodiments, the compositions reduce development of Best disease or its clinical symptoms. In certain embodiments, the compositions relieve the subject of Best disease. In certain embodiments, the compositions cause regression, reversal, or amelioration of Best disease. In certain embodiments, the compositions reduce the number, frequency, duration, or severity of Best disease clinical symptoms.

[0183] In some embodiments, the compositions are used prophylactically. In certain embodiments, the compositions are used to prevent or reduce the risk of developing Best disease. In certain embodiments, the compositions cause the clinical symptoms of Best disease to not develop in a subject who may be predisposed to Best disease but who does not yet experience or display symptoms of Best disease.Geographic Atrophy

[0184] Geographic atrophy is a chronic progressive degeneration of the macula and can be seen as part of late-stage age-related macular degeneration (AMD). The condition leads to central scotomas and permanent loss of visual acuity. The disease is characterized by localizedAtorney Docket No. 56350-744.601sharply demarcated atrophy of outer retinal tissue, retinal pigment epithelium and choriocapillaris.

[0185] Some embodiments provided herein describe the use of the compositions described herein for treating geographic atrophy in a subject in need thereof. In some embodiments, the compositions inhibit geographic atrophy. In certain embodiments, the compositions arrest development of geographic atrophy or its clinical symptoms. In certain embodiments, the compositions reduce development of geographic atrophy or its clinical symptoms. In certain embodiments, the compositions relieve the subject of geographic atrophy. In certain embodiments, the compositions cause regression, reversal, or amelioration of geographic atrophy. In certain embodiments, the compositions reduce the number, frequency, duration, or severity of geographic atrophy clinical symptoms.

[0186] In some embodiments, the compositions are used prophylactically. In certain embodiments, the compositions are used to prevent or reduce the risk of developing geographic atrophy. In certain embodiments, the compositions cause the clinical symptoms of geographic atrophy to not develop in a subject who may be predisposed to geographic atrophy but who does not yet experience or display symptoms of geographic atrophy.Adult Vitelliform Maculopathy

[0187] Adult vitelliform maculopathy is an eye disorder that can cause progressive vision loss. The condition causes the accumulation of lipofuscin in the cells underlying the macula. The condition typically manifests after the age of 40. The condition can be caused by mutations in the RDS and VMD2 genes.

[0188] Some embodiments provided herein describe the use of the compositions described herein for treating adult vitelliform maculopathy in a subject in need thereof. In some embodiments, the compositions inhibit adult vitelliform maculopathy. In certain embodiments, the compositions arrest development of adult vitelliform maculopathy or its clinical symptoms. In certain embodiments, the compositions reduce development of adult vitelliform maculopathy clinical symptoms or its clinical symptoms. In certain embodiments, the compositions relieve the subject of adult vitelliform maculopathy. In certain embodiments, the compositions cause regression, reversal, or amelioration of adult vitelliform maculopathy. In certain embodiments, the compositions reduce the number, frequency, duration, or severity of adult vitelliform maculopathy clinical symptoms.

[0189] In some embodiments, the compositions) are used prophylactically. In certain embodiments, the compositions are used to prevent or reduce the risk of developing adult vitelliform maculopathy. In certain embodiments, the compositions cause the clinical symptoms of adult vitelliform maculopathy to not develop in a subject who may be predisposed to adultAtorney Docket No. 56350-744.601vitelliform maculopathy but who does not yet experience or display symptoms of adult vitelliform maculopathy.Stargardt-like macular dystrophy

[0190] Stargardt-like macular dystrophy is similar in symptoms and presentation to Stargardt disease, but typically presents later in childhood than Stargardt disease. Stargardt-like macular dystrophy is linked with mutations in the EVOVL4 gene.

[0191] Some embodiments provided herein describe the use of the compositions described herein for treating Stargardt-like macular dystrophy in a subject in need thereof. In some embodiments, the compositions inhibit Stargardt-like macular dystrophy. In certain embodiments, the compositions arrest development Stargardt -like macular dystrophy or its clinical symptoms. In certain embodiments, the compositions reduce development of Stargardt-like macular dystrophy or its clinical symptoms. In certain embodiments, the compositions relieve the subject of Stargardt-like macular dystrophy. In certain embodiments, the compositions cause regression, reversal, or amelioration of Stargardt-like macular dystrophy. In certain embodiments, the compositions reduce the number, frequency, duration, or severity of Stargardt-like macular dystrophy clinical symptoms.

[0192] In some embodiments, the compositions are used prophylactically. In certain embodiments, the compositions are used to prevent or reduce the risk of developing Stargardt-like macular dystrophy. In certain embodiments, the compositions cause the clinical symptoms of Stargardt-like macular dystrophy to not develop in a subject who may be predisposed to Stargardt-like macular dystrophy but who does not yet experience or display symptoms of Stargardt-like macular dystrophy.Diabetic Retinopathy

[0193] Diabetic retinopathy is a diabetes complication that affects the eyes. It may be caused by damage to the blood vessels of the light sensitive tissue at the back of the eye, and can eventually cause blindness. Diabetic retinopathy can be caused when new blood vessels in the retina fail to grow. Diabetic retinopathy may also result from blood vessels becoming damaged and closing off, causing the growth of new, abnormal blood vessels in the retina.

[0194] Some embodiments provided herein describe the use of the compositions described herein for treating diabetic retinopathy in a subject in need thereof. In some embodiments, the compositions inhibit diabetic retinopathy. In certain embodiments, the compositions arrest development diabetic retinopathy or its clinical symptoms. In certain embodiments, the compositions reduce development of diabetic retinopathy or its clinical symptoms. In certain embodiments, the compositions relieve the subject’s diabetic retinopathy. In certain embodiments, the compositions cause regression, reversal, or amelioration of diabeticAtorney Docket No. 56350-744.601retinopathy. In certain embodiments, the compositions reduce the number, frequency, duration, or severity of diabetic retinopathy clinical symptoms.

[0195] In some embodiments, the compositions are used prophylactically. In certain embodiments, the compositions are used to prevent or reduce the risk of developing diabetic retinopathy. In certain embodiments, the compositions cause the clinical symptoms of diabetic retinopathy to not develop in a subject who may be predisposed to diabetic retinopathy but who does not yet experience or display symptoms of diabetic retinopathy.ABCA4 gene associated retinal diseases

[0196] ATP -binding cassette, subfamily A, member 4 (ABCA4) is a protein encoded by the ABCA4 gene in humans and other eukaryotes. The ABCA4 protein is expressed almost exclusively in the retina and is implicated in Stargardt and other eye diseases, including but not limited to fundus flavimaculatus, cone-rod dystrophy, retinitis pigmentosa, and age-related macular degeneration. Diminished ABCA4 activity is linked with excessive accumulation of toxic retinoids and lipofuscin. Such mutations in some instances are detected by sequencing a subject’s DNA or RNA.

[0197] Some embodiments provided herein describe the use of the compositions described herein for treating ABCA4 gene associated retinal diseases in a subject in need thereof. In some embodiments, the compositions inhibit ABCA4 gene associated retinal diseases. In certain embodiments, the compositions arrest development ABCA4 gene associated retinal diseases or their clinical symptoms. In certain embodiments, the compositions reduce development of ABCA4 gene associated retinal diseases or their clinical symptoms. In certain embodiments, the compositions relieve the subject ABCA4 gene associated retinal diseases. In certain embodiments, the compositions cause regression, reversal, or amelioration ABCA4 gene associated retinal diseases. In certain embodiments, the compositions reduce the number, frequency, duration, or severity of ABCA4 gene associated retinal disease clinical symptoms.

[0198] In some embodiments, the compositions are used prophylactically. In certain embodiments, the compositions are used to prevent or reduce the risk of developing ABCA4 gene associated retinal diseases. In certain embodiments, the compositions cause the clinical symptoms ABCA4 gene associated retinal diseases to not develop in a subject who may be predisposed to ABCA4 gene associated retinal diseases but who does not yet experience or display symptoms of ABCA4 gene associated retinal diseases.Methods of Dosing and Treatment Regimens

[0199] The dose of the composition differ, depending upon the patient's condition, that is, stage of the disease, general health status, age, and other factors.Atorney Docket No. 56350-744.601

[0200] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome), or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0201] In one embodiment, the composition comprising Compound 1 described herein, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from administration of the compound disclosed. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.

[0202] In certain embodiments, Compound 1 described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0203] In prophylactic applications, compositions described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, in which the mammal previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition described herein, in order to prevent a return of the symptoms of the disease or condition.Atorney Docket No. 56350-744.601

[0204] In certain embodiments wherein the patient's condition does not improve, upon the doctor's discretion the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0205] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day. In general, however, doses employed for adult human treatment are typically in the range of 0.01 mg to 5000 mg per day. In certain embodiments, oral doses range from about 0.1 mg to about 20 mg per day. In certain embodiments, oral doses range from about 0.5 mg to about 50 mg per day. In certain embodiments, oral dosages range from about 1 mg to about 10 mg per day. In one aspect, doses employed for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiments, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub -doses per day.

[0206] In some embodiments, Compound 1 described herein is administered to a subject or patient in an amount of about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, or about 400 mg. In some embodiments, a compound described herein is administered to a subject or patient in an amount of about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, or about 20 mg. In some embodiments, a compound described herein is administered to a subject or patient in an amount of up to 0.1 mg, up to 0.5 mg, up to 1 mg, up to 5 mg, up to 10 mg, up to 25 mg, up to 50 mg, up tolOO mg, or up to 200 mg. In some embodiments, a compound described herein is administered to a subject or patient in an amount of at least 0.1 mg, at least 0.5 mg, at least 1 mg, at least 5 mg, at least 10 mg, at least 25 mg, at least 50 mg, at least 100 mg, or at least 200 mg.

[0207] In some embodiments, a compound described herein is administered to a subject or patient in an amount of about 0.1 mg per day, about 0.5 mg per day, about 1 mg per day, about 5 mg per day, about 10 mg per day, about 15 mg per day, about 20 mg per day, about 25 mg per day, about 50 mg per day, about 75 mg per day, about 100 mg per day, about 150 mg per day, about 200 mg per day, or about 400 mg per day. In some embodiments, a compound described herein is administered to a subject or patient in an amount of about 0.1 mg per day, about 0.5 mg per day, about 1 mg per day, about 5 mg per day, about 10 mg per day, about 25 mg per day, or about 50mg per day. In some embodiments, a compound described herein is administered to a subject or patient in an amount of up to 0.1 mg per day, up to 0.5 mg per day, up to 1 mg per day, up to 5 mg per day, up to 10 mg per day, up to 25 mg per day, up to 50 mg per day, up to 100 mg per day, or up to 200 mg per day. In some embodiments, a compound described hereinAtorney Docket No. 56350-744.601is administered to a subject or patient in an amount of at least 0.1 mg per day, at least 0.5 mg per day, at least 1 mg per day, at least 5 mg per day, at least 10 mg per day, at least 25 mg per day, at least 50 mg per day, at least 100 mg per day, or at least 200 mg per day.

[0208] In some embodiments, compositions described herein is administered to a subject or patient comprising an amount of about 1 mg to about 20 mg of Compound 1. In some embodiments, a composition described herein is administered to a subject or patient comprising an amount of about 1 mg to about 10 mg of Compound 1. In some embodiments, a composition described herein is administered to a subject or patient comprising an amount of about 0.1 mg to about 20 mg of Compound 1. In some embodiments, a composition described herein is administered to a subject or patient comprising an amount of about 0.5 mg to about 50 mg of Compound 1. In some embodiments, a composition described herein is administered to a subject or patient comprising an amount of about 0.1 mg to about 10 mg of Compound 1. In some embodiments, a composition described herein is administered to a subject or patient comprising an amount of about 0.1 mg to about 100 mg of Compound 1. In some embodiments, a composition described herein is administered to a subject or patient comprising an amount of about 1 mg to about 500 mg of Compound 1.

[0209] In one embodiment, the daily dosages appropriate for Compound 1 described herein, are from about 0.01 to about 50 mg / kg per body weight. In certain embodiments the daily dosages are from about 0.01 to about 25, about 0.01 to about 1, about 0.1 to about 5, about 1 to about 10, about 1 to about 5, about 0.5 to about 5 or about 5 to about 50 mg / kg per body weight. In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0210] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0211] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 and the ED50. The dose ratio between the toxic andAtorney Docket No. 56350-744.601therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and / or the therapeutically effective unit dosage amount for use in mammals, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50 with minimal toxicity. In certain embodiments, the daily dosage range and / or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.

[0212] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and / or (b) administered orally to the mammal; and / or (c) intravenously administered to the mammal; and / or (d) administered by injection to the mammal; and / or (e) administered topically to the mammal; and / or (f) administered non-systemically or locally to the mammal. In some embodiments, a composition is administered orally or parenterally to the subject in need thereof. Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration. In some embodiments, a composition is administered orally or intravenously to a subject in need thereof. In some embodiments, a composition is administered orally to a subject in need thereof.

[0213] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day, e.g., two, three, four or more times daily. In some embodiments, the compounds of Formula (I) described herein are administered daily, every other day, every other day 3 times a week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 3 days, every 4 days, every 5 days, every 6 days, weekly, bi-weekly, 3 times a week, 4 times a week, 5 times a week, 6 times a week, once a month, twice a month, 3 times a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months. In some embodiments, the compositions herein, are administered daily.

[0214] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered toAttorney Docket No. 56350-744.601the mammal every 8 hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to the mammal every 24 hours.

[0215] In certain embodiments wherein a patient's status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (e.g., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 7 days. In one embodiment, the length of the drug holiday is 7 days. In one embodiment, the length of the drug holiday is 14 days. In one embodiment, the length of the drug holiday is 28 days.EXAMPLESExample 1: Characterization of Compound 1XRPD Characterization of Compound 1

[0216] An X-Ray Powder Diffraction (XRPD) diffractogram of Compound 1 (CMPD-1) was acquired using Rigaku Miniflex 6G according to standard instrument procedures provided by manufacturer. Parameters used for the analysis are shown below in Table 1.Table 1XRPD ParametersInstrument: RigakuMiniflex6GRadiation Source: Cu-Ka (1.5406 A)Scan Mode: Coupled 29 / 9Scan Range: 5°-40°Scan Speed: 0.9° / minStep Increment: 0.005°Voltage: 40 kVCurrent: 15 mARotation: 30 rpmDivergence Slit: 0.625 mmSample Holder: Zero-BackgroundCupAtorney Docket No. 56350-744.601DSC Characterization of Compound 1

[0217] A sample of Compound 1 was analyzed by Differential Scanning Calorimetry using a TA Discovery DSC2500 with RCS90 chiller according to standard instrument procedures provided by manufacturer. Parameters used for the analysis are shown below in Table 2. Two replicates of the experiment were run with reproducible results.Table 2DSC ParametersInstrument: TA DiscoveryDSC2500with RCS90 chillerScan Mode: RampTemp. Range: 35°C-275°CHeating Rate: 10.0°C / minMod. Period: NAMod. Amplitude: NAPan / Lid type Non-HermeticReplicates n=2Melt-Quench by DSC Characterization of Compound 1

[0218] A sample of Compound 1 was analyzed by Modulated Differential Scanning Calorimetry using a TA Discovery DSC2500 with RCS90 chiller according to standard instrument procedures provided by manufacturer. Parameters used for the analysis are shown below in Table 3. Two replicates of the experiment were run with reproducible results.Table 3DSC ParametersInstrument: TA Discovery DSC2500withRCS90 chillerMelt Parameters:Scan Mode: RampTemp. Range: 0°C-245°CHeating Rate: 10°C / min.Isothermal Time: 1 minQuench Parameters:Equilibration Temp: 0°CIsothermal Time: 5 minQuench Temp. Liquid N2Isothermal Time: 10sModulatedDSC Parameters:ScanMode: ModulatedTemp. Range: 0°C-275°CHeating Rate: 2°C / min.Modulation Period: 60 sec.Modulation Amplitude: ±1.0°CReplicates n=2Atorney Docket No. 56350-744.601SEM Characterization of Compound 1

[0219] A sample of Compound 1 (CMPD-1) was analyzed by scanning electron microscopy (SEM). Compound 1 morphology consisted of high aspect ratio orthogonal acicular crystals. This morphology was favorable for the detection of low level crystallinity in amorphous solid dispersions by SEM.Example 2A: Generation and Characterization of Polymorphic Form A of Compound 1

[0220] Approximately 40g of crystalline Form A polymorph of Compound 1 was successfully prepared by concentrating solution using rotary evaporation. Residual BHT was largely removed by washing with THF. Characterization of the product formed is shown in FIGs. 21-24. FIG. 21 shows the XRPD characterization of Form A, with reference Form A compound 1 and Form C compound 1 also shown. FIG. 22 shows the results of thermogravimetric analysis (TGA) (left panel) and differential scanning calorimetry (DSC) (right panel) characterization of the Form A formed. FIG. 23 shows images of the Form A polymorph formed from polarized light microscopy (PLM) (left panel) and scanning electron microscopy (SEM) (right panel). FIG. 24 shows the particle size distribution (PSD) of the Form A product formed. The product contained a Dv (90) of 490 micron.

[0221] The Form A polymorph product was then subject to sieving to reduce particle size. Following the sieving procedure, the resulting sieved product was evaluated by XRPD (FIG. 18), PSD and PLM (FIG. 19 and FIG. 20).Example 2B: Generation and Characterization of Polymorphic Form C of Compound 1

[0222] Approximately 3.9g of recrystallized Form C was successfully prepared by slow cooling experiment. Characterization of the product formed is shown in FIG. 14 (XRPD showing comparison to reference Form C) and FIG. 15 (TGA and DSC analysis of the recrystallized Form C).

[0223] The Form C polymorph product was then subject to sieving to reduce particle size. Following the sieving procedure, the resulting sieved product was evaluated by PSD and PLM (FIG. 16 and FIG. 17)Example 2C: Solubility Assessment of Polymorphic Forms of Compound 1

[0224] The polymorphic solid forms described above were assessed for solubility and resulting solubilized stability in the buffers described in Table 4 below, which also shows results. Solubility was tested in each buffer at 37°C, target concentration 2 mg / mL (in free form), equilibration for 24 hours. Samples tested were the sieved samples (200 mesh sieve). FIG. 9 shows resulting XRPDs of residual solids of the tested Form Ain buffer ESI (left panel) and ES2 (right panel). FIG. 10 shows resulting XRPDs of residual solids of the tested Form A in buffer ES3 (left panel) and ES4 (right panel). FIG. 11 shows resulting XRPD of residual solidsAtorney Docket No. 56350-744.601of the tested Form A in buffers ES5, E6, and ES7. FIG. 12 shows resulting XRPDs of residual solids of the tested Form BA in buffer ESI (left panel) and ES2 (right panel). FIG. 13 shows resulting XRPDs of residual solids of the tested Form BA in buffer ES3 (left panel) and ES4, ES5, ES6, and ES7 (right panel).

[0225] The solubility exhibits a strong correlation with physical form. Form A demonstrated higher solubility in all tested media after 2 h.

[0226] After 24 h, the solubility of Form A decreased to equal or similar levels as Form C.This aligns with the observed form change where Form A was fully or partially converted to Form C.

[0227] Based on the solubility results, four media (0.25% SDS in pH 1.2 HC1 buffer, 0.25% SDS in pH 6.8 phosphate buffer (50 mM), 0.25% SDS in water, and FeSSIF-v2, pH 5.8 are employed to initiate the intrinsic dissolution rate (IDR) test.Table 4. shows solubility for Form A and Form C with larger particles.Solubility at 37°C, target concentration 2 mg / mL (in free form), equilibration for 24 hours, LOQ: 0.625 |ig / mLFree form Form A Free form Form CSolubility (mg / mL) XRPD of residual solids Solubility (mg / mL) XRPD of residual solids Solubility media2h 24h (pH) 2h 24h (pH)Form C Form C0.25% SDS in pH 1.2 0.63 0.40 (1.3) + extra peaks 0.40 0.34 (1.3) + extra peaks HC1 buffer (precipitated from (precipitated from buffer) buffer)Form C Form C0.25% SDS in pH 4.5+ extra peaks + extra peaks acetate buffer 0.62 0.45(4.5) 0.42 0.41(4.5)(precipitated from (precipitated from (50mM) buffer) buffer)0.25% SDS in pH 6.8 Form C Form C+ extra peaks + extra peaks phosphate buffer 0.60 0.38 (6.8) 0.35 0.28 (6.8)(50mM) (precipitated from (precipitated from buffer) buffer)Form C+ extra peaks0.25% SDS in water 0.54 0.37 (8.3) 0.34 0.33 (8.3) Form C (precipitated frombuffer)FaSSGF, pH 1.6 0.004 <LOQ Form C <LOQ <LOQ (1.7) Form C(1.7)FaSSIF-v2, pH 6.5 0.009 0.004 (6.4) Form A + Form C <LOQ 0.02 (6.4) Form CFeSSIF-v2, pH 5.8 0.10 0.10 (5.7) Form A + Form C 0.05 0.05 (5.7) Form CAtorney Docket No. 56350-744.601Example 2D: Jet Milling of Polymorphs of Compound 1 to Reduce Particle Size

[0228] Approximately 15.9g of micronized Form A was successfully prepared by jet milling. The resulting size of the product as determined by PSD was as follows: Dv (10): 1.05 micron; Dv (50): 2.94 micron; Dv (90): 8.21 micron. Resulting micronized sample was assessed by XRPD (FIG. 5), TGA and DSC (FIG. 6), PLM / SEM (FIG. 7), and PSD (FIG. 8).

[0229] Micronized From C is prepared analogously.Example 2E: Two-step dissolution of Form A and Form C in Before (larger particles) and After (Small Particles) Jet Milling

[0230] Form A free base (20 mg) or Form C free base (20 mg), both in small particle (jet milling) and large particle (sieve only) formats, were each weighed into a 20 mL glass vial. Solubility medium (10 mL) was added and the resulting suspensions were stirred at 37 °C at 400 rpm and sampled at 2 and 24 hrs. The samples were centrifuged at 37 °C at 14,000 rpm for 5 min. Then the supernatants were analyzed by HPLC for solubility and the pH was obtained. Residual solids (wet cakes) from the 24 h samples was additionally characterized by XRPD to determine the physical form.

[0231] Step 1. FaSSGF, 10 mL of pH 1.6 (pre-heated to 37 °C), was be added to a 40 mL glass vial to disperse the free Form A, free Form A micronization, free Form C, and free Form C micronization with target concentration of 2.0 mg / mL. The glass vials were placed on a 37 °C stirring plate with magnetic stirring at 200 rpm. At 5, 15, 30, and 60 min, 0.5mL of the obtained suspension was withdrawn and centrifuged at 14,000 rpm at 37 °C for 5 min to isolate the supernatant. The supernatant was then analyzed by HPLC for solubility after proper dilution. Residual solids (wet cakes) were analyzed by XRPD and the pH was measured at 60 min.

[0232] Step 2. After sampling from FaSSGF at 60 min, 8 mL of pH 6.5 FaSSIF (pre-heated to 37 °C) was added to the FaSSGF suspension to make the target concentration of the drug substance 1.0 mg / mL. At 90, 120, and 180 minutes, 0.5 mL of the obtained suspension was withdrawn and centrifuged at 14,000 rpm at 37 °C for 5 min to isolate the supernatant. The supernatant was then analyzed by HPLC for solubility after proper dilution. Residual solids (wet cakes) were analyzed by XRPD and the pH was measured at 180 min.

[0233] Resulting XRPD measurements from these experiments are shown in FIG. 3 (Form A) and FIG. 4 (Form C). Solubility results are shown in Table 5 below.

[0234] Free form Form A demonstrated higher solubility than Form C, irrespective of particle sizes. Form A with smaller particles partially converted to Form C, while the large particle sizes exhibited no form change. Despite this, the two-step dissolution of Form A, regardless of particle size, maintained the same level, potentially due to low solubility of Form A. The Form C samples remained unchanged.Attorney Docket No. 56350-744.601Table 5. Two-step dissolutionFree form A Free form A Free form C Free form C Physical form (large (small (large (small particles) particles) particles) particles) Particle size166 pm 8 pm 181 pm 10 pm Dv (90)Solubility (mg / mL) LOQ: 0.0006 mg / mLStep 1: 5 min 0.005 0.002 <LOQ <LOQ FaSSGF (pH 15 min 0.004 0.002 <LOQ <LOQ 1.6) Target 30 min 0.003 0.002 <LOQ <LOQ cone.: 2.0 60 min (pH) 0.002 0.003 <LOQ <LOQ mg / mL XRPD at Form A Form A + C Form C Form C 60minStep 2: add 1 60 min (pH) 0.003 0.002 <LOQ <LOQ volume of 90 min 0.004 0.004 <LOQ <LOQ FaSSIF-v2 120 min 0.003 0.004 <LOQ <LOQ (pH 6.5) 180 min (pH) 0.003 0.004 <LOQ <LOQ Target cone.: XRPD at Form A Form A + C Form C Form C 1.0 mg / mL 180minExample 3A: Formula of a Tablet

[0235] The following is a formula of a tablet containing Compound 1 manufactured according to a method disclosed herein as shown in Table 6.Table 6: Tablet formulationIngredients Percentage by weight of the Tablet Compound 1 5.00CCNa 0.75HPC 6.00MCC 43.25LMH 43.50CSD 0.50Magnesium Stearate 1.00Total 100%Atorney Docket No. 56350-744.601Example 3B: Characterization of a drug product, excipient mixture, and drug substance described herein.

[0236] FIG. 25 shows XRPD pattern overlay of Compound 1 Form C, drug substance (DS), drug product (DP) and excipient mixture.Example 4: Manufacturing Process for a Tablet

[0237] This example illustrates a manufacturing process executed for a tablet formulation disclosed herein according to Table 7.Table 7.Input Materials Manufacturing Steps and IPC / Quality Attributes of Process Parameters Output Materials Compound 1Microcrystalline cellulose(MCC)Hydroxypropyl cellulose (HPC) Dispensing N / A Croscarmellose sodium (CCNa)Silicon dioxide colloidMagnesium stearatePre-BlendingCompound 1 Co-sift with excipientsLactose monohydrate sequentially through 30-meshMicrocrystalline cellulose screen Bulk uniformity: 90.0-110.0% (MCC) Bulk / Tapped Density Hydroxypropyl cellulose (HPC) V-blender PDI: 25 RPM for 3Croscarmellose sodium (CCNa) min or V-blender PD139: 18RPM for 4 min 10 secRoller Compaction and MillingCompression Force: 4 kN / cm(3.0-5.0 kN / cmPress Roller Speed: 2 RPM (1.0- Mesh analysis3.0 RPM) Bulk / Tapped Density Roller Gap Width: 4 mm (4.0- 6.0 mm)Granulator Gap: 1 mmFinal Blending Bulk Uniformity: 90.0-110.0% Roller compacted granulesCo-sift materials through 60- Mesh analysis Magnesium stearatemesh screen Bulk / Tapped DensityAttorney Docket No. 56350-744.601V-blender PDI: 25 RPM for 3min or V-blender PD129: 18RPM for 4 min 10 secIndividual weight: 100.0 mg (92.5-107.5 mg) Average weight: 100.0 mg (95- Tablet Compression 105 mg) Rotor Speed: 10-40 RPM Tablet Thickness: 3.3 mm (3.0- Final blend mixturePrecompression force 3.6 mm) Main compression force Average Hardness: 7.1 kP (4.6- 9.7 kP) Friability: NMT 1% Disintegration Time: <15 min Packaging 100% tablet filler count Bulk Tablet Buttling in HDPE bottle with foil Closure torque test > 3 in-lbs seal Foil Seal check

[0238] The tablet manufactured from the method contained Compound 1. Step (i): co-sifting Compound 1, MCC, LMH, HPC and CCNa through a 30-mesh screen. Step (ii): loading the sifted materials from step (i) to a 100 L blender and blending for 15 min at 15 rpm. Step (iii): unloading the blended materials from step (ii) and sifting through a 30-mesh screen. Step (iv): adding the sifted materials from step (iii) to a 100 L blender and blending for 15 min at 15 rpm. Step (v): co-sifting CSD and intragranular magnesium stearate through a 60-mesh screen and lubricating the blended materials from the step (iv) with a 100 L blender for 5 min at 15 rpm. Step (vi): granulating the lubricated materials from step (v) by roller compaction at a roll pressure of 3 MPa, roll gap of 2.0 mm, roll speed of 4.0 rpm, feed screw speed of 20 rpm and producing a bulk density of 0.5 g / ml. Step (vii): sifting intragranular magnesium stearate through a 60-mesh screen and lubricating with granulated materials from the step (vi) for 5 min at 15 rpm. Step (viii): compressing the materials from the step (vii) into the tablet pharmaceutical composition using a 6.0 mm round shaped punch at a rotary speed of 30 rpm, thickness scale of 2.0 mm, fill depth scale of 6.0 mm and main compression force of 7.0 kN. The tablet produced from step (viii) was 100 mg and had a thickness of 3.00 mm, hardness of 70 N, friability of no more than 1.0% by weight, and disintegration time of less than 15 min. Step (ix): packaging the manufactured tablet into a 45 HDPE and fill the bottle with 30 tablets. After the step (iv), sampling was carried out by taking a sample from each of 10 locations of the blender. A sample from each location was about 197 mg and the sampling was carried out so that all theAtorney Docket No. 56350-744.601individual assays are within mean ±10% (absolute) and RSD% and the NMT is about 5%. After the step (v), BD / TD of the lubricated blend was tested by taking approximately 30 g of the lubricated granule blend from the bin to test the bulk density (BD), tapped density (TD) and compressibility index parameters. The acceptable density is around 0.50 g / ml or in the range of 0.45 to 0.60 g / ml. The standard protocol USP <701> was used to determine disintegration. The standard protocol USP <1217> was used to determine hardness. The standard protocol USP < 1216> was used to determine friability.

Claims

Attorney Docket No. 56350-744.601CLAIMS WHAT IS CLAIMED IS:

1. A method of manufacturing a crystalline compound comprising the steps:milling a crystalline compound,wherein the crystalline compound has the structure:wherein the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three characteristic peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 18.2, 23.5, 27.1, and / or 29.0; andsieving the crystalline compound.

2. The method of claim 1, wherein the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least four peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 18.2, 23.5, 27.1, and / or 29.0.

3. The method of claim 1 or 2, wherein the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, and / or 17.2 at least one peak at 23.5, 27.1, and / or 29.0.

4. The method of any one of claims 1-3, wherein the crystalline compound exhibits an X- ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) 6.7, 9.3, 14.1, and / or 17.2 at least two peaks at 23.5, 27.1, and / or 29.0.

5. The process of any one of claims 1-4, wherein the crystalline compound is micronized.

6. The method of any one of claims 1-5, wherein the crystalline compound comprises a particle size from about 100 nm to about 10 pm, about 1 pm to about 5 pm, about 1 pm to about 2.5 pm, about 1 pm to about 5 pm, or about 1 pm to about 10 pm.

7. The method of any one of claims 1-6, wherein the crystalline compound comprises a particle size of less than 10 pm, less than 5 pm, or less than 2 pm.Attorney Docket No. 56350-744.6018. The method of any one of claims 1-7, wherein the crystalline compound comprises a particle size distribution of no more than 10 pm.

9. The method of any one of claims 1-8, wherein the crystalline compound comprise a particle size distribution of no more than 5 pm.

10. The method of any one of claims 1-9, wherein the crystalline compound comprises a particle size distribution of no more than 2 pm.

11. The method of any one of claims 1-10, wherein the crystalline compound has a solubility of about 0.001 mg / mL to about 0.005 mg / mL.

12. The method of claim 11, wherein the crystalline compound has a solubility of about 0.001 mg / mL after 60 min.

13. The method of claim 11, wherein the crystalline compound has a solubility of about 0.005 mg / mL after 180 min.

14. The method of any one of claims 1-13, wherein the method further comprises manufacturing the crystalline compound comprising the steps of:dissolving a compound in a solvent, the compound having the structure:crystallizing the compound to obtain the crystalline compound.

15. The method of claim 14, wherein the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 9.7, 11.1, 14.5, 16.7, 21.8, 22.3, and 25.5 .

16. The method of claim 14 or 15, wherein the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having peaks at 21.8, and 22.3 and at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 9.7, 11.1, 14.5, 16.7, 21.8, 22.3, and 25.5.Attorney Docket No. 56350-744.60117. The method of claim 14, wherein the crystalline compound is at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% pure.

18. The method of claim 14, wherein the crystalline compound comprises no more than 5% (w / w), no more than 2.5% (w / w), no more than 1% (w / w), no more than 0.5% (w / w), or no more than 0.1% (w / w) impurities.

19. The method of any one of claims 14-18, wherein the solvent comprises methanol, ethanol, acetone, acetonitrile, dichloromethane, dimethyl formamide, ethyl acetate, ethyl ether, isopropanol, tetrahydrofuran, water, or a combination thereof.

20. The method of any one of claims 1-18, wherein the compound is further formulated as a tablet.

21. The method of claim 18, wherein the method further comprises compressing the crystalline compound to provide the tablet.

22. The method of claim 20, wherein the tablet comprises from about 0.5 mg to about 50 mg of the compound.

23. The method of claim 22, wherein the tablet comprises about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, or about 50 mg of the compound.

24. A method of manufacturing a tablet formulation of a crystalline form of a compound, the method comprising the steps:blending a crystalline compound having the structure:with one or more excipients to obtain a mixture, wherein the crystalline compound exhibits a X-ray powder diffraction pattern (XRPD) having at least three characteristic peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0;roller compacting the mixture;Attomey Docket No. 56350-744.601milling the mixture;sieving the mixture to obtain one or more granules comprising a substantially uniform particle size; andcompressing the one or more granules into a tablet.

25. The method of claim 24, wherein the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, and / or 14.1 at least one peak at 17.2, 23.5, 27.1, and / or 29.0.

26. The method of claim 24 or 25, wherein the milling and sieving produces a particle distribution of no more than 10 pm.

27. The method of claim 24 or 25, wherein the milling and sieving produces a particle distribution of no more than 5 pm.

28. The method of claim 24 or 25, wherein the milling and sieving produces a particle distribution of no more than 2 pm.

29. The method of any one of claims 24-28, wherein a D90 of the granules is about 5 pm to about 50 pm, about 5 pm to about 40 pm, about 5 pm to about 30 pm, about 5 pm to about 20 pm, or about 5 pm to about 10 pm.

30. The method of any one of claims 24-28, wherein a D50 of the granules is about 3 pm to about 20 pm, about 3 pm to about 15 pm, about 3 pm to about 10 pm, or about 3 pm to about 5 pm.

31. The method of any one of claims 24-28, wherein a Dio of the granules is about 0.5 pm to about 3 pm, about 0.5 pm to about 2 pm, about 0.5 pm to about 1 pm, about 1 pm to about 2 pm, or about 1 pm to about 1.5 pm.

32. The method of any one of claims 24-29, wherein the tablet comprises from about 0.5 mg to about 50 mg of the crystalline compound.

33. The process of claim 32, wherein the tablet comprises about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, or about 50 mg of the crystalline compound.

34. The method of any one of claims 24-33, wherein the tablet has an average weight of about 50 mg to about 500 mg, about 50 mg to about 400 mg, about 50 mg to about 300Attomey Docket No. 56350-744.601mg, about 50 mg to about 200 mg, about 50 mg to about 100 mg, or about 100 mg to about 200 mg.

35. The method of claim 34, wherein the tablet has an average weight of about 100 mg.

36. The method of any one of claims 24-35, wherein the tablet has an average thickness of about 1 mm to about 10 mm, about 1 mm to about 9 mm, about 1 mm to about 8 mm, about 1 mm to about 7 mm, about 1 mm to about 6 mm, about 1 mm to about 5 mm, about 1 mm to about 4 mm, about 1 mm to about 3 mm, or about 1 mm to about 2 mm.

37. The method of any one of claims 24-36, wherein the tablet has a thickness of about 3.3 mm.

38. The method of any one of claims 24-37, wherein the tablet has an average hardness of about 2 kP to about 10 kP, about 2 kP to about 9 kP, about 2 kP to about 8 kP, about 2 kP to about 7 kP, about 2 kP to about 6 kP, about 2 kP to about 5 kP, about 5 kP to about 10 kP, about 5 kP to about 9 kP, or about 5 kP to about 8 kP.

39. The method of any one of claims 24-38, wherein the tablet has an average hardness of about 7.1 kP.

40. The method of any one of claims 24-39, wherein the tablet has a dissolution time of less than about 15 min.

41. The method of any one of claims 24-40, wherein the one or more excipients comprises a filler, a dispersion polymer, a disintegrant, a glidant, a lubricant, a solid carrier, or a combination thereof.

42. The method of claim 41, wherein the filler comprises lactose monohydrate, mannitol, sorbitol, cellulose, calcium phosphate, starch, sugar, cellulose, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, dibasic calcium phosphate, sucrose, lactose, com starch, potato starch, or a combination thereof.

43. The method of claim 41 or 42, wherein the dispersion polymer comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycolAttorney Docket No. 56350-744.601copolymers, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers, or a combination thereof.

44. The method of any one of claims 41-42, wherein the disintegrant comprises croscarmellose sodium (CCNa), microcrystalline cellulose (MCC), crospovidone, tapioca starch, or a combination thereof.

45. The method of any one of claims 41-43, wherein the glidant comprises colloidal silicon dioxide, talc, com starch, metal silicates, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, metal hydroxides, or combination thereof.

46. The method of any one of claims 41-44, wherein the lubricant comprises magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate, or a combination thereof.

47. The method of any one of claims 41-45, wherein the solid carrier comprises mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, or a combination thereof.

48. The method of any one of claims 41-46, wherein the blending comprises blending the crystalline compound with a filler, a lubricant, a dispersion polymer, or a combination thereof.

49. A method of providing a crystalline compound, the method comprising:contacting a compound with a solution having a pH of about 1.5 to about 6.0, thereby forming a crystalline compound,wherein the crystalline compound exhibits a X-ray powder diffraction pattern (XRPD) having at least three characteristic peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0.

50. The method of claim 48, wherein the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least four peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, 14.1, 17.2, 23.5, 27.1, and / or 29.0.

51. The method of claim 48 or 50, wherein the crystalline compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees twoAttomey Docket No. 56350-744.601theta (± 0.2 degree theta) at 6.7, 9.3, and / or 14.1 at least one peak at 17.2, 23.5, 27.1, and / or 29.0.

52. The method of any one of claims 48-51, wherein the crystalline compound exhibits an X- ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, and / or 14.1 at least two peaks at 17.2, 23.5, 27.1, and / or 29.0.

53. The method of any one of claims 48-52, wherein the compound exhibits an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 9.7, 11.1, 14.5, 16.7, 21.8, 22.3, and 25.5.

54. The method of any one of claims 48-53, wherein the compound exhibits an X-ray powder diffraction pattern (XRPD) having peaks at 21.8, and 22.3 and at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 9.7, 11.1, 14.5, 16.7, 21.8, 22.3, and 25.5.

55. The method of any one of claims 48-52, wherein the solution comprises a surfactant, a phospholipid, a salt, an enzyme, a buffer, or a combination thereof.

56. The method of claim 54, wherein the surfactant comprises sodium lauryl sulfate, sodium dodecyl sulfate, or both.

57. The method of claim 54, wherein the phospholipid comprises lecithin, phosphatidylcholine, or a combination thereof.

58. The method of claim 54, wherein the salt comprises sodium chloride, calcium chloride, potassium chloride, sodium taurocholate, sodium glycocholate, sodium taurochenodeoxycholate, sodium glycochenodeoxycholate, sodium deoxycholate, sodium lithocholate, or a combination thereof.

59. The method of claim 54, wherein the enzyme comprises pepsin, chymotrypsin, trypsin, or a combination thereof.

60. The method of claim 54, wherein the buffer comprises acetate, Tris, phosphate, or a combination thereof.

61. The method of any one of claims 48-58, wherein the compound is micronized.Atorney Docket No. 56350-744.60162. The method of claim 60, wherein the micronized compound has an average particle size of about 100 nm, about 200 nm, about 500 nm, about 1 pm, about 2 pm, about 3 pm, about 5 pm, about 10 pm, or about 20 pm.

63. The method of any one of claims 48-61, wherein the solution has a pH of about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, or about 6.

64. A pharmaceutical composition comprising:one or more granules comprising a compound having the structure:N HNN -.CF3wherein the granules are micronized and have an average particle size of about 0.5 pm to about 20 pm,wherein the compound is crystalline and has an X-ray powder diffraction pattern (XRPD) having at least three peaks expressed in degrees two theta (± 0.2 degree theta) at 6.7, 9.3, and / or 14.1 at least one peak at 17.2, 23.5, 27.1, and / or 29.0; andone or more pharmaceutically acceptable excipients.

65. The pharmaceutical composition of claim 63, wherein the one or more excipients comprises a filler, a dispersion polymer, a disintegrant, a glidant, a lubricant, a solid carrier, an anti -adherent, a filler, a sweetener, a wetting agent, a binder, or a combination thereof.

66. The pharmaceutical composition of claim 64 or 65, wherein the filler comprises lactose monohydrate, mannitol, sorbitol, cellulose, calcium phosphate, starch, sugar, cellulose, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, hydroxypropylcellulose, cellulose acetate, microcrystalline cellulose, dibasic calcium phosphate, sucrose, lactose, corn starch, potato starch, or a combination thereof.

67. The pharmaceutical composition of any one of claims 63-66, wherein the dispersion polymer comprises hydroxypropyl methylcellulose (HPMC), hydroxypropylAttomey Docket No. 56350-744.601methylcellulose-acetate succinate (HPMC-AS), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, polyvinyl alcohol polyvinyl acetate copolymers, polyethylene glycol, polyethylene glycol polypropylene glycol copolymers, polyvinylpyrrolidone (PVP), polyethylene polyvinyl alcohol copolymers, polyoxyethylene-polyoxypropylene block copolymers, or a combination thereof.

68. The pharmaceutical composition of any one of claims 63-66, wherein the disintegrant comprises croscarmellose sodium (CCNa), microcrystalline cellulose (MCC), crospovidone, tapioca starch, or a combination thereof.

69. The pharmaceutical composition of any one of claims 63-67, wherein the glidant comprises colloidal silicon dioxide, talc, corn starch, metal silicates, higher fatty acid metal salts, metal oxides, alkaline earth metal salts, metal hydroxides, or combination thereof.

70. The pharmaceutical composition of any one of claims 63-68, wherein the lubricant comprises magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, leucine, glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate, or a combination thereof.

71. The pharmaceutical composition of any one of claims 63-69, wherein the solid carrier comprises mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, or a combination thereof.

72. The pharmaceutical composition of any one of claims 63-70, wherein the anti-adherent comprises microcrystalline cellulose, lactose monohydrate, hydroxypropyl cellulose, colloidal silicon dioxide, magnesium stearate, or a combination thereof.

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