Crystalline forms, pharmaceutical compositions and methods of use thereof

Abstract

Pharmaceutical compositions and dosage forms of crystalline form A of a PRMT5 inhibitor of formula (I), methods of making and methods of use thereof.

Description

CRYSTALLINE FORMS, PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application Nos. 63 / 627.470. filed on January 31, 2024. 63 / 658.368, filed on June 10, 2024, 63 / 658.373. filed on June 10, 2024, and 63 / 716,637, filed on November 5, 2024, the entire contents of which are incorporated by reference herein.BACKGROUND

[0002] Development of pharmaceutical compositions comprising one or more novel active ingredients requires a variety of considerations, such as route of administration (e.g., enteral, parenteral, topical, etc.), dosage form (e.g., solid - tablet, capsule, etc.; liquid - solution, suspension, syrup, etc.), strength of active ingredient(s) (e.g., 1 mg - 1,000 mg), non-therapeutic component(s) (e.g., excipients) and their respective amounts, and each of these considerations may involve additional considerations such as stability, degradation, sensitivity to light, solubility, taste if administered enterally, palatability, pH, skin irritability, microbial growth, etc. Advancing a novel active ingredient (e.g., a PRMT5 inhibitor) through rigorous regulatory entities requires discovering and developing a pharmaceutical composition that addresses these, or other, considerations.

[0003] PRMT5 inhibitor A-(6-amino-5-ethylpyndin-3-yl)-2-((2 / ?.5X)-5-methyl-2-(2-( l- methyl piperidin-4-yl )benzo|<7|thiazol-5-yl )pi peridin- 1 -yl)-2-oxoacetamide (TNG462) has been disclosed in WO 2022 / 026892. First-generation pharmaceutical compositions and dosage forms of the compound have been disclosed in WO2024091551. The pharmaceutical compositions described in WO2024091551 are relatively low-drug load compositions, and the dosage forms disclosed therein comprise up to 100 mg of active ingredient (the exemplary dosage forms described in Example 7 therein contain 10 mg and 50 mg of active ingredient, at a drug load of 10%).

[0004] To facilitate patient compliance (low pill burden, convenient to swallow pills) and therapeutic efficacy, which may require higher daily doses of the compound (e.g., doses above 50-100 mg / day) there is a need for pharmaceutical compositions containing high loads of the compound of formula (I) with good physical and chemical properties (e.g., hardness, friability, blend flow, density, particle size distribution, dissolution) that could be used for the convenient,reproducible, large scale manufacturing of dosage forms for late-stage clinical development and commercialization.SUMMARY

[0005] In some embodiments, provided is a pharmaceutical composition comprising crystalline Form A of Ar-(6-amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(l -methylpiperidin-4- yl)benzo[<7]thiazol-5-yl)piperidin-l-yl)-2-oxoacetamide (a compound of formula (I))and at least one pharmaceutically acceptable excipient, wherein crystalline Form A has an X- Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2. 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees and wherein the pharmacally acceptable excipient comprises microcrystalline cellulose PH 101.

[0006] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I)(b) a filler comprising microcrystalline cellulose PH 101; wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees.

[0007] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I)(b) a filler comprising microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102; wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees.

[0008] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one. two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) a filler comprising microcrystalline cellulose PH 101;(c) a glidant (e.g., colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g., magnesium stearate).

[0009] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline fonn A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) a filler comprising microcrystalline cellulose PH 101 and PH 102;(c) a glidant (e.g., colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g., magnesium stearate).

[0010] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) about 40% (w / w) to about 60% (w / w) of a filler wherein the filler comprises microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) a glidant (e.g., colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g., magnesium stearate).

[0011] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees; (b) microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 andPH 102;(c) colloidal silicon dioxide;(d) croscarmellose sodium; and(e) magnesium stearate.

[0012] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2. 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2. 23.7±0.2 and 24.5±0.2 degrees;(b) an intragranular filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients.

[0013] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of crystalline form A of the compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) an intragranular filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients.

[0014] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one. two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) an intragranular filler comprising microcrystalline cellulose PH 101;(c) an intragranular glidant (e.g. colloidal silicon dioxide);(d) an intragranular disintegrant (e.g, croscarmellose sodium);(e) an extragranular lubricant (e.g., magnesium stearate);(f) an extragranular filler (e.g., microcrystalline cellulose PH 102);(g) an extragranular glidant (e.g., colloidal silicon dioxide);(h) an extragranular disintegrant (e.g, croscarmellose sodium); and(i) an extragranular lubricant (e.g., magnesium stearate).

[0015] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) intragranular microcrystalline cellulose PH 101;(c) intragranular colloidal silicon dioxide;(d) intragranular croscarmellose sodium;(e) extragranular magnesium stearate;(f) extragranular microcrystalline cellulose PH 102;(g) extragranular colloidal silicon dioxide;(h) extragranular croscarmellose sodium; and(i) extragranular magnesium stearate.

[0016] In some embodiments, provided is a pharmaceutical composition comprising:(a) between 39% (w / w) and 41% (w / w) of crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) between 41% (w / w) and 43% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) between 0.95% (w / w) and 1.05% (w / w) of an intragranular glidant (e.g, colloidal silicon dioxide);(d) between 1.45% (w / w) and 1.55% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium);(e) between 0.45% (w / w) and 0.55% (w / w) of an intragranular lubricant (e.g., magnesium stearate);(f) between 11.5% (w / w) and 12.5% (w / w) of an extragranular filler (e.g, microcrystalline cellulose PH 102);(g) between 0.95% (w / w) and 1.05% (w / w) of an extragranular glidant (e.g., colloidal silicon dioxide);(h) between 1.45% (w / w) and 1.55% (w / w) of an extragranular disintegrant (e.g, croscarmellose sodium); and(i) between 0.95% (w / w) and 1.05% (w / w) of an extragranular lubricant (e.g, magnesium stearate).

[0017] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 40% (w / w) of crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2. 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2.23.7±0.2 and 24.5±0.2 degrees;(b) about 42% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of an intragranular glidant (e.g, colloidal silicon dioxide);(d) about 1.5% (w / w) of an intragranular disintegrant (e.g, croscarmellose sodium);(e) about 0.5% (w / w) of an intragranular lubricant (e.g, magnesium stearate);(f) about 12% (w / w) of an extragranular filler (e.g, microcrystalline cellulose PH 102):(g) about 1.0% (w / w) of an extragranular glidant (e.g, colloidal silicon dioxide);(h) about 1.5% (w / w) of an extragranular disintegrant (e.g, croscarmellose sodium); and(i) about 1.0% (w / w) of an extragranular lubricant (e.g. magnesium stearate).

[0018] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 39.8% (w / w) of crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) about 41.8% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of an intragranular glidant (e.g., colloidal silicon dioxide);(d) about 1.5% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium);(e) about 0.5% (w / w) of an intragranular lubricant (e.g. magnesium stearate);(f) about 11.9% (w / w) of an extragranular filler (e.g, microcrystalline cellulose PH 102);(g) about 1.0% (w / w) of an extragranular glidant (e.g, colloidal silicon dioxide);(h) about 1.5% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 1.0% (w / w) of an extragranular lubricant (e.g., magnesium stearate).

[0019] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 40% (w / w) of crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) about 42% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101:(c) about 1.0% (w / w) of an intragranular glidant (e.g., colloidal silicon dioxide);(d) about 1.5% (w / w) of an intragranular disintegrant (e.g, croscarmellose sodium);(e) about 0.5% (w / w) of an intragranular lubricant (e.g., magnesium stearate);(f) about 12% (w / w) of an extragranular filler (e.g., microcrystallinc cellulose PH 102);(g) about 1.0% (w / w) of an extragranular glidant (e.g., colloidal silicon dioxide);(h) about 1.5% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.5% (w / w) of an extragranular lubricant (e.g., magnesium stearate).

[0020] In some embodiments, provided is a pharmaceutical composition comprising:(a) between 39% (w / w) and 41% (w / w) of crystalline Form A of a compound of formula (I)wherein cry stalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 29, selected from the peaks at 4.4±0.2, 9.6±0.2. 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2.23.7±0.2 and 24.5±0.2 degrees;(b) between 41% (w / w) and 43% (w / w) of intragranular microcry stalline cellulose PH 101;(c) between 0.95% (w / w) and 1.05% (w / w) of intragranular colloidal silicon dioxide;(d) between 1.45% (w / w) and 1.55% (w / w) of intragranular croscarmellose sodium;(e) between 0.45% (w / w) and 0.55% (w / w) of intragranular magnesium stearate;(f) between 11.5% (w / w) and 12.5% (w / w) of extragranular microcry stalline cellulose PH 102;(g) between 0.95% (w / w) and 1.05% (w / w) of extragranular colloidal silicon dioxide;(h) between 1.45% (w / w) and 1.55% (w / w) of extragranular croscarmellose sodium; and(i) between 0.95% (w / w) and 1.05% (w / w) of extragranular magnesium stearate).

[0021] In some embodiments, provided is a pharmaceutical composition comprising:(a) betw een 39% (w / w) and 41% (w / w) of crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in termsof 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) between 41% (w / w) and 43% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.5% (w / w) of intragranular magnesium stearate;(f) between 11.5% (w / w) and 12.5% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 1.0% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.5% (w / w) of extragranular croscarmellose sodium; and(i) about 1.0% (w / w) of extragranular magnesium stearate).

[0022] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 40% (w / w) of crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) about 42% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.5% (w / w) of intragranular magnesium stearate;(1) about 12% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 1.0% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.5% (w / w) of extragranular croscarmellose sodium; and(i) about 1.0% (w / w) of extragranular magnesium stearate).

[0023] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 39.8% (w / w) of crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) about 41.8% (w / w) of intragranular microcrystallme cellulose PH 101;(c) about 1.0% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.5% (w / w) of intragranular magnesium stearate;(1) about 11.9% (w / w) of extragranular microcrystallme cellulose PH 102;(g) about 1.0% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.5% (w / w) of extragranular croscarmellose sodium; and(i) about 1.0% (w / w) of extragranular magnesium stearate).

[0024] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 40% (w / w) of crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) about 42% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.5% (w / w) of intragranular magnesium stearate;(f) about 12% (w / w) of extragranular microcrystallinc cellulose PH 102;(g) about 1.0% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.5% (w / w) of extragranular croscarmellose sodium; and(i) about 0.5% (w / w) of extragranular magnesium stearate).

[0025] In some embodiments, provided is a dosage form comprising a pharmaceutical composition as described herein.

[0026] In some embodiments, provided is a dosage form intended for oral administration comprising a pharmaceutical composition as described herein.

[0027] In some embodiments, provided is a process for preparing a pharmaceutical composition as described herein, comprising:(a) Charging crystalline form A of a compound of Formula (I), an intragranular fdler, an intragranular glidant and an intragranular disintegrant and blending to obtain a prelubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Charging and blending the milled granules with an extragranular fdler, an extragranular disintegrant and an extragranular glidant to obtain a pre-lubrication extragranular blend;(1) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition;

[0028] In some embodiments, provided is a process for preparing a dosage form of as described herein, comprising:(a) Charging crystalline form A of a compound of Formula (1), an intragranular fdler, an intragranular glidant and an intragranular disintegrant and blending to obtain a pre- lubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Pre-blending, sieving, charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre-lubrication extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition;(g) Compressing the pharmaceutical composition into a dosage form; and, optionally(h) Coating the dosage form.

[0029] In some embodiments, provided is a process for preparing a pharmaceutical composition as described herein, comprising:(a) Pre-blending, sieving and charging crystalline form A of a compound of Formula (I), an intragranular filler, an intragranular glidant and an intragranular disintegrant and blending to obtain a pre-lubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Pre-blending, sieving, charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre-lubrication extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition;

[0030] In some embodiments, provided is a process for preparing a dosage form of as described herein, comprising:(a) Pre-blending, sieving and charging crystalline form A of a compound of Formula (1), an intragranular filler, an intragranular glidant and an intragranular disintegrant and blending to obtain a pre-lubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Pre-blending, sieving, charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre-lubrication extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition;(g) Compressing the pharmaceutical composition into a dosage form; and, optionally(h) Coating the dosage form.

[0031] In some embodiments, provided is a processes for preparing a pharmaceutical composition as described herein, comprising:(a) Charging in order: i. 50% of a desired total amount of intragranular filler; ii. a desired total amount of crystalline form A of a compound of Formula (I); iii. a desired total amount of intragranular disintegrant; iv. a desired total amount of intragranular glidant; and v. 50% of the desired total amount of intragranular filler;(b) pre-blending and sieving the components charged at step (a) to obtain a pre-blending intragranular mixture;(c) blending the pre-blending intragranular mixture to obtain a pre-lubrication intragranular blend;(d) Charging, in order: i. 50% of the pre-lubrication intragranular blend; ii. 100% of a desired amount of intragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication intragranular blend; to obtain a lubricated intragranular mixture;(e) Blending the lubricated intragranular mixture to obtain an intragranular blend;(f) Granulating the intragranular blend to obtain granules;(g) Milling the granules to obtain milled granules;(h) Charging, in order: i. 50% of a desired amount of extragranular filler; ii. the milled granules obtained at step (g); iii. a desired amount of extragranular disintegrant; iv. a desired amount of extragranular glidant; v. 50% of a desired amount of extragranular filler;(i) Pre-blending and sieving the components charged at step (h) to obtain a pre-blending extragranular mixture;(j) Blending the pre-blending extragranular mixture to obtain a pre-lubrication extragranular blend;(k) Charging, in order: i. 50% of the pre-lubrication extragranular blend; ii. a desired amount of extragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication extragranular blend; to obtain a lubricated extragranular mixture;(l) Blending the lubricated intragranular mixture to obtain the pharmaceutical composition.

[0032] In some embodiments, provided is a process for preparing a dosage form as described herein, comprising:(a) Charging, in order: i. 50% of a desired total amount of intragranular filler; ii. a desired total amount of crystalline form A of a compound of Formula (I); iii. a desired total amount of intragranular disintegrant; iv. a desired total amount of intragranular glidant; and v. 50% of the desired total amount of intragranular filler;(b) pre-blending and sieving the components charged at step (a) to obtain a pre-blending intragranular mixture;(c) blending the pre-blending intragranular mixture to obtain a pre-lubrication intragranular blend;(d) Charging, in order: i. 50% of the pre-lubrication intragranular blend; ii. 100% of a desired amount of intragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication intragranular blend; to obtain a lubricated intragranular mixture;(e) Blending the lubricated intragranular mixture to obtain an intragranular blend;(f) Granulating the intragranular blend to obtain granules;(g) Milling the granules to obtain milled granules;(h) Charging, in order: i. 50% of a desired amount of extragranular filler; ii. the milled granules obtained at step (g); iii. a desired amount of extragranular disintegrant;iv. a desired amount of extragranular glidant; v. 50% of a desired amount of extragranular filler;(i) Pre-blending and sieving the components charged at step (h) to obtain a pre-blending extragranular mixture;(j) Blending the pre-blending extragranular mixture to obtain a pre-lubrication extragranular blend;(k) Charging, in order: i. 50% of the pre-lubrication extragranular blend; ii. a desired amount of extragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication extragranular blend; to obtain a lubricated extragranular mixture;(l) Blending the lubricated intragranular mixture to obtain the pharmaceutical composition.(m) Compressing the pharmaceutical composition into a dosage form; and, optionally(n) Coating the dosage form.

[0033] In some embodiments, provided is a pharmaceutical composition or a dosage form prepared by any of the processes described herein.

[0034] In some embodiments, provided is a method for treating an MTAP-deficient and / or an MTA-accumulating disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or dosage form described herein.

[0035] In some embodiments, provided is a method of treating a cancer in a subject in need thereof comprising the steps of: a) assessing the level of MTAP and / or MTA in a test sample obtained from said subject, wherein the MTA level can be assessed directly (e.g, by ELISA or LC- MS / MS) or indirectly (e.g., by SDMA-modified protein ELISA or IHC, or by RNA splicing); b) comparing the test sample with a reference, wherein MTAP deficiency and / or MTA accumulation in said test sample compared to the reference indicates the cancer in said subject will respond to therapeutic treatment with a PRMT5 inhibitor; and c) administering an effective amount (e.g., a therapeutically effective amount) of a pharmaceutical composition or dosage form as described herein to the subject identified in step b).

[0036] In some embodiments, provided is a use of a pharmaceutical composition or dosage form described herein in a method for treating an MT AP -deficient and / or an MTA-accumulating disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or dosage form described herein.

[0037] In some embodiments, provided is a use of a pharmaceutical composition or dosage form described herein in the manufacture of a medicament for treating an MTAP-deficient and / or an MTA-accumulating disease in a subject in need thereof.

[0038] In some embodiments, provided is a pharmaceutical composition or dosage form described herein for use in a method for treating an MTAP-deficient and / or an MTA- accumulating disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or dosage form described herein.

[0039] In some embodiments, a pharmaceutical composition or dosage form described herein for use in the manufacture of a medicament for treating an MTAP-deficient and / or an MTA- accumulating disease in a subject in need thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0040] FIG. 1 is an exemplary X-ray powder diffraction pattern of crystalline Form A of the compound of Formula (I).

[0041] FIG. 2A shows an exemplary thermogravimetric analysis (TGA) thermogram of the compound of Formula (I).

[0042] FIG. 2B shows a differential scanning calorimetry (DSC) thermogram for crystalline Form A the compound of Formula (I), under a heat-cool -heat protocol, show ing a melt peak at about 145.8 °C.

[0043] FIG. 3A shows the change of water content (solid curve) and relative humidity (hashed curve) as a function of time in an exemplary DVS experiment for the compound of Formula (I) (Crystalline form A).

[0044] FIG. 3B show s the change of w ater content as a function of relative humidity in an exemplary DVS experiment for the compound of Formula (I) (Crystalline form A).

[0045] FIG. 4A shows the antiproliferative activity (viability at different concentrations) of the compound of Formula (I) in an MT AP -isogenic cell line pair engineered by CRISPR-mediated MTAP gene knockout of the HAP1 chronic myeloid leukemia cell line.

[0046] FIG. 4B shows the antiproliferative activity (viability7at different concentrations) of the compound of Formula (I) in an MT AP -isogenic cell line pair engineered by CRISPR-mediated MTAP gene knockout of the HCT116 colorectal cancer cell line.

[0047] FIG. 4C shows the antiproliferative activity (viability at different concentrations) of the compound of Formula (I) in an MTAP -isogenic cell line pair engineered by reconstituting exogenous MTAP in an endogenous MTAP-deleted LU99 non-small cell lung cancer cell line.

[0048] FIG. 4D shows the antiproliferative activity (viability at different concentrations) of the compound of Formula (I) in an MTAP -isogenic cell line pair engineered by reconstituting exogenous MTAP in an endogenous MTAP-deleted LN18 glioblastoma cell line.

[0049] FIG. 5 A shows the pharmacodynamic activity of the compound of Formula (I) against PRMT5, by showing a graph of a normalized single SDMA-modified protein level at various concentrations of PRMT5 inhibitor of Formula (I) in a HAP 1 MTAP-isogenic cell line pair. Normalized to a DMSO control for each cell tine and represented as mean ± SD.

[0050] FIG. 5B shows the pharmacodynamic activity of the compound of Formula (I) against Type I PRMTs, by showing a graph of a normalized single ADMA-modified protein level at various concentrations of PRMT5 inhibitor of Formula (I) in a HAP 1 MTAP-isogenic cell line pair. Normalized to a DMSO control for each cell tine and represented as mean ± SD.

[0051] FIG. 5C shows a dendrogram of biochemical selectivity7of the compound of formula (I) for PRMT5 in a histone methyltransferase panel.

[0052] FIG. 6 shows the pharmacokinetic profile in cynomolgus monkey of the compound of Formula (I), depicting the free plasma exposures following 3 mg / kg oral gavage of the compound of Formula (I). The GI50 for WT and MTAP -null cells is indicated by dotted lines.

[0053] FIG. 7 shows the results of a 7-day PK / PD study using a LU99 (lung giant cell carcinoma) MTAP -null xenograft model. The compound of Formula (I) was dosed as indicated, and PK and tumor samples were harvested at the indicated timepoints; the SDMA-modified protein levels for each dose as a proportion of vehicle are shown. N=4 tumors per group, and data are presented as mean ± SEM.

[0054] FIG. 8A shows the dose-dependent antitumor activity of the compound of Formula (I) against an LN18 MTAP -null cell line-derived xenograft model. Data are presented as mean ± SEM.

[0055] FIG. 8B shows the dose-dependent antitumor activity of the compound of Formula (I) against an OCI-LY19 MTAP -null cell line-derived xenograft model. Data are presented as mean ± SEM.

[0056] FIG. 8C shows the dose-dependent antitumor activity of the compound of Formula (I) against an MT AP -null mesothelioma patient-derived xenograft model. Data are presented as mean ± SEM.

[0057] FIG. 8D shows the dose-dependent antitumor activity of the compound of Formula (I) against an MT AP -null bladder cancer patient-derived xenograft model. Data are presented as mean ± SEM.

[0058] FIG. 8E shows the dose-dependent antitumor activity of the compound of Formula (I) against an MTAP-null cholangiocarcinoma patient-derived xenograft model. Data are presented as mean ± SEM.

[0059] FIG. 8F shows the dose-dependent antitumor activity7of the compound of Formula (I) against an MTAP-null NSCLC (squamous) patient-derived xenograft model. Data are presented as mean ± SEM.

[0060] FIG. 8G shows the dose-dependent antitumor activity of the compound of Formula (I) (40 mg / kg BID and 100 mg / kg QD) against a LU-99 NSCLC MTAP-null cell line-derived xenograft model. The dotted line is the regression line, which is defined as final mean tumor volume that is 30% less than the initial mean tumor volume. Data are presented as mean ± SEM.

[0061] FIG. 8H shows the dose-dependent antitumor activity of 30 mg / kg BID and 60 mg / kg BID of the compound of Formula (I) against a LU-99 NSCLC MTAP-null cell line-derived xenograft model. The dotted line is the regression line, which is defined as final mean tumor volume that is 30% less than initial mean tumor volume. Data are presented as mean ± SEM.

[0062] FIG. 9A shows the antitumor activity of the compound of Formula (I) in patient-derived xenograft models obtained from bladder cancer, cholangiocarcinoma, mesothelioma, non-small cell lung cancer (e.g, adenocarcinoma and squamous cell carcinoma), and pancreatic cancer (e.g., pancreatic ductal adenocarcinoma). If the final mean tumor volume for the PRMT5 inhibitor-treated mice was greater than the initial mean tumor volume, the data are presented in relation to vehicle-treated tumors (greater than 0). If the final mean tumor volume for the PRMT5 inhibitor-treated mice was less than the initial mean tumor volume, then the data are presented relative to mean tumor volume (less than 0).

[0063] FIG. 9B shows an updated representation of the data from 9A with an additional 3 datapoints for cholangiocarcinoma (1), bladder (1) and lung (1) cancer xenografts. The data for adenocarcinoma and squamous carcinoma of the lung is consolidated in a single category. The graph represents final tumor volume as a percentage of initial tumor volume - the 100 linerepresents no change in tumor volume, values between 0-100% of initial tumor represent reductions in tumor volume, and values above 100 represent increases in tumor volume.

[0064] FIG. 10A shows the ability of compound of Formula (I) to overcome resistance to the MTA-cooperative PRMT5 inhibitor in a diffuse large B cell lymphoma cell line-derived xenograft model. Data are presented as mean ± SEM.

[0065] FIG. 10B shows the enlarged portion of FIG. 10A with broken y-axis to highlight the region of interest.

[0066] FIG. 11 shows waterfall plots of 180 cancer cell lines representing multiple cancer lineages including NSCLC, PDAC, bladder, CNS, and heme malignancies, which were profiled with PRMT5 inhibitor of Formula (I) in a 7-day CellTiter-Glo assay. The maximum effect at a concentration equal to 10X the HAP1 MT AP -null GIso is reported and the cell lines are fill- coded by MTAP status.

[0067] FIG. 12 shows the antitumor activity of the compound of Formula (I), at 30 mg / kg BID, alone or in combination with 1 mg / kg QD osimertinib, against an NCI-H1650 NSCLC MTAP- null cell line-derived xenograft model. Data are presented as mean ± SEM.

[0068] FIG. 13 shows the antitumor activity of the compound of Formula (I), at 30 and 60 mg / kg BID alone and at 30 mg / kg BID in combination with 10 mg / kg BID AGI-41998, against an NCI-H838 NSCLC MTAP -null cell line-derived xenograft model. Data are presented as mean ± SEM.

[0069] FIG. 14 shows a schematic representation of the process for manufacturing the pharmaceutical compositions and dosage forms of the present disclosure.

[0070] FIG. 15 shows a schematic representation of the original clinical trial design described in Example 20.

[0071] FIG. 16 shows preliminary mean steady -state conc-time profiles and standard deviations (SD) (linear scale) for TNG462 administered at doses of 160 mg QD (n=8) and 300 mg QD (n=4) as described in Example 20.

[0072] FIG. 17 shows preliminary mean steady-state pharmacokinetic parameters and standard deviations (SD) as fold over the in vitro HAP1 MTAP del GI90 for TNG462 administered at a dose of 300 mg QD as described in Example 20 (n=4).

[0073] FIG. 18 shows the Mean AUC on cycle 1, day 15 for all cohorts (20 mg QD, 40 mg QD, 80 mg QD, 160 mg QD, 300 mg QD and 600 mg QD. A dashed line represents the in vitro HAP1 MTAP Del GI90 and a dotted line represents the non-human primates no observed adverse effect level / highest non-severely toxic dose (NHP NOAEL) / HNSTD.

[0074] FIG. 19 shows the compaction profile for the crystalline form A of the compound of Formula (I), two different batches.

[0075] FIG. 20 shows the compaction profile for dosage forms containing 10 mg and 50 mg of crystalline form A of the compound of Formula (I) at 10% drug-load formulation as described in WO2024091551 and a dosage form containing 150 mg crystalline form A of the compound of Fonnula (I) at 40% drug-load formulation as described in the instant application.

[0076] FIG. 21 shows the particle size distribution for two lots of milled granules of a formulation as described in the instant application containing 40% drug-load of crystalline form A of the compound of Fonnula (I).DETAILED DESCRIPTION

[0077] As generally described herein, the present disclosure provides pharmaceutical compositions and dosage forms containing crystalline form A of a compound of formula (1):methods of making the pharmaceutical compositions and dosage forms, and methods of using the pharmaceutical compositions to treat medical conditions, diseases, and disorders e.g., proliferation diseases such as cancers.Definitions

[0078] As used in the present disclosure, the following words and phrases are generally intended to have the meanings as set forth below unless expressly indicated otherwise or the context in which they are used indicates otherwise.

[0079] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0080] Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0081] In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

[0082] Further, it should be understood that elements and / or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present invention and / or in methods of the present invention, unless otherwise understood from the context. Where elements are presented as lists, e.g, in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.

[0083] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i. e.. to at least one) of the grammatical object of the article, unless the context is inappropriate. By way of example, in certain contexts, “an element” means one element and / or in certain contexts more than one element. By way of another example, in certain contexts “a filler” means one filler and / or in certain contexts more than one filler (e.g, a mixture of two or more fillers).

[0084] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0085] It should be understood that the expression “at least one of’ includes individually each of the recited objects after the expression and the various combinations of two or more of therecited objects unless otherwise understood from the context and use. The expression “and / or’" in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.

[0086] The use of the term “include,” "‘includes,” "‘including,” “have,” "‘has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0087] Where the use of the term “about” is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred from the context.

[0088] At various places in the present specification, variables or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22. 23. 24. 25. 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0089] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present invention and does not pose a limitation on the scope of the invention unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention.

[0090] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

[0091] As used herein, “XRPD” refers to X-ray powder diffraction. An XRPD pattern is an x-y graph with 20 (diffraction angle) plotted on the x-axis and intensity plotted on the y-axis. These are the diffraction peaks which may be used to characterize a crystalline material. The diffraction peaks are usually represented and referred to by their position on the x-axis rather than the intensity of the diffraction peaks on the y-axis because diffraction peak intensity can be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee & Web, pp. 255- 257 (2003)). Thus, intensity is not typically used by those of skill in the art to characterize acrystalline material. As with any data measurement, there may be variability7in XRPD data. In addition to the variability7in diffraction peak intensity, there may also be variability in the position of the diffraction peaks on the x-axis. This variability can, however, typically be accounted for when reporting the positions of diffraction peaks for purposes of characterization. Such variability in the position of diffraction peaks along the x-axis may be derived from several sources. One such source can be sample preparation. Samples of the same cry stalline material prepared under different conditions may yield slightly different diffractograms. Factors such as particle size, moisture content, solvent content, temperature, and orientation may all affect how a sample diffracts X-rays. Another source of variability comes from instrument parameters. Different X-ray powder diffractometers operate using different parameters and may lead to slightly different diffraction patterns from the same crystalline material. Likewise, different software packages process XRPD data differently and this may also lead to variability. These and other sources of variability are known to those of ordinary skill in the art. Due to such sources of variability, the values of each X-ray diffraction peak may be preceded with the term “about"’ or proceeded with an appropriate range defining the experimental variability (e.g., ± 0.1°, ± 0.2°, ± 0.3°, ± 0.4°. ± 0.5°. etc.).

[0092] Crystalline forms, such as crystalline forms of a compound of formula (I), are readily analyzed by XRPD. The data from x-ray powder diffraction may be used in multiple ways to characterize cry stalline forms. For example, the entire x-ray powder diffraction pattern output from a diffractometer may be used to characterize a crystalline form (e.g., of a compound of formula (I). A smaller subset of such data, however, may also be suitable and used for characterizing such cry stalline forms. Indeed, often even a single x-ray powder diffraction peak may be used to characterize such a cry stalline form. With respect to cry stalline forms of a compound of formula (I), any one or more of the peaks in the x-ray powder diffraction pattern of FIG. 1 may be used to characterize the crystalline form of a compound of formula (I) disclosed herein.

[0093] The term “characteristic peaks” when referring to the peaks in an XRPD pattern of a crystalline form of a given chemical entity (e.g., a crystalline form of a compound of formula (I)) refers to a collection of specific diffraction peaks whose values span a range of 20 values (e.g., 0°-40°) that are, as a whole, unique to that specific cry stalline form.

[0094] As used herein, “crystalline” refers to a solid phase of a given chemical entity having well-defined 3 -dimensional structural order. The atoms, ions, and / or molecules are arranged in aregular, periodic manner within a repeating 3-dimensional lattice. In various embodiments, a crystalline material may comprise one or more discreet crystalline forms.

[0095] As used herein, the terms “crystalline form,’7“crystalline solid form,” “crystal form,” “solid form,” and related terms herein refer to crystalline modifications comprising a given substance (e.g, the compound of formula (I)), including single-component crystal forms and multiple-component crystal forms, and including, but not limited to, polymorphs, solvates, hydrates, and salts.

[0096] The term “substantially crystalline" refers to solid forms that may be at least a particular weight percent crystalline. Particular weight percentages may include 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 70% and 100%. In some embodiments, the particular weight percent of crystallinity is at least 90%. In certain other embodiments, the particular weight percent of crystallinity is at least 95%. In some embodiments, the compound of formula (I) can be a substantially crystalline sample of any of the cry stalline solid forms described herein (e.g, a crystalline form with the XRPD pattern shown in FIG. 1).

[0097] The term “substantially pure” relates to the composition of a specific crystalline solid form (e.g., a crystalline form of the compound of formula (I)) that may be at least a particular weight percent free of impurities and / or other solid forms. Particular weight percentages may include 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In some embodiments, the compound of formula (I) can be a substantially pure sample of any of the crystalline solid forms described herein, (e.g., a crystalline form with the XRPD pattern show n in FIG. 1 (Form A)). In some embodiments, the compound of formula (I) can be a substantially pure cry stalline form with the XRPD pattern shown in FIG. 1 (Form A).

[0098] As used herein, the term “anhydrous” or “anhydrate” when referring to a crystalline form (e.g.. a crystalline form of the compound of formula (I)) means that no water molecules form a portion of the unit cell of the crystalline form. An anhydrous crystalline form may nonetheless contain water molecules that do not form part of the unit cell of the anhydrous crystalline form (e.g., , as residual solvent molecule left behind from the production of the crystalline form). In a preferred embodiment, water can make up about 0.5% by weight of the total composition of a sample of an anhydrous form. In a more preferred embodiment, water can make up about 0.2% by weight of the total composition of a sample of an anhydrous form. In some embodiments, a sample of an anhydrous cry stalline form of the compound of formula (I) contains no water molecules, e.g, no detectable amount of water.

[0099] As used herein, the term “desolvated” or “unsolvated” when referring to a crystalline form (e.g, a crystalline form of the compound of formula (I)) means that no solvent molecules form a portion of the unit cell of the crystalline form. An unsolvated crystalline form may nonetheless contain solvent molecules that do not form part of the unit cell of the unsolvated crystalline form (e.g, as residual solvent molecule left behind from the production of the crystalline form). In a preferred embodiment, the solvent can make up 0.5% by weight of the total composition of a sample of an unsolvated form. In a more preferred embodiment, solvent can make up 0.2% by weight of the total composition of a sample of an unsolvated form. In some embodiments, a sample of an unsolvated crystalline form of the compound of formula (I) contains no solvent molecules, e.g, no detectable amount of solvent.

[0100] As used herein, the terms “polymorph.” “polymorphic form,” “polymorphs,” “polymorphic forms” and related terms herein refer to two or more crystal forms that consist essentially of the same molecule, molecules, or ions (e g., the compound of formula (I)). Different polymorphs may exhibit different physicochemical properties including, but not limited to, melting temperatures, solubilities, dissolution rates, and physical stabilities as a result of differences in the arrangement or conformation of the molecules or ions in the crystal lattice.

[0101] The term “solvate” when referring to a crystalline form of the compound of formula (I) means that solvent molecules (e.g., organic solvents and water), form a portion of the unit cell of the crystalline form. Solvates that contain water as the solvent are also referred to herein as “hydrates.”

[0102] As used herein, “dissolution profile” refers to dissolution testing of a drug substance or drug product at multiple time points. Dissolution profiles for drug substances (e.g., the compound of formula (I)) or drug products (e.g., the pharmaceutical compositions described herein) may be performed for characterization and quality control to ensure the drug is released at a defined range of rates in a well-defined dissolution aqueous media that is at least sink conditions for that drug, or in biorelevant media such as simulated gastric or intestinal fluids representing either the fasted or fed states. In certain cases, but not others, dissolution testing may be predictive of or give insight into in vivo bioavailability of the drug substance. Dissolution testing may be performed using USP testing protocols and dissolution apparatus.

[0103] As used herein, “granulation” refers to a process of forming granules from a powdered or particulate material. As used herein, “Dry granulation” refers to a process in which granules are formed without the presence of a liquid solution and may be useful in the preparation of granules of materials sensitive to heat, moisture, or solvents. For example, roller compaction is a drygranulation process. As used herein, “Wet granulation” refers to the formation of granules wherein the particles are bound together using a binder or a liquid solution. Examples of wet granulation are high shear granulation and fluid bed granulation.

[0104] As used herein, “pharmaceutical composition” or “pharmaceutical formulation” refer to the combination of a therapeutically active agent with a pharmaceutically acceptable excipient, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0105] “Pharmaceutically acceptable” refers to compounds, molecular entities, compositions, materials and / or dosage forms that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or human, as appropriate; or means approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0106] As used herein, “pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present disclosure (e.g., the compound of formula (I)), which salt is compatible with pharmaceutical administration.

[0107] As is known to those of skill in the art, “salts” of compounds may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acid. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0108] Examples of bases include, but are not limited to, alkali metal (e.g.. sodium and potassium) hydroxides, alkaline earth metal (e.g, magnesium and calcium) hydroxides, ammonia, and compounds of formula NW4+, wherein W is Ci-4 alkyl, and the like.

[0109] Examples of salts include, but are not limited, to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate,picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present disclosure compounded with a suitable cation such as Na+. K+. Ca2+. NH4+, and NW4+(where W can be a Ci-4 alkyl group), and the like.

[0110] For therapeutic use, salts of the compounds of the present disclosure are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.[OHl] As used herein, “pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and / or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include binders, diluents, carriers, adjuvants, fillers (e.g., brittle diluents or fillers and ductile diluents or fillers), disintegrants, lubricants, coatings, sweeteners, flavors, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxypropyl methylcellulose, polyvinyl pyrrolidine, and colors, and the like. For examples of excipients, see Gennaro. Remington's Pharmaceutical Sciences, 18thEd., Mack Publ. Co., Easton, PA (1990) or Shesky, Hancock, Moss and Goldfarb, Handbook of Pharmaceutical Excipients, 9thEd. Pharmaceutical Press, London, UK (2020).

[0112] Examples of diluents or fillers include, but are not limited to, a sugar (e.g., mannitol, lactose, sorbitol, lactitol, erythritol, sucrose, fructose, glucose, agarose, maltose, isomalt, poly dextrose, and combinations thereof), an inorganic material (e.g., dibasic calcium phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, bentonite, kaolin), calcium lactate, a starch (e.g., a pregelatinized starch), a microcrystalline cellulose, a silicified microcrystalline cellulose, a polysacchande, a cellulose (e.g.. a hydroxypropyl cellulose, a hypromellose, a carboxymethylcellulose, a methylcellulose, a hydroxypropyl methylcellulose, a hydroxy ethylcellulose), a dextrin, a maltodextrin, an alginate, a collagen, a polyvinylpyrrolidone, a polyvinyl acrylate, polyethylene oxide, and polyethylene glycol. Sugar is defined herein to include sugar alcohols.

[0113] Examples of disintegrants include, but are not limited to, alginic acid, an alginate, primogel, a cellulose (e.g., hydroxypropyl cellulose), polacrillin potassium, sodium starch glycolate, sodium croscarmellose, a polyplasdone (e.g., a crospovidone), and a starch (e.g., com starch, pregelatinized starch, hydroxypropyl starch, and carboxymethyl starch).

[0114] Examples of binders include, but are not limited to, a hydroxypropyl cellulose, hydroxyethylcellulose, a hydroxypropyl methylcellulose (e.g., a low viscosity' hydroxypropyl methylcellulose), a sugar, a polyvinylpyrrolidone, a polyvinyl alcohol, a polyvinyl acetate, a poly dextrose, a chitosan, a carrageenan, carbophil, a microcrystalline cellulose, gum tragacanth, guar gum, gellan gum, gelatin, and a starch (e.g., com starch).

[0115] Examples of wetting agents include, but are not limited to, a poloxamer (e.g., poloxamer 407), sodium dodecyl sulfate, sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), a poly dimethylsiloxane, a polysorbate (e.g., polyoxyethylene 20 sorbitan mono-oleate (Tween® 20)), sorbitan monooleate, sorbitan trioleate, sorbitan laurate, sorbitan stearate, sorbitan monopalmitate, lecithin, sodium taurocholate, ursodeoxy cholate, poly ethoxylated castor oil, cetyl trimethylammonium bromide, nonoxynol, a-tocopherol polyethylene glycol 1000 succinate, and docusate sodium.

[0116] Examples of lubricants and glidants include, but are not limited to, a wax, a glyceride, a light mineral oil, a polyethylene glycol, sodium steary l fumarate, magnesium stearate, stearic acid, hydrogenated oil (e.g., hydrogenated vegetable oil), an alkyl sulfate, sodium benzoate, sodium acetate, glyceryl behenate, palmitic acid, and coconut oil.

[0117] Examples of glidants include, but are not limited to, colloidal silicon dioxide, colloidal silicon dioxide, talc, kaolin, bentonite, and activated carbon / charcoal.

[0118] Examples of colorants include, but are not limited to, titanium dioxide, aluminum lakes, iron oxides and carbon black.

[0119] Examples of coatings include but are not limited to, a film forming polymer (e.g., a hypromellose, a methyl cellulose, an ethylcellulose, cellulose acetate, a hydroxypropyl methyl cellulose, a hydroxypropyl cellulose, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, a polyvinylpyrrolidone, polyvinyl alcohol, a Eudragit / acrylate) and a plasticizer (e.g, triacetin, polyethylene glycol, propylene glycol).

[0120] Pharmaceutical compositions for oral administration (e.g., pharmaceutical compositions of the compound of formula (I) described herein) can take the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term ‘"unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pills, tablets, capsules or the like in the case of solid compositions.

[0121] A “subject’' to which administration is contemplated includes, but is not limited to, humans (i.e. , a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a nonhuman animal, e.g., a mammal such as primates (e.g, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is anon-human animal.

[0122] As used herein, “solid dosage form” means a pharmaceutical dose(s) in solid form, e.g., tablets, capsules, granules, powders, minitabs, sachets, stickpacks, reconstitutable powders, dry powder inhalers, lozenges, and chewables.

[0123] As used herein, “administering” means oral administration, administration as a pulmonary, suppository, intramuscular administration, intrathecal administration, intranasal administration or subcutaneous administration, or the implantation of a slow-release device, e.g, a mini-osmotic pump, to a subject. Administration is by any route, including transmucosal (e.g. , buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or). Parenteral administration includes, e.g., intramuscular and subcutaneous. Other modes of delivery' include, but are not limited to, the use of liposomal formulations, etc. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., anti-cancer agent, chemotherapeutic, or treatment for a neurodegenerative disease). The compound of formula (I) can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g, to reduce metabolic degradation).

[0124] The terms “disease,” “disorder,” and “condition” are used interchangeably herein.

[0125] As used herein, and unless otherwise specified, the terms “treat.” "treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment'’), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”). In one embodiment, the compounds provided herein are contemplated to be used in methods of therapeutic treatment wherein the action occurs while a subject is suffering from the specified disease, disorder or condition and results in a reduction in the severity of the disease, disorder or condition, or retardation orslowing of the progression of the disease, disorder or condition. In an alternate embodiment, the compounds provided herein are contemplated to be used in methods of prophylactic treatment wherein the action occurs before a subject begins to suffer from the specified disease, disorder or condition and results in preventing a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or preventing the recurrence of the disease, disorder or condition.

[0126] In general, the "‘effective amount” of a compound refers to an amount sufficient to elicit the desired biological response e.g, to treat a disease or disorder described herein. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment (z.e., encompasses a “therapeutically effective amount” and a “prophylactically effective amount”).

[0127] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the therapeutic treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the therapeutic treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0128] As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0129] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are descnbed in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March 's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York. 1989; and Carruthers. Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0130] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al.. Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981 ); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). Additionally encompassed are compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0131] The “enantiomeric excess” (“e.e.”) or “% enantiomeric excess” (“%e.e.”) of a composition as used herein refers to an excess of one enantiomer relative to the other enantiomer present in the composition. For example, a composition can contain 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer. e.e. = (90-10) / 100 = 80%.

[0132] Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%.

[0133] The “diastereomeric excess” (“d.e.”) or “% diastereomeric excess” (“%d.e.”) of a composition as used herein refers to an excess of one diastereomer relative to one or more different diastereomers present in the composition. For example, a composition can contain 90% of one diastereomer, and 10% of one or more different diastereomers.d.e. = (90-10) / 100 = 80%.

[0134] Thus, a composition containing 90% of one diastereomers and 10% of one or more different diastereomers is said to have a diastereomeric excess of 80%.Compound

[0135] In some embodiments, provided herein is jV-(6-amino-5-ethylpyridin-3-yl)-2-((2 ?,5S)-5- methyl-2-(2-(l-methylpiperidin-4-yl)benzo[<7]thiazol-5-yl)piperidin-l-yl)-2-oxoacetamide, a PRMT5 inhibitor (e.g.. an MTA-uncompetitive PRMT5 inhibitor) compound of formula (I).

[0136] The compound of formula (I) is also known as TNG462.

[0137] Tn some embodiments, the compound of formula (I) is a crystalline form of the compound of formula (I). The compound of formula (I) can also be referred to as “Compound I.”

[0138] In certain embodiments, Form A has an XRPD pattern with one or more (e.g, one, two, three or four) characteristic peaks between and including the following values of 20 in degrees: 4.2 to 4.6 (e.g, 4.4±0.2), 9.4 to 9.8 (e.g., 9.6±0.2), 16.6 to 17.0 (e.g, 16.8±0.2) and 24.3 to 24.7 (e.g, 24.5±0.2). In certain embodiments, Form A has an XRPD pattern comprising characteristic peaks between and including the following values of 20 in degrees: 4.2 to 4.6 (e.g. 4.4±0.2). 9.4 to 9.8 (e.g.. 9.6±0.2), 16.6 to 17.0 (e.g., 16.8±0.2) and 24.3 to 24.7 (e.g., 24.5±0.2).

[0139] In certain embodiments, Form A has an XRPD pattern with one or more (e.g., one, two, three, four, five, six, seven or eight) characteristic peaks between and including the following values of 20 in degrees: 4.2 to 4.6 (e.g., 4.4±0.2), 9.4 to 9.8 (e.g., 9.6±0.2), 16.6 to 17.0 (e.g., 16.8±0.2), 18.4 to 18.8 (e.g.. 18.6±0.2), 19.2 to 19.6 (e.g.. 19.4±0.2), 20.7 to 21. l(e.g., 20.9±0.2), 23.5 to 23.9 (e.g., 23.7±0.2) and 24.3 to 24.7 (e.g., 24.5±0.2). In certain embodiments. Form A has an XRPD pattern comprising characteristic peaks between and including the following values of 20 in degrees: 4.2 to 4.6 (e.g., 4.4±0.2), 9.4 to 9.8 (e.g, 9.6±0.2), 16.6 to 17.0 (e.g, 16.8±0.2) and 24.3 to 24.7 (e.g, 24.5±0.2) and at least one additional characteristic peak selected from peaks between and including the following values of 20 in degrees: 18.4 to18.8 (e.g, 18.6±0.2), 19.2 to 19.6 (e.g., 19.4±0.2), 20.7 to 21.1(e.g, 20.9±0.2), 23.5 to 23.9 (e.g., 23.7±0.2).

[0140] In certain embodiments, Form A has an XRPD pattern comprising characteristic peaks between and including the following values of 29 in degrees: 4.2 to 4.6 (e.g., 4.4±0.2), 9.4 to 9.8 (e.g, 9.6±0.2), 16.6 to 17.0 (e.g, 16.8±0.2), 18.4 to 18.8 (e.g, 18.6±0.2), 19.2 to 19.6 (e.g, 19.4±0.2), 20.7 to 21.1(e.g, 20.9±0.2), 23.5 to 23.9 (e.g., 23.7±0.2) and 24.3 to 24.7 (e.g., 24.5±0.2).

[0141] In certain embodiments, Form A has an XRPD pattern with one or more (e.g, one, two, three, four, five, six, seven, eight, nine or ten) characteristic peaks between and including the following values of 20 in degrees: 4.2 to 4.6 (e.g., 4.4±0.2), 9.4 to 9.8 (e.g., 9.6±0.2), 15.7 to 16.1 (e.g, 15.9±0.2). 16.6 to 17.0 (e.g, 16.8±0.2). 18.4 to 18.8 (e.g, 18.6±0.2), 19.1 to 19.5 (e.g, 19.3±0.2), 19.2 to 19.6 (e.g, 19.4±0.2), 20.7 to 21.1 (e.g, 20.9±0.2), 20.8 to 21.2 (e.g, 21.0±0.2), 23.5 to 23.9 (e.g., 23.7±0.2), 24.3 to 24.5 (e.g., 24.5±0.2), 25.5 to 25.9 (e.g., 25.7±0.2) and 33.8 to 34.2 (e.g, 34.0±0.2).

[0142] In certain embodiments, the X-ray powder diffraction pattern for Form A may comprise one or more (e.g, one. two, three or four) characteristic peaks, in terms of 20, selected from the peaks at degrees: 4.4±0.2, 9.6±0.2, 16.8±0.2 and 24.5±0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least one characteristic peak, in terms of 20, selected from the peaks at degrees: 4.4±0.2, 9.6±0.2, 16.8±0.2 and 24.5±0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least two characteristic peaks, in terms of 20, selected from the peaks at degrees: 4.4±0.2, 9.6±0.2, 16.8±0.2 and 24.5±0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least three characteristic peaks, in terms of 29, selected from the peaks at degrees: 4.4±0.2, 9.6±0.2. 16.8±0.2 and 24.5±0.2.

[0143] In certain embodiments, Form A has an XRPD pattern comprising characteristic peaks at the following values of 20 in degrees: 4.4±0.2, 9.6±0.2, 16.8±0.2 and 24.5±0.2.

[0144] In certain embodiments, the X-ray powder diffraction pattern for Form A may comprise one or more (e.g., one, two. three, four, five, six, seven or eight) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2. 9.6±0.2, 16.8±0.2, 18.6±0.2. 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2.

[0145] In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least one characteristic peak, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2. 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least two characteristic peaks, in terms of 20, selected from the peaks at 4.4+0.2. 9.6+0.2, 16.8±0.2, 18.6±0.2. 19.4±0.2, 20.9±0.2, 23.7+0.2 and 24.5+0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least three characteristic peaks, in terms of 29, selected from the peaks at 4.4+0.2, 9.6+0.2, 16.8+0.2, 18.6+0.2, 19.4+0.2, 20.9+0.2, 23.7+0.2 and 24.5+0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least four characteristic peaks, in terms of 20, selected from the peaks at 4.4+0.2, 9.6+0.2, 16.8+0.2, 18.6+0.2, 19.4+0.2, 20.9+0.2, 23.7±0.2 and 24.5±0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least five characteristic peaks, in terms of 20, selected from the peaks at 4.4+0.2, 9.6+0.2, 16.8+0.2, 18.6+0.2, 19.4+0.2, 20.9+0.2, 23.7+0.2 and 24.5±0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least six characteristic peaks, in terms of 20, selected from the peaks at 4.4+0.2, 9.6+0.2, 16.8+0.2, 18.6+0.2, 19.4+0.2, 20.9±0.2, 23.7+0.2 and 24.5+0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least seven characteristic peaks, in terms of 20, selected from the peaks at 4.4+0.2, 9.6+0.2, 16.8+0.2, 18.6+0.2. 19.4+0.2, 20.9+0.2, 23.7±0.2 and 24.5±0.2.

[0146] In certain embodiments, Form A has an XRPD pattern comprising characteristic peaks at the following values of 20 in degrees :4.4±0.2, 9.6+0.2, 16.8+0.2, 19.3+0.2, 19.4+0.2, 20.9+0.2, 23.7+0.2, 24.5+0.2 and at least one additional characteristic peak at a value of 20 in degrees selected from: 19.3±0.2, 19.4±0.2. 20.9±0.2 and 23.7±0.2. In certain embodiments. Form A has an XRPD pattern comprising characteristic peaks at the following values of 20 in degrees :4.4±0.2, 9.6+0.2, 16.8+0.2, 19.3+0.2, 19.4+0.2, 20.9+0.2, 23.7+0.2, 24.5+0.2 and at least two additional characteristic peaks at a value of 20 in degrees selected from: 19.3+0.2, 19.4+0.2, 20.9+0.2 and 23.7+0.2. In certain embodiments. Form A has an XRPD pattern comprising characteristic peaks at the following values of 20 in degrees :4.4±0.2. 9.6+0.2, 16.8+0.2.19.3+0.2, 19.4+0.2, 20.9+0.2, 23.7+0.2, 24.5+0.2 and at least three additional characteristic peak at a value of 20 in degrees selected from: 19.3+0.2, 19.4+0.2, 20.9+0.2 and 23.7+0.2.

[0147] In certain embodiments, Form A has an XRPD pattern comprising characteristic peaks at the following values of 20 in degrees :4.4±0.2, 9.6+0.2, 16.8+0.2. 18.6+0.2, 19.4+0.2, 20.9+0.2, 23.7+0.2, 24.5+0.2.

[0148] In certain embodiments, the X-ray powder diffraction pattern for Form A may comprise one or more (e.g., one, tw o, three, four, five, six, seven, eight, nine, or ten) characteristic peaks,in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6±0.2, 19.3±0.2. 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2 and 34.0±0.2.

[0149] In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least one characteristic peak, in terms of 29, selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6±0.2, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2 and 34.0±0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least two characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2 and 34.0±0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least three characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2. 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2 and 34.0±0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least four characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2 and 34.0±0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least five characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2 and 34.0±0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least six characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2. 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2 and 34.0±0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least seven characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2 and 34.0±0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least eight characteristic peaks, in terms of 20. selected from the peaks at 4.4±0.2. 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2, 25.7±0.2 and 34.0±0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least nine characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2. 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2. 24.5±0.2, 25.7±0.2 and 34.0±0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least ten characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 15.9±0.2, 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2, 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2. 25.7±0.2 and 34.0±0.2.

[0150] In certain embodiments, Form A has an XRPD pattern comprising characteristic peaks at the following values of 20 in degrees: 4.4±0.2, 9.6±0.2, 15.9±0.2. 16.8±0.2, 18.6, 19.3±0.2, 19.4±0.2. 20.9±0.2, 21.0±0.2, 23.7±0.2, 24.5±0.2 and 25.7±0.2. 34.0±0.2.

[0151] In some embodiments, Form A has an XRPD pattern (obtained using CuKa radiation) substantially corresponding to the XRPD diffraction pattern shown in FIG. 1.

[0152] In some embodiments, Form A has an XRPD pattern (obtained using CuKa radiation) with characteristic peaks comprising one, two, three, four, five, six. seven, eight, nine, or ten characteristic peaks, in terms of 20 values in degrees shown in Table 1 (±0.2 degrees).Table. 1. XRPD peaks for Form A of a compound of formula (I)

[0153] In certain embodiments, Form A is substantially characterized by the thermal gravimetric analysis (TGA) as shown in FIG. 2A.

[0154] In certain embodiments, Form A is substantially characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 2B. In some embodiments. Form A can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 2B, showing a melt peak at about 145.8 °C.

[0155] In certain embodiments, Form A is substantially characterized by the DVS profile as shown in FIG. 3A and FIG. 3B.

[0156] In some embodiments, the crystalline form of the compound of formula (I) comprises a mixture of two or more crystalline forms. In some embodiments, the crystalline form of the compound of formula (I) is substantially pure crystalline Form A.

[0157] In some embodiments, the crystalline form A of the compound of formula (I) has a DIO of between 2-4 pm. In some embodiments, the API comprising crystalline form A of the compound of formula (I) has a D50 of betw een 6-10 pm. In some embodiments, the API comprising crystalline form A of the compound of formula (I) has a D90 of between 18-35 pm. In some embodiments, the API comprising crystalline form A of the compound of formula (I) D90 of between 25-30 pm. In some embodiments, the API comprising crystalline form A of the compound of formula (I) has a D90 of less than 30 pm.

[0158] In some embodiments, API comprising cry stalline form A of the compound of formula (I) is subjected to wet milling prior to incorporation in the pharmaceutical compositions and dosage forms described herein to optimize particle size.Pharmaceutical Compositions

[0159] Recent clinical studies performed by the inventors (e.g., Example 20) determined that the balance of clinical efficacy and safety in treating MTAP-deleted cancers with a compound of Formula (I) was obtained when the compound was administered at doses between 200 mg and 300 mg once daily (QD). The exemplary pharmaceutical compositions of crystalline form A of the compound of Formula (I) described in WO2024091551, containing 10% drug load would be suboptimal for preparing dosage forms capable of delivering a daily dose of 200-300 mg of active pharmaceutical ingredient (API). Use of a low drug-load formulation would result either in very large tablets that would be inconvenient for the patients to swallow, or in a need to administer multiple smaller tablets, which would increase pill burden and potentially decrease patient compliance.

[0160] The crystalline Form A of the compound of Formula (I) is partly plastic (not highly compressible) as shown in FIG. 19. In the two batches analyzed, a change in compression force from 2-5 kN and from 4-8 kN, respectively, only resulted in an increase in hardness from 60-80 N to 130-140N, with signs of plateauing at the higher compression forces.

[0161] The inventors have found that the compressibility index for the API is -43-49% (for the same two batches used for the data shown in FIG. 19), which is considered extremely poor under United States Pharmacopeia (USP) guidelines (see Table. 2). The compressibility index is calculated as: lOO(Vo-Vf) / Vo where Vf is the tapped volume and Vo is the untapped volume of a given amount of compound.

[0162] The Hausner ratio for the API was found to be in the range of 1.76-1.95 for the two batches, which is also considered extremely poor under USP guidelines. The Hausner ratio is the ratio of bulk density to tapped density, also expressed as Vf / Vo (where Vf is the tapped volume and Vo is the untapped volume of a given amount of compound). Vo and Vf can be determined, for example, as described in USP<616>.Table. 2. USP Pharmacopeia guidelines for flowability, compressibility and Hausner Ratio

[0163] Good flowability (low Hausner Ratio and Compressibility Index) are important in ensuring uniform mixing and consistent distribution of API and excipients, as well as more efficient processing due to smoother movement through hoppers and feeders. Powders with poor flowability are prone to segregation of API and excipients, and to manufacturing challenges such as interruptions, blockages and variable feed rates. Additionally, high compressibility’ (low compressibility indices) is beneficial for obtaining denser tablets with adequate tablet hardness and smaller tablet size, whereas powders with poor compressibility can result in tablets with low strength, which are prone to issues such as lamination, capping or tablet breakage.

[0164] The first-generation formulation containing 10% drug load resulted in an improvement in compressibility compared to API alone, as seen in FIG. 20. but due to the poor compressibility' of the API it would not be expected that the improvement in compressibility would be maintained for higher API loads without additional changes to the formulation. Simply increasing the drug load in the first-generation formulation would result in poorer flowability' of the powder blend, which in turn would lead to manufacturability issues such as inadequate blend uniformity, insufficient compressibility and sticking to equipment.

[0165] The common knowledge in the art suggests that for compositions comprising API’s with poor compressibility ("plastic" APIs), a combination of fillers including “brittle” fillers such as lactose or mannitol is recommended in the intragranular blend to achieve high drug loads (See, e.g., Teng, et al.. “Systematical approach of formulation and process development using roller compaction”, European Journal of Pharmaceutics and Biopharmaceutics, 73 (2009) 219-229, Section 2.1.2). The literature also suggests that binders are generally required for intragranular blends to be used in dry granulation processes to ensure granules that have adequate strength, can be deformed, and can be mixed homogenously with extragranular components (See Teng, section 2.2). However, using a high number of excipients (such as multiple intragranular fillers, one or more binders, etc.) in high-drug load blends where the total amount excipients is relatively low increases the risk for lack of uniformity in the blends and in the resulting tablets. Minimizing the number of excipients, for example by eliminating binders and using a single filler is preferable to ensure blend uniformity.

[0166] The pharmaceutical compositions described herein surprisingly achieve good density and flowability even at high API loads (e.g., 40%) using a single intragranular filler and no binder, despite the very poor compressibility' and flowability of the API (crystalline form A of the compound of Formula (I)).

[0167] Surprisingly, the high API-load pharmaceutical compositions described herein, in which granules represent -85% of the formulation achieve higher compressibility (FIG. 20) and granule density (Table. 3) than the first-generation low API-load compositions. Generally, higher granule density corelates with better compressibility.Table. 3. Granule density7for first and second generation formulations

[0168] In a separate measurement, the angle of repose (which is another way to measure flowability) for the granules of the current formulation was determined to be -33, which places it in the “good” category according to the USP (Table. 4).Table. 4. USP Pharmacopeia guidelines for flowability' based on angle of repose

[0169] Additionally, the granules obtained with the instant formulations can be milled to obtain a favorable and reproducible mix of small and large particles (FIG. 21).

[0170] Thus, contrary to expectations based on general knowledge, the pharmaceutical compositions disclosed herein achieve high API loads (e.g.. 40%) and adequate properties such as tablet strength, particle size distribution, density and flow while using a single intragranular filler, a glidant, a disintegrant and a lubricant only, with no addition of binders. The instant formulations display consistent performance for small and large scale production (Table. 3) with equal or better properties compared to the low API-load formulations previously disclosed.

[0171] In some embodiments, provided are pharmaceutical compositions comprising crystalline Form A of a compound of formula (I)and at least one pharmaceutically acceptable excipient, wherein cry stalline Form A is as described herein.

[0172] In some embodiments, provided are pharmaceutical compositions comprising as the pharmaceutically active ingredient a compound of formula (I)and at least one pharmaceutically acceptable excipient, wherein the compound of formula (I) is present as cry stalline Form A as described herein.

[0173] In some embodiments, provided are pharmaceutical compositions comprising crystalline Form A of a compound of formula (I)and at least one pharmaceutically acceptable excipient, wherein crystalline Form A is as described herein and the pharmaceutically acceptable excipient comprises microcrystal line cellulose PH 101.

[0174] In some embodiments, provided are pharmaceutical compositions comprising as the pharmaceutically active ingredient a compound of formula (I)and at least one pharmaceutically acceptable excipient, wherein the compound of formula (I) is present as crystalline Form A as described herein and the pharmaceutically acceptable excipient comprises microcrystalline cellulose PH 101.

[0175] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 60% (w / w) of the crystalline form A of compound of formula (I) as described herein(b) a filler comprising microcrystalline cellulose PH 101.

[0176] In some embodiments, provided is a pharmaceutical composition compnsing:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (1) as described herein(b) a filler comprising microcrystalline cellulose PH 101.

[0177] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 60% (w / w) of the crystalline form A of compound of formula (I) as descnbed herein(b) a filler comprising microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102.

[0178] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I) as described herein(b) a filler comprising microcrystalline cellulose PH 101 and merocrystalline cellulose PH 102.

[0179] In some embodiments the composition comprises one or more additional pharmaceutically acceptable excipients.

[0180] The amounts and ranges described below as pertaining to ”a compound of formula (1)” can refer to the compound of formula (I) generally, to a crystalline form of a compound of formula (I), or to the crystalline form A of the compound of formula (I) described herein.

[0181] The pharmaceutical compositions and dosage forms described herein are characterized by relatively high API loads, which are beneficial for minimizing dosage form (e g., tablet) size, thus improving patient dosing convenience. High API loads, particularly in the case of crystalline APIs such as the instant case can result in blends with sub-optimal manufacturability properties (e.g., uniformity, flow, compressibility, API release profiles) requiring careful optimization of the pharmaceutical excipients.

[0182] In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 60% (w / w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 55% (w / w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 50% (w / w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 50% (w / w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 60% (w / w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 55% (w / w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 50% (w / w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 45% (w / w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 45% (w / w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 37% (w / w) to about 43% (w / w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 38% (w / w) to about 42% (w / w) of crystalline form A of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 39% (w / w) to about 41% (w / w) of a compound of formula (I).

[0183] In some embodiments, the pharmaceutical composition comprises about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w),about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w) or about 50% (w / w) of the compound of formula (I).

[0184] In some embodiments, the pharmaceutical composition comprises about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w) or about 45% (w / w) of the compound of formula (I).

[0185] In some embodiments, the pharmaceutical composition comprises about 35% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 36% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 37% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 38% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 39% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 39.8% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 40% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 41% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 42% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 43% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 44% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 45% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 46% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 47% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 48% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 49% (w / w). In some embodiments, the pharmaceutical composition comprises about 50% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 55% (w / w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 60% (w / w) of the compound of formula (I).

[0186] In some embodiments, the filler comprises a sugar, an inorganic material, a microcry stalline cellulose, a starch, a polysaccharide, a cellulose, a polyvinylpyrrolidone, a polyvinyl acrylate or combinations thereof.

[0187] In some embodiments, the filler comprises a sugar, an inorganic material, and combinations thereof. In some embodiments, the sugar is selected from the group consisting of mannitol, lactose, sucrose, fructose, glucose, maltose, and combinations thereof. In some embodiments, the inorganic material is selected from the group consisting of dibasic calcium phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, bentonite, kaolin, and combinations thereof.

[0188] In some embodiments, the filler comprises a microcrystalline cellulose, a starch, a polysaccharide, a cellulose, a polyvinylpyrrolidone, a polyvinyl acrylate, and combinations thereof. In some embodiments, the cellulose is selected from the group consisting of a hydroxypropyl cellulose, ahypromellose, a carboxymethylcellulose, a methylcellulose, a hydroxypropyl methylcellulose, or combinations thereof.

[0189] In some embodiments, the filler comprises microcrystalline cellulose (e.g, Avicel®). The microcrystalline cellulose filler can be of different grades. In some embodiments, the filler comprises microcrystalline cellulose PH 101, PH 102 or a mixture thereof. In some embodiments, the filler comprises microcry stalline cellulose PH 101 (e.g., Avicel® PH 101). In some embodiments, a portion of the filler comprises microcrystalline cellulose PH 101 (e.g. Avicel® PH 101) and another portion of the filler comprises microcrystalline cellulose PH 102 (e.g, Avicel® PH 102). In some embodiments, the filler used in the intragranular blend comprises microcrystalline cellulose PH 101 and the filler used in the extragranular blend comprises microcrystalline cellulose PH 102. In some embodiments, the filler used in the intragranular blend consists substantially of microcrystalline cellulose PH 101 and the filler used in the extragranular blend consists substantially of microcrystalline cellulose PH 102.

[0190] In some embodiments, the pharmaceutical composition comprises about 30% (w / w) to about 60% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 60% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) to about 60% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 52% (w / w) to about 58% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 52% (w / w) to about 56% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 53% (w / w) to about 54% (w / w) filler.

[0191] In some embodiments, the pharmaceutical composition comprises about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w). about 48% (w / w), about 49% (w / w), about 50% (w / w),about 51% (w / w), about 52% (w / w), about 53% (w / w), about 54% (w / w), about 55% (w / w), about 56% (w / w), about 57% (w / w). about 58% (w / w) filler or about 60% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 50% (w / w), about 51% (w / w). about 52% (w / w), about 53% (w / w), about 54% (w / w), about 55% (w / w), about 56% (w / w), about 57% (w / w), about 58% (w / w) filler or about 60% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 42% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 43% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 44% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 45% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 46% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 47% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 48% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 49% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 51 % (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 52% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 53% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 53.7% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 54% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 55% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 56% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 57% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 58% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 59% (w / w) filler. In some embodiments, the pharmaceutical composition comprises about 60% (w / w) filler.

[0192] In some embodiments, the pharmaceutical composition comprises about 30% (w / w) to about 60% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 60% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) to about 60% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 52% (w / w) to about 58% (w / w) microcrystalline cellulose. In some embodiments, thepharmaceutical composition comprises about 52% (w / w) to about 56% (w / w) microcry stallinc cellulose.

[0193] In some embodiments, the pharmaceutical composition comprises about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w), about 50% (w / w), about 51% (w / w), about 52% (w / w), about 53% (w / w), about 54% (w / w), about 55% (w / w), about 56% (w / w), about 57% (w / w). about 58% (w / w) or about 60% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 50% (w / w), about 51% (w / w), about 52% (w / w), about 53% (w / w), about 54% (w / w), about 55% (w / w), about 56% (w / w), about 57% (w / w), about 58% (w / w) microcrystalline cellulose or about 60% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 42% (w / w) microcry stalline cellulose. In some embodiments, the pharmaceutical composition comprises about 43% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 44% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 45% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 46% (w / w) microcry stalline cellulose. In some embodiments, the pharmaceutical composition comprises about 47% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 48% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 49% (w / w) microcry stalline cellulose. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 51% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 52% (w / w) microcry stalline cellulose. In some embodiments, the pharmaceutical composition comprises about 53% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 53.7% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 54% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 55% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 56% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 57% (w / w)microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 58% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 59% (w / w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 60% (w / w) microcrystalline cellulose.

[0194] In some embodiments, the pharmaceutical composition comprises a glidant. In some embodiments, the glidant comprises colloidal silicon dioxide, talc, kaolin, bentonite, or combinations thereof.

[0195] In some embodiments, the glidant comprises colloidal silicon dioxide. In some embodiments, the glidant consists substantially of colloidal silicon dioxide. In some embodiments, the colloidal silicon dioxide is prepared through a process involving flame hydrolysis of silicon tetrachloride in an oxy -hydrogen flame and is referred to as “fumed silica” or “untreated fumed silica” (e.g., Aerosil® 200, CAB-O-SIL® M-5P).

[0196] The amount of glidant in the composition influences blend flow and compressibility, and the selected amounts of glidant in the pharmaceutical compositions described herein result in improved blend flow, contributing to adequate granulation for the intragranular blend and improved compressibility for the extragranular blend. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 3.0% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) to about 2.5% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) to about 2.25% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 1.9% (w / w) to about 2. 1% (w / w) glidant.

[0197] In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w), about 1.75% (w / w), about 1.9% (w / w), about 2% (w / w), about 2.1% (w / w), about 2.25% (w / w), about 2.5% (w / w) or about 3% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 1.9% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 2.1% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) glidant. In some embodiments, the pharmaceutical composition comprises about 3% (w / w) glidant.

[0198] In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 3.0% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) to about 2.5% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) to about 2.25% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.9% (w / w) to about 2.1% (w / w) colloidal silicon dioxide.

[0199] In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w). about 1.75% (w / w), about 1.9% (w / w), about 2.0% (w / w), about 2.1% (w / w), about 2.25% (w / w), about 2.5% (w / w) or about 3% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.9% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 2.1% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 3% (w / w) colloidal silicon dioxide.

[0200] In some embodiments, the pharmaceutical composition comprises a disintegrant. In some embodiments, the disintegrant comprises sodium starch glycolate, a crospovidone, croscarmellose sodium, or combinations thereof. In some embodiments, the disintegrant comprises croscarmellose sodium (e.g., Ac-Di-Sol®). In some embodiments, the disintegrant consists substantially of croscarmellose sodium (e.g, Ac-Di-Sol®).

[0201] In some embodiments, the pharmaceutical composition comprises about 2% (w / w) to about 4% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) to about 3.5% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.75% (w / w) to about 3.25% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.9% (w / w) to about 3. 1% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 2.9% (w / w), about 3% (w / w), about 3.1% (w / w), about 3.25% (w / w), about 3.5% (w / w), about 3.75% (w / w) or about 4.0% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprisesabout 2.0% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.75% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.9% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 3% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.1% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.25% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.5% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.75% (w / w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 4.0% (w / w) disintegrant.

[0202] In some embodiments, the pharmaceutical composition comprises about 2% (w / w) to about 4% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) to about 3.5% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.75% (w / w) to about 3.25% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.9% (w / w) to about 3.1% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w), about 2.25% (w / w), about 2.5% (w / w), about 2.75% (w / w), about 2.9% (w / w). about 3% (w / w). about 3. 1% (w / w). about 3.25% (w / w), about 3.5% (w / w), about 3.75% (w / w) or about 4.0% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.75% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.9% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.1% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.25% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.5% (w / w) croscarmellose sodium. In some embodiments, the pharmaceuticalcomposition comprises about 3.75% (w / w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 4.0% (w / w) croscarmellose sodium.

[0203] In some embodiments, the pharmaceutical composition comprises a lubricant. In some embodiments, the lubricant comprises sodium stearyl fumarate, magnesium stearate, stearic acid, glyceryl behenate, or combinations thereof.

[0204] In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the lubricant consists substantially of magnesium stearate.

[0205] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 2.0% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) to about 1.25% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) to about 1.75% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1 .45% (w / w) to about 1.55% (w / w) lubricant.

[0206] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.75% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.25% (w / w), about 1.5% (w / w) about 1.75% (w / w) or about 2% (w / w) of lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) lubricant. In some embodiments, thepharmaceutical composition comprises about 1.75% (w / w) lubricant. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) lubricant.

[0207] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) to about 1.25% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) to about 1.75% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) to about 1.55% (w / w) magnesium stearate.

[0208] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.75% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w). about 1.2% (w / w), about 1.25% (w / w) or about 1.5% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) magnesium stearate.

[0209] In some embodiments, provided is a pharmaceutical composition comprising: (a) cry stalline form A of a compound of formula (I) as described herein(b) a filler comprising microcrystalline cellulose PH 101;(c) a glidant (e.g., colloidal silicon dioxide);(d) a disintegrant (e.g.. croscarmellose sodium); and(e) a lubricant (e.g., magnesium stearate); wherein the compound of formula (I), the filler, the glidant, the disintegrant and the lubricant are present in the amounts described herein.

[0210] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline form A of a compound of formula (I) as described herein(b) a filler comprising microcrystalline cellulose PH 101 and PH 102;(c) a glidant (e.g., colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g., magnesium stearate); wherein the compound of formula (I), the filler, the glidant. the disintegrant and the lubricant are present in the amounts described herein.

[0211] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 60% (w / w) of the crystalline form A of compound of formula (I) as described herein(b) about 30% (w / w) to about 60% (w / w) of a filler wherein the filler comprises microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) a glidant (e.g., colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g., magnesium stearate).

[0212] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I) as described herein(b) about 40% (w / w) to about 60% (w / w) of a filler wherein the filler comprises microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) a glidant (e.g., colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g., magnesium stearate).

[0213] In some embodiments, the composition comprises:(a) about 35% (w / w) to about 60% (w / w) of the cry stalline form A of compound of formula (I);(b) about 30% (w / w) to about 60% (w / w) of a filler comprising microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of a glidant (e.g., colloidal silicon dioxide);(d) about 2% (w / w) to about 4% (w / w) of a disintegrant (e.g., croscarmellose sodium);(e) about 1.0% (w / w) to about 2.0% (w / w) of a lubricant (e.g., magnesium stearate);thereby totaling no more than 100% (w / w) of the composition.

[0214] In some embodiments, the composition comprises:(a) about 35% (w / w) to about 60% (w / w) of the crystalline form A of compound of formula (1);(b) about 30% (w / w) to about 60% (w / w) of a filler comprising microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of a glidant (e.g., colloidal silicon dioxide);(d) about 2% (w / w) to about 4% (w / w) of a disintegrant (e.g.. croscarmellose sodium);(e) about 0.5% (w / w) to about 1.5% (w / w) of a lubricant (e.g, magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0215] In some embodiments, the composition comprises:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I);(b) about 40% (w / w) to about 60% (w / w) of a filler compnsing microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of a glidant (e.g, colloidal silicon dioxide);(d) about 2% (w / w) to about 4% (w / w) of a disintegrant (e.g, croscarmellose sodium);(e) about 1.0% (w / w) to about 2.0% (w / w) of a lubricant (e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0216] In some embodiments, the composition comprises:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I);(b) about 40% (w / w) to about 60% (w / w) of a filler comprising microcry stalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of a glidant (e.g., colloidal silicon dioxide);(d) about 2% (w / w) to about 4% (w / w) of a disintegrant (e.g., croscarmellose sodium);(e) about 0.5% (w / w) to about 1.5% (w / w) of a lubricant (e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0217] In some embodiments, the composition comprises:(a) about 35% (w / w) to about 45% (w / w) of the crystalline form A of compound of formula (I);(b) about 50% (w / w) to about 60% (w / w) of a filler comprising microcry stalline PH 101 or a combination of microcry stalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of a glidant (e.g., colloidal silicon dioxide);(d) about 2% (w / w) to about 4% (w / w) of a disintegrant (e.g., croscarmellose sodium);(e) about 1.0% (w / w) to about 2.0% (w / w) of a lubricant (e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0218] In some embodiments, the composition comprises:(a) about 35% (w / w) to about 45% (w / w) of the crystalline form A of compound of formula (I);(b) about 50% (w / w) to about 60% (w / w) of a filler comprising microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of a glidant (e.g., colloidal silicon dioxide);(d) about 2% (w / w) to about 4% (w / w) of a disintegrant (e.g., croscarmellose sodium);(e) about 0.5% (w / w) to about 1.5% (w / w) of a lubricant (e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0219] In some embodiments, the composition comprises:(a) about 37% (w / w) to about 43% (w / w) of the crystalline form A of compound of formula (I) ;(b) about 52% (w / w) to about 56% (w / w) of a filler comprising microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1.5% (w / w) to about 2.5% (w / w) of a glidant (e.g., colloidal silicon dioxide);(d) about 2.5% (w / w) to about 3.5% (w / w) of a disintegrant (e.g, croscarmellose sodium);(e) about 1.25% (w / w) to about 1.75% (w / w) of a lubricant (e.g, magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0220] In some embodiments, the composition comprises:(a) about 37% (w / w) to about 43% (w / w) of the crystalline form A of compound of formula (I) ;(b) about 52% (w / w) to about 56% (w / w) of a filler comprising microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1.5% (w / w) to about 2.5% (w / w) of a glidant (e.g, colloidal silicon dioxide);(d) about 2.5% (w / w) to about 3.5% (w / w) of a disintegrant (e.g, croscarmellose sodium);(e) about 0.75% (w / w) to about 1.25% (w / w) of a lubricant (e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0221] In some embodiments, the composition comprises:(a) 39% (w / w) to 41% (w / w) of the crystalline form A of compound of formula (I) ;(b) 53% (w / w) to 55 % (w / w) of a filler e.g, microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) 1.9% (w / w) to 2.1 % (w / w) of a glidant (e.g, colloidal silicon dioxide);(d) 2.9% (w / w) to 3.1 % (w / w) of a disintegrant (e.g, croscarmellose sodium);(e) 1.4% (w / w) to 1.6 % (w / w) of a lubricant (e.g, magnesium stearate); thereby totaling 100% (w / w) of the composition.

[0222] In some embodiments, the composition comprises:(a) about 39% (w / w) to 41% (w / w) of the cry stalline form A of compound of formula (I) ;(b) about 53 % (w / w) to 55 % (w / w) of a filler e.g., microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 2 % (w / w) of a glidant e.g., colloidal silicon dioxide);(d) about 3 % (w / w) of a disintegrant (e.g., croscarmellose sodium);(e) about 1.5 % (w / w) of a lubricant (e.g., magnesium stearate); thereby totaling 100% (w / w) of the composition.

[0223] In some embodiments, the composition comprises:(a) about 40% (w / w) of the cry stalline form A of compound of formula (I) ;(b) about 54 % (w / w) of a filler e.g., microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 2 % (w / w) of a glidant (e.g, colloidal silicon dioxide);(d) about 3 % (w / w) of a disintegrant (e.g., croscarmellose sodium);(e) about 1.5 % (w / w) of a lubricant (e.g., magnesium stearate); thereby totaling 100% (w / w) of the composition.

[0224] In some embodiments, the composition comprises:(a) about 39.8% (w / w) of the cry stalline form A of compound of formula (I) ;(b) about 53.7 % (w / w) of a filler e.g., microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 2 % (w / w) of a glidant (e.g, colloidal silicon dioxide);(d) about 3 % (w / w) of a disintegrant (e.g., croscarmellose sodium);(e) about 1.5 % (w / w) of a lubricant (e.g., magnesium stearate); thereby totaling 100% (w / w) of the composition.

[0225] In some embodiments, the composition comprises:(a) about 40% (w / w) of the crystalline form A of compound of formula (I) ;(b) about 54 % (w / w) of a filler e.g., microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 2 % (w / w) of a glidant (e.g., colloidal silicon dioxide);(d) about 3 % (w / w) of a disintegrant (e.g, croscarmellose sodium);(e) about 1 % (w / w) of a lubricant (e.g., magnesium stearate); thereby totaling 100% (w / w) of the composition.

[0226] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline form A of a compound of formula (I) as described herein(b) microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) colloidal silicon dioxide;(d) croscarmellose sodium; and(e) magnesium stearate.

[0227] In some embodiments, the composition comprises:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I);(b) about 40% (w / w) to about 60% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of colloidal silicon dioxide;(d) about 2% (w / w) to about 4% (w / w) of croscarmellose sodium;(e) about 1.0% (w / w) to about 2.0% (w / w) of magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0228] In some embodiments, the composition comprises:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I);(b) about 40% (w / w) to about 60% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of colloidal silicon dioxide;(d) about 2% (w / w) to about 4% (w / w) of croscarmellose sodium;(e) about 0.5% (w / w) to about 1.5% (w / w) of magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0229] In some embodiments, the composition comprises:(a) about 35% (w / w) to about 45% (w / w) of the crystalline form A of compound of formula (I);(b) about 50% (w / w) to about 60% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of colloidal silicon dioxide;(d) about 2% (w / w) to about 4% (w / w) of croscarmellose sodium;(e) about 1.0% (w / w) to about 2.0% (w / w) of magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0230] In some embodiments, the composition comprises:(a) about 35% (w / w) to about 45% (w / w) of the crystalline form A of compound of formula (I);(b) about 50% (w / w) to about 60% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of colloidal silicon dioxide;(d) about 2% (w / w) to about 4% (w / w) of croscarmellose sodium;(e) about 0.5% (w / w) to about 1.5% (w / w) of magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0231] In some embodiments, the composition comprises:(a) about 37% (w / w) to about 43% (w / w) of the crystalline form A of compound of formula (I);(b) about 52% (w / w) to about 56% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1.5% (w / w) to about 2.5% (w / w) of colloidal silicon dioxide;(d) about 2.5% (w / w) to about 3.5% (w / w) of croscarmellose sodium;(e) about 1 .25% (w / w) to about 1.75% (w / w) of magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0232] In some embodiments, the composition comprises:(a) about 37% (w / w) to about 43% (w / w) of the crystalline form A of compound of formula (I);(b) about 52% (w / w) to about 56% (w / w) of microcrystalhne cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1.5% (w / w) to about 2.5% (w / w) of colloidal silicon dioxide;(d) about 2.5% (w / w) to about 3.5% (w / w) of croscarmellose sodium;(e) about 0.75% (w / w) to about 1.25% (w / w) of magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0233] In some embodiments, the composition comprises:(a) 39% (w / w) to 41% (w / w) of the cry stalline form A of compound of formula (I);(b) 53 % (w / w) to 55 % (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) 1.9% (w / w) to 2.1 % (w / w) of colloidal silicon dioxide;(d) 2.9% (w / w) to 3.1 % (w / w) of croscarmellose sodium;(e) 1.4 % (w / w) to 1.6 % (w / w) of magnesium stearate;thereby totaling 100% (w / w) of the composition.

[0234] In some embodiments, the composition comprises:(a) about 39% (w / w) to 41% (w / w) of the crystalline form A of compound of formula (I);(b) about 53 % (w / w) to 55 % (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 2 % (w / w) of colloidal silicon dioxide:(d) about 3 % (w / w) of croscarmellose sodium;(e) about 1.5 % (w / w) of magnesium stearate; thereby totaling 100% (w / w) of the composition.

[0235] In some embodiments, the composition comprises:(a) about 40% (w / w) of the crystalline form A of compound of formula (I);(b) about 54 % (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 2 % (w / w) of colloidal silicon dioxide;(d) about 3 % (w / w) of croscarmellose sodium;(e) about 1.5 % (w / w) of magnesium stearate; thereby totaling 100% (w / w) of the composition.

[0236] In some embodiments, the composition comprises:(a) about 39.8% (w / w) of the crystalline form A of compound of formula (I);(b) about 53.7 % (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 2 % (w / w) of colloidal silicon dioxide;(d) about 3 % (w / w) of croscarmellose sodium;(e) about 1.5 % (w / w) of magnesium stearate; thereby totaling 100% (w / w) of the composition.

[0237] In some embodiments, the composition comprises:(a) about 40% (w / w) of the cry stalline form A of compound of formula (I);(b) about 54 % (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 2 % (w / w) of colloidal silicon dioxide;(d) about 3 % (w / w) of croscarmellose sodium;(e) about 1 % (w / w) of magnesium stearate; thereby totaling 100% (w / w) of the composition.

[0238] The pharmaceutically acceptable excipients can be present in either the intragranular or the extragranular components of the pharmaceutical composition. In some embodiments, one or more pharmaceutically acceptable excipients are present in both the intragranular and the extragranular components.

[0239] In some embodiments, the pharmaceutical composition contains an intragranular filler is selected from the fillers described herein. In some embodiments, the intragranular filler comprises microcrystalline cellulose (e.g. Avicel*). In some embodiments, the intragranular filler consists substantially of a microcrystalline cellulose (e.g., Avicel®). The average particle size of the microcrystalline cellulose affects binding to the active ingredient and additional excipients and a closer match between the particle size of the API and the particle size of the microcrystalline cellulose is believed to contribute to better binding and better manufacturability. The median particle size of microcrystalline cellulose PH 101 and PH 102 is -50 pm and -100 pm, respectively and the smaller particle size for PH 101 is a closer match for the average particle size of the API. Thus, in some embodiments, the intragranular filler comprises a microcrystalline cellulose PH 101 (e.g., Avicel® PH 101). In some embodiments, the intragranular filler consists substantially of a microcrystalline cellulose PH 101 (e.g.. Avicel® PH 101).

[0240] The ratio of API to intragranular filler can influence the uniformity of API in the blend and lower ratios of API to intragranular filler can make it more difficult to achieve acceptable API uniformity.. In some embodiments, the w / w ratio of API to intragranular filler is between 0.9 and 1.6. In some embodiments, the w / w ratio of API to intragranular filler is between 0.9 and 1.4. In some embodiments, the w / w ratio of API to intragranular filler is between 0.9 and 1.2. In some embodiments, the w / w ratio of API to intragranular filler is between 0.9 and 1. 1. In some embodiments, the w / w ratio of API to intragranular filler is between 0.9 and 1.05. In some embodiments, the w / w ratio of API to intragranular filler is between 0.9 and 1.0. In some embodiments, the w / w ratio of API to intragranular filler is between 0.95 and 1.05. In some embodiments, the w / w ratio of API to intragranular filler is between 0.95 and 1.0. In some embodiments, the w / w ratio of API to intragranular filler is about 0.95.

[0241] In some embodiments, the pharmaceutical composition comprises about 20% (w / w) to about 50% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 25% (w / w) to about 50% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 30% (w / w) to about 50% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about50% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 38% (w / w) to about 46% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 44% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) to about 43% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 41.5% (w / w) to about 42.5% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 25% (w / w), about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29% (w / w), about 30% (w / w), about 31% (w / w), about 32%(w / w), about 33% (w / w), about 34% (w / w), about 35% (w / w), about 36% (w / w), about 37%(w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42%(w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w). about 47%(w / w), about 48% (w / w), about 49% (w / w), or about 50% (w / w) intragranular filler.

[0242] In some embodiments, the pharmaceutical composition comprises about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w). about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w). about 48% (w / w), about 49% (w / w), or about 50% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w) or about 47% (w / w) intragranular filler.

[0243] In some embodiments, the pharmaceutical composition comprises about 25% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 26% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 27% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 28% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 29% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 30% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 31% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 32% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 33% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 34% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 35% (w / w) intragranular filler. In some embodiments, the pharmaceuticalcomposition comprises about 36% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 37% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 38% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 39% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 41.8% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 42% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 43% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 44% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 45% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 46% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 47% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 48% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 49% (w / w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) intragranular filler.

[0244] In some embodiments, the pharmaceutical composition comprises about 20% (w / w) to about 50% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 25% (w / w) to about 50% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 30% (w / w) to about 50% (w / w) intragranular microcrystallinc cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 50% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 38% (w / w) to about 46% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 44% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) to about 43% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 41.5% (w / w) to about 42.5% (w / w) microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 25% (w / w). about 26% (w / w), about 27% (w / w), about 28% (w / w), about 29%(w / w), about 30% (w / w), about 31% (w / w), about 32% (w / w), about 33% (w / w), about 34%(w / w), about 35% (w / w), about 36% (w / w), about 37% (w / w), about 38% (w / w), about 39%(w / w), about 40% (w / w), about 41% (w / w). about 42% (w / w), about 43% (w / w). about 44%(w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49%(w / w), or about 50% (w / w) intragranular microcrystalline cellulose PH 101.

[0245] In some embodiments, the pharmaceutical composition comprises about 35% (w / w), about 36% (w / w), about 37% (w / w). about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w), about 47% (w / w), about 48% (w / w), about 49% (w / w), or about 50% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 38% (w / w), about 39% (w / w), about 40% (w / w), about 41% (w / w), about 42% (w / w), about 43% (w / w), about 44% (w / w), about 45% (w / w), about 46% (w / w) or about 47% (w / w) intragranular microcrystalline cellulose PH 101.

[0246] In some embodiments, the pharmaceutical composition comprises about 25% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 26% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 27% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 28% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 29% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 30% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 31% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 32% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 33% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 34% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 35% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 36% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 37% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical compositioncomprises about 38% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 39% (w / w) intragranular microcry stalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) intragranular microcry stalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 41.8% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 42% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 43% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 44% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 45% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 46% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 47% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 48% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 49% (w / w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) intragranular microcrystalline cellulose PH 101.

[0247] In some embodiments, the pharmaceutical composition contains an extragranular filler selected from the fillers described herein. Addition of an extragranular filler results in better compression compared to high API compositions lacking an extragranular filler. In some embodiments, the extragranular filler comprises a microcrystalline cellulose (e.g, Avicel®). In some embodiments, the extragranular filler consists substantially of a microcrystalline cellulose (e.g., Avicel®). Because the intragranular phase represents a large proportion of the final composition, the properties of the extragranular filler (e.g. , filler particle size distribution, flow, etc.) should be selected to match the behavior of the granules and to avoid a negative impact on the flow and compressibility of the final mixture. In some embodiments, the extragranular filler comprises microcrystalline cellulose PH 102 (e.g., Avicel® PH 102). In some embodiments, the extragranular filler consists substantially of microcrystalline cellulose PH 102 (e.g., Avicel® PH 102).

[0248] In some embodiments, the pharmaceutical composition comprises about 5% (w / w) to about 20% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 8% (w / w) to about 16% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 10% (w / w) to about 14% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 11% (w / w) to about 13% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 11.5% (w / w) to about 12.5% (w / w) extragranular filler.

[0249] In some embodiments, the pharmaceutical composition comprises about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w), about 16% (w / w) , about 17% (w / w) , about 18% (w / w) , about 19% (w / w) or about 20% (w / w) extragranular filler.

[0250] In some embodiments, the pharmaceutical composition comprises about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w) or about 16% (w / w) extragranular filler.

[0251] In some embodiments, the pharmaceutical composition comprises about 5% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 6% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 7% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 8% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 9% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 10% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 11% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 12% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 13% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 14% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 15% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 16% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 17% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 18% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about19% (w / w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 20% (w / w) extragranular filler.

[0252] In some embodiments, the pharmaceutical composition comprises about 5% (w / w) to about 20% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 8% (w / w) to about 16% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 10% (w / w) to about 14% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 1 1% (w / w) to about 13% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 11.5% (w / w) to about 12.5% (w / w) extragranular microcrystalline cellulose PH 102.

[0253] In some embodiments, the pharmaceutical composition comprises about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w), about 16% (w / w) , about 17% (w / w) , about 18% (w / w) , about 19% (w / w) or about 20% (w / w) extragranular microcrystalline cellulose PH 102.

[0254] In some embodiments, the pharmaceutical composition comprises about 8% (w / w), about 9% (w / w), about 10% (w / w), about 11% (w / w), about 12% (w / w), about 13% (w / w), about 14% (w / w), about 15% (w / w) or about 16% (w / w) extragranular microcry stalline cellulose PH 102.

[0255] In some embodiments, the pharmaceutical composition comprises about 5% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 6% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 7% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 8% (w / w) extragranular microcrystalhne cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 9% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 10% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 11% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 12% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 13% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical compositioncomprises about 14% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 15% (w / w) extragranular microcry stalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 16% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 17% (w / w) extragranular microcry stalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 18% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 19% (w / w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 20% (w / w) extragranular microcrystalline cellulose PH 102.

[0256] In some embodiments, the pharmaceutical composition comprises an intragranular ghdant selected from the ghdants described herein. In some embodiments, the intragranular glidant consists substantially of colloidal silicon dioxide (e g., Aerosil® 200, CAB-O-SIL® M- 5P). The amount of intragranular glidant influences blend flow and the selected amounts of intragranular glidant contribute to rendering the intragranular blend amenable to dry granulation.

[0257] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) to about 1.2% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) intragranular ghdant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) intragranular glidant.

[0258] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.3% (w / w), about 1.4% (w / w) or about 1.5% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w), about 0.8% (w / w), about 0.85 (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.15% (w / w), about 1.2% (w / w) or about 1.25% (w / w) intragranular glidant.

[0259] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.6% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.7% (w / w) intragranular ghdant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) intragranular glidant. In some embodiments, thepharmaceutical composition comprises about 0.8% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.85 (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.15% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) intragranular glidant.

[0260] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) to about 1.2% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) intragranular colloidal silicon dioxide.

[0261] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.3% (w / w). about 1.4% (w / w) or about 1.5% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w), about 0.8% (w / w), about 0.85 (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.15% (w / w), about 1.2% (w / w) or about 1.25% (w / w) intragranular colloidal silicon dioxide.

[0262] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.6% (w / w) intragranular colloidal silicon dioxide. In some embodiments, thepharmaceutical composition comprises about 0.7% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.85 (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.15% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) intragranular colloidal silicon dioxide.

[0263] In some embodiments, the pharmaceutical composition comprises an extragranular glidant selected from the glidants described herein. In some embodiments, the extragranular glidant consists substantially of colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M- 5P). The amount of extragranular glidant in the composition influences blend flow and compressibility, and the selected amounts of glidant in the pharmaceutical compositions described herein contribute to improved blend flow for the extragranular blend and improved compressibility.

[0264] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) to about 1.2% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) extragranular glidant.

[0265] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.3% (w / w). about 1.4% (w / w) or about 1.5% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w), about 0.8% (w / w), about 0.85 (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.15% (w / w), about 1.2% (w / w) or about 1.25% (w / w) extragranular glidant.

[0266] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.6% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.7% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.85 (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.15% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) extragranular glidant.

[0267] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) to about 1.2% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) extragranular colloidal silicon dioxide. In someembodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) extragranular colloidal silicon dioxide.

[0268] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w). about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.2% (w / w), about 1.3% (w / w), about 1.4% (w / w) or about 1.5% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w), about 0.8% (w / w), about 0.85 (w / w), about 0.9% (w / w), about 0.95% (w / w), about 1.0% (w / w), about 1.05% (w / w), about 1.1% (w / w), about 1.15% (w / w), about 1.2% (w / w) or about 1.25% (w / w) extragranular colloidal silicon dioxide.

[0269] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.6% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.7% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.85 (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.15% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) extragranular colloidal silicon dioxide.

[0270] In some embodiments, the pharmaceutical composition comprises an intragranular disintegrant selected from the disintegrants described herein. In some embodiments, the intragranular disintegrant consists substantially of croscarmellose sodium.

[0271] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 2.5% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 2.0% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) to about 1.75% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) to about 1.55% (w / w) intragranular disintegrant.

[0272] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.75% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.3% (w / w), about 1.35% (w / w), about 1.4% (w / w), about 1.45% (w / w), about 1.5% (w / w), about 1.55% (w / w), about 1.6% (w / w), about 1.65% (w / w), about 1.7% (w / w). about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w) or about 2.5% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1% (w / w), about 1.25% (w / w), about 1.3% (w / w), about 1.35% (w / w), about 1.4% (w / w), about 1.45% (w / w), about 1.5% (w / w), about 1.55% (w / w), about 1.6% (w / w), about 1.65% (w / w), about 1.7% (w / w), about 1.75% (w / w) or about 2.0% (w / w) intragranular disintegrant.

[0273] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.35% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.55% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical compositioncomprises about 1.6% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.65% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.7% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) intragranular disintegrant.

[0274] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 2.5% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 2.0% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) to about 1.75% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1 .45% (w / w) to about 1 .55% (w / w) intragranular croscarmellose sodium.

[0275] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.75% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.3% (w / w), about 1.35% (w / w), about 1.4% (w / w), about 1.45% (w / w). about 1.5% (w / w). about 1.55% (w / w), about 1.6% (w / w), about 1.65% (w / w), about 1.7% (w / w), about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w) or about 2.5% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1% (w / w), about 1.25% (w / w), about 1.3% (w / w), about 1.35% (w / w), about 1.4% (w / w), about 1.45% (w / w), about 1.5% (w / w), about 1.55% (w / w), about 1.6% (w / w). about 1.65% (w / w), about 1.7% (w / w), about 1.75% (w / w) or about 2.0% (w / w) intragranular croscarmellose sodium.

[0276] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceuticalcomposition comprises about 1.35% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.55% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.6% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.65% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.7% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) intragranular croscarmellose sodium.

[0277] In some embodiments, the pharmaceutical composition comprises an extragranular disintegrant selected from the disintegrants described herein. In some embodiments, the extragranular disintegrant consists substantially of croscarmellose sodium.

[0278] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 2.5% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 2.0% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) to about 1.75% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) to about 1.55% (w / w) extragranular disintegrant.

[0279] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w). about 0.75% (w / w), about 1% (w / w), about 1.25% (w / w). about 1.3% (w / w), about 1.35% (w / w), about 1.4% (w / w), about 1.45% (w / w), about 1.5% (w / w), about 1.55% (w / w), about 1.6% (w / w), about 1.65% (w / w), about 1.7% (w / w), about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w) or about 2.5% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1% (w / w), about 1.25% (w / w), about 1.3% (w / w),about 1.35% (w / w), about 1.4% (w / w), about 1.45% (w / w), about 1.5% (w / w), about 1.55% (w / w), about 1.6% (w / w), about 1.65% (w / w). about 1.7% (w / w). about 1.75% (w / w) or about 2.0% (w / w) extragranular disintegrant.

[0280] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.35% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.55% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.6% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.65% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.7% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) extragranular disintegrant.

[0281] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 2.5% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 2.0% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) to about 1.75% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) to about 1.55% (w / w) extragranular croscarmellose sodium.

[0282] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w), about 0.75% (w / w), about 1% (w / w), about 1.25% (w / w), about 1.3% (w / w), about 1.35% (w / w), about 1.4% (w / w), about 1.45% (w / w). about 1.5% (w / w). about 1.55% (w / w), about 1.6% (w / w), about 1.65% (w / w), about 1.7% (w / w), about 1.75% (w / w), about 2.0% (w / w), about 2.25% (w / w) or about 2.5% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1% (w / w), about 1.25% (w / w), about 1.3% (w / w), about 1.35% (w / w), about 1.4% (w / w), about 1.45% (w / w), about 1.5% (w / w), about 1.55% (w / w), about 1.6% (w / w), about 1.65% (w / w), about 1.7% (w / w), about 1.75% (w / w) or about 2.0% (w / w) extragranular croscarmellose sodium.

[0283] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.35% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.55% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.6% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.65% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.7% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) extragranular croscarmellose sodium.

[0284] In some embodiments, the pharmaceutical composition comprises an intragranular lubricant selected from the lubricants described herein. In some embodiments, the intragranular lubricant consists substantially of magnesium stearate.

[0285] In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.3% (w / w) to about 0.7% (w / w) intragranular lubricant.

[0286] In some embodiments, the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) to about 0.55% (w / w) intragranular lubricant.

[0287] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w), about 0.46% (w / w), about 0.47% (w / w). about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w), about 0.52% (w / w), about 0.53% (w / w), about 0.54% (w / w) or about 0.55% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w) or about 0.52% (w / w) intragranular lubricant.

[0288] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.46% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.47% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.49% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.51% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.52% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.53% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.54% (w / w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.55% (w / w) intragranular lubricant.

[0289] In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.3% (w / w) to about 0.7% (w / w) intragranular magnesium stearate.

[0290] In some embodiments, the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) to about 0.55% (w / w) intragranular magnesium stearate.

[0291] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w), about 0.46% (w / w), about 0.47% (w / w), about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w), about 0.52% (w / w), about 0.53% (w / w), about 0.54% (w / w) or about 0.55% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w) or about 0.52% (w / w) intragranular magnesium stearate.

[0292] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.46% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.47% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.49% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.51% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.52% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.53% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.54% (w / w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.55% (w / w) intragranular magnesium stearate.

[0293] In some embodiments, the pharmaceutical composition comprises an extragranular lubricant selected from the lubricants described herein. In some embodiments, the extragranular lubricant consists substantially of magnesium stearate.

[0294] In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 1.5% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 1.25% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.25% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical compositioncomprises about 0.75% (w / w) to about 1.25% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.3% (w / w) to about 0.7% (w / w) extragranular lubricant.

[0295] In some embodiments, the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) to about 0.55% (w / w) extragranular lubricant.

[0296] In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w), about 0.96% (w / w), about 0.97% (w / w), about 0.98% (w / w), about 0.99% (w / w), about 1.0% (w / w), about 1.01% (w / w), about 1.02% (w / w), about 1.03% (w / w), about 1.0% (w / w) or about 1.05% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.98% (w / w), about 0.99% (w / w), about 1.0% (w / w), about 1.01% (w / w) or about 1.02% (w / w) extragranular lubricant.

[0297] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w), about 0.46% (w / w), about 0.47% (w / w), about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w), about 0.52% (w / w), about 0.53% (w / w), about 0.54% (w / w) or about 0.55% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w) or about 0.52% (w / w) extragranular lubricant.

[0298] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.46% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.47% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.49% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.51% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.52% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.53% (w / w) extragranular lubricant. In some embodiments, the pharmaceuticalcomposition comprises about 0.54% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.55% (w / w) extragranular lubricant.

[0299] In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.96% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.97% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.98% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.99% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 1.01% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 1.02% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 1.03% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 1.04% (w / w) or about 1.05% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.98% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.99% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 1.01% (w / w) or about 1.02% (w / w) extragranular lubricant.

[0300] In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 1.5% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 1.25% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.25% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) to about 1.25% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.3% (w / w) to about 0.7% (w / w) extragranular magnesium stearate.

[0301] In some embodiments, the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) to about 0.55% (w / w) extragranular magnesium stearate.

[0302] In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w), about 0.96% (w / w), about 0.97% (w / w), about 0.98% (w / w), about 0.99% (w / w), about 1.0% (w / w), about 1.01% (w / w), about 1.02% (w / w), about 1.03% (w / w), about 1.0% (w / w) or about 1.05% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.98% (w / w), about 0.99% (w / w), about 1.0% (w / w), about 1.01% (w / w) or about 1.02% (w / w) extragranular magnesium stearate.

[0303] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w), about 0.46% (w / w), about 0.47% (w / w), about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w), about 0.52% (w / w), about 0.53% (w / w), about 0.54% (w / w) or about 0.55% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w), about 0.49% (w / w), about 0.5% (w / w), about 0.51% (w / w) or about 0.52% (w / w) extragranular magnesium stearate.

[0304] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.46% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.47% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.49% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.51% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.52% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.53% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.54% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.55% (w / w) extragranular magnesium stearate.

[0305] In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical compositioncomprises about 0.96% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.97% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.98% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.99% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.01% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.02% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.03% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.04% (w / w) or about 1.05% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.98% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.99% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.01% (w / w) or about 1.02% (w / w) extragranular magnesium stearate.

[0306] In some embodiments, provided is a pharmaceutical composition comprising: (a) cry stalline Form A of a compound of formula (I)(b) an intragranular filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients. In some embodiments, the compound of formula (I), the intragranular filler and the additional excipients are present in the w / w percentages recited in any of the embodiments described herein.

[0307] In some embodiments, provided is a pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of crystalline form A of the compound of formula (I)(b) an intragranular filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients.

[0308] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline Form A of a compound of formula (I)(b) an intragranular filler comprising microcrystalline cellulose PH 101;(c) an intragranular glidant (e.g, colloidal silicon dioxide);(d) an intragranular disintegrant (e.g, croscarmellose sodium);(e) an extragranular lubricant (e.g, magnesium stearate);(f) an extragranular filler (e.g, microcrystalline cellulose PH 102);(g) an extragranular glidant (e.g, colloidal silicon dioxide);(h) an extragranular disintegrant (e.g, croscarmellose sodium); and(i) an extragranular lubricant (e.g. magnesium stearate).

[0309] In some embodiments, the compound of formula (I), the intragranular filler, the extragranular filler, the intragranular glidant, the extragranular glidant, the intragranular disintegrant, the extragranular disintegrant, the intragranular lubricant and the extragranular lubricant are present in the w / w percentages recited in any of the embodiments described herein.

[0310] In some embodiments, provided is a pharmaceutical composition comprising:(a) crystalline Form A of a compound of formula (I)(b) intr agranular microcrystalline cellulose PH 101;(c) intragranular colloidal silicon dioxide;(d) intragranular croscarmellose sodium;(e) extragranular magnesium stearate;(f) extragranular microcrystalline cellulose PH 102;(g) extragranular colloidal silicon dioxide;(h) extragranular croscarmellose sodium; and(i) extragranular magnesium stearate.

[0311] In some embodiments, the compound of formula (I), the intragranular microcrystalline cellulose, the extragranular microcry stalline cellulose, the intragranular silicon dioxide, the extragranular silicon dioxide, the intragranular croscarmellose sodium, the extragranular croscarmellose sodium, the intragranular magnesium stearate and the extragranular magnesium stearate are present in the w / w percentages recited in any of the embodiments described herein.

[0312] In some embodiments, the pharmaceutical composition comprises:(a) about 35% (w / w) to about 60% (w / w) of crystalline form A of the compound of formula (I);(b) about 20% (w / w) to about 50% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 0.5% (w / w) to about 1.5% (w / w) of an intragranular glidant (e.g, colloidal silicon dioxide);(d) about 0.5% (w / w) to about 2.5% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium);(e) about 0.25% (w / w) to about 0.75% (w / w) of an intragranular lubricant (e.g, magnesium stearate);(!) about 5% (w / w) to about 20% (w / w) of an extragranular filler (e.g, microcrystalline cellulose PH 102);(g) about 0.5% (w / w) to about 1.5% (w / w) of an extragranular glidant (e.g., colloidal silicon dioxide);(h) about 0.5% (w / w) to about 2.5% (w / w) of an extragranular disintegrant (e.g, croscarmellose sodium); and(i) about 0.25% (w / w) to about 0.75% (w / w) of an extragranular lubricant (e.g, magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0313] In some embodiments, the pharmaceutical composition comprises:(a) about 35% (w / w) to about 50% (w / w) of crystalline form A of the compound of formula (I);(b) about 30% (w / w) to about 50% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 0.5% (w / w) to about 1.5% (w / w) of an intragranular glidant (e.g, colloidal silicon dioxide);(d) about 0.5% (w / w) to about 2.5% (w / w) of an intragranular disintegrant (e.g, croscarmellose sodium);(e) about 0.25% (w / w) to about 0.75% (w / w) of an intragranular lubricant (e.g, magnesium stearate);(!) about 5% (w / w) to about 20% (w / w) of an extragranular filler (e.g, microcrystalline cellulose PH 102);(g) about 0.5% (w / w) to about 1.5% (w / w) of an extragranular glidant (e.g, colloidal silicon dioxide);(h) about 0.5% (w / w) to about 2.5% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.25% (w / w) to about 0.75% (w / w) of an extragranular lubricant (e.g, magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0314] In some embodiments, the pharmaceutical composition comprises:(a) about 35% (w / w) to about 45% (w / w) of crystalline form A of the compound of formula (I);(b) about 35% (w / w) to about 50% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 0.5% (w / w) to about 1.5% (w / w) of an intragranular glidant (e.g. colloidal silicon dioxide);(d) about 0.5% (w / w) to about 2.5% (w / w) of an intragranular disintegrant (e.g, croscarmellose sodium);(e) about 0.25% (w / w) to about 0.75% (w / w) of an intragranular lubricant (e.g, magnesium stearate);(f) about 5% (w / w) to about 20% (w / w) of an extragranular filler (e.g, microcrystalline cellulose PH 102);(g) about 0.5% (w / w) to about 1.5% (w / w) of an extragranular glidant (e.g, colloidal silicon dioxide);(h) about 0.5% (w / w) to about 2.5% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.25% (w / w) to about 0.75% (w / w) of an extragranular lubricant (e.g, magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0315] In some embodiments, the pharmaceutical composition comprises:(a) about 37% (w / w) to about 43% (w / w) of crystalline form A of the compound of formula (I);(b) about 38% (w / w) to about 46% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 0.8% (w / w) to about 1.2% (w / w) of an intragranular glidant (e.g. colloidal silicon dioxide);(d) about 1.25% (w / w) to about 1.75% (w / w) of an intragranular disintegrant (e.g, croscarmellose sodium);(e) about 0.3% (w / w) to about 0.7% (w / w) of an intragranular lubricant (e.g, magnesium stearate);(f) about 8% (w / w) to about 16% (w / w) of an extragranular filler (e.g, microcrystalline cellulose PH 102);(g) about 0.8% (w / w) to about 1.2% (w / w) of an extragranular glidant (e.g., colloidal silicon dioxide);(h) about 1.25% (w / w) to about 1.75% (w / w) of an extragranular disintegrant (e.g, croscarmellose sodium); and(i) about 0.3% (w / w) to about 0.7% (w / w) of an extragranular lubricant (e.g, magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0316] In some embodiments, the pharmaceutical composition comprises:(a) about 38% (w / w) to about 42% (w / w) of crystalline form A of the compound of formula (I);(b) about 40% (w / w) to about 44% (w / w) of an intragranular filler comprising nncrocrystallinc cellulose PH 101;(c) about 0.9% (w / w) to about 1.1% (w / w) of an intragranular ghdant (e.g.. colloidal silicon dioxide);(d) about 1.4% (w / w) to about 1.6% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium);(e) about 0.4% (w / w) to about 0.6% (w / w) of an intragranular lubricant (e.g.. magnesium stearate);(f) about 10% (w / w) to about 14% (w / w) of an extragranular filler (e.g., microcrystalline cellulose PH 102);(g) about 0.9% (w / w) to about 1.1% (w / w) of an extragranular glidant (e.g., colloidal silicon dioxide);(h) about 1.4% (w / w) to about 1.6% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.4% (w / w) to about 0.6% (w / w) of an extragranular lubricant (e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0317] In some embodiments, the pharmaceutical composition comprises:(a) about 39% (w / w) to about 41% (w / w) of crystalline form A of the compound of formula (I);(b) about 41% (w / w) to about 43% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 0.95% (w / w) to about 1.05% (w / w) of an intragranular glidant (e.g., colloidal silicon dioxide);(d) about 1.45% (w / w) to about 1.55% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium);(e) about 0.45% (w / w) to about 0.55% (w / w) of an intragranular lubricant (e.g., magnesium stearate);(1) about 11% (w / w) to about 13% (w / w) of an extragranular filler (e.g., microcrystalline cellulose PH 102);(g) about 0.95% (w / w) to about 1.05% (w / w) of an extragranular glidant (e.g., colloidal silicon dioxide);(h) about 1.45% (w / w) to about 1.55% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.45% (w / w) to about 0.55% (w / w) of an extragranular lubricant (e.g, magnesium stearate); thereby totaling no more than 100% (w / w) of the composition.

[0318] In some embodiments, the pharmaceutical composition comprises:(a) about 40% (w / w) of crystalline form A of the compound of formula (I);(b) about 42% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of an intragranular glidant (e.g. colloidal silicon dioxide);(d) about 1.5% (w / w) of an intragranular disintegrant (e.g, croscarmellose sodium);(e) about 0.5% (w / w) of an intragranular lubricant (e.g, magnesium stearate);(1) about 12% (w / w) of an extragranular filler (e.g, microcrystalline cellulose PH 102);(g) about 1.0% (w / w) of an extragranular glidant (e.g, colloidal silicon dioxide);(h) about 1.5% (w / w) of an extragranular disintegrant (e.g, croscarmellose sodium); and(i) about 0.5% (w / w) of an extragranular lubricant (e.g, magnesium stearate).

[0319] In some embodiments, the pharmaceutical composition comprises:(a) about 45% (w / w) of crystalline form A of the compound of formula (I);(b) about 37% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 1 .0% (w / w) of an intragranular glidant (e.g, colloidal silicon dioxide);(d) about 1.5% (w / w) of an intragranular disintegrant (e.g, croscarmellose sodium);(e) about 0.5% (w / w) of an intragranular lubricant (e.g, magnesium stearate);(1) about 12% (w / w) of an extragranular filler (e.g, microcrystalline cellulose PH 102);(g) about 1.0% (w / w) of an extragranular glidant (e.g, colloidal silicon dioxide);(h) about 1.5% (w / w) of an extragranular disintegrant (e.g, croscarmellose sodium); and(i) about 0.5% (w / w) of an extragranular lubricant (e.g, magnesium stearate).

[0320] In some embodiments, the pharmaceutical composition comprises:(a) about 50% (w / w) of crystalline form A of the compound of formula (I);(b) about 32% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of an intragranular glidant (e.g, colloidal silicon dioxide);(d) about 1.5% (w / w) of an intragranular disintegrant (e.g, croscarmellose sodium);(e) about 0.5% (w / w) of an intragranular lubricant (e.g. magnesium stearate);(f) about 12% (w / w) of an extragranular filler (e.g, microcrystalline cellulose PH 102);(g) about 1.0% (w / w) of an extragranular glidant (e.g, colloidal silicon dioxide);(h) about 1.5% (w / w) of an extragranular disintegrant (e.g, croscarmellose sodium); and(i) about 0.5% (w / w) of an extragranular lubricant (e.g. magnesium stearate).

[0321] In some embodiments, the pharmaceutical composition comprises:(a) about 55% (w / w) of crystalline form A of the compound of formula (I);(b) about 27% (w / w) of an intragranular filler compnsing microcrystalline cellulose PH 101:(c) about 1.0% (w / w) of an intragranular glidant (e.g., colloidal silicon dioxide);(d) about 1.5% (w / w) of an intragranular disintegrant (e.g, croscarmellose sodium);(e) about 0.5% (w / w) of an intragranular lubricant (e.g., magnesium stearate);(!) about 12% (w / w) of an extragranular filler (e.g., microcrystalline cellulose PH 102);(g) about 1.0% (w / w) of an extragranular glidant (e.g, colloidal silicon dioxide);(h) about 1.5% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.5% (w / w) of an extragranular lubricant (e.g., magnesium stearate).

[0322] In some embodiments, the pharmaceutical composition comprises:(a) about 60% (w / w) of crystalline form A of the compound of formula (I);(b) about 22% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of an intragranular glidant (e.g., colloidal silicon dioxide);(d) about 1.5% (w / w) of an intragranular disintegrant (e.g, croscarmellose sodium);(e) about 0.5% (w / w) of an intragranular lubricant (e.g.. magnesium stearate);(f) about 12% (w / w) of an extragranular filler (e.g, microcrystalline cellulose PH 102);(g) about 1.0% (w / w) of an extragranular glidant (e.g., colloidal silicon dioxide);(h) about 1.5% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.5% (w / w) of an extragranular lubricant (e.g. magnesium stearate).

[0323] In some embodiments, the pharmaceutical composition comprises:(a) about 35% (w / w) to about 50% (w / w) of crystalline form A of the compound of formula (I);(b) about 30% (w / w) to about 50% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 0.5% (w / w) to about 1.5% (w / w) of intragranular colloidal silicon dioxide;(d) about 0.5% (w / w) to about 2.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.25% (w / w) to about 0.75% (w / w) of intragranular magnesium stearate;(1) about 5% (w / w) to about 20% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 0.5% (w / w) to about 1.5% (w / w) of extragranular colloidal silicon dioxide;(h) about 0.5% (w / w) to about 2.5% (w / w) of extragranular croscarmellose sodium; and(i) about 0.25% (w / w) to about 0.75% (w / w) of extragranular magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0324] In some embodiments, the pharmaceutical composition comprises:(a) about 35% (w / w) to about 45% (w / w) of crystalline form A of the compound of formula (I);(b) about 35% (w / w) to about 50% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 0.5% (w / w) to about 1.5% (w / w) of intragranular colloidal silicon dioxide;(d) about 0.5% (w / w) to about 2.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.25% (w / w) to about 0.75% (w / w) of intragranular magnesium stearate;(1) about 5% (w / w) to about 20% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 0.5% (w / w) to about 1.5% (w / w) of extragranular colloidal silicon dioxide;(h) about 0.5% (w / w) to about 2.5% (w / w) of extragranular croscarmellose sodium; and(i) about 0.25% (w / w) to about 0.75% (w / w) of extragranular magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0325] In some embodiments, the pharmaceutical composition comprises:(a) about 37% (w / w) to about 43% (w / w) of crystalline form A of the compound of formula (I);(b) about 38% (w / w) to about 46% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 0.8% (w / w) to about 1.2% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.25% (w / w) to about 1.75% (w / w) of intragranular croscarmellose sodium;(e) about 0.3% (w / w) to about 0.7% (w / w) of intragranular magnesium stearate;(1) about 8% (w / w) to about 16% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 0.8% (w / w) to about 1 .2% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.25% (w / w) to about 1.75% (w / w) of extragranular croscarmellose sodium; and(i) about 0.3% (w / w) to about 0.7% (w / w) of extragranular magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0326] In some embodiments, the pharmaceutical composition comprises:(a) about 38% (w / w) to about 42% (w / w) of crystalline form A of the compound of formula (I);(b) about 40% (w / w) to about 44% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 0.9% (w / w) to about 1.1% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.4% (w / w) to about 1.6% (w / w) of intragranular croscarmellose sodium;(e) about 0.4% (w / w) to about 0.6% (w / w) of intragranular magnesium stearate;(1) about 10% (w / w) to about 14% (w / w) of extragranular microcry stalline cellulose PH 102;(g) about 0.9% (w / w) to about 1.1% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.4% (w / w) to about 1.6% (w / w) of extragranular croscarmellose sodium; and(i) about 0.4% (w / w) to about 0.6% (w / w) of extragranular magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0327] In some embodiments, the pharmaceutical composition comprises:(a) about 39% (w / w) to about 41% (w / w) of crystalline form A of the compound of formula (I);(b) about 41% (w / w) to about 43% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 0.95% (w / w) to about 1.05% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.45% (w / w) to about 1.55% (w / w) of intragranular croscarmellose sodium;(e) about 0.45% (w / w) to about 0.55% (w / w) of intragranular magnesium stearate;(f) about 11% (w / w) to about 13% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 0.95% (w / w) to about 1.05% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.45% (w / w) to about 1.55% (w / w) of extragranular croscarmellose sodium; and(i) about 0.45% (w / w) to about 0.55% (w / w) of extragranular magnesium stearate; thereby totaling no more than 100% (w / w) of the composition.

[0328] In some embodiments, the pharmaceutical composition comprises:(a) about 40% (w / w) of crystalline form A of the compound of formula (I);(b) about 42% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.5% (w / w) of intragranular magnesium stearate;(1) about 12% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 1 .0% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.5% (w / w) of extragranular croscarmellose sodium; and(i) about 0.5% (w / w) of extragranular magnesium stearate).

[0329] In some embodiments, the pharmaceutical composition comprises:(a) about 45% (w / w) of crystalline form A of the compound of formula (I);(b) about 37% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.5% (w / w) of intragranular magnesium stearate;(f) about 12% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 1.0% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.5% (w / w) of extragranular croscarmellose sodium; and(i) about 0.5% (w / w) of extragranular magnesium stearate).

[0330] In some embodiments, the pharmaceutical composition comprises:(a) about 50% (w / w) of crystalline form A of the compound of formula (I);(b) about 32% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.5% (w / w) of intragranular magnesium stearate;(1) about 12% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 1.0% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.5% (w / w) of extragranular croscarmellose sodium; and(i) about 0.5% (w / w) of extragranular magnesium stearate).

[0331] In some embodiments, the pharmaceutical composition comprises:(a) about 55% (w / w) of crystalline form A of the compound of formula (I);(b) about 27% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.5% (w / w) of intragranular magnesium stearate;(f) about 12% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 1.0% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.5% (w / w) of extragranular croscarmellose sodium; and(i) about 0.5% (w / w) of extragranular magnesium stearate).

[0332] In some embodiments, the pharmaceutical composition comprises:(a) about 60% (w / w) of crystalline form A of the compound of formula (I);(b) about 22% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.5% (w / w) of intragranular magnesium stearate;(1) about 12% (w / w) of extragranular microcrystal I inc cellulose PH 102;(g) about 1.0% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.5% (w / w) of extragranular croscarmellose sodium; and(i) about 0.5% (w / w) of extragranular magnesium stearate).Dosage Forms

[0333] In some embodiments, provided are dosage forms comprising a pharmaceutical composition described herein.

[0334] In some embodiments, provided are dosage forms intended for oral administration comprising a pharmaceutical composition described herein.

[0335] In some embodiments, the dosage form is selected from the group consisting of a powder, a sachet, a stickpack, a capsule, a minitab, and a tablet.[0336 J In some embodiments, the dosage form is a tablet.

[0337] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 200 mg to 1000 mg.

[0338] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 200 mg to 750 mg.

[0339] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 225 mg to 650 mg.

[0340] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 240 mg to about 260 mg, about 300 mg to about 325 mg, about 360 mg to about 390 mg, about 480 mg to about 520 mg or about 600 mg to about 650 mg,.

[0341] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 250 mg, about 312.5 mg, about 375 mg, about 500 mg, or about 625 mg.

[0342] In some embodiments, the dosage form comprises about 50 mg to about 350 mg of the crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises about 100 mg to about 300 mg of the crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises about 100 mg to about 250 mg of the crystalline form A of the compound of formula (I).

[0343] In some embodiments, the dosage form comprises about 50 mg. about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg or about 350 mg of crystalline form A of the compound of formula (I).

[0344] In some embodiments, the dosage form comprises about 100 mg, about 125 mg, about 150 mg, about 175 mg. about 200 mg. about 225 mg, about 250 mg, about 275 mg or about 300 mg of crystalline form A of the compound of formula (I).

[0345] In some embodiments, the dosage form comprises about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg or about 300 mg of crystalline form A of the compound of formula (I).

[0346] In some embodiments, the dosage form comprises about 100 mg, about 125 mg, about 150 mg, about 200 mg or about 250 mg of cry stalline form A of the compound of formula (I). In some embodiments, the dosage form comprises about 150 mg, about 200 mg or about 250 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage formcomprises about 150 mg or about 250 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises about 200 mg or about 250 mg of crystalline form A of the compound of formula (1). In some embodiments, the dosage form comprises about 100 mg, about 200 mg or about 300 mg of crystalline form A of the compound of formula (I).

[0347] In some embodiments, the dosage form comprises about 100 mg or about 200 mg of crystalline form A of the compound of formula (I).

[0348] In some embodiments, the dosage form comprises about 50 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 75 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 100 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 125 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 150 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 175 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 200 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 225 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 250 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 275 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 300 mg of cry stalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 325 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 350 mg of crystalline form A of the compound of formula (I).

[0349] In some embodiments, the dosage form comprises 100 mg Compound of formula (I), 105 mg intragranular microcrystalline cellulose PH 101, 2.5 mg intragranular colloidal silicon dioxide (e.g.. Aerosil® 200, CAB-O-SIL® M-5P), 3.7 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.3 mg intragranular magnesium stearate, 29.9 mg extragranular microcrystalline cellulose PH 102, 2.5 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O- SIL® M-5P), 3.7 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 2.5 mg extragranular magnesium stearate.

[0350] In some embodiments, the dosage form comprises 100 mg Compound of formula (I), 105 mg intragranular microcrystalline cellulose PH 101, 2.5 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 3.75 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.25 mg intragranular magnesium stearate, 30 mg extragranular microcrystallinecellulose PH 102, 2.5 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O- SIL® M-5P), 3.75 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 1.25 mg extragranular magnesium stearate.

[0351] In some embodiments, the dosage form comprises 125 mg Compound of formula (I), 131 mg intragranular microcrystalline cellulose PH 101, 3.2 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 4.7 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.6 mg intragranular magnesium stearate, 37.4 mg extragranular microcrystalline cellulose PH 102, 3.2 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O- SIL® M-5P), 4.7 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 3.2 mg extragranular magnesium stearate.

[0352] In some embodiments, the dosage form comprises 125 mg Compound of formula (I). 131.25 mg intragranular microcrystalline cellulose PH 101, 3.13 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 4.69 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.56 mg intragranular magnesium stearate, 37.50 mg extragranular microcrystalline cellulose PH 102, 3.13 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 4.69 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 1.56 mg extragranular magnesium stearate.

[0353] In some embodiments, the dosage form comprises 150 mg Compound of formula (I), 157.5 mg intragranular microcrystalline cellulose PH 101, 3.8 mg intragranular colloidal silicon dioxide (e.g. Aerosil® 200, CAB-O-SIL® M-5P), 5.6 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.9 mg intragranular magnesium stearate, 44.9 mg extragranular microcrystalline cellulose PH 102, 3.8 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O- SIL® M-5P), 5.6 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 3.8 mg extragranular magnesium stearate.

[0354] In some embodiments, the dosage form comprises 150 mg Compound of formula (I). 157 mg intragranular microcrystalline cellulose PH 101, 3.75 mg intragranular colloidal silicon dioxide (e.g, Aerosil® 200, CAB-O-SIL® M-5P), 5.63 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.88 mg intragranular magnesium stearate, 45 mg extragranular microcrystalline cellulose PH 102, 3.75 mg extragranular colloidal silicon dioxide (e.g, Aerosil® 200, CAB-O- SIL® M-5P), 5.63 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 1.88 mg extragranular magnesium stearate.

[0355] In some embodiments, the dosage form comprises 200 mg Compound of formula (I), 210 mg intragranular microcrystalline cellulose PH 101. 5. 1 mg intragranular colloidal silicondioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 7.5 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 2.5 mg intragranular magnesium stearate, 59.9 mg extragranular microcrystalline cellulose PH 102, 5.1 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O- SIL® M-5P), 7.5 mg extragranular croscarmellose sodium (Ac-Di-Sol*) and 5.1 mg extragranular magnesium stearate.

[0356] In some embodiments, the dosage form comprises 200 mg Compound of formula (I). 210 mg intragranular microcrystalline cellulose PH 101. 5.0 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 7.5 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 2.5 mg intragranular magnesium stearate, 60 mg extragranular microcrystalline cellulose PH 102, 5.0 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O- SIL® M-5P), 7.5 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 2.5 mg extragranular magnesium stearate.

[0357] In some embodiments, the dosage form comprises 250 mg Compound of formula (I), 262.5 mg intragranular microcrystalline cellulose PH 101, 6.3 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 9.3 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 3.2 mg intragranular magnesium stearate, 74.8 mg extragranular microcrystalline cellulose PH 102, 6.3 mg extragranular colloidal silicon dioxide (e.g., Aerosil* 200, CAB-O- SIL® M-5P), 9.3 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 6.3 mg extragranular magnesium stearate.

[0358] In some embodiments, the dosage form comprises 250 mg Compound of formula (I).262.5 mg intragranular microcrystalline cellulose PH 101, 6.25 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 9.38 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 3.13 mg intragranular magnesium stearate, 75 mg extragranular microcrystalline cellulose PH 102, 6.25 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O- SIL® M-5P). 9.38 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 3.13 mg extragranular magnesium stearate.

[0359] In some embodiments, the dosage form is a tablet.

[0360] In some embodiments, the tablet further comprises a coating. In some embodiments, the coating is selected from the group consisting of a film forming polymer, a plasticizer, and combinations thereof. In some embodiments, the film forming polymer is selected from the group consisting of a hypromellose, an ethylcellulose, cellulose acetate, a polyvinylpyrrolidone, a polyvinyl alcohol, a polyacrylate, and combinations thereof. In some embodiments, the plasticizer is selected from the group consisting of triacetin, polyethylene glycol, propyleneglycol, and combinations thereof. In some embodiments, the coating comprises polyvinyl alcohol.

[0361] In some embodiments, the coating compnses a colorant selected from the group consisting of titanium dioxide, an aluminum lake, an iron oxide, carbon black, and combinations thereof. In some embodiments, the colorant is titanium dioxide.Methods of Making

[0362] In some embodiments, provided are processes for preparing a pharmaceutical composition as described herein.

[0363] In some embodiments, provided is a process for preparing a pharmaceutical composition comprising cry stalline form A of a compound of formula (I) as described in any of the embodiments herein, comprising:(a) Charging and blending cry stalline form A of a compound of Formula (I), an intragranular filler, an intragranular glidant and an intragranular disintegrant and blending to obtain a pre-lubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre-lubrication extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition;

[0364] In another aspect, provided are processes for preparing the dosage forms comprising crystalline form A of a compound of formula (I) described in any of the embodiments herein, for example, comprising:(a) Charging and blending crystalline form A of a compound of Formula (I), an intragranular filler, an intragranular glidant and an intragranular disintegrant and blending to obtain a pre-lubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre-lubncation extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition;(g) Compressing the pharmaceutical composition into dosage forms; and. optionally(h) Coating the dosage forms.

[0365] The pharmaceutical compositions and dosage forms described herein are amenable to manufacture using a streamlined manufacturing process. A schematic process for preparing the dosage forms described herein is depicted in FIG. 14.

[0366] The order of addition of components for the blending steps influences the uniformity of API in the blend and impacts the distribution of low-level components in the blend. Uniform distribution of low-level components in the intragranular blend is important to successfully achieve dry granulation of the intragranular blend. For example, lack of uniform distribution of glidant in the intragranular blend can result in sub-optimal granulation with a wide particle size distribution, which would negatively impact extragranular blending and eventually compressibility of the final blend. In some embodiments, the order of addition is as show n in Table. 5.Table. 5. Order of addition of ingredientsMCC - microcrystalline celluloseCCS - croscarmellose sodiumAPI - compound of formula (1)

[0367] In some embodiments, provided are processes for preparing a pharmaceutical composition as described herein, for example, comprising:(a) Charging, in order:i. 50% of a desired total amount of intragranular filler; ii. a desired total amount of crystalline form A of a compound of Formula (I) as described herein; iii. a desired total amount of intragranular disintegrant; iv. a desired total amount of intragranular glidant; and v. 50% of the desired total amount of intragranular filler;(b) pre-blending and sieving the components charged at step (a) to obtain a pre-blending intragranular mixture;(c) blending the pre-blending intragranular mixture to obtain a pre-lubrication intragranular blend;(d) Charging, in order: i. 50% of the pre-lubrication intragranular blend; ii. 100% of a desired amount of intragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication intragranular blend; to obtain a lubricated intragranular mixture;(e) Blending the lubricated intragranular mixture to obtain an intragranular blend;(f) Granulating the intragranular blend to obtain granules;(g) Milling the granules to obtain milled granules;(h) Charging, in order: i. 50% of a desired amount of extragranular filler; ii. the milled granules obtained at step (g); iii. a desired amount of extragranular disintegrant; iv. a desired amount of extragranular glidant; v. 50% of a desired amount of extragranular filler;(i) Pre-blending and sieving the components charged at step (h) to obtain a pre-blending extragranular mixture;(j) Blending the pre-blending extragranular mixture to obtain a pre-lubrication extragranular blend;(k) Charging, in order: i. 50% of the pre-lubrication extragranular blend; ii. a desired amount of extragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication extragranular blend; to obtain a lubricated extragranular mixture;(1) Blending the lubricated intragranular mixture to obtain the pharmaceutical composition.

[0368] In another aspect, provided are processes for preparing the dosage forms described herein, for example, comprising:(a) Charging, in order: i. 50% of a desired total amount of intragranular filler; ii. a desired total amount of crystalline form A of a compound of Formula (I) as described herein; iii. a desired total amount of intragranular disintegrant; iv. a desired total amount of intragranular glidant; and v. 50% of the desired total amount of intragranular filler;(b) pre-blending and sieving the components charged at step (a) to obtain a pre-blending intragranular mixture;(c) blending the pre-blending intragranular mixture to obtain a pre-lubrication intragranular blend;(d) Charging, in order: i. 50% of the pre-lubrication intragranular blend; ii. 100% of a desired amount of intragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication intragranular blend; to obtain a lubricated intragranular mixture;(e) Blending the lubricated intragranular mixture to obtain an intragranular blend;(f) Granulating the intragranular blend to obtain granules;(g) Milling the granules to obtain milled granules;(h) Charging, in order: i. 50% of a desired amount of extragranular filler; ii. the milled granules obtained at step (g); iii. a desired amount of extragranular disintegrant; iv. a desired amount of extragranular glidant; v. 50% of a desired amount of extragranular filler;(i) Pre-blending and sieving the components charged at step (h) to obtain a pre-blending extragranular mixture;(j) Blending the pre-blending extragranular mixture to obtain a pre-lubrication extragranular blend;(k) Charging, in order: i. 50% of the pre-lubrication extragranular blend; ii. a desired amount of extragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication extragranular blend; to obtain a lubricated extragranular mixture;(l) Blending the lubricated intragranular mixture to obtain the pharmaceutical composition.(m) Compressing the pharmaceutical composition into dosage forms; and, optionally(n) Coating the dosage forms.

[0369] The selection of granule milling screen size in the milling step influences the particle size distribution of the resulting granules. In some embodiments, the milling step employs 3.15 mm wired screen size followed by 1 mm wired screen size, resulting in a profile of milled granules with acceptable particle size distribution, including low levels of fines, amenable for processing during tablet compression, which is ty pically difficult to achieve for a cry stalline drug substance formulation with a high drug load.

[0370] In some embodiments, the intragranular filler consists substantially of microcrystalline cellulose PH 101.

[0371] In some embodiments, the intragranular disintegrant consists substantially of croscarmellose sodium.

[0372] In some embodiments, the intragranular glidant consists substantially of colloidal silicon dioxide.

[0373] In some embodiments, the intragranular lubricant consists substantially of magnesium stearate.

[0374] In some embodiments, the extragranular filler consists substantially of microcrystalline cellulose PH 102.

[0375] In some embodiments, the extragranular disintegrant consists substantially of croscarmellose sodium.

[0376] In some embodiments, the extragranular glidant consists substantially of colloidal silicon dioxide.

[0377] In some embodiments, the extragranular lubricant consists substantially of magnesium stearate.

[0378] In some embodiments, the desired amounts of crystalline form A of a compound of Formula (I), intragranular filler, intragranular disintegrant, intragranular glidant, intragranularlubricant, extragranular filler, extragranular disintegrant, extragranular glidant and extragranular lubricant are selected to result in pharmaceutical compositions having the w / w percentages of ingredients described in the “Pharmaceutical composition7’ section.

[0379] In some embodiments, granulating the intragranular blend to obtain granules comprises a dry granulation process step. In some embodiments, granulating the intragranular blend to obtain granules comprises a wet granulation process step.

[0380] In some embodiments, the tablet comprises a coating. In some embodiments, the coating comprises one or more film-forming polymers selected from the group consisting of a hypromellose, an ethylcellulose, a polyvinylpyrrolidone, a polyacrylate, a plasticizer, and combinations thereof. In some embodiments, the coating comprises a polyvinyl alcohol.

[0381] In some embodiments, the coating comprises a colorant selected from the group consisting of titanium dioxide, an aluminum lake, an iron oxide, carbon black, and combinations thereof. In some embodiments, the colorant is titanium dioxide.

[0382] In some embodiments, provided is a pharmaceutical composition or a dosage form as described herein prepared by the processes described herein.Methods of Use and TreatmentTreatment of MTAP-deficient and / or MTA-accumulating proliferation disorders

[0383] 5-Methylthioadenosine phosphorylase (MTAP) catalyzes the reversible phosphorylation of S-methyl-5'-thioadenosine (MTA) to adenine and 5-methylthioribose- 1 -phosphate. MTAP- deletion is a common genetic event in human cancer. MTAP deletion frequency in a subset of human cancers is described in Cerami et al., Cancer Discov. (2012);2(5):401-4; Gao et al., Sci Signal. (2013);6(269):pll; and Lee et al., Nat. Gen. (2014) 46(11): 1227-32. For example, more than 50% of malignant peripheral nerve sheath tumor (MPNST) have deletions in MTAP (Lee et al., Nat. Gen. (2014)). Other cancers with high MTAP deletion frequencies are glioblastoma (GBM), mesothelioma, bladder cancer, pancreatic cancer, esophageal cancer, squamous lung cancer, melanoma, diffuse large B cell lymphoma (DLBCL), head and neck cancer, cholangiocarcinoma, lung adenoma, sarcoma, stomach cancer, glioma, adrenal carcinoma, thymoma, breast cancer, liver cancer, ovarian cancer, renal papillary cancer, uterine cancer, prostate cancer, and renal clear cell cancer. MTAP deletion in cells is one of the mechanisms that leads to MTAP-deficiency, increased intracellular MTA accumulation, and confers enhanced dependency on the protein arginine methyltransferase 5 (PRMT5) in cancer cells. Other mechanisms leading to MTAP deficiency include, inter alia, MTAP translocations andMTAP epigenetic silencing which could also lead to MTAP-null and / or MTAP deficient tumors. PRMT5 mediates the formation of symmetric dimethylarginine (SDMA); thus, the PRMT5 activity can be assessed by measuring the SDMA levels using the antibody against an SDMA or SDMA modified polypeptide.

[0384] In some embodiments, provided are methods of treating human or animal subjects having or having been diagnosed with an MTAP-deficiency-related and / or MTA-accumulating proliferative disorder (e.g.. cancer) comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g, a crystalline form of a compound of formula (I), crystalline Form A of the compound of formula (I)), a pharmaceutical composition comprising a compound of formula (I) as described herein, or a dosage form as described herein. In some cases, the MTAP-deficiency is an MTAP-deletion.

[0385] In some embodiments, provided is a compound of the present disclosure (e.g., a crystalline form of a compound of formula (I), crystalline Form A of the compound of formula (I)), or a pharmaceutical composition comprising a compound of formula (I) of the present disclosure for use in a method of treating human or animal subjects having or having been diagnosed with an MTAP-deficiency-related and / or MTA-accumulating proliferative disorder (e.g., cancer). In some embodiments, the compound or composition is provided in a therapeutically effective amount.

[0386] In some embodiments, provided is a compound of the present disclosure (e.g., a crystalline form of a compound of formula (I), crystalline Form A of the compound of formula (I)), or a pharmaceutical composition comprising a compound of formula (I) of the present disclosure for use in the manufacturing of a medicament for treating human or animal subjects having or having been diagnosed with an MTAP-deficiency-related and / or MTA-accumulating proliferative disorder (e.g.. cancer). In some embodiments, the compound or composition is provided in a therapeutically effective amount.

[0387] In some embodiments, provided is a use of a compound of the present disclosure (e.g., a crystalline form of a compound of formula (I), crystalline Form A of the compound of formula (I)), or of a pharmaceutical composition comprising a compound of formula (I) of the present disclosure in a method of treating human or animal subjects having or having been diagnosed with an MTAP-deficiency-related and / or MTA-accumulating proliferative disorder (e.g., cancer). In some embodiments, the use is of a therapeutically effective amount of the compound or composition.

[0388] In some embodiments, provided is use of a compound of the present disclosure (e.g, a crystalline form of a compound of formula (I), crystalline Form A of the compound of formula (1)), or of a pharmaceutical composition comprising a compound of formula (I) of the present disclosure in the manufacturing of a medicament for treating human or animal subjects having or having been diagnosed with an MTAP-deficiency-related and / or MTA-accumulating proliferative disorder (e.g., cancer). In some embodiments, the use is of a therapeutically effective amount of the compound or composition.

[0389] In some embodiments, provided are methods for treating an MTAP-deficiency-related and / or MTA-accumulating proliferative disorder (e.g., cancer) in a subject in need thereof comprising administering to the subject an effective amount (e.g, a therapeutically effective amount) of a compound of the present disclosure (e.g., a crystalline form of a compound of formula (I), crystalline Form A of the compound of formula (I)), a pharmaceutical composition comprising a compound of formula (I) as described herein, or a dosage form as described herein.

[0390] In some embodiments, provided are methods of treating human or animal subjects having or having been diagnosed with an MTAP-deficiency-related and / or MTA-accumulating proliferative disorder (e.g.. cancer) comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition of the present disclosure. In some embodiments, the method comprises administering to the subject a dosage form of the present disclosure. In one embodiment, the compound or composition is administered in combination with a second therapeutic agent.

[0391] In some embodiments, provided are methods of treating an MTAP-deficiency-related and / or MTA-accumulating proliferative disorder (e.g., cancer) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition of the present disclosure. In some embodiment, the method comprises administering to the subject a dosage form of the present disclosure. In one embodiment, the compound or composition is administered in combination with a second therapeutic agent.

[0392] In some embodiments, the subject is human.

[0393] In some embodiments, the disease is an MTAP-deficient and / or MTA-accumulating cancer. In some embodiments, the cancer is an MTAP-deleted cancer.

[0394] In some embodiments, the cancer is malignant peripheral nerve sheath tumor (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g.. lungsquamous or lung adenocarcinoma), undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, stomach cancer, kidney cancer, breast cancer, endometrium cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleura cancer, large intestine cancer or sarcoma.

[0395] In some embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma. stomach cancer, kidney cancer, breast cancer, endometnum cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleura cancer, large intestine cancer or sarcoma.

[0396] In some embodiments, the cancer is an MTAP-deficient and / or MTA-accumulating esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g.. pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, stomach cancer, kidney cancer, breast cancer, endometrium cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleura cancer, large intestine cancer or sarcoma.

[0397] In some embodiments of any of the methods, uses, compounds for use or compositions for use described herein, the cancer is a cancer selected from the group of malignant peripheral nerve sheet tumor (MPNST), pancreatic cancer. NSCLC, mesothelioma and sarcoma.

[0398] In some embodiments of any of the methods, uses, compounds for use or compositions for use described herein, the cancer is a cancer selected from the group of pancreatic cancer, NSCLC, mesothelioma and sarcoma.

[0399] In some embodiments of any of the methods, uses, compounds for use or compositions for use described herein, the cancer is pancreatic cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is histologyagnostic (i.e. is any MTAP-deficient and / or MTA-accumulating cancer) regardless of histology. In some embodiments, the cancers recited herein are MTAP-deleted cancers.

[0400] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of nonsmall cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma and urothelial carcinoma. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL. In some embodiments, the cancer is MPNST.

[0401] In some embodiments, the cancer is a cancer selected from the group consisting of nonsmall cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma and urothelial carcinoma.

[0402] In some embodiments, the compound of formula (I), crystalline forms (e.g, cry stalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) and dosage forms thereof, as described herein can be used in a method of inhibiting proliferation of MTAP- deficient cells in a subject in need thereof, the method comprising the step of administering to the subject a compound of formula (I), cry stalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein in an amount that is effective to inhibit proliferation of the MTAP- deficient cells. In one embodiment, the subject in need thereof suffers from a cancer selected from the group consisting of esophageal cancer (e.g, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC: e.g., lung squamous or lung adenocarcinoma), undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, stomach cancer, kidney cancer, breast cancer, endometrium cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleura cancer, large intestine cancer or sarcoma.

[0403] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of non- small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma andurothelial carcinoma. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0404] In some embodiments, the cancer is a cancer selected from the group consisting of nonsmall cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma and urothelial carcinoma.

[0405] In some embodiments, the compound of formula (I), crystalline forms (e.g, cry stalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein can be used in a method of inhibiting proliferation of MTA- accumulating cells in a subject in need thereof, the method comprising the step of administering to the subject a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein in an amount that is effective to inhibit proliferation of the MTA- accumulating cells. In one embodiment, the subject in need thereof suffers from a cancer selected from the group consisting of esophageal cancer (e.g. esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, stomach cancer, kidney cancer, breast cancer, endometrium cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleura cancer, large intestine cancer or sarcoma.

[0406] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma. NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of non- small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, and urothelial carcinoma. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0407] In some embodiments, the cancer is a cancer selected from the group consisting of nonsmall cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma and urothelial carcinoma.

[0408] In some embodiments, the compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein can be used in a method of inhibiting proliferation of MTAP deficient and / or MTA-accumulating cells in a subject in need thereof, the method comprising the step of administering to the subject a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein in an amount that is effective to inhibit proliferation of the MTAP deficient and / or MTA-accumulating cells. In one embodiment, the subject in need thereof suffers from a cancer selected from the group consisting of esophageal cancer (e.g, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e g., lung squamous or lung adenocarcinoma), undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, stomach cancer, kidney cancer, breast cancer, endometrium cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleura cancer, large intestine cancer or sarcoma.

[0409] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of non- small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma and urothelial carcinoma. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0410] In some embodiments, the cancer is a cancer selected from the group consisting of non- small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma and urothelial carcinoma.Combination therapies

[0411] In some embodiments, provided are methods of treatment of MTAP-deficient and / or MTA accumulating proliferative disorders (e.g, cancers) with a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein in combination wi th one or more therapeutic agents.

[0412] In some embodiments, provided are methods of treatment of MTAP-deficient and / or MTA accumulating proliferative disorders (e.g. cancers) with a compound of formula (I), crystalline forms (e.g.. crystalline form A), pharmaceutical compositions (e.g.. compnsing a compound of formula (I)) or dosage forms thereof, as described herein in combination with a second therapeutic agent. In some embodiments, provided are methods of treatment of MTAP- deficient and / or MTA accumulating proliferative disorders (e.g., cancers) with a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g.. comprising a compound of formula (I)) or dosage forms thereof, as described herein in combination with a second therapeutic agent and a third therapeutic agent. In some embodiments, provided are methods of treatment of MTAP-deficient and / or MTA accumulating proliferative disorders (e.g, cancers) with a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein in combination with a second therapeutic agent, a third therapeutic agent, and a fourth therapeutic agent.

[0413] The term “Combination’' refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of formula (I), crystalline forms (e.g.. crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein and a combination partner (e.g. , another drug as explained below, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g., synergistic effect. The single components may be packaged in a kit or separately. One or both of the components (e.g, powders or liquids) may be reconstituted or diluted to a desired dose prior to administration. The terms “coadministration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g., a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term“pharmaceutical combination’" as used herein means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and non-fixed combinations of the therapeutic agents. The term “fixed combination” means that the therapeutic agents, e.g., a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the therapeutic agents, e.g., a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more therapeutic agent.

[0414] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple, or in separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. Powders and / or liquids may be reconstituted or diluted to a desired dose prior to administration. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner, either at approximately the same time or at different times.

[0415] In some embodiments, a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g.. comprising a compound of formula (1)) or dosage forms thereof, as described herein are combined with other therapeutic agents, including, but not limited to, other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof.

[0416] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a general chemotherapeutic agent selected from anastrozole (Arimidex®),bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®). dexamethasone, docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), nab- paclitaxel (Abraxane®), phoenix (Yttrium90 / MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®). tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6- thioguanine, thiotepa, tirapazamine (Tirazone*), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0417] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein, and an EGFR-inhibitor (e.g, cetuximab, panitumimab, erlotinib, gefitinib, osimertinib and EGFRi NOS). In some embodiments, provided is a method of treating a disease or disorder (e.g, cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a MAPK-pathway inhibitor (e.g., BRAFi, panRAFi, MEKi, ERKi; PI3K-mT0R pathway inhibitors, such as alpha-specific PI3Ki, pan-class I PI3Ki and mTOR / PI3Ki, particularly everolimus and analogues thereof).

[0418] MTAP-deletion can co-occur with mutations in the KRAS gene (e g, KRASG12C). In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceuticalcompositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a KRAS inhibitor (e.g., a pan-KRAS or a specific G12C, G12D, G13C inhibitor, e.g., adagrasib, sotorasib, LY3537982, RMC-6236. RMC-6291, RMC-9805, RMC-8839).

[0419] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), cry stalline forms (e.g., cry stalline form A), pharmaceutical compositions (e.g.. comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a Spliceosome inhibitor (e.g., SF3bl inhibitors; e.g., E7107).

[0420] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein, and an HD AC inhibitor or DNA methyltransferase inhibitor. In some embodiments, the HD AC inhibitor is Trichostatin A. In some embodiments, the DNA methyltransferase inhibitor is 5-azacytidine.

[0421] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a MAT2A inhibitor (e.g., AG-270, IDE397, S95035).

[0422] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), cry stalline forms (e.g., cry stalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and an inhibitor of a protein which interacts with or is required for PRMT5 function, including, but not limited to, pICIN, WDR77 or RIOK1.

[0423] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and an HDM2 inhibitor and / or 5-FU or other purine analogues (e.g, 6-thioguanine, 6- mercaptopurine).

[0424] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (1), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a CDK4 inhibitor, including, but not limited to, LEE011 or a CDK 4 / 6 inhibitor (e.g., palbociclib (Ibrance®), riboci clib (Kisqali®). and abemaciclib (Verzenio®).

[0425] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and targeted treatments contingent on the dependency of individual target tumors on relevant pathways as determined by suitable predictive markers, including but not limited to: inhibitors of HDM2i, PI3K / mTOR-I, MAPKi, RTKi (EGFRi, FGFRi, METi, IGFiRi, JAKi, and WNTi.

[0426] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein) and immunotherapy.

[0427] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a cancer immunotherapy (e.g., a checkpoint blocking antibody) to treat a subject (e.g., a human subject), e.g., having a disease or disorder described herein (e.g., a cancer described herein)).

[0428] In some embodiments, the immunotherapeutic agent is an anti-CTLA-4 antibody (e.g, ipilimumab, tremelimumab).

[0429] In some embodiments, the immunotherapeutic agent is an anti-PD-1 antibody (e g., anti- PD-1 or anti-PD-Ll). In some embodiments, the immunotherapeutic agent is an anti-PD-1 agent (e.g., an anti-PD-1 antibody, e.g., nivolumab (i.e., MDX-1106, BMS-936558, ONO-4538); CT- 011; AMP-224; pembrolizumab (MK-3475); pidilizumab; cemiplimab; dostarlimab; prolgolimab; spartalizumab; camrelizumab; sasanlimab, sintilimab; tislelizumab; toripalimab; retifanlimab; MEDI0680; budigalimab; geptanolimab). In some embodiments, the immunotherapeutic agent is an anti-PD-Ll agent (e.g., an anti-PD-Ll antibody, e.g., BMS936559 (i.e., MDX-1105); durvalumab (MEDI4736); avelumab (MSB0010718C);envafolimab; cosibelimab; sugemalimab, AUNP-12 or atezolizumab (MPDL-3280A) or an anti- PD-L1 small molecule (e.g, CA-170)).

[0430] In some embodiments, the immunotherapeutic agent is a checkpoint blocking antibody (e.g., anti-TIM3, anti-LAG3, anti-TIGIT including IMP321 and MGA271).

[0431] In some embodiments, the immunotherapeutic agent is a cell-based therapy. In some embodiments, the cell-based therapy is a CAR-T therapy.

[0432] In some embodiments, the immunotherapeutic agent is a co-stimulatory antibody (e.g, anti-4-1 BB, anti-OX40, anti-GITR, anti-CD27, anti-CD40).

[0433] In some embodiments, the immunotherapeutic agent is a cancer vaccine such as a neoantigen. These vaccines can be developed using peptides or RNA.

[0434] In some embodiments, the immunotherapeutic agent is an oncolytic virus.

[0435] In some embodiments, the immunotherapeutic agent is a STING pathway agonist. Exemplary STING agonists include MK-1454 and ADU-S100.

[0436] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a disease-specific huMAB (e.g, an anti-HER3 huMAB).

[0437] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and an ADC / ADCC contingent on the expression of relevant surface targets on target tumors of interest.

[0438] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., cr s tai line form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and one or more DNA damage pathway inhibitor. In some embodiments, a DNA damage pathway inhibitor is selected from the group consisting of bleomycin, an ATM inhibitor (e.g., AZD1390), a USP1 inhibitor, a WEE1 inhibitor (e.g., AZD1775), and a Chkl inhibitor (e.g., AZD7762). In some embodiments, a DNA damage pathway inhibitor is a DNA alkylating agent.

[0439] In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (1), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a PARP inhibitor. In some embodiments, a PARP inhibitor is selected from the group consisting of olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, CEP 9722, E7016, iniparib, and 3-aminobenzamide.

[0440] Some patients may experience allergic reactions to the PRMT5 inhibitors described herein and / or other anti-cancer agent(s) during or after administration; therefore, anti-allergic agents are often administered to minimize the risk of an allergic reaction. In some embodiments, provided is a method of treating a disease or disorder (e g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), cry stalhne forms (e g., crystalline form A), pharmaceutical compositions (e g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and an anti-allergic agent (e.g, corticosteroids, including, but not limited to, dexamethasone (e.g., Decadron®), beclomethasone (e.g, Beclovent®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala-Cort®, hydrocortisone phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), prednisolone (sold under the tradenames Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the tradenames Deltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, sold under the tradenames Duralone®, Medralone®, Medrol®, M-Prednisol® and Solu- Medrol®); antihistamines, such as diphenhydramine (e.g, Benadry l®), hydroxyzine, and cyproheptadine; and bronchodilators, such as the beta-adrenergic receptor agonists, albuterol (e.g. Proventil®), and terbutaline (Brethine®)).

[0441] Some patients may experience nausea during and after administration of the PRMT5 inhibitors described herein and / or other anti-cancer agent(s); therefore, anti-emetics are used in preventing nausea (upper stomach) and vomiting. In some embodiments, provided is a method of treating a disease or disorder (e.g.. cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and an anti-emetic (e.g, aprepitant (Emend®), ondansetron(Zofran®), granisetron HC1 (Kytril®), lorazepam (Ativan®, dexamethasone (Decadron®), prochlorperazine (Compazine®), casopitant (Rezonic® and Zunrisa®). and combinations thereof).

[0442] Medication to alleviate the pain experienced during the treatment period is often prescribed to make the patient more comfortable. In some embodiments, provided is a method of treating a disease or disorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g.. comprising a compound of formula (I)) or dosage forms thereof, as described herein, and an analgesic (e.g., an over-the-counter analgesic (e.g., Tylenol®), an opioid analgesic (e.g, hydrocodone / paracetamol or hydrocodone / acetaminophen (e.g., Vicodin®), morphine (e.g, Astramorph® or Avinza®), oxycodone (e.g., OxyContin® or Percocet®). oxymorphone hydrochloride (Opana®), and fentanyl (e.g, Duragesic®)).

[0443] In an effort to protect normal cells from treatment toxicity and to limit organ toxicities, cytoprotective agents (such as neuroprotectants, free-radical scavengers, cardioprotectors, anthracy cline extravasation neutralizers, nutrients and the like) may be used as an adjunct therapy. In some embodiments, provided is a method of treating a disease or disorder (e.g.. cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein, and a cytoprotective agent (e.g., Amifostine (Ethyol®), glutamine, dimesna (Tavocept®), mesna (Mesnex®), dexrazoxane (Zinecard® or Totect®). xaliproden (Xaprila®), and leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid)).

[0444] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium “The Merck Index” or from databases, e.g., Patents International (e.g., IMS World Publications).

[0445] The above-mentioned compounds, which can be used in combination with a PRMT5 inhibitor as described herein, can be prepared and administered as described in the art, including, but not limited to, in the documents cited above.

[0446] In one embodiment, provided are pharmaceutical compositions comprising at least one compound of the present disclosure (e.g., a crystalline form of a compound of formula (I), e.g, crystalline form A) together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject, either alone or together with other anti-cancer agents.

[0447] In particular, compositions will either be formulated together as a combination therapeutic or administered separately.

[0448] In combination therapy, a PRMT5 inhibitor as described herein and other anti-cancer agent(s) may be administered either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.

[0449] In a preferred embodiment, the compound of the present disclosure (a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein) and the other anti-cancer agent(s) is generally administered sequentially in any order by infusion or orally. The dosing regimen may van’ depending upon the stage of the disease, physical fitness of the patient, safety profiles of the individual drugs, and tolerance of the individual drugs, as well as other criteria well-known to the attending physician and medical practitioner(s) administering the combination. The PRMT5 inhibitor as described herein and other anti-cancer agent(s) may be administered within minutes of each other, hours, days, or even weeks apart depending upon the particular cycle being used for treatment. In addition, the cycle could include administration of one drug more often than the other during the treatment cycle and at different doses per administration of the drug.

[0450] In another aspect, provided are kits that include one or more PRMT5 inhibitor(s) as described herein (a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein) and a second therapeutic agent as disclosed herein are provided. Representative kits include (a) a PRMT5 inhibitor as described herein (a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (1)) or dosage forms thereof, as described herein), (b) at least one other therapeutic agent, e.g., as indicated above, whereby such kit may comprise a package insert or other labeling including directions for administration.

[0451] A compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g.. comprising a compound of formula (I)) or dosage forms thereof, as described herein may also be used in combination with known therapeutic processes, for example, the administration of hormones or especially radiation. A compound of the present disclosure may in particular be used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy. In some embodiments, provided is a method of treating a disease ordisorder (e.g., cancer) comprising administering or coadministering, in any order, to a patient in need thereof a compound of formula (I), crystalline forms (e.g.. crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (1)) or dosage forms thereof, as described herein, and radiation.Patient Selection and Monitoring

[0452] In some embodiments, provided is a method of determining if a subject having or having been diagnosed with a cancer (e.g, a cancer patient) will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive PRMT5 inhibitor, e.g., a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein), comprising the steps of: a) contacting a test sample obtained from said subject with a reagent capable of detecting human cancer cells that have MTAP deficiency and / or MTA accumulation; and b) comparing the test sample with a reference (e.g., a reference sample taken from a non- cancerous or normal control subject), wherein the presence of MTAP deficiency and / or MTA accumulation in said test sample indicates that the subject will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent, e.g., a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein).

[0453] In some embodiments, provided is a method of determining if a cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent, a compound of formula (I), crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein), comprising the steps of: a) contacting a test sample obtained from a subject having or having been diagnosed with said cancer with a reagent capable of detecting human cancer cells that have MTAP deficiency and / or MTA accumulation; and b) comparing the test sample with a reference (e.g., a reference sample taken from a non- cancerous or normal control subject),wherein the presence of MTAP deficiency and / or MTA accumulation in said test sample indicates that the cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g, an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent, e.g, a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein). In some embodiments, the cancer is esophageal cancer (e.g, esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g. bladder urothelial carcinoma), pancreatic cancer (e.g, pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g, lung squamous or lung adenocarcinoma), undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, stomach cancer, kidney cancer, breast cancer, endometrium cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleura cancer, large intestine cancer or sarcoma.

[0454] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of non- small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, and urothelial carcinoma. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0455] In some embodiments, the cancer is a cancer selected from the group consisting of non- small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma and urothelial carcinoma.

[0456] In some embodiments, the method further comprises the step of determining the level of PRMT5 in the cancer cells. The level of expression of PRMT5 can be considered when determining the therapeutically effective dosage of a PRMT5 inhibitor.

[0457] In one aspect, provided is a method of determining the sensitivity of a cancer cell to PRMT5 inhibition (e.g, inhibition with an MTA-uncompetitive PRMT5 inhibitor, e.g, a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein), comprising the steps of:a) assaying the production, level, activity, expression or presence of MTAP), in said cancer cell; b) comparing the production, level, activity, expression or presence of MTAP in the cancer cell with the production, level, activity, expression or presence of MTAP, respectively, in a non-cancerous or normal control cell, wherein a decreased level, activity or expression in the cancer cell indicates MTAP deficiency and wherein MTAP deficiency indicates that said cancer cell is sensitive to the PRMT5 inhibitor.

[0458] In some embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g.. pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g.. lung squamous or lung adenocarcinoma), undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, stomach cancer, kidney cancer, breast cancer, endometrium cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleura cancer, large intestine cancer or sarcoma.

[0459] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of non- small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma. and urothelial carcinoma. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0460] In some embodiments, the cancer is a cancer selected from the group consisting of non- small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma and urothelial carcinoma.

[0461] In one embodiment, provided is a method of determining the sensitivity of a cancer cell to a PRMT5 inhibitor (e.g., an MTA-uncompetitive. non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent, e.g., a compound of formula (I), crystalline forms (e.g., cry stalline form A), pharmaceutical compositions (e.g., comprising a compound of formula (I)) or dosage forms thereof, as described herein), comprising the steps of:a) assaying for level, activity or expression of the MTAP gene or its gene product in both the cancer cell and a normal control cell, wherein a decreased level, activity or expression in the cancer cell indicates MTAP deficiency; b) assaying for PRMT5 expression in said cancer cell; c) comparing the PRMT5 expression with PRMT5 expression in the cancer cell and a normal control cell; wherein the similarity in PRMT5 expression, and the presence of said MTAP deficiency in said cancer cell, indicates said cell is sensitive to a PRMT5 inhibitor.

[0462] In some embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g.. pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g.. lung squamous or lung adenocarcinoma), undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, stomach cancer, kidney cancer, breast cancer, endometrium cancer, urinary' tract cancer, liver cancer, soft tissue cancer, pleura cancer, large intestine cancer or sarcoma.

[0463] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of non- small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma and urothelial carcinoma. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0464] In some embodiments, the cancer is a cancer selected from the group consisting of non- small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma and urothelial carcinoma.

[0465] In one aspect the provided is a therapeutic method of treating a subject having or having been diagnosed with a cancer (e.g., a cancer associated with MTAP deficiency and / or MTA accumulation) comprising the steps of: a) assessing the level of MTAP and / or MTA in a test sample obtained from said subject (e.g., by contacting the sample with a reagent capable of detecting human MTAP- deficient and / or MTA-accumulating cancer cells in a test sample obtained from saidsubject), wherein the MTA level can be assessed directly (e.g, by ELISA or LC-MS / MS) or indirectly (e.g., by SDMA-modified protein ELISA or IHC, or by RNA splicing); b) comparing the test sample with a reference (e.g, a reference sample taken from a non- cancerous or normal control subject), wherein MTAP deficiency and / or MTA accumulation in said test sample indicates said subject will respond to therapeutic treatment with a PRMT5 inhibitor; and c) administering a therapeutically effective amount of PRMT5 inhibitor (e.g, an MTA- uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA- cooperative binding agent, e.g, a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein) to the subject identified in step b).

[0466] In one aspect provided is a therapeutic method of treating a cancer (e.g, a cancer associated with MTAP deficiency and / or MTA accumulation) in a subject in need thereof comprising the steps of: a) assessing the level of MTAP and / or MTA in a test sample obtained from said subject (e.g, by contacting the sample with a reagent capable of detecting human MTAP- deficient and / or MTA-accumulating cancer cells), wherein the MTA level can be assessed directly (e.g, by ELISA or LC-MS / MS) or indirectly (e.g, by SDMA-modified protein ELISA or IHC, or by RNA splicing); b) comparing the test sample with a reference (e.g, a reference sample taken from a non- cancerous or normal control subject), wherein MTAP deficiency and / or MTA accumulation in said test sample indicates said cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g, an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent); and c) administering a therapeutically effective amount of PRMT5 inhibitor (e.g, an MTA- uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA- cooperative binding agent, e.g, a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein) to the subject identified in step b).

[0467] In some embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g.. pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, stomach cancer, kidney cancer, breast cancer, endometrium cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleura cancer, large intestine cancer or sarcoma.

[0468] In some embodiments, the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous), bladder cancer, and DLBCL. In some embodiments, the cancer is a cancer selected from the group consisting of non- small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma and urothelial carcinoma. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is NSCLC (adenocarcinoma). In some embodiments, the cancer is NSCLC (squamous). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0469] In some embodiments, the cancer is a cancer selected from the group consisting of non- small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma and urothelial carcinoma.

[0470] In some embodiments, the method further comprises the step of determining the level of PRMT5 in the cancer cells.

[0471] In one aspect provided is a therapeutic method of treating a subject having or having been diagnosed with a cancer associated with MTAP deficiency and / or MTA accumulation comprising the steps of: a) assessing the level of MTAP and / or MTA in a test sample obtained from said subject (e.g., by contacting the sample with a reagent capable of detecting human MTAP- deficient and / or MTA-accumulating cancer cells), wherein the MTA level can be assessed directly (e g, by ELISA or LC-MS / MS) or indirectly (e.g., by SDMA-modified protein ELISA or IHC. or by RNA splicing); b) comparing the test sample with a reference sample (e.g., a reference sample taken from a non-cancerous or normal control subject), wherein MTAP deficiency and / or MTA accumulation in said test sample indicates said cancer will respond to therapeutictreatment with a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent); and c) administering a therapeutically effective amount of a composition comprising a PRMT5 inhibitor (e.g., an MTA-uncompetitive, non-competitive, or mixed mode PRMT5 inhibitor or an MTA-cooperative binding agent, e.g, a compound of formula (I), crystalline forms (e.g, crystalline form A), pharmaceutical compositions (e.g, comprising a compound of formula (I)) or dosage forms thereof, as described herein) to the subject identified in step b).

[0472] In one aspect provided is a therapeutic method of treating cancer associated with MTAP deficiency and / or MTA accumulation in a subject in need thereof comprising the steps of: a) assessing the level of MTAP and / or MTA in a test sample obtained from said subject (e.g, by contacting the sample with a reagent capable of detecting human MTAP- deficient and / or MTA-accumulating cancer cells), wherein the MTA level can be assessed directly (e.g, by ELISA or LC-MS / MS) or indirectly (e.g., by SDMA-modified protein ELISA or IHC. or by RNA splicing); b) comparing the test sample with ...

Claims

CLAIMS1. A pharmaceutical composition comprising crystalline Form A of a compound of formula (I)and at least one pharmaceutically acceptable excipient; wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 29, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees; and wherein the pharmaceutically acceptable excipient comprises microcrystalline cellulose PH 101.

2. A pharmaceutical composition comprising: (a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I)(b) a filler comprising microcrystalline cellulose PH 101; wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e. ., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees.

3. A pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I)(b) a filler comprising microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102; wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees.

4. The pharmaceutical composition of any one of claims 1-3, wherein the pharmaceutical composition comprises about 35% (w / w) to about 45% (w / w) of a compound of formula (I).

5. The pharmaceutical composition of any one of claims 1-3, wherein the pharmaceutical composition comprises about 37% (w / w) to about 43% (w / w) of a compound of formula (I).

6. The pharmaceutical composition of any one of claims 1-3, wherein the pharmaceutical composition comprises about 40% (w / w) of the compound of formula (I).

7. The pharmaceutical composition of any one of claims 1-6, wherein the filler used in an intragranular blend consists substantially of microcrystalline cellulose PH 101 and the filler used in an extragranular blend consists substantially of microcrystalline cellulose PH 102.

8. The pharmaceutical composition of any one of claims 1-7, wherein the pharmaceutical composition comprises about 40% (w / w) to about 60% (w / w) filler.

9. The pharmaceutical composition of any one of claims 1-7, wherein the pharmaceutical composition comprises about 52% (w / w) to about 56% (w / w) filler.

10. The pharmaceutical composition of any one of claims 1-7, wherein the pharmaceutical composition comprises about 54% (w / w) filler.

11. The pharmaceutical composition of any one of claims 1-10, wherein the pharmaceutical composition comprises a glidant.

12. The pharmaceutical composition of claim 11, wherein the glidant consists substantially of colloidal silicon dioxide.

13. The pharmaceutical composition of any one of claims 1-12, wherein the pharmaceutical composition comprises about 1.0% (w / w) to about 3.0% (w / w) glidant.

14. The pharmaceutical composition of any one of claims 1-12, wherein the pharmaceutical composition comprises about 1.75% (w / w) to about 2.25% (w / w) glidant.

15. The pharmaceutical composition of any one of claims 1-12, wherein the pharmaceutical composition comprises about 2.0% (w / w) glidant.

16. The pharmaceutical composition of any one of claims 1-12, wherein the pharmaceutical composition comprises about 2% (w / w) silicon dioxide.

17. The pharmaceutical composition of any one of claims 1-16, wherein the pharmaceutical composition comprises a disintegrant.

18. The pharmaceutical composition of claim 17, wherein the disintegrant consists substantially of croscarmellose sodium (e.g., Ac-Di-Sol®).

19. The pharmaceutical composition of any one of claims 1-18, wherein the pharmaceutical composition comprises about 2% (w / w) to about 4% (w / w) disintegrant.

20. The pharmaceutical composition of any one of claims 1-18, wherein the pharmaceutical composition comprises about 2.75% (w / w) to about 3.25% (w / w) disintegrant.

21. The pharmaceutical composition of any one of claims 1-18, wherein the pharmaceutical composition comprises about 3% (w / w) disintegrant.

22. The pharmaceutical composition of any one of claims 1-18, wherein the pharmaceutical composition comprises about 3% (w / w) croscarmellose sodium.

23. The pharmaceutical composition of any one of claims 1-22, wherein the pharmaceutical composition comprises a lubricant.

24. The pharmaceutical composition of claim 23, wherein the lubricant consists substantially of magnesium stearate.

25. The pharmaceutical composition of any one of claims 1-24, wherein the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) lubricant.

26. The pharmaceutical composition of any one of claims 1-24, wherein the pharmaceutical composition comprises about 0.75% (w / w) to about 1.25% (w / w) lubricant.

27. The pharmaceutical composition of any one of claims 1-24, wherein the pharmaceutical composition comprises about 1.0% (w / w) lubricant.

28. The pharmaceutical composition of any one of claims 1-24, wherein the pharmaceutical composition comprises about 1.0% (w / w) magnesium stearate.

29. A pharmaceutical composition comprising:(a) crystalline form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) a filler comprising microcrystalline cellulose PH 101;(c) a glidant (e.g., colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g, magnesium stearate).

30. A pharmaceutical composition comprising:(a) about 35% (w / w) to about 50% (w / w) of crystalline form A of compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 29, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) about 40% (w / w) to about 60% (w / w) of a filler wherein the filler comprises microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) a glidant (e.g, colloidal silicon dioxide);(d) a disintegrant (e.g., croscarmellose sodium); and(e) a lubricant (e.g, magnesium stearate).

31. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition comprises:(a) about 35% (w / w) to about 60% (w / w) of the crystalline form A of compound of formula (I);(b) about 30% (w / w) to about 60% (w / w) of a filler comprising microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of a glidant (e.g., colloidal silicon dioxide);(d) about 2% (w / w) to about 4% (w / w) of a disintegrant (e.g., croscarmellose sodium);(e) about 0.5% (w / w) to about 1.5% (w / w) of a lubricant (e.g, magnesium stearate); thereby totaling no more than 100% (w / w) of the pharmaceutical composition.

32. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition comprises:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I);(b) about 40% (w / w) to about 60% (w / w) of a filler comprising microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of a glidant (e.g., colloidal silicon dioxide);(d) about 2% (w / w) to about 4% (w / w) of a disintegrant (e.g, croscarmellose sodium);(e) about 0.5% (w / w) to about 1.5% (w / w) of a lubricant (e.g, magnesium stearate); thereby totaling no more than 100% (w / w) of the pharmaceutical composition.

33. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition comprises:(a) about 35% (w / w) to about 45% (w / w) of the crystalline form A of compound of formula (I);(b) about 50% (w / w) to about 60% (w / w) of a filler comprising microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of a glidant (e.g., colloidal silicon dioxide);(d) about 2% (w / w) to about 4% (w / w) of a disintegrant (e.g, croscarmellose sodium);(e) about 0.5% (w / w) to about 1.5% (w / w) of a lubricant (e.g, magnesium stearate); thereby totaling no more than 100% (w / w) of the pharmaceutical composition.

34. The pharmaceutical composition claim 29, wherein the pharmaceutical composition comprises:(a) about 40% (w / w) of the crystalline form A of compound of formula (I) ;(b) about 54 % (w / w) of a filler e.g, microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 2 % (w / w) of a glidant (e.g, colloidal silicon dioxide);(d) about 3 % (w / w) of a disintegrant (e.g, croscarmellose sodium);(e) about 1 % (w / w) of a lubricant (e.g., magnesium stearate); thereby totaling 100% (w / w) of the pharmaceutical composition.

35. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition comprises:(a) about 35% (w / w) to about 50% (w / w) of the crystalline form A of compound of formula (I);(b) about 40% (w / w) to about 60% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 1% (w / w) to about 3% (w / w) of colloidal silicon dioxide;(d) about 2% (w / w) to about 4% (w / w) of croscarmellose sodium;(e) about 0.5% (w / w) to about 1.5% (w / w) of magnesium stearate; thereby totaling no more than 100% (w / w) of the pharmaceutical composition.

36. The pharmaceutical composition claim 29, wherein the pharmaceutical composition comprises:(a) about 40% (w / w) of the crystalline form A of compound of formula (I);(b) about 54 % (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;(c) about 2 % (w / w) of colloidal silicon dioxide;(d) about 3 % (w / w) of croscarmellose sodium;(e) about 1 % (w / w) of magnesium stearate; thereby totaling 100% (w / w) of the pharmaceutical composition.

37. The pharmaceutical composition of any one of claims 1-36, wherein the pharmaceutical composition comprises an intragranular fdler.

38. The pharmaceutical composition of claim 37, wherein the intragranular filler consists substantially of a microcrystalline cellulose PH 101 (e.g., Avicel® PH 101).

39. The pharmaceutical composition of any one of claims 37-38, wherein the w / w ratio of API to intragranular filler is between 0.9 and 1.4.

40. The pharmaceutical composition of any one of claims 37-38, wherein the w / w ratio of API to intragranular filler is between 0.9 and 1.0.

41. The pharmaceutical composition of any one of claims 37-38, wherein the w / w ratio of API to intragranular filler is about 0.95.

42. The pharmaceutical composition of any one of claims 37-38, wherein the pharmaceutical composition comprises about 30% (w / w) to about 50% (w / w) intragranular filler.

43. The pharmaceutical composition of any one of claims 37-38, wherein the pharmaceutical composition comprises about 40% (w / w) to about 44% (w / w) intragranular filler.

44. The pharmaceutical composition of any one of claims 37-38, wherein the pharmaceutical composition comprises about 42% (w / w) intragranular filler.

45. The pharmaceutical composition of any one of claims 37-38, wherein the pharmaceutical composition comprises about 42% (w / w) intragranular microcrystalline cellulose PH 101.

46. The pharmaceutical composition of any one of claims 1-45, wherein the pharmaceutical composition comprises an extragranular filler.

47. The pharmaceutical composition of claim 46, wherein the extragranular filler consists substantially of microcrystalline cellulose PH 102 (e.g, Avicel® PH 102).

48. The pharmaceutical composition of any one of claims 46-47, wherein the pharmaceutical composition comprises about 5% (w / w) to about 20% (w / w) extragranular filler.

49. The pharmaceutical composition of any one of claims 46-47, wherein the pharmaceutical composition comprises about 8% (w / w) to about 16% (w / w) extragranular filler.

50. The pharmaceutical composition of any one of claims 46-47, wherein the pharmaceutical composition comprises about 11% (w / w) to about 13% (w / w) extragranular filler.

51. The pharmaceutical composition of any one of claims 46-47, wherein the pharmaceutical composition comprises about 12% (w / w) extragranular filler.

52. The pharmaceutical composition of any one of claims 46-47, wherein the pharmaceutical composition comprises about 12% (w / w) extragranular microcrystalline cellulose PH 102.

53. The pharmaceutical composition of any one of claims 1-52, wherein the pharmaceutical composition comprises an intragranular glidant.

54. The pharmaceutical composition of claim 53, wherein the intragranular glidant consists substantially of colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P).

55. The pharmaceutical composition of claim 53 or 54, wherein the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) intragranular glidant.

56. The pharmaceutical composition of claim 53 or 54, wherein the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) intragranular glidant.

57. The pharmaceutical composition of claim 53 or 54, wherein the pharmaceutical composition comprises about 1.0% (w / w) intragranular glidant.

58. The pharmaceutical composition of any one of claims 1-57, wherein the pharmaceutical composition comprises an extragranular glidant.

59. The pharmaceutical composition of claim 58, wherein the extragranular glidant consists substantially of colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P).

60. The pharmaceutical composition of claim 58 or 59, wherein the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) extragranular glidant.

61. The pharmaceutical composition of claim 58 or 59, wherein the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) extragranular glidant.

62. The pharmaceutical composition of claim 58 or 59, wherein the pharmaceutical composition comprises about 1.0% (w / w) extragranular glidant.

63. The pharmaceutical composition of claim 58 or 59, wherein the pharmaceutical composition comprises about 1.0% (w / w) extragranular colloidal silicon dioxide.

64. The pharmaceutical composition of any one of claims 1-63, wherein the pharmaceutical composition comprises an intragranular disintegrant.

65. The pharmaceutical composition of claim 64, wherein the intragranular disintegrant consists substantially of croscarmellose sodium.

66. The pharmaceutical composition of claim 64 or 65, wherein the pharmaceutical composition comprises about 0.5% (w / w) to about 2.5% (w / w) intragranular disintegrant.

67. The pharmaceutical composition of claim 64 or 65, wherein the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) intragranular disintegrant.

68. The pharmaceutical composition of claim 64 or 65, wherein the pharmaceutical composition comprises about 1.5% (w / w) intragranular disintegrant.

69. The pharmaceutical composition of claim 64 or 65, wherein the pharmaceutical composition comprises about 1.5% (w / w) intragranular croscarmellose sodium.

70. The pharmaceutical composition of any one of claims 1-69, wherein the pharmaceutical composition comprises an extragranular disintegrant.

71. The pharmaceutical composition of claim 70, wherein the extragranular disintegrant consists substantially of croscarmellose sodium.

72. The pharmaceutical composition of claim 70 or 71, wherein the pharmaceutical composition comprises about 0.5% (w / w) to about 2.5% (w / w) extragranular disintegrant.

73. The pharmaceutical composition of claim 70 or 71, wherein the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) extragranular disintegrant.

74. The pharmaceutical composition of claim 70 or 71, wherein the pharmaceutical composition comprises about 1.5% (w / w) extragranular disintegrant.

75. The pharmaceutical composition of claim 70 or 71, wherein the pharmaceutical composition comprises about 1.5% (w / w) extragranular croscarmellose sodium.

76. The pharmaceutical composition of any one of claims 1-75, wherein the pharmaceutical composition comprises an intragranular lubricant.

77. The pharmaceutical composition of claim 76, wherein the intragranular lubricant consists substantially of magnesium stearate.

78. The pharmaceutical composition of claim 76 or 77, wherein the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) intragranular lubricant.

79. The pharmaceutical composition of claim 76 or 77, wherein the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) intragranular lubricant.

80. The pharmaceutical composition of claim 76 or 77, wherein the pharmaceutical composition comprises about 0.5% (w / w) intragranular lubricant.

81. The pharmaceutical composition of claim 76 or 77, wherein the pharmaceutical composition comprises about 0.5% (w / w) intragranular magnesium stearate.

82. The pharmaceutical composition of any one of claims 1-81, wherein the pharmaceutical composition comprises an extragranular lubricant.

83. The pharmaceutical composition of claim 82, wherein the extragranular lubricant consists substantially of magnesium stearate.

84. The pharmaceutical composition of claim 82 or 83, wherein the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) extragranular lubricant.

85. The pharmaceutical composition of claim 82 or 83, wherein the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) extragranular lubricant.

86. The pharmaceutical composition of claim 82 or 83, wherein the pharmaceutical composition comprises about 0.5% (w / w) extragranular lubricant.

87. The pharmaceutical composition of claim 82 or 83, wherein the pharmaceutical composition comprises about 0.5% (w / w) extragranular magnesium stearate.

88. A pharmaceutical composition comprising:(a) crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (c.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees; (b) an intragranular filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients.

89. A pharmaceutical composition comprising:(a) crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of20, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) an intragranular filler comprising microcrystalline cellulose PH 101;(c) an intragranular glidant (e.g, colloidal silicon dioxide); (d) an intragranular disintegrant (e.g., croscarmellose sodium);(e) an extragranular lubricant (e.g., magnesium stearate);(f) an extragranular filler (e.g, microcrystalline cellulose PH 102);(g) an extragranular glidant (e.g, colloidal silicon dioxide);(h) an extragranular disintegrant (e.g, croscarmellose sodium); and(i) an extragranular lubricant (e.g., magnesium stearate).

90. A pharmaceutical composition comprising:(a) crystalline Form A of a compound of formula (I)wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 29, selected from the peaks at 4.4±0.2, 9.6±0.2, 16.8±0.2, 18.6±0.2, 19.4±0.2, 20.9±0.2, 23.7±0.2 and 24.5±0.2 degrees;(b) intragranular microcrystalline cellulose PH 101;(c) intragranular colloidal silicon dioxide;(d) intragranular croscarmellose sodium;(e) extragranular magnesium stearate;(f) extragranular microcrystalline cellulose PH 102;(g) extragranular colloidal silicon dioxide;(h) extragranular croscarmellose sodium; and(i) extragranular magnesium stearate.

91. The pharmaceutical composition of claim 89, wherein the pharmaceutical composition comprises:(a) about 35% (w / w) to about 50% (w / w) of crystalline form A of the compound of formula (I);(b) about 30% (w / w) to about 50% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 0.5% (w / w) to about 1.5% (w / w) of an intragranular glidant (e.g., colloidal silicon dioxide);(d) about 0.5% (w / w) to about 2.5% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium);(e) about 0.25% (w / w) to about 0.75% (w / w) of an intragranular lubricant (e.g., magnesium stearate);(f) about 5% (w / w) to about 20% (w / w) of an extragranular filler (e.g., microcrystalline cellulose PH 102);(g) about 0.5% (w / w) to about 1.5% (w / w) of an extragranular glidant (e.g., colloidal silicon dioxide);(h) about 0.5% (w / w) to about 2.5% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.25% (w / w) to about 0.75% (w / w) of an extragranular lubricant (e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the pharmaceutical composition.

92. The pharmaceutical composition of claim 89, wherein the pharmaceutical composition comprises:(a) about 37% (w / w) to about 43% (w / w) of crystalline form A of the compound of formula (I);(b) about 38% (w / w) to about 46% (w / w) of an intragranular fdler comprising microcrystalline cellulose PH 101;(c) about 0.8% (w / w) to about 1.2% (w / w) of an intragranular glidant (e.g., colloidal silicon dioxide);(d) about 1.25% (w / w) to about 1.75% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium);(e) about 0.3% (w / w) to about 0.7% (w / w) of an intragranular lubricant (e.g., magnesium stearate);(f) about 8% (w / w) to about 16% (w / w) of an extragranular filler (e.g., microcrystalline cellulose PH 102);(g) about 0.8% (w / w) to about 1.2% (w / w) of an extragranular glidant (e.g., colloidal silicon dioxide);(h) about 1.25% (w / w) to about 1.75% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.3% (w / w) to about 0.7% (w / w) of an extragranular lubricant (e.g., magnesium stearate); thereby totaling no more than 100% (w / w) of the pharmaceutical composition.

93. The pharmaceutical composition of claim 89, wherein the pharmaceutical composition comprises:(a) about 40% (w / w) of crystalline form A of the compound of formula (I);(b) about 42% (w / w) of an intragranular filler comprising microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of an intragranular glidant (e.g., colloidal silicon dioxide);(d) about 1.5% (w / w) of an intragranular disintegrant (e.g., croscarmellose sodium);(e) about 0.5% (w / w) of an intragranular lubricant (e.g., magnesium stearate);(f) about 12% (w / w) of an extragranular filler (e.g., microcrystalline cellulose PH 102);(g) about 1.0% (w / w) of an extragranular glidant (e.g., colloidal silicon dioxide);(h) about 1.5% (w / w) of an extragranular disintegrant (e.g., croscarmellose sodium); and(i) about 0.5% (w / w) of an extragranular lubricant (e.g., magnesium stearate).

94. The pharmaceutical composition of claim 89, wherein the pharmaceutical composition comprises:(a) about 37% (w / w) to about 43% (w / w) of crystalline form A of the compound of formula (I);(b) about 38% (w / w) to about 46% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 0.8% (w / w) to about 1.2% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.25% (w / w) to about 1.75% (w / w) of intragranular croscarmellose sodium;(e) about 0.3% (w / w) to about 0.7% (w / w) of intragranular magnesium stearate;(f) about 8% (w / w) to about 16% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 0.8% (w / w) to about 1.2% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.25% (w / w) to about 1.75% (w / w) of extragranular croscarmellose sodium; and(i) about 0.3% (w / w) to about 0.7% (w / w) of extragranular magnesium stearate; thereby totaling no more than 100% (w / w) of the pharmaceutical composition.

95. The pharmaceutical composition of claim 89, wherein the pharmaceutical composition comprises:(a) about 40% (w / w) of crystalline form A of the compound of formula (I);(b) about 42% (w / w) of intragranular microcrystalline cellulose PH 101;(c) about 1.0% (w / w) of intragranular colloidal silicon dioxide;(d) about 1.5% (w / w) of intragranular croscarmellose sodium;(e) about 0.5% (w / w) of intragranular magnesium stearate;(f) about 12% (w / w) of extragranular microcrystalline cellulose PH 102;(g) about 1.0% (w / w) of extragranular colloidal silicon dioxide;(h) about 1.5% (w / w) of extragranular croscarmellose sodium; and(i) about 0.5% (w / w) of extragranular magnesium stearate).

96. A dosage form intended for oral administration comprising a pharmaceutical composition of any one of claims 1-95.

97. The dosage form of claim 96, wherein the total weight of the pharmaceutical composition in the dosage form is about 200 mg to 1000 mg.

98. The dosage form of claim 96 or 97, wherein the total weight of the pharmaceutical composition in the dosage form is about 240 mg to about 260 mg, about 300 mg to about 325 mg, about 360 mg to about 390 mg, about 480 mg to about 520 mg or about 600 mg to about 650 mg,.

99. The dosage form of claim 96 or 97, wherein the dosage form comprises about 50 mg to about 350 mg of the crystalline form A of the compound of formula (I).

100. The dosage form of claim 96 or 97, wherein the dosage form comprises about 100 mg to about 250 mg of the crystalline form A of the compound of formula (I).

101. The dosage form of claim 96 or 97, wherein the dosage form comprises about 100 mg, about 125 mg, about 150 mg, about 200 mg or about 250 mg of crystalline form A of the compound of formula (I).

102. The dosage form of any one of claims 96-101, wherein the dosage form is a tablet.

103. The dosage form of claim 102, wherein the tablet further comprises a coating.

104. A process for preparing a pharmaceutical composition of any one of claims 1-95, comprising:(a) Charging and blending crystalline form A of a compound of Formula (I), an intragranular fdler, an intragranular glidant and an intragranular disintegrant and blending to obtain a prelubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre-lubrication extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition.

105. A process for preparing a pharmaceutical composition of any one of claims 1-95, comprising:(a) Pre-blending, sieving and charging crystalline form A of a compound of Formula (I), an intragranular filler, an intragranular glidant and an intragranular disintegrant and blending to obtain a pre-lubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Pre-blending, sieving, charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre- lubrication extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition.

106. A process for preparing a dosage form of any one of claims 96-103, comprising:(a) Charging and blending crystalline form A of a compound of Formula (I), an intragranular filler, an intragranular glidant and an intragranular disintegrant and blending to obtain a pre- lubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre-lubrication extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition;(g) Compressing the pharmaceutical composition into a dosage form; and, optionally(h) Coating the dosage form.

107. A process for preparing a dosage form of any one of claims 96-103, comprising:(a) Pre-blending, sieving and charging crystalline form A of a compound of Formula (I), an intragranular filler, an intragranular glidant and an intragranular disintegrant and blending to obtain a pre-lubrication intragranular blend;(b) Charging a lubricant to the pre-lubrication intragranular blend and blending to obtain a lubricated intragranular blend;(c) Granulating the intragranular blend to obtain granules;(d) Milling the granules to obtain milled granules;(e) Pre-blending, sieving, charging and blending the milled granules with an extragranular filler, an extragranular disintegrant and an extragranular glidant to obtain a pre-lubrication extragranular blend;(f) Charging a lubricant to the pre-lubrication extragranular blend and blending to obtain the pharmaceutical composition;(g) Compressing the pharmaceutical composition into a dosage form; and, optionally(h) Coating the dosage form.

108. A process for preparing a pharmaceutical composition of any one of claims 1-95, comprising:(a) Charging, in order: i. 50% of a desired total amount of intragranular filler;ii. a desired total amount of crystalline form A of a compound of Formula (I); iii. a desired total amount of intragranular disintegrant; iv. a desired total amount of intragranular glidant; and v. 50% of the desired total amount of intragranular filler;(b) pre-blending and sieving the components charged at step (a) to obtain a pre-blending intragranular mixture;(c) blending the pre-blending intragranular mixture to obtain a pre-lubri cation intragranular blend;(d) Charging, in order: i. 50% of the pre-lubrication intragranular blend; ii. 100% of a desired amount of intragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication intragranular blend; to obtain a lubricated intragranular mixture;(e) Blending the lubricated intragranular mixture to obtain an intragranular blend;(f) Granulating the intragranular blend to obtain granules;(g) Milling the granules to obtain milled granules;(h) Charging, in order: i. 50% of a desired amount of extragranular filler; ii. the milled granules obtained at step (g); iii. a desired amount of extragranular disintegrant; iv. a desired amount of extragranular glidant;V. 50% of a desired amount of extragranular filler;(i) Pre-blending and sieving the components charged at step (h) to obtain a pre-blending extragranular mixture;(j) Blending the pre-blending extragranular mixture to obtain a pre-lubrication extragranular blend;(k) Charging, in order: i. 50% of the pre-lubrication extragranular blend; ii. a desired amount of extragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication extragranular blend; to obtain a lubricated extra-granular mixture;(l) Blending the lubricated intragranular mixture to obtain the pharmaceutical composition.

109. A process for preparing a dosage form of any one of claims 96-103, comprising:(a) Charging, in order: i. 50% of a desired total amount of intragranular filler; ii. a desired total amount of crystalline form A of a compound of Formula (I); iii. a desired total amount of intragranular disintegrant; iv. a desired total amount of intragranular glidant; and v. 50% of the desired total amount of intragranular filler;(b) pre-blending and sieving the components charged at step (a) to obtain a pre-blending intragranular mixture;(c) blending the pre-blending intragranular mixture to obtain a pre-lubrication intragranular blend;(d) Charging, in order: i. 50% of the pre-lubrication intragranular blend; ii. 100% of a desired amount of intragranular lubricant, charged by sieving; iii. 50% of the pre-lubrication intragranular blend; to obtain a lubricated intragranular mixture;(e) Blending the lubricated intragranular mixture to obtain an intragranular blend;(f) Granulating the intragranular blend to obtain granules;(g) Milling the granules to obtain milled granules;(h) Charging, in order: i. 50% of a desired amount of extragranular filler; ii. the milled granules obtained at step (g); iii. a desired amount of extragranular disintegrant; iv. a desired amount of extragranular glidant; v. 50% of a desired amount of extragranular filler;(i) pre-blending and sieving the components charged at step (h) to obtain a pre-blending extragranular mixture;(j) Blending the pre-blending extragranular mixture to obtain a pre-lubrication extragranular blend;(k) Charging, in order: i. 50% of the pre-lubrication extragranular blend; ii. a desired amount of extragranular lubricant, charged by sieving;iii. 50% of the pre-lubrication extragranular blend; to obtain a lubricated extra-granular mixture;(l) Blending the lubricated intragranular mixture to obtain the pharmaceutical composition.(m) Compressing the pharmaceutical composition into a dosage form; and, optionally(n) Coating the dosage form.

110. A pharmaceutical composition or a dosage form prepared by the process of any one of claims 104-109.

111. A pharmaceutical composition of any one of claims 1 to 95 or dosage form of any one of claims 96-103 containing a therapeutically effective amount of the compound of formula (I) for use in a method of treating an MTAP-deficient and / or an M A-accumulating disease in a subject in need thereof, wherein the method comprises administering to the subject the pharmaceutical composition of any one of claims 1 to 95 or dosage form of any one of claims 96-103 .

112. The pharmaceutical composition for use or dosage form for use of claim 111 wherein the disease is an MTAP-deficient and / or MTA-accumulating cancer.

113. The pharmaceutical composition for use or dosage form for use of claim 112 wherein the cancer is histology agnostic.

114. The pharmaceutical composition for use or dosage form for use of claim 112 wherein the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), undifferentiated pleiomorphic sarcoma, diffuse large B- cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, stomach cancer, kidney cancer, breast cancer, endometrium cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleura cancer, large intestine cancer or sarcoma.

115. The pharmaceutical composition for use or dosage form for use of claim 112 wherein the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (nonsquamous), bladder cancer, and DLBCL.

116. The pharmaceutical composition for use or dosage form for use of claim 112 wherein the cancer is a cancer selected from the group of pancreatic cancer, NSCLC, mesothelioma and sarcoma.

117. The pharmaceutical composition for use or dosage form for use of claim 112 wherein the cancer is a histology-agnostic MTAP-deleted cancer.

118. The pharmaceutical composition for use or dosage form for use of any one of claims 111- 117, wherein the pharmaceutical composition for use or dosage form for use comprises administering to the subject a dose of about 200 mg to about 300 mg of the compound of formula (I) once or twice daily.

119. The pharmaceutical composition for use or dosage form for use of any one of claims 111- 117, wherein the pharmaceutical composition for use or dosage form for use comprises administering to the subject a dose of about 150 mg, about 200 mg, about 250 mg or about 300 mg of the compound of formula (I) once or twice daily.

120. The pharmaceutical composition for use or dosage form for use of any one of claims 111- 117, wherein the pharmaceutical composition for use or dosage form for use comprises administering to the subject a dose of about 200 mg, about 250 mg or about 300 mg of the compound of formula (I) once or twice daily.

121. The pharmaceutical composition for use or dosage form for use of any one of claims 111- 117, wherein the pharmaceutical composition for use or dosage form for use comprises administering to the subject a dose of about 200 mg or about 250 mg of the compound of formula (I) once or twice daily.

122. The method, use, pharmaceutical composition for use or dosage form for use of any one of claims 111-121 wherein the method, use, pharmaceutical composition for use or dosage form for use further comprises administration of a second therapeutic agent.

123. A compound of formula (I)r use in a method of treating an MTAP-deficient and / or an MTA- accumulating disease in a subject in need thereof, wherein the method comprises administering to the subject a dose between about 100 mg and about 1000 mg of compound of formula (I) once or twice daily.

124. The compound for use of claim 123 wherein the disease is an MTAP-deficient and / or MTA- accumulating cancer.

125. The compound for use of claim 124 wherein the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, stomach cancer, kidney cancer, breast cancer, endometrium cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleura cancer, large intestine cancer or sarcoma.

126. The compound for use of claim 124 wherein the cancer is a cancer selected from the group of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (nonsquamous), bladder cancer, and DLBCL.

127. The compound for use of claim 124 wherein the cancer is a cancer selected from the group of pancreatic cancer, NSCLC, mesothelioma and sarcoma.

128. The compound for use of claim 124 wherein the cancer is a histology-agnostic MTAP- deleted cancer.

129. The compound for use of any one of claims 123-128, wherein the dose is about 200 mg to about 300 mg of the compound of formula (I), administered once or twice daily.

130. The compound for use of any one of claims 123-128, wherein the dose is about 150 mg, about 200 mg, about 250 mg or about 300 mg of the compound of formula (I), administered once or twice daily.

131. The compound for use of any one of claims 123-128, wherein the dose is about 200 mg, about 250 mg or about 300 mg of the compound of formula (I), administered once or twice daily.

132. The compound for use of any one of claims 123-128, wherein the dose is about 200 mg or about 250 mg of the compound of formula (I), administered once or twice daily.

133. The compound for use of any one of claims 123-128 wherein dose is administered once daily.

134. The compound for use of any one of claims 123-128 wherein dose is administered twice daily.

135. The method, use, or compound for use of any one of claims 123-128, wherein the dose is about 150 mg, about 200 mg, about 250 mg or about 300 mg of the compound of formula (I), administered once daily.

136. The method, use, or compound for use of any one of claims 123-128, wherein the dose is about 200 mg or about 250 mg of the compound of formula (I), administered once daily.

137. The compound for use of any one of claims 123-136, wherein the method, use, or compound for use further comprises administration of a second therapeutic agent.