Crystalline forms, pharmaceutical compositions, and methods of use thereof

Abstract

Pharmaceutical compositions and dosage forms of crystalline form A of the PRMT5 inhibitor of formula (I), their preparation methods and methods of use.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 627,470, filed January 31, 2024; 63 / 658,368, filed June 10, 2024; 63 / 658,373, filed June 10, 2024; and 63 / 716,637, filed November 5, 2024, the entire contents of which are incorporated herein by reference. Background Technology

[0003] The development of pharmaceutical compositions containing one or more novel active ingredients requires consideration of various factors, such as route of administration (e.g., enteric, parenteral, topical, etc.), dosage form (e.g., solid tablets, capsules, etc.; liquid solutions, suspensions, syrups, etc.), strength of the active ingredient (e.g., 1 mg–1,000 mg), non-therapeutic components (e.g., excipients) and their respective amounts, and each of these considerations may involve additional considerations, such as stability, degradation, photosensitivity, solubility, taste, palatability, pH, skin irritation, microbial growth, etc. Advancing novel active ingredients (e.g., PRMT5 inhibitors) to stringent regulatory agencies requires the discovery and development of pharmaceutical compositions that address these or other considerations.

[0004] PRMT5 inhibitors N -(6-amino-5-ethylpyridin-3-yl)-2-((2 R 5 S )-5-methyl-2-(2-(1-methylpiperidin-4-yl)benzo[ d Thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide (TNG462) has been disclosed in WO 2022 / 026892. First-generation pharmaceutical compositions and dosage forms of this compound have been disclosed in WO2024091551. The pharmaceutical compositions described in WO2024091551 are compositions with relatively low drug loadings, wherein the disclosed dosage forms contain up to 100 mg of the active ingredient (wherein the exemplary dosage form described in Example 7 contains 10 mg and 50 mg of the active ingredient, with a drug loading of 10%).

[0005] To improve patient compliance (low pill burden, easy pill swallowing) and therapeutic efficacy, this may require higher daily doses of the compound (e.g., doses higher than 50-100 mg / day). Therefore, there is a need for pharmaceutical compositions containing high loadings of the compound of formula (I) with favorable physical and chemical properties (e.g., hardness, friability, mixture rheology, density, particle size distribution, dissolution) that can be conveniently, reproducibly, and on a large scale manufactured for later clinical development and commercialization. Summary of the Invention

[0006] In some embodiments, a pharmaceutical composition is provided comprising: N -(6-amino-5-ethylpyridin-3-yl)-2-((2 R 5 S )-5-methyl-2-(2-(1-methylpiperidin-4-yl)benzo[ d The crystalline form A of thiazolyl-5-yl)piperidin-1-yl)-2-oxoacetamide (compound of formula (I)) (I); And at least one pharmaceutically acceptable excipient, wherein the 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 selected from the following, expressed in 2θ: 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.

[0007] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) in approximately 35% (w / w) to approximately 50% (w / w) (I); and (b) A filler containing microcrystalline cellulose PH 101; Crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four, or five) characteristic peaks selected from the following, represented by 2θ: 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, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) in approximately 35% (w / w) to approximately 50% (w / w) (I); and (b) A filler containing microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102; Crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four, or five) characteristic peaks selected from the following, represented by 2θ: 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.

[0009] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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 containing microcrystalline cellulose PH 101; (c) Flow aids (e.g., colloidal silica); (d) Disintegrants (e.g., croscarmellose sodium); and (e) Lubricants (e.g., magnesium stearate).

[0010] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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 containing microcrystalline cellulose PH 101 and PH 102; (c) Flow aids (e.g., colloidal silica); (d) Disintegrants (e.g., croscarmellose sodium); and (e) Lubricants (e.g., magnesium stearate).

[0011] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) in approximately 35% (w / w) to approximately 50% (w / w) (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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 PH101 or a combination of microcrystalline cellulose PH101 and PH102; (c) Flow aids (e.g., colloidal silica); (d) Disintegrants (e.g., croscarmellose sodium); and (e) Lubricants (e.g., magnesium stearate).

[0012] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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 and PH 102; (c) Colloidal silica; (d) Crosslinked sodium carboxymethyl cellulose; and (e) Magnesium stearate.

[0013] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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 in-particle filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients.

[0014] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) in approximately 35% (w / w) to approximately 50% (w / w) (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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 in-particle filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients.

[0015] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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) In-particle filler containing microcrystalline cellulose PH 101; (c) In-particle flow aids (e.g., colloidal silica); (d) Intraparticle disintegrants (e.g., croscarmellose sodium carboxymethyl cellulose); (e) External lubricants (e.g., magnesium stearate); (f) External fillers (e.g., microcrystalline cellulose PH 102); (g) Particulate flow aids (e.g., colloidal silica); (h) Extraparticle disintegrants (e.g., croscarmellose sodium); and (i) External lubricant (e.g., magnesium stearate).

[0016] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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 within the particles, pH 101; (c) Colloidal silica within particles; (d) Intragranular cross-linked sodium carboxymethyl cellulose; (e) Magnesium stearate outside the particles; (f) Microcrystalline cellulose outside the particles, pH 102; (g) Colloidal silica particles; (h) cross-linked sodium carboxymethyl cellulose particles; and (i) Magnesium stearate outside the particles.

[0017] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) between 39% (w / w)% and 41% (w / w)% (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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) In-particle fillers containing microcrystalline cellulose PH 101, ranging from 41% (w / w)% to 43% (w / w)%; (c) In-particle flow aids (e.g., colloidal silica) ranging from 0.95% (w / w)% to 1.05% (w / w)%; (d) Intraparticle disintegrants (e.g., croscarmellose sodium); between 1.45% (w / w)% and 1.55% (w / w)% (e) In-particle lubricants (e.g., magnesium stearate) ranging from 0.45% (w / w)% to 0.55% (w / w)%; (f) Extragranular fillers (e.g., microcrystalline cellulose PH102) ranging from 11.5% (w / w)% to 12.5% ​​(w / w)%; (g) 0.95% (w / w)% to 1.05% (w / w)% of particulate flow aids (e.g., colloidal silica); (h) 1.45% (w / w)% to 1.55% (w / w)% of an external disintegrant (e.g., croscarmellose sodium); and (i) External lubricant (e.g., magnesium stearate) between 0.95% (w / w)% and 1.05% (w / w)%.

[0018] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of approximately 40% (w / w) of compound of formula (I). (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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) Approximately 42% (w / w) of in-particle filler containing microcrystalline cellulose PH 101; (c) Approximately 1.0% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) Approximately 1.5% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) Approximately 0.5% (w / w) of in-particle lubricant (e.g., magnesium stearate); (f) Approximately 12% (w / w) of ex-particle filler (e.g., microcrystalline cellulose PH 102); (g) Approximately 1.0% (w / w) of particulate flow aid (e.g., colloidal silica); (h) Approximately 1.5% (w / w) of an external disintegrant (e.g., croscarmellose sodium); and (i) Approximately 1.0% (w / w) of an external particulate lubricant (e.g., magnesium stearate).

[0019] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) comprising approximately 39.8% (w / w). (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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) Approximately 41.8% (w / w) of in-particle filler containing microcrystalline cellulose PH 101; (c) Approximately 1.0% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) Approximately 1.5% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) Approximately 0.5% (w / w) of in-particle lubricant (e.g., magnesium stearate); (f) Approximately 11.9% (w / w) of particulate filler (e.g., microcrystalline cellulose PH 102); (g) Approximately 1.0% (w / w) of particulate flow aid (e.g., colloidal silica); (h) Approximately 1.5% (w / w) of an external disintegrant (e.g., croscarmellose sodium); and (i) Approximately 1.0% (w / w) of an external particulate lubricant (e.g., magnesium stearate).

[0020] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of approximately 40% (w / w) of compound of formula (I). (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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) Approximately 42% (w / w) of in-particle filler containing microcrystalline cellulose PH 101; (c) Approximately 1.0% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) Approximately 1.5% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) Approximately 0.5% (w / w) of in-particle lubricant (e.g., magnesium stearate); (f) Approximately 12% (w / w) of ex-particle filler (e.g., microcrystalline cellulose PH 102); (g) Approximately 1.0% (w / w) of particulate flow aid (e.g., colloidal silica); (h) Approximately 1.5% (w / w) of an external disintegrant (e.g., croscarmellose sodium); and (i) Approximately 0.5% (w / w) of an external particulate lubricant (e.g., magnesium stearate).

[0021] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) between 39% (w / w)% and 41% (w / w)% (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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 within particles with a pH of 101, ranging from 41% (w / w)% to 43% (w / w)%; (c) In-particle colloidal silica between 0.95% (w / w)% and 1.05% (w / w)%; (d) Intragranular crosslinked sodium carboxymethyl cellulose between 1.45% (w / w)% and 1.55% (w / w)%; (e) Magnesium stearate within particles, ranging from 0.45% (w / w)% to 0.55% (w / w)%. (f) Microcrystalline cellulose with exfoliated particles, pH 102, ranging from 11.5% (w / w)% to 12.5% ​​(w / w)%; (g) 0.95% (w / w)% to 1.05% (w / w)% of particulate colloidal silica; (h) 1.45% (w / w)% to 1.55% (w / w)% of externally cross-linked sodium carboxymethyl cellulose; and (i) Magnesium stearate in particulate form, ranging from 0.95% (w / w)% to 1.05% (w / w)%.

[0022] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) between 39% (w / w)% and 41% (w / w)% (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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 within particles with a pH of 101, ranging from 41% (w / w)% to 43% (w / w)%; (c) Approximately 1.0% (w / w) of intraparticle colloidal silica; (d) Approximately 1.5% (w / w) of intraparticle cross-linked sodium carboxymethyl cellulose; (e) Approximately 0.5% (w / w) of magnesium stearate within the particles; (f) Microcrystalline cellulose with exfoliated particles, pH 102, ranging from 11.5% (w / w)% to 12.5% ​​(w / w)%; (g) Approximately 1.0% (w / w) of particulate colloidal silica; (h) Approximately 1.5% (w / w) of externally cross-linked sodium carboxymethyl cellulose; and (i) Approximately 1.0% (w / w) of particulate magnesium stearate.

[0023] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of approximately 40% (w / w) of compound of formula (I). (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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) Approximately 42% (w / w) of microcrystalline cellulose within the granules at pH 101; (c) Approximately 1.0% (w / w) of intraparticle colloidal silica; (d) Approximately 1.5% (w / w) of intraparticle cross-linked sodium carboxymethyl cellulose; (e) Approximately 0.5% (w / w) of magnesium stearate within the particles; (f) Approximately 12% (w / w) of exogranular microcrystalline cellulose at pH 102; (g) Approximately 1.0% (w / w) of particulate colloidal silica; (h) Approximately 1.5% (w / w) of externally cross-linked sodium carboxymethyl cellulose; and (i) Approximately 1.0% (w / w) of particulate magnesium stearate.

[0024] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) comprising approximately 39.8% (w / w). (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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) Approximately 41.8% (w / w) of intragranular microcrystalline cellulose at pH 101; (c) Approximately 1.0% (w / w) of intraparticle colloidal silica; (d) Approximately 1.5% (w / w) of intraparticle cross-linked sodium carboxymethyl cellulose; (e) Approximately 0.5% (w / w) of magnesium stearate within the particles; (f) Approximately 11.9% (w / w) of exogranular microcrystalline cellulose at pH 102; (g) Approximately 1.0% (w / w) of particulate colloidal silica; (h) Approximately 1.5% (w / w) of externally cross-linked sodium carboxymethyl cellulose; and (i) Approximately 1.0% (w / w) of particulate magnesium stearate.

[0025] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of approximately 40% (w / w) of compound of formula (I). (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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) Approximately 42% (w / w) of microcrystalline cellulose within the granules at pH 101; (c) Approximately 1.0% (w / w) of intraparticle colloidal silica; (d) Approximately 1.5% (w / w) of intraparticle cross-linked sodium carboxymethyl cellulose; (e) Approximately 0.5% (w / w) of magnesium stearate within the particles; (f) Approximately 12% (w / w) of exogranular microcrystalline cellulose at pH 102; (g) Approximately 1.0% (w / w) of particulate colloidal silica; (h) Approximately 1.5% (w / w) of externally cross-linked sodium carboxymethyl cellulose; and (i) Approximately 0.5% (w / w) of particulate magnesium stearate.

[0026] In some embodiments, a dosage form comprising the pharmaceutical composition described herein is provided.

[0027] In some embodiments, a dosage form intended for oral administration is provided, comprising the pharmaceutical composition described herein.

[0028] In some embodiments, a method for preparing the pharmaceutical composition described herein is provided, comprising: (a) Adding the crystalline form A of compound (I), in-particle filler, in-particle flow aid and in-particle disintegrant, and mixing them to obtain a pre-lubricated in-particle mixture; (b) Adding a lubricant to the pre-lubricated intragranular mixture and mixing to obtain a lubricated intragranular mixture; (c) Granulating the mixture within the particles to obtain particles; (d) Grinding the particles to obtain ground particles; (e) Add the ground particles, external filler, external disintegrant and external flow aid, and mix to obtain a pre-lubricated external mixture; (f) Adding a lubricant to the pre-lubricated extragranular mixture and mixing to obtain the pharmaceutical composition; In some embodiments, a method for preparing the dosage form described herein is provided, comprising: (a) Adding the crystalline form A of compound (I), in-particle filler, in-particle flow aid and in-particle disintegrant, and mixing them to obtain a pre-lubricated in-particle mixture; (b) Adding a lubricant to the pre-lubricated intragranular mixture and mixing to obtain a lubricated intragranular mixture; (c) Granulating the mixture within the particles to obtain particles; (d) Grinding the particles to obtain ground particles; (e) The ground particles are premixed with the external filler, external disintegrant and external flow aid, sieved, added and mixed to obtain a pre-lubricated external mixture; (f) Adding a lubricant to the pre-lubricated extragranular mixture and mixing 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, a method for preparing the pharmaceutical composition described herein is provided, comprising: (a) The crystalline form A of compound of formula (I), the in-particle filler, the in-particle flow aid and the in-particle disintegrant are premixed, sieved and added to the mixture to obtain a pre-lubricated in-particle mixture. (b) Adding a lubricant to the pre-lubricated intragranular mixture and mixing to obtain a lubricated intragranular mixture; (c) Granulating the mixture within the particles to obtain particles; (d) Grinding the particles to obtain ground particles; (e) The ground particles are premixed with the external filler, external disintegrant and external flow aid, sieved, added and mixed to obtain a pre-lubricated external mixture; (f) Adding a lubricant to the pre-lubricated extragranular mixture and mixing to obtain the pharmaceutical composition; In some embodiments, a method for preparing the dosage form described herein is provided, comprising: (a) The crystalline form A of the compound of formula (I), the in-particle filler, the in-particle flow aid and the in-particle disintegrant are premixed, sieved and added to the mixture to obtain a pre-lubricated in-particle mixture. (b) Adding a lubricant to the pre-lubricated intragranular mixture and mixing to obtain a lubricated intragranular mixture; (c) Granulating the mixture within the particles to obtain particles; (d) Grinding the particles to obtain ground particles; (e) The ground particles are premixed with the external filler, external disintegrant and external flow aid, sieved, added and mixed to obtain a pre-lubricated external mixture; (f) Adding a lubricant to the pre-lubricated extragranular mixture and mixing to obtain the pharmaceutical composition; (g) Compressing the pharmaceutical composition into a dosage form; and, optionally... (h) Coating the dosage form.

[0030] In some embodiments, a method for preparing the pharmaceutical composition described herein is provided, comprising: (a) The following shall be added in sequence: i. 50% of the total required amount of in-particle filler; ii. The required total amount of the crystalline form A of compound of formula (I); iii. The required total amount of intraparticle disintegrant; iv. The required total amount of in-particle flow aid; and v. 50% of the total required amount of in-particle filler; (b) The components added in step (a) are premixed and sieved to obtain a premixed intragranular mixture; (c) Mix the premixed intraparticle mixture to obtain a pre-lubricated intraparticle mixture; (d) The following shall be added in sequence: i. 50% of the pre-lubricated intragranular mixture; ii. The required amount of 100% intragranular lubricant is added by sieving; iii. 50% of the pre-lubricated intraparticle mixture; to obtain a lubricated intraparticle mixture; (e) Mix the lubricated intraparticle mixture to obtain an intraparticle mixture; (f) Granulating the intragranular mixture to obtain granules; (g) Grinding the particles to obtain ground particles; (h) Add the following in sequence: i. 50% of the required amount of particulate filler; ii. The ground particles obtained in step (g); iii. The required amount of external disintegrant; iv. The required amount of particulate external flow aid; v. 50% of the required amount of particulate filler; (i) The components added in step (h) are premixed and sieved to obtain a premixed non-particle mixture; (j) Mix the premixed off-particle mixture to obtain a pre-lubricated off-particle mixture; (k) The following shall be added in sequence: i. 50% of the pre-lubricated extra-particle mixture; ii. The required amount of particulate external lubricant is added by sieving; iii. 50% of the pre-lubricated extra-particle mixture; to obtain a lubricated extra-particle mixture; (l) Mixing the lubricated intragranular mixture to obtain the pharmaceutical composition.

[0031] In some embodiments, a method for preparing the dosage form described herein is provided, comprising: (a) The following shall be added in sequence: i. 50% of the total required amount of in-particle filler; ii. The required total amount of the crystalline form A of compound of formula (I); iii. The required total amount of intraparticle disintegrant; iv. The required total amount of in-particle flow aid; and v. 50% of the total required amount of in-particle filler; (b) The components added in step (a) are premixed and sieved to obtain a premixed intragranular mixture; (c) Mix the premixed intraparticle mixture to obtain a pre-lubricated intraparticle mixture; (d) The following shall be added in sequence: i. 50% of the pre-lubricated intragranular mixture; ii. The required amount of 100% intragranular lubricant is added by sieving; iii. 50% of the pre-lubricated intraparticle mixture; to obtain a lubricated intraparticle mixture; (e) Mix the lubricated intraparticle mixture to obtain an intraparticle mixture; (f) Granulating the intragranular mixture to obtain granules; (g) Grinding the particles to obtain ground particles; (h) Add the following in sequence: i. 50% of the required amount of particulate filler; ii. The ground particles obtained in step (g); iii. The required amount of external disintegrant; iv. The required amount of particulate external flow aid; v. 50% of the required amount of particulate filler; (i) The components added in step (h) are premixed and sieved to obtain a premixed non-particle mixture; (j) Mix the premixed off-particle mixture to obtain a pre-lubricated off-particle mixture; (k) The following shall be added in sequence: i. 50% of the pre-lubricated extra-particle mixture; ii. The required amount of particulate external lubricant is added by sieving; iii. 50% of the pre-lubricated extra-particle mixture; to obtain a lubricated extra-particle mixture; (l) Mixing the lubricated intragranular mixture to obtain the pharmaceutical composition.

[0032] (m) compressing the pharmaceutical composition into a dosage form; and, optionally...

[0033] (n) Coating the dosage form.

[0034] In some embodiments, a pharmaceutical composition or dosage form prepared by any of the methods described herein is provided.

[0035] In some embodiments, a method is provided for treating MTAP deficiency and / or MTA accumulation in a subject with this need, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition or dosage form described herein.

[0036] In some implementations, a method for treating cancer in a subject with this need is provided, comprising the following steps: a) Assess the levels of MTAP and / or MTA in test samples obtained from the 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 to a reference, wherein a lack of MTAP and / or accumulation of MTA in the test sample compared to the reference indicates that the subject's cancer will respond to therapeutic treatment with a PRMT5 inhibitor; and c) Administer an effective amount (e.g., a therapeutically effective amount) of the pharmaceutical composition or dosage form described herein to the subject identified in step b).

[0037] In some embodiments, the use of the pharmaceutical composition or dosage form described herein is provided in a method for treating MTAP deficiency and / or MTA accumulation in a subject with such need, the method comprising administering a therapeutically effective amount of the pharmaceutical composition or dosage form described herein to the subject.

[0038] In some embodiments, the use of the pharmaceutical compositions or dosage forms described herein is provided in the preparation of a medicament for treating MTAP deficiency and / or MTA accumulation in subjects with such need.

[0039] In some embodiments, a method is provided for treating MTAP deficiency and / or MTA accumulation in a subject with this need, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition or dosage form described herein.

[0040] In some embodiments, the pharmaceutical compositions or dosage forms described herein are provided for use in preparing a medicine for treating MTAP deficiency and / or MTA accumulation in subjects with this need.

[0041] Brief description of the attached figures

[0042] Figure 1 This is an exemplary X-ray powder diffraction pattern of crystalline form A of compound (I).

[0043] Figure 2A An exemplary thermogravimetric analysis (TGA) chromatogram of the compound of formula (I) is shown.

[0044] Figure 2B The differential scanning calorimetry (DSC) thermogram of the crystalline form A of compound (I) under a heating-cooling-heating scheme is shown, revealing a melting peak at approximately 145.8 °C.

[0045] Figure 3A The variations in water content (solid curve) and relative humidity (dashed curve) over time are shown in an exemplary DVS experiment of compound (I) (crystalline form A).

[0046] Figure 3B The variation of water content with relative humidity in an exemplary DVS experiment of compound (I) (crystalline form A) is shown.

[0047] Figure 4A The antiproliferative activity (at different concentrations) of the compound of formula (I) in a pair of gene-dependent cell lines engineered by knocking out the MTAP gene in the HAP1 chronic myeloid leukemia cell line via CRISPR is shown.

[0048] Figure 4B The antiproliferative activity (at different concentrations) of the compound of formula (I) in a pair of MTAP and other gene-derived cell lines engineered by CRISPR-mediated knockout of the MTAP gene in the HCT116 colorectal cancer cell line is shown.

[0049] Figure 4C The antiproliferative activity (at different concentrations) of the compound of formula (I) in MTAP and other gene-based cell lines engineered by reconstructing exogenous MTAP in the LU99 non-small cell lung cancer cell line lacking endogenous MTAP is shown.

[0050] Figure 4D The antiproliferative activity (at different concentrations) of the compound of formula (I) in MTAP and other gene cell lines engineered by reconstructing exogenous MTAP in the LN18 glioblastoma cell line lacking endogenous MTAP is shown.

[0051] Figure 5A The pharmacodynamic activity of compound (I) against PRMT5 is shown, with plots illustrating the levels of a single SDMA-modified protein normalized to different concentrations of the PRMT5 inhibitor of formula (I) in HAP 1 MTAP and other gene cell lines. Each cell line is normalized against the DMSO control and expressed as mean ± SD.

[0052] Figure 5B The pharmacodynamic activity of compound (I) against type I PRMT is shown, with plots illustrating the levels of a single ADMA-modified protein normalized to different concentrations of the PRMT5 inhibitor of formula (I) in HAP 1 MTAP and other gene cell lines. Each cell line is normalized against the DMSO control and is expressed as mean ± SD.

[0053] Figure 5C A dendrogram showing the biochemical selectivity of compound (I) for PRMT5 in the histone methyltransferase group is presented.

[0054] Figure 6 The pharmacokinetic curves of compound (I) in cynomolgus monkeys are shown, depicting free plasma exposure following oral administration of 3 mg / kg of compound (I) via tube feeding. Dashed lines indicate the gamma kinase activity (GI) in WT and MTAP-deficient cells. 50 .

[0055] Figure 7 Results of a 7-day PK / PD study using a LU99 (giant cell lung cancer) MTAP-deficient xenograft model are presented. Compound (I) was administered as directed, and PK and tumor samples were collected at indicated time points; SDMA-modified protein levels at each dose are shown as a ratio to the mediator. N=4 tumors per group, and data are presented as mean ± SEM.

[0056] Figure 8A The dose-dependent antitumor activity of compound (I) against xenograft models derived from the LN18 MTAP-deficient cell line is shown. Data are presented as mean ± SEM.

[0057] Figure 8B The dose-dependent antitumor activity of compound (I) against xenograft models derived from the OCI-LY19 MTAP-deficient cell line is shown. Data are presented as mean ± SEM.

[0058] Figure 8C The dose-dependent antitumor activity of compound (I) against a xenograft model of MTAP-deficient mesothelioma patients is shown. Data are presented as mean ± SEM.

[0059] Figure 8D The dose-dependent antitumor activity of compound (I) against a xenograft model derived from MTAP-deficient bladder cancer patients is shown. Data are presented as mean ± SEM.

[0060] Figure 8E The dose-dependent antitumor activity of compound (I) against a xenograft model of MTAP-deficient cholangiocarcinoma patients is shown. Data are presented as mean ± SEM.

[0061] Figure 8F The dose-dependent antitumor activity of compound (I) against a xenograft model of MTAP-deficient NSCLC (squamous) patients is shown. Data are presented as mean ± SEM.

[0062] Figure 8G The dose-dependent antitumor activity of compound (I) (40 mg / kg BID and 100 mg / kg QD) against xenograft models derived from the LU-99 NSCLC MTAP-deficient cell line is shown. The dashed line is the regression line, defined as the final mean tumor volume that is 30% smaller than the initial mean tumor volume. Data are presented as mean ± SEM.

[0063] Figure 8H The dose-dependent antitumor activity of compound (I) at 30 mg / kg BID and 60 mg / kg BID against xenograft models derived from the LU-99 NSCLC MTAP-deficient cell line is shown. The dashed line is the regression line, defined as the final mean tumor volume that is 30% smaller than the initial mean tumor volume. Data are presented as mean ± SEM.

[0064] Figure 9A The antitumor activity of compounds of formula (I) in patient-derived xenograft models derived 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) is illustrated. Data are presented relative to the tumor volume treated with the PRMT5 inhibitor (greater than 0) if the final mean tumor volume in mice treated with the PRMT5 inhibitor is greater than the initial mean tumor volume. Data are presented relative to the mean tumor volume (less than 0) if the final mean tumor volume in mice treated with the PRMT5 inhibitor is less than the initial mean tumor volume.

[0065] Figure 9BAn updated representation of the data from 9A is shown, including three additional data points: bile duct cancer (1), bladder cancer (1), and lung cancer (1) xenografts. Data for lung adenocarcinoma and squamous cell carcinoma are merged into one category. The graph represents the percentage of the final tumor volume to the initial tumor volume - a line of 100 indicates no change in tumor volume, values ​​between 0 and 100% of the initial tumor volume indicate a decrease in tumor volume, and values ​​above 100 indicate an increase in tumor volume.

[0066] Figure 10A The ability of compound (I) to overcome resistance to MTA-synergistic PRMT5 inhibitors in a xenograft model derived from diffuse large B-cell lymphoma cell lines is demonstrated. Data are presented as mean ± SEM.

[0067] Figure 10B It shows Figure 10A The magnified portion, where the y-axis is broken to highlight the region of interest.

[0068] Figure 11 A waterfall plot of 180 cancer cell lines, representing a diverse cancer spectrum including NSCLC, PDAC, bladder, CNS, and heme malignancies, is presented, plotted using PRMT5 inhibitors of formula (I) in a 7-day CellTiter-Glo assay. Concentrations equal to HAP1 MTAP-deficient GI are also reported. 50 The maximum effect is 10 times that of the cell line, and the cell line is filled with MTAP state encoding.

[0069] Figure 12 The antitumor activity of compound (I) at a BID of 30 mg / kg (alone or in combination with osimertinib at a QD of 1 mg / kg) against xenograft models derived from the NCI-H1650 NSCLC MTAP-deficient cell line is shown. Data are presented as mean ± SEM.

[0070] Figure 13 The antitumor activity of compounds of formula (I) (30 and 60 mg / kg BID alone, and in combination with AGI-41998 at 30 mg / kg BID and 10 mg / kg BID) against xenograft models derived from the NCI-H838 NSCLC MTAP-deficient cell line is shown. Data are presented as mean ± SEM.

[0071] Figure 14 A schematic diagram of the manufacturing process of the pharmaceutical compositions and dosage forms disclosed herein is shown.

[0072] Figure 15 A schematic diagram of the original clinical trial design described in Example 20 is shown.

[0073] Figure 16 Preliminary mean steady-state concentration-time curves and standard deviations (SD) (linear scaling) of TNG462 as described in Example 20 after administration at doses of 160 mg QD (n=8) and 300 mg QD (n=4) are shown.

[0074] Figure 17 Preliminary mean steady-state pharmacokinetic parameters and standard deviations (SD) of TNG462 after administration at a 300 mg QD dose as described in Example 20 are shown, expressed as multiples of in vitro HAP1 MTAP Del GI90 (n=4).

[0075] Figure 18 The mean AUC for all cohorts (20 mg QD, 40 mg QD, 80 mg QD, 160 mg QD, 300 mg QD, and 600 mg QD) on day 15 of cycle 1 is shown. The dashed line represents the in vitro HAP1 MTAP Del GI90, and the dotted line represents the non-human primate no adverse reaction dose / highest non-serious toxicity dose (NHP NOAEL) / HNSTD.

[0076] Figure 19 The compaction curves of two different batches of the compound of formula (I) in crystalline form A are shown.

[0077] Figure 20 Compaction curves are shown for a 10% loading formulation containing 10 mg and 50 mg of crystalline form A of compound (I) (as described in WO2024091551) and a 40% loading formulation containing 150 mg of crystalline form A of compound (I) (as described in this application).

[0078] Figure 21 The particle size distribution of two batches of a formulation containing 40% drug loading of crystalline form A of compound (I) is shown. Detailed Implementation

[0079] As generally described herein, this disclosure provides pharmaceutical compositions and dosage forms containing crystalline form A of compound (I): (I), Methods for preparing the pharmaceutical composition and dosage form, and methods for using the pharmaceutical composition to treat medical conditions, diseases, and disorders (e.g., proliferative diseases such as cancer).

[0080] definition

[0081] As used in this disclosure, unless otherwise expressly stated or indicated by the context, the following words and phrases are generally intended to have the meanings described below.

[0082] Unless otherwise defined, 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 pertains. Abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described herein are constructed according to the standard rules of chemical valence known in the field of chemistry.

[0083] Throughout this specification, where compositions and kits are described as having, including, or containing specific components, or where processes and methods are described as having, including, or containing specific steps, it is also contemplated that there are compositions and kits of the invention that are substantially composed of or comprised of the listed components, and that there are processes and methods of the invention that are substantially composed of or comprised of the listed processing steps.

[0084] In this application, when an element or component is included in and / or selected from the list of elements or components, it should be understood that the element or component may be any one of the listed elements or components, or the element or component may be selected from a group of two or more of the listed elements or components.

[0085] Furthermore, it should be understood that elements and / or features in the compositions or methods described herein can be combined in various ways without departing from the spirit and scope of the invention, whether explicit or implicit herein. For example, unless the context otherwise requires, when referring to a particular compound, that compound may be used in multiple embodiments of the compositions of the invention and / or in the methods of the invention. When elements are presented in list form, such as in Markush group format, each subgroup of elements is also disclosed, and any element may be removed from that group. In other words, within this application, embodiments have been described and depicted in a manner that allows for concise writing and drawing, but it is intended and should be understood that embodiments may be combined or separated in various ways without departing from the teachings and the invention. For example, it will be understood that all features described and depicted herein are applicable to all aspects of the invention described and depicted herein.

[0086] In this disclosure, the articles “a,” “an,” and “the” are used to refer to one or more (i.e., at least one) grammatical objects of the article, unless the context is inappropriate. For example, in some contexts, “an element” means one element and / or in some contexts, more than one element. As another example, in some contexts, “a filler” means one filler and / or in some contexts, more than one filler (e.g., a mixture of two or more fillers).

[0087] Unless otherwise indicated, the term “and / or” as used in this disclosure means “and” or “or”.

[0088] It should be understood that, unless otherwise understood from the context and usage, the expression "at least one of..." individually includes each of the listed objects following the expression and various combinations of two or more of the listed objects. Unless otherwise understood from the context, the expression "and / or" with respect to three or more listed objects should be understood to have the same meaning.

[0089] Unless otherwise specifically stated or understood from the context, the terms “including,” “having,” or “containing,” including their grammatical equivalents, are used and should generally be understood as open-ended and non-restrictive, e.g., not excluding other unlisted elements or steps.

[0090] When the term "about" is used before a quantity value, the invention also includes the specific quantity value itself, unless otherwise specifically stated. Unless otherwise indicated or inferred from the context, as used herein, the term "about" means a variation of ±10% from the nominal value.

[0091] In various places throughout this specification, variables or parameters are disclosed in groups or ranges. It is particularly important to note that this specification includes each individual subgroup of the members of the stated groups and ranges. For example, integers in the range 0 to 40 are specifically intended to be disclosed individually as 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 integers in the range 1 to 20 are specifically intended to be disclosed individually as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0092] Unless otherwise claimed, the use of any and all instances or exemplary language (e.g., "such as" or "including") herein is intended only to better illustrate the invention and does not limit the scope of the invention. No language in this specification should be construed as indicating any unclaimed element necessary for practicing the invention.

[0093] Generally, unless otherwise specified, the percentages of a composition are expressed by weight. Furthermore, if a variable is not defined, its previously defined form shall prevail.

[0094] As used herein, “XRPD” refers to X-ray powder diffraction. An XRPD plot is an xy plot, where 2θ (diffraction angle) is plotted on the x-axis and intensity on the y-axis. These are diffraction peaks that can be used to characterize crystalline materials. Diffraction peaks are typically represented and designated by their position on the x-axis rather than their intensity on the y-axis, because peak intensity can be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee & Web, pp. 255-257 (2003)). Therefore, those skilled in the art would not typically use intensity to characterize crystalline materials. As with any data measurement, XRPD data can be variable. In addition to variability in peak intensity, the position of diffraction peaks on the x-axis can also vary. However, this variability is usually taken into account when reporting peak positions for characterization purposes. This variability in the position of diffraction peaks along the x-axis can originate from several sources. One such source is sample preparation. Samples of the same crystalline material prepared under different conditions may yield slightly different diffraction patterns. Factors such as particle size, moisture content, solvent content, temperature, and orientation can all affect how a sample diffracts X-rays. Another source of variability comes from instrument parameters. Different X-ray powder diffractometers operate with different parameters, and these parameters can cause slight differences in the diffraction patterns of the same crystalline material. Similarly, different software packages process XRPD data in different ways, and this can also lead to variability. These and other sources of variability are known to those skilled in the art. Attributing variability to such sources, the values ​​of each X-ray diffraction peak can be described using the term “about” before modification or accompanied by an appropriate range defining the experimental variability (e.g., ±0.1°, ±0.2°, ±0.3°, ±0.4°, ±0.5°, etc.).

[0095] Crystallization forms, such as those of compounds of formula (I), are readily analyzed by XRPD. X-ray powder diffraction data can be used to characterize crystalline forms in various ways. For example, the entire X-ray powder diffraction pattern output from the diffractometer can be used to characterize crystalline forms (e.g., the crystalline form of compounds of formula (I)). However, smaller subsets of such data may also be applicable and used to characterize such crystalline forms. In fact, often even a single X-ray powder diffraction peak can be used to characterize such crystalline forms. Regarding the crystalline form of compounds of formula (I), Figure 1 Any one or more peaks in the X-ray powder diffraction pattern can be used to characterize the crystalline form of the compound of formula (I) disclosed herein.

[0096] The term “characteristic peak” when referring to a peak in an XRPD plot of a given chemical entity’s crystalline form (e.g., the crystalline form of the compound of formula (I)) refers to a set of specific diffraction peaks whose values ​​span a certain range of 2θ values ​​(e.g., 0° to 40°) and are unique to the particular crystalline form as a whole.

[0097] As used herein, “crystallization” refers to a solid phase of a given chemical entity having a well-defined three-dimensional structural order. Atoms, ions, and / or molecules are arranged in a regular, periodic manner within a repeating three-dimensional lattice. In various embodiments, crystalline materials may comprise one or more discrete crystalline forms.

[0098] As used herein, the terms “crystalline form,” “crystalline solid form,” “crystalline form,” “solid form,” and related terms herein refer to crystalline variants of a given substance (e.g., a compound of formula (I)), including monocomponent crystalline forms and multicomponent crystalline forms, and including, but not limited to, polymorphs, solvates, hydrates, and salts.

[0099] The term "substantially crystalline" refers to a solid form that can be at least a specific weight percentage of crystallinity. This specific weight percentage can 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 specific weight percentage of crystallinity is at least 90%. In some other embodiments, the specific weight percentage of crystallinity is at least 95%. In some embodiments, the compound of formula (I) can be the crystalline solid form described herein (e.g., having...). Figure 1 A substantially crystalline sample of any of the crystallization forms of the XRPD pattern shown.

[0100] The term "substantially pure" refers to a composition in a specific crystalline solid form (e.g., the crystalline form of a compound of formula (I)) having at least a specific weight percentage free from impurities and / or other solid forms. The specific weight percentage may include 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In some embodiments, the compound of formula (I) may be any crystalline solid form described herein (e.g., having…). Figure 1 The XRPD pattern shown is of a substantially pure sample in its crystalline form (Form A). In some embodiments, the compound of Formula (I) may be substantially pure and possess... Figure 1 The XRPD pattern shown is in crystalline form (Form A).

[0101] As used herein, the terms “anhydrous” or “anhydrous form” when referring to a crystalline form (e.g., a crystalline form of the compound of formula (I)) mean that anhydrous molecules form a portion of the unit cell of the crystalline form. Anhydrous crystalline forms may still contain water molecules that do not form a portion of the unit cell of the anhydrous crystalline form (e.g., in the form of residual solvent molecules left over from the formation of the crystalline form). In a preferred embodiment, water may constitute about 0.5% by weight of the total composition of the anhydrous form of the sample. In a more preferred embodiment, water may constitute about 0.2% by weight of the total composition of the anhydrous form of the sample. In some embodiments, the sample of the anhydrous crystalline form of the compound of formula (I) contains no water molecules, e.g., no detectable amount of water.

[0102] As used herein, the terms “desolventized” or “nonsolventized” when referring to a crystalline form (e.g., the crystalline form of a compound of formula (I)) mean a portion of the crystalline form in which no solvent molecules form. The nonsolventized crystalline form may still contain solvent molecules that do not form a portion of the crystalline form's unit cell (e.g., in the form of residual solvent molecules left over from the formation of the crystalline form). In a preferred embodiment, the solvent may constitute 0.5% by weight of the total composition of the nonsolventized sample. In a more preferred embodiment, the solvent may constitute 0.2% by weight of the total composition of the nonsolventized sample. In some embodiments, the nonsolventized crystalline form of the compound of formula (I) contains no solvent molecules, e.g., no detectable amount of solvent.

[0103] As used herein, the terms “polymorph,” “polymorphic form,” and related terms herein refer to two or more crystalline forms (e.g., compounds of formula (I)) that are essentially composed of the same molecules, molecules, or ions. Different polymorphs can exhibit different physicochemical properties, including but not limited to melting temperature, solubility, dissolution rate, and physical stability, due to differences in the arrangement or configuration of molecules or ions in the crystal lattice.

[0104] The term "solvent" when referring to the crystalline form of a compound of formula (I) means the portion of the unit cell in which solvent molecules (e.g., organic solvents and water) form the crystalline form. Solvents containing water as a solvent are also referred to herein as "hydrates".

[0105] As used herein, a “dissolution profile” refers to a dissolution test of a drug substance or pharmaceutical product at multiple time points. Dissolution profiles of drug substances (e.g., compounds of formula (I)) or pharmaceutical products (e.g., the pharmaceutical compositions described herein) can be performed for characterization and quality control to ensure that the drug is released at a defined rate range in a well-defined aqueous dissolution medium (at least under the sink conditions of the drug) or a biologically relevant medium (such as simulated gastric or intestinal fluid representing a fasting or feeding state). In some cases (but not others), dissolution testing can predict or provide insight into the in vivo bioavailability of a drug substance. Dissolution testing can be performed using USP test protocols and dissolution equipment.

[0106] As used herein, “granulation” refers to the process of forming particles from powdered or granular materials. As used herein, “dry granulation” refers to the process of forming particles in the absence of a solution and is applicable to the preparation of particles from materials sensitive to heat, moisture, or solvents. For example, roll forming is a dry granulation process. As used herein, “wet granulation” refers to the formation of particles by binding them together using a binder or solution. Examples of wet granulation are high-shear granulation and fluidized bed granulation.

[0107] As used herein, a “pharmaceutical composition” or “pharmaceutical formulation” means a combination of a therapeutically active agent with a pharmaceutically acceptable inert or active excipient, such that the composition is particularly suitable for in vivo or in vitro diagnostic or therapeutic use.

[0108] "Pharmaceutical acceptable" means a compound, molecular entity, composition, material, and / or dosage form that, when administered to animals or humans, does not produce harmful, allergic, or other adverse reactions; or it means a compound, molecular entity, composition, material, and / or dosage form approved or permitted by a federal or state regulatory agency or its counterpart in a country other than the United States, or listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in animals and, in particular, for use in humans.

[0109] As used herein, “pharmaceuticalally acceptable salt” means any acid salt or base salt that may be present in the compounds of this disclosure (e.g., compounds of formula (I)) and that is compatible with drug administration.

[0110] As those skilled in the art will recognize, the “salt” of a compound can be derived from an inorganic acid and a base or an organic acid and a base. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-2-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Other acids, such as oxalic acid, although not pharmaceutically acceptable on their own, can be used to prepare salts suitable as intermediates to obtain the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0111] Examples of alkalis 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 the formula NW4. + Compound, where W is C 1-4 Alkyl groups, etc.

[0112] Examples of salts include, but are not limited to, acetates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, butates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, disaccharides, dodecyl sulfates, ethanesulfonates, fumarates, flucoheptanoates, glycerophosphates, hemisulfates, heptanates, hexanoates, hydrochlorides, hydrobromates, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, oxalates, palmate, pectates, persulfates, phenylpropionates, picrates, pentylates, propionates, succinates, tartrates, thiocyanates, toluenesulfonates, undecanoates, etc. Other examples of salts include anions of the compounds disclosed herein and suitable cations (such as Na+). + K + Ca 2+ NH4 + and NW4 + (where W can be C) 1-4 Alkyl salts, etc.

[0113] For therapeutic purposes, salts of the compounds disclosed herein are considered pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0114] As used herein, the term "pharmaceuticalally acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject and / or is absorbed by the subject, and may be included in the compositions of the present invention without causing significant adverse toxicological effects on the patient. Non-limiting examples of pharmaceutically acceptable excipients include binders, diluents, carriers, adjuvants, fillers (e.g., brittle diluents or fillers and spreading diluents or fillers), disintegrants, lubricants, coatings, sweeteners, flavorings, gelatin, carbohydrates (such as lactose, amylose, or starch), fatty acid esters, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and colorants, etc. For examples of excipients, see Gennaro, Remington's Pharmaceutical Sciences, 18. th Ed., Mack Publ. Co., Easton, PA (1990) or Shesky, Hancock, Mossand Goldfarb, Handbook of Pharmaceutical Excipients, 9 th Ed. Pharmaceutical Press, London, UK (2020).

[0115] Examples of diluents or fillers include, but are not limited to, sugars (e.g., mannitol, lactose, sorbitol, lactitol, erythritol, sucrose, fructose, glucose, agarose, maltose, isomaltitol, polydextrose, and combinations thereof), inorganic materials (e.g., dicalcium phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, bentonite, kaolin), calcium lactate, starch (e.g., pregelatinized starch), microcrystalline cellulose, silicified microcrystalline cellulose, polysaccharides, cellulose (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose), dextrin, maltodextrin, alginate, collagen, polyvinylpyrrolidone, polyethylene acrylate, polyethylene oxide, and polyethylene glycol. Sugars are defined herein as including sugar alcohols.

[0116] Examples of disintegrants include, but are not limited to, alginate, primogel, cellulose (e.g., hydroxypropyl cellulose), poracrillin potassium, sodium glycolate starch, crospovidone sodium, polyvinylpyrrolidone (e.g., crospovidone), and starch (e.g., corn starch, pregelatinized starch, hydroxypropyl starch, and carboxymethyl starch).

[0117] Examples of adhesives include, but are not limited to, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose (e.g., low-viscosity hydroxypropyl methyl cellulose), sugars, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, polydextrose, chitosan, carrageenan, carbophil, microcrystalline cellulose, tragacanth gum, guar gum, gellan gum, gelatin, and starch (e.g., corn starch).

[0118] Examples of wetting agents include, but are not limited to, poloxamer (e.g., poloxamer 407), sodium dodecyl sulfate, sodium lauryl sulfate (SLS), sodium stearoyl fumarate (SSF), polydimethylsiloxane, and polysorbates (e.g., polyoxyethylene 20 sorbitan monooleate). ® 20), Sorbitan monooleate, Sorbitan trioleate, Sorbitan laurate, Sorbitan stearate, Sorbitan monopalmitate, Lecithin, Sodium taurocholate, Ursodeoxycholic acid (salt), Polyethoxylated castor oil, Hexadecyltrimethylammonium bromide, Nonoxynol ether, -Tocopherol polyethylene glycol 1000 succinate and docusate sodium.

[0119] Examples of lubricants and flow aids include, but are not limited to, waxes, glycerides, light mineral oils, polyethylene glycol, sodium stearoyl fumarate, magnesium stearate, stearic acid, hydrogenated oils (e.g., hydrogenated vegetable oils), alkyl sulfates, sodium benzoate, sodium acetate, glyceryl behenate, palmitic acid, and coconut oil.

[0120] Examples of gliding agents include, but are not limited to, colloidal silica, talc, kaolin, bentonite, and activated carbon / char.

[0121] Examples of colorants include, but are not limited to, titanium dioxide, aluminum lake, iron oxide, and carbon black.

[0122] Examples of coatings include, but are not limited to, film-forming polymers (e.g., hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate, cellulose acetate acetate, polyvinylpyrrolidone, polyvinyl alcohol, Eudragit / acrylate) and plasticizers (e.g., triacetin, polyethylene glycol, propylene glycol).

[0123] Pharmaceutical compositions intended for oral administration (e.g., pharmaceutical compositions of compounds of formula (I) described herein) may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, compositions are more commonly present in unit dosage forms to facilitate accurate administration. The term "unit dosage form" refers to a physically discrete unit suitable for administration to human subjects and other mammals in unit doses, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, bound to a suitable pharmaceutical excipient. Typical unit dosage forms, in the case of solid compositions, include pills, tablets, capsules, etc.

[0124] The term "subject" considered for administration includes, but is not limited to, humans (i.e., males or females of any age, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, 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 a non-human animal.

[0125] As used in this article, "solid dosage form" means a drug dosage in solid form, such as tablets, capsules, granules, powders, small tablets, capsules, sticks, reconstituteable powders, dry powder inhalers, lozenges, and chewable tablets.

[0126] As used herein, “administration” means oral administration, pulmonary administration, suppository administration, intramuscular administration, intrathecal administration, intranasal administration, or subcutaneous administration, or implantation of a slow-release device, such as a microosmotic pump, to a subject. Administration via any route includes transmucosal administration (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or). Parenteral administration includes, for example, intramuscular and subcutaneous administration. Other delivery methods include, but are not limited to, the use of liposomal formulations. “Co-administration” means administration of the composition described herein concurrently with, before, or after administration of one or more additional therapies (e.g., anticancer agents, chemotherapy, or treatment for neurodegenerative diseases). Compounds of formula (I) may be administered alone or co-administered to a patient. Co-administration is intended to include administration of the compound simultaneously or sequentially, either alone or in combination (more than one compound or agent). Therefore, the product may also be combined with other active substances as needed (e.g., to reduce metabolic degradation).

[0127] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0128] As used herein, unless otherwise stated, the terms “treatment,” “cure,” and “therapeutic approach” encompass actions that occur when a subject has a particular disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow its progression (“therapeutic treatment”), and also encompass actions that occur before a subject begins to have a particular disease, disorder, or condition (“preventive treatment”). In one embodiment, the compounds provided herein are intended for use as a therapeutic treatment method, wherein the action occurs when a subject has a particular disease, disorder, or condition and results in a reduction in the severity of the disease, disorder, or condition, or a delay or slowing of its progression. In an alternative embodiment, the compounds provided herein are intended for use as a preventive treatment method, wherein the action occurs before a subject begins to have a particular disease, disorder, or condition and results in prevention of the disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or prevention of recurrence of the disease, disorder, or condition.

[0129] Generally, an "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response (e.g., treatment of the disease or disorder described herein). As will be understood by those skilled in the art, the effective amount of the compounds disclosed herein may vary due to factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the route of administration, and the age, health, and condition of the subject. Effective amounts encompass both therapeutic and prophylactic treatment (i.e., encompass both "therapeutic effective amounts" and "prophylactic effective amounts").

[0130] As used herein, unless otherwise stated, a "therapeuticly effective amount" of a compound is a sufficient amount to provide therapeutic benefit or delay or minimize one or more symptoms associated with a disease, disorder, or condition in the therapeutic treatment of that disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the therapeutic treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may encompass amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic efficacy of another therapeutic agent.

[0131] As used herein, unless otherwise stated, a "preventively effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with it, or to prevent its recurrence. A preventively effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides a preventive benefit in the prevention of a disease, disorder, or condition. The term "preventively effective amount" may also encompass amounts that improve overall prevention or enhance the preventive efficacy of another preventive agent.

[0132] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are determined according to the periodic table (CAS version) on the inside cover of the 75th edition of *Handbook of Chemistry and Physics*, and specific functional groups are generally defined as described therein. Furthermore, the general principles of organic chemistry, as well as the description of specific functional groups and reactivity, are found in Thomas Sorrell's work. Organic Chemistry , University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry , 5 th Edition, 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 , 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0133] The compounds described herein may contain one or more asymmetric centers and therefore may exist in a variety of isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of a single enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched with one or more stereoisomers. Isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. 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 Resolutionsp. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This also covers the compounds described herein as a single isomer essentially free of other isomers, or as a mixture of various isomers.

[0134] As used herein, “enantiomer excess” (“ee”) or “enantiomer excess %” (“%ee”) of a composition refers to the presence of one enantiomer in the composition in excess of another enantiomer. For example, a composition may contain 90% of one enantiomer, such as the S enantiomer, and 10% of the other enantiomer, namely the R enantiomer.

[0135] ee = (90-10) / 100 = 80%.

[0136] Therefore, a composition containing 90% of one enantiomer and 10% of the other enantiomer is referred to as having an 80% enantiomer excess.

[0137] As used herein, “diastereomer excess” (“de”) or “diastereomer excess %” (“%de”) of a composition refers to an excess of one diastereomer in the composition relative to one or more different diastereomers. For example, a composition may contain 90% of one diastereomer and 10% of one or more different diastereomers.

[0138] de = (90-10) / 100 = 80%.

[0139] Therefore, a composition containing 90% of one diastereomer and 10% of one or more different diastereomers is referred to as having an 80% diastereomer excess.

[0140] compound

[0141] In some implementation schemes, this document provides the following: N -(6-amino-5-ethylpyridin-3-yl)-2-((2 R 5 S )-5-methyl-2-(2-(1-methylpiperidin-4-yl)benzo[ d Thiazol-5-yl)piperidin-1-yl)-2-oxoacetamide, a PRMT5 inhibitor (e.g., MTA-noncompetitive PRMT5 inhibitor) compound of formula (I).

[0142] (I).

[0143] Compound (I) is also known as TNG462.

[0144] In some embodiments, the compound of formula (I) is the crystalline form of the compound of formula (I). The compound of formula (I) may also be referred to as "compound I".

[0145] In some embodiments, form A has an XRPD plot containing one or more (e.g., one, two, three, or four) characteristic peaks between and including the following 2θ (degree) values: 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 some embodiments, form A has an XRPD plot containing characteristic peaks between and including the following 2θ (degree) values: 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).

[0146] In some embodiments, form A has an XRPD plot containing one or more (e.g., one, two, three, four, five, six, seven, or eight) characteristic peaks between the following 2θ (degree) values ​​and including said values: 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). In some embodiments, form A has an XRPD plot containing characteristic peaks between and including the following 2θ (degree) values: 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 2θ (degree) values: 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), and 23.5 to 23.9 (e.g., 23.7 ± 0.2).

[0147] In some embodiments, form A has an XRPD plot containing characteristic peaks between and including the following 2θ (degree) values: 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).

[0148] In some embodiments, form A has an XRPD plot containing one or more (e.g., one, two, three, four, five, six, seven, eight, nine, or ten) characteristic peaks between the following 2θ (degree) values ​​and including said values: 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), and 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).

[0149] In some embodiments, the X-ray powder diffraction pattern of form A may contain one or more (e.g., one, two, three, or four) characteristic peaks represented by 2θ, said characteristic peaks being selected from peaks located at the following degrees: 4.4±0.2, 9.6±0.2, 16.8±0.2, and 24.5±0.2. In some embodiments, the X-ray powder diffraction pattern of form A contains at least one characteristic peak represented by 2θ, said characteristic peaks being selected from peaks located at the following degrees: 4.4±0.2, 9.6±0.2, 16.8±0.2, and 24.5±0.2. In some embodiments, the X-ray powder diffraction pattern of form A contains at least two characteristic peaks represented by 2θ, said characteristic peaks being selected from peaks located at the following degrees: 4.4±0.2, 9.6±0.2, 16.8±0.2, and 24.5±0.2. In some embodiments, the X-ray powder diffraction pattern of form A contains at least three characteristic peaks represented by 2θ, said characteristic peaks being selected from peaks located at the following degrees: 4.4±0.2, 9.6±0.2, 16.8±0.2, and 24.5±0.2.

[0150] In some implementations, form A has an XRPD plot containing characteristic peaks at the following 2θ (degree) values: 4.4±0.2, 9.6±0.2, 16.8±0.2, and 24.5±0.2.

[0151] In some embodiments, the X-ray powder diffraction pattern of form A may contain one or more (e.g., one, two, three, four, five, six, seven, or eight) characteristic peaks represented by 2θ, said characteristic peaks being selected from peaks located at the following 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, and 24.5±0.2.

[0152] In some embodiments, the X-ray powder diffraction pattern of form A includes at least one characteristic peak represented by 2θ, said characteristic peak being selected from peaks located at the following θ values: 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 some embodiments, the X-ray powder diffraction pattern of form A includes at least two characteristic peaks represented by 2θ, said characteristic peaks being selected from peaks located at the following θ values: 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 some embodiments, the X-ray powder diffraction pattern of form A contains at least three characteristic peaks represented by 2θ, said characteristic peaks being selected from the following peaks: 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 some embodiments, the X-ray powder diffraction pattern of form A contains at least four characteristic peaks represented by 2θ, said characteristic peaks being selected from the following peaks: 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 some embodiments, the X-ray powder diffraction pattern of form A contains at least five characteristic peaks represented by 2θ, said characteristic peaks being selected from the peaks located 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 some embodiments, the X-ray powder diffraction pattern of form A contains at least six characteristic peaks represented by 2θ, said characteristic peaks being selected from the peaks located 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 some embodiments, the X-ray powder diffraction pattern of form A contains at least seven characteristic peaks represented by 2θ, said characteristic peaks being selected from the following peaks: 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.

[0153] In some embodiments, form A has an XRPD plot containing characteristic peaks at the following 2θ (degree) values: 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 selected from the following 2θ (degree) values: 19.3±0.2, 19.4±0.2, 20.9±0.2, and 23.7±0.2. In some embodiments, form A has an XRPD plot containing characteristic peaks at the following 2θ (degree) values: 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 selection from the following 2θ (degree) values: 19.3±0.2, 19.4±0.2, 20.9±0.2, and 23.7±0.2. In some implementations, Form A has an XRPD plot containing characteristic peaks at the following 2θ (degree) values: 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 peaks at a selection from the following 2θ (degree) values: 19.3±0.2, 19.4±0.2, 20.9±0.2, and 23.7±0.2.

[0154] In some implementations, form A has an XRPD plot containing characteristic peaks at the following 2θ (degree) values: 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.

[0155] In some embodiments, the X-ray powder diffraction pattern of form A may contain one or more (e.g., one, two, three, four, five, six, seven, eight, nine, or ten) characteristic peaks represented by 2θ, said characteristic peaks being selected from peaks located at the following degrees: 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.

[0156] In some embodiments, the X-ray powder diffraction pattern of form A includes at least one characteristic peak represented by 2θ, said characteristic peak being selected from the following peaks: 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 some embodiments, the X-ray powder diffraction pattern of form A contains at least two characteristic peaks represented by 2θ, said characteristic peaks being selected from the following peaks: 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 some embodiments, the X-ray powder diffraction pattern of form A contains at least three characteristic peaks represented by 2θ, said characteristic peaks being selected from the following peaks: 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 some embodiments, the X-ray powder diffraction pattern of form A contains at least four characteristic peaks represented by 2θ, said characteristic peaks being selected from the following peaks: 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 some embodiments, the X-ray powder diffraction pattern of form A contains at least five characteristic peaks represented by 2θ, said characteristic peaks being selected from the following peaks: 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 some embodiments, the X-ray powder diffraction pattern of form A contains at least six characteristic peaks represented by 2θ, said characteristic peaks being selected from the following peaks: 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 some embodiments, the X-ray powder diffraction pattern of form A contains at least seven characteristic peaks represented by 2θ, said characteristic peaks being selected from the following peaks: 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 some embodiments, the X-ray powder diffraction pattern of form A contains at least eight characteristic peaks represented by 2θ, said characteristic peaks being selected from the following peaks: 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 some embodiments, the X-ray powder diffraction pattern of form A contains at least nine characteristic peaks represented by 2θ, said characteristic peaks being selected from the following peaks: 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 some embodiments, the X-ray powder diffraction pattern of form A contains at least ten characteristic peaks represented by 2θ, said characteristic peaks being selected from the following peaks: 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.

[0157] In some implementations, form A has an XRPD plot containing characteristic peaks at the following 2θ (degree) values: 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.

[0158] In some implementations, form A has substantially corresponding to Figure 1 The XRPD pattern shown is an XRPD map obtained using CuKa radiation.

[0159] In some implementations, Form A has an XRPD plot (obtained using CuKa radiation) containing one, two, three, four, five, six, seven, eight, nine, or ten characteristic peaks represented by 2θ (degree) values, as shown in Table 1 (±0.2 degrees).

[0160] Table 1. XRPD peaks of compound form A of formula (I)

[0161]

[0162] In some implementation schemes, form A is essentially composed of Figure 2A Thermogravimetric analysis (TGA) characterization is shown.

[0163] In some implementation schemes, form A is essentially composed of Figure 2B The differential scanning calorimetry (DSC) curves shown are used for characterization. In some embodiments, form A can be characterized by... Figure 2B The differential scanning calorimetry (DSC) curve shown indicates a melting peak at approximately 145.8 °C.

[0164] In some implementation schemes, form A is essentially composed of Figure 3A and Figure 3B The DVS curve shown represents this.

[0165] In some embodiments, the crystalline form of the compound of formula (I) comprises a mixture of two or more crystal forms. In some embodiments, the crystalline form of the compound of formula (I) is essentially pure crystalline form A.

[0166] In some embodiments, the crystalline form A of compound (I) has a D10 between 2-4 μm. In some embodiments, the API containing crystalline form A of compound (I) has a D50 between 6-10 μm. In some embodiments, the API containing crystalline form A of compound (I) has a D90 between 18-35 μm. In some embodiments, the API containing crystalline form A of compound (I) has a D90 between 25-30 μm. In some embodiments, the API containing crystalline form A of compound (I) has a D90 less than 30 μm.

[0167] In some embodiments, the API comprising the crystalline form A of compound (I) is wet-milled to optimize particle size before being incorporated into the pharmaceutical composition and dosage form described herein.

[0168] Pharmaceutical Composition

[0169] Recent clinical studies conducted by the inventors (e.g., Example 20) have determined that a balance between clinical efficacy and safety is achieved at once-daily (QD) doses of 200 to 300 mg when treating MTAP-deficient cancers with the compound of formula (I). The exemplary pharmaceutical composition comprising crystalline form A of the compound of formula (I) described in WO2024091551 contains a 10% drug loading, which would be suboptimal for preparing dosage forms capable of delivering a 200-300 mg daily dose of the active pharmaceutical ingredient (API). Using low-drug-loading formulations would result in very large tablets, making them difficult for patients to swallow, or requiring the administration of multiple smaller tablets, which would increase pill burden and potentially reduce patient compliance.

[0170] The crystalline form A of compound (I) is partially plastic (not very compressible), such as... Figure 19 As shown. In the two batches analyzed, changes in compressive force from 2-5 kN and 4-8 kN, respectively, only resulted in an increase in hardness from 60-80 N to 130-140 N, indicating a plateau at higher compressive forces.

[0171] The inventors discovered that the compressibility index of the API is approximately 43-49% (used for...). Figure 19 The data shown (two identical batches) is considered very poor according to the United States Pharmacopeia (USP) guidelines (see Table 2). The compressibility index is calculated as: 100(V0-V f ) / V0 Where V f V0 is the tap volume of a given amount of compound, and V1 is the untackled volume of a given amount of compound.

[0172] The API's Hausner ratio was found to be in the range of 1.76–1.95 for both batches, which is considered poor according to the USP guidelines. The Hausner ratio is the ratio of bulk density to tap density, also expressed as V. f / V0 (where V) f V0 is the tap volume of a given amount of compound, and V0 is the untapped volume of a given amount of compound. V0 and V0 f For example, USP <616> The determination described in the document.

[0173] Table 2. USP Pharmacopeia Guidelines on Flowability, Compressibility, and Hausnerby

[0174] Good flowability (low HUNSNA ratio and compressibility index) is crucial for ensuring uniform mixing and consistent distribution of APIs and excipients, as well as for more efficient processing due to smoother movement through the hopper and feeder. Powders with poor flowability are prone to API and excipient segregation, leading to manufacturing challenges such as interruptions, blockages, and variable feed rates. Furthermore, high compressibility (low compressibility index) is beneficial for obtaining tablets with higher density, sufficient hardness, and smaller dimensions, while powders with poor compressibility may result in low tablet strength and susceptibility to problems such as delamination, cracking, or tablet breakage.

[0175] First-generation formulations containing 10% drug loading improve compressibility compared to APIs alone, such as... Figure 20 As shown, however, due to the poor compressibility of APIs, this improvement in compressibility is not expected to be maintained at higher API loadings without additional formulation changes. Simply increasing the drug loading in first-generation formulations will result in poorer flowability of the powder mixture, which in turn will lead to manufacturability problems such as insufficient mixture homogeneity, insufficient compressibility, and adhesion to equipment.

[0176] Common sense in the art suggests that for compositions containing poorly compressible APIs (“plastic” APIs), it is recommended to use a combination of fillers containing “brittle” fillers such as lactose or mannitol in the intragranular mixture to achieve high drug loading (see, for example, 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 indicates that binders are typically required in the intragranular mixture used in dry granulation processes to ensure that the granules have sufficient strength, can be deformed, and can be uniformly mixed with the extragranular components (see Teng, Section 2.2). However, using large amounts of excipients (such as multiple intragranular fillers, one or more binders, etc.) in high drug-loading mixtures, where the total amount of excipients is relatively low, increases the risk of a lack of homogeneity in the mixture and the resulting tablets. Minimizing the number of excipients, for example by eliminating binders and using a single filler, is preferred for ensuring mixture homogeneity.

[0177] The pharmaceutical compositions described herein surprisingly achieve good density and flowability even at high API loadings (e.g., 40%), where a single in-particle filler and no binder are used despite the extremely poor compressibility and flowability of the API (formula (I) compound crystalline form A).

[0178] Surprisingly, the high API loading drug composition described in this article (in which particles constitute approximately 85% of the formulation) achieves greater compressibility than first-generation low API loading compositions. Figure 20 And particle density (Table 3). Generally, higher particle density is associated with better compressibility.

[0179] Table 3. Particle density of first-generation and second-generation formulations

[0180] In another assay, the angle of repose of the particles of this application formulation (another measure of flowability) was measured to be approximately 33°; according to USP standards (Table 4), this value falls into the “good” category.

[0181] Table 4. USP Pharmacopeia Guidelines on Flow Based on Angle of Repose

[0182] Furthermore, the particles obtained using the formulation of this application can be ground to obtain a favorable and reproducible mixture of small and large particles. Figure 21 ).

[0183] Therefore, contrary to expectations based on general knowledge, the pharmaceutical compositions disclosed herein achieve high API loading (e.g., 40%) and appropriate properties such as tablet strength, particle size distribution, density, and flowability, while using only a single in-particle filler, gliding agent, disintegrant, and lubricant, without the addition of binders. This formulation exhibits consistent performance in production at different scales (Table 3), and its properties are comparable to or better than those of previously disclosed low API loading formulations.

[0184] In some embodiments, a pharmaceutical composition is provided that comprises a compound of formula (I) in crystalline form A. (I); And at least one pharmaceutically acceptable excipient, wherein the crystalline form A is as described herein.

[0185] In some embodiments, a pharmaceutical composition is provided comprising a compound of formula (I) as a pharmacologically active ingredient. (I); And at least one pharmaceutically acceptable excipient, wherein the compound of formula (I) is present in crystalline form A as described herein.

[0186] In some embodiments, a pharmaceutical composition is provided that comprises a compound of formula (I) in crystalline form A. (I); And at least one pharmaceutically acceptable excipient, wherein the crystalline form A is as described herein, and the pharmaceutically acceptable excipient comprises microcrystalline cellulose PH 101.

[0187] In some embodiments, a pharmaceutical composition is provided comprising a compound of formula (I) as a pharmacologically active ingredient. (I); And at least one pharmaceutically acceptable excipient, wherein the compound of formula (I) is present in crystalline form A as described herein, and the pharmaceutically acceptable excipient comprises microcrystalline cellulose PH 101.

[0188] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of the compound of formula (I) as described herein, in approximately 35% (w / w) to approximately 60% (w / w). (I); and (b) A filler containing microcrystalline cellulose PH 101.

[0189] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of the compound of formula (I) as described herein, in approximately 35% (w / w) to approximately 50% (w / w) (I); and (b) A filler containing microcrystalline cellulose PH 101.

[0190] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of the compound of formula (I) as described herein, in approximately 35% (w / w) to approximately 60% (w / w). (I); and (b) A filler containing microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102.

[0191] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of the compound of formula (I) as described herein, in approximately 35% (w / w) to approximately 50% (w / w) (I); and (b) A filler containing microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102.

[0192] In some embodiments, the composition comprises one or more additional pharmaceutically acceptable excipients.

[0193] The quantities and ranges referred to below as “compound of formula (I)” may refer to the compound of formula (I) itself, the crystalline form of the compound of formula (I), or the crystalline form A of the compound of formula (I) described herein.

[0194] The pharmaceutical compositions and dosage forms described herein are characterized by relatively high API loadings, which are beneficial for minimizing dosage form (e.g., tablet) size and thus improving patient administration convenience. High API loadings, particularly in the case of crystalline APIs as described in this application, can result in mixtures with suboptimal manufacturability properties (e.g., homogeneity, flowability, compressibility, API release profile), requiring careful optimization of pharmaceutical excipients.

[0195] In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 60% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 55% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 50% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 50% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 60% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 55% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 50% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 45% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 45% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 37% (w / w) to about 43% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 38% (w / w) to about 42% (w / w) of crystalline form A of compound (I). In some embodiments, the pharmaceutical composition comprises about 39% (w / w) to about 41% (w / w) of compound (I).

[0196] 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 a compound of formula (I).

[0197] 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 a compound of formula (I).

[0198] In some embodiments, the pharmaceutical composition comprises about 35% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 36% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 37% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 38% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 39% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 39.8% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 40% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 41% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 42% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 43% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 44% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 45% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 46% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 47% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 48% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 49% (w / w). In some embodiments, the pharmaceutical composition comprises about 50% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 55% (w / w) of compound (I). In some embodiments, the pharmaceutical composition comprises about 60% (w / w) of compound (I).

[0199] In some embodiments, the filler comprises sugar, inorganic material, microcrystalline cellulose, starch, polysaccharide, cellulose, polyvinylpyrrolidone, polyvinyl acrylate, or a combination thereof.

[0200] In some embodiments, the filler comprises sugar, inorganic materials, 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 calcium hydrogen phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, bentonite, kaolin, and combinations thereof.

[0201] In some embodiments, the filler comprises microcrystalline cellulose, starch, polysaccharides, cellulose, polyvinylpyrrolidone, polyethylene acrylate, and combinations thereof. In some embodiments, the cellulose is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose, or combinations thereof.

[0202] In some implementations, the filler comprises microcrystalline cellulose (e.g., Avicel). ® Microcrystalline cellulose fillers 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 microcrystalline cellulose PH 101 (e.g., Avicel). ® PH 101). In some embodiments, a portion of the filler comprises microcrystalline cellulose PH 101 (e.g., Avicel). ® The filler also contains microcrystalline cellulose (pH 101), and another portion of the filler contains microcrystalline cellulose (pH 102, e.g., Avicel). ® (PH 102). In some embodiments, the filler for the in-particle mixture comprises microcrystalline cellulose PH 101, and the filler for the out-of-particle mixture comprises microcrystalline cellulose PH 102. In some embodiments, the filler for the in-particle mixture consists essentially of microcrystalline cellulose PH 101, and the filler for the out-of-particle mixture consists essentially of microcrystalline cellulose PH 102.

[0203] In some embodiments, the pharmaceutical composition comprises about 30% (w / w) to about 60% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 60% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) to about 60% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 52% (w / w) to about 58% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 52% (w / w) to about 56% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 53% (w / w) to about 54% (w / w) of a filler.

[0204] 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) of 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) of a filler, or about 60% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 42% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 43% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 44% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 45% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 46% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 47% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 48% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 49% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 51% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 52% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 53% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 53.7% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 54% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 55% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 56% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 57% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 58% (w / w) of filler.In some embodiments, the pharmaceutical composition comprises about 59% (w / w) of a filler. In some embodiments, the pharmaceutical composition comprises about 60% (w / w) of a filler.

[0205] In some embodiments, the pharmaceutical composition comprises about 30% (w / w) to about 60% (w / w) of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 60% (w / w) of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) to about 60% (w / w) of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 52% (w / w) to about 58% (w / w) of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 52% (w / w) to about 56% (w / w) of microcrystalline cellulose.

[0206] 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) of 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) of microcrystalline cellulose, or about 60% (w / w) of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 42% (w / w) of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 43% (w / w) of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 44% (w / w) of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 45% (w / w) of microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 46% (w / w) microcrystalline 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) microcrystalline 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) microcrystalline 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.

[0207] In some embodiments, the pharmaceutical composition comprises a flow aid. In some embodiments, the flow aid comprises colloidal silica, talc, kaolin, bentonite, or a combination thereof.

[0208] In some embodiments, the flow aid comprises colloidal silica. In some embodiments, the flow aid consists essentially of colloidal silica. In some embodiments, the colloidal silica is prepared by a process involving the flame hydrolysis of silicon tetrachloride in an oxyhydrogen flame, referred to as "fumed silica" or "untreated fumed silica" (e.g., Aerosil). ® 200, CAB-O-SIL ® M-5P).

[0209] The amount of a flow aid in the composition affects the flowability and compressibility of the mixture. The amount of the selected flow aid in the pharmaceutical compositions described herein results in improved flowability of the mixture, facilitates adequate granulation of the mixture within granules, and improves the compressibility of the mixture outside granules. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 3.0% (w / w) of a flow aid. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) to about 2.5% (w / w) of a flow aid. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) to about 2.25% (w / w) of a flow aid. In some embodiments, the pharmaceutical composition comprises about 1.9% (w / w) to about 2.1% (w / w) of a flow aid.

[0210] 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) of a flow aid. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) of a flow aid. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) of a flow aid. In some embodiments, the pharmaceutical composition comprises about 1.9% (w / w) of a flow aid. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) of a flow aid. In some embodiments, the pharmaceutical composition comprises about 2.1% (w / w) of a flow aid. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) of a flow aid. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) of a flow aid. In some embodiments, the pharmaceutical composition comprises about 3% (w / w) of a flow aid.

[0211] In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 3.0% (w / w) of colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) to about 2.5% (w / w) of colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) to about 2.25% (w / w) of colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.9% (w / w) to about 2.1% (w / w) of colloidal silica.

[0212] 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) of colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) of colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) of colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.9% (w / w) of colloidal silica. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) of colloidal silica. In some embodiments, the pharmaceutical composition comprises about 2.1% (w / w) of colloidal silica. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) of colloidal silica. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) colloidal silica. In some embodiments, the pharmaceutical composition comprises about 3% (w / w) colloidal silica.

[0213] In some embodiments, the pharmaceutical composition comprises a disintegrant. In some embodiments, the disintegrant comprises sodium glycolate starch, crospovidone, croscarmellose sodium, or a combination thereof. In some embodiments, the disintegrant comprises croscarmellose sodium (e.g., Ac-Di-Sol). ® In some implementations, the disintegrant is essentially croscarmellose sodium (e.g., Ac-Di-Sol). ® )composition.

[0214] In some embodiments, the pharmaceutical composition comprises about 2% (w / w) to about 4% (w / w) of a disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) to about 3.5% (w / w) of a disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.75% (w / w) to about 3.25% (w / w) of a disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.9% (w / w) to about 3.1% (w / w) of a 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) of a disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) of a disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) of a disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) of a disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.75% (w / w) of a disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.9% (w / w) of a disintegrant. In some embodiments, the pharmaceutical composition comprises about 3% (w / w) of a disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.1% (w / w) of a disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.25% (w / w) of a disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.5% (w / w) of a disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.75% (w / w) of a disintegrant. In some embodiments, the pharmaceutical composition comprises about 4.0% (w / w) of a disintegrant.

[0215] In some embodiments, the pharmaceutical composition comprises about 2% (w / w) to about 4% (w / w) of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) to about 3.5% (w / w) of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.75% (w / w) to about 3.25% (w / w) of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.9% (w / w) to about 3.1% (w / w) of 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) of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.75% (w / w) of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.9% (w / w) of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3% (w / w) of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.1% (w / w) of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.25% (w / w) of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.5% (w / w) of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.75% (w / w) of croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 4.0% (w / w) of croscarmellose sodium.

[0216] In some embodiments, the pharmaceutical composition comprises a lubricant. In some embodiments, the lubricant comprises sodium stearate, magnesium stearate, stearic acid, glyceryl behenate, or a combination thereof.

[0217] In some embodiments, the lubricant comprises magnesium stearate. In some embodiments, the lubricant consists essentially of magnesium stearate.

[0218] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 2.0% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) to about 1.25% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) to about 1.75% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) to about 1.55% (w / w) of a lubricant.

[0219] 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) of lubricant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) of lubricant. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) of lubricant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) of lubricant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) of a lubricant. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) of a lubricant.

[0220] 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.

[0221] 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.

[0222] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of the compound of formula (I) as described herein (I); (b) A filler containing microcrystalline cellulose PH 101; (c) Flow aids (e.g., colloidal silica); (d) Disintegrants (e.g., croscarmellose sodium); and (e) a lubricant (e.g., magnesium stearate); wherein the compound of formula (I), filler, flow aid, disintegrant and lubricant are present in the amounts described herein.

[0223] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of the compound of formula (I) as described herein (I); (b) A filler containing microcrystalline cellulose PH 101 and PH 102; (c) Flow aids (e.g., colloidal silica); (d) Disintegrants (e.g., croscarmellose sodium); and (e) a lubricant (e.g., magnesium stearate); wherein the compound of formula (I), filler, flow aid, disintegrant and lubricant are present in the amounts described herein.

[0224] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of the compound of formula (I) as described herein, in approximately 35% (w / w) to approximately 60% (w / w). (I); (b) about 30% (w / w) to about 60% (w / w) of a filler, wherein the filler comprises microcrystalline cellulose PH101 or a combination of microcrystalline cellulose PH101 and PH102; (c) Flow aids (e.g., colloidal silica); (d) Disintegrants (e.g., croscarmellose sodium); and (e) Lubricants (e.g., magnesium stearate).

[0225] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of the compound of formula (I) as described herein, in approximately 35% (w / w) to approximately 50% (w / w) (I); (b) about 40% (w / w) to about 60% (w / w) of a filler, wherein the filler comprises microcrystalline cellulose PH101 or a combination of microcrystalline cellulose PH101 and PH102; (c) Flow aids (e.g., colloidal silica); (d) Disintegrants (e.g., croscarmellose sodium); and (e) Lubricants (e.g., magnesium stearate).

[0226] In some embodiments, the composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 60% (w / w); (b) about 30% (w / w) to about 60% (w / w) of a filler containing microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 1% (w / w) to approximately 3% (w / w) of a flow aid (e.g., colloidal silica); (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); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0227] In some embodiments, the composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 60% (w / w); (b) about 30% (w / w) to about 60% (w / w) of a filler containing microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 1% (w / w) to approximately 3% (w / w) of a flow aid (e.g., colloidal silica); (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); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0228] In some embodiments, the composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 50% (w / w); (b) About 40% (w / w) to about 60% (w / w) of a filler containing microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 1% (w / w) to approximately 3% (w / w) of a flow aid (e.g., colloidal silica); (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); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0229] In some embodiments, the composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 50% (w / w); (b) About 40% (w / w) to about 60% (w / w) of a filler containing microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 1% (w / w) to approximately 3% (w / w) of a flow aid (e.g., colloidal silica); (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); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0230] In some embodiments, the composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 45% (w / w); (b) About 50% (w / w) to about 60% (w / w) of a filler containing microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 1% (w / w) to approximately 3% (w / w) of a flow aid (e.g., colloidal silica); (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); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0231] In some embodiments, the composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 45% (w / w); (b) About 50% (w / w) to about 60% (w / w) of a filler containing microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 1% (w / w) to approximately 3% (w / w) of a flow aid (e.g., colloidal silica); (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); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0232] In some embodiments, the composition comprises: (a) Crystalline form A of compound of formula (I) in approximately 37% (w / w) to approximately 43% (w / w); (b) About 52% (w / w) to about 56% (w / w) of a filler comprising 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 a flow aid (e.g., colloidal silica); (d) About 2.5% (w / w) to about 3.5% (w / w) of a disintegrant (e.g., croscarmellose sodium); (e) a lubricant (e.g., magnesium stearate) of about 1.25% (w / w) to about 1.75% (w / w); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0233] In some embodiments, the composition comprises: (a) Crystalline form A of compound of formula (I) in approximately 37% (w / w) to approximately 43% (w / w); (b) About 52% (w / w) to about 56% (w / w) of a filler comprising 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 a flow aid (e.g., colloidal silica); (d) About 2.5% (w / w) to about 3.5% (w / w) of a disintegrant (e.g., croscarmellose sodium); (e) a lubricant (e.g., magnesium stearate) of about 0.75% (w / w) to about 1.25% (w / w); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0234] In some embodiments, the composition comprises: (a) Crystalline form A of compound (I) in 39% (w / w) to 41% (w / w); (b) 53% (w / w) to 55% (w / w) of filler, such as 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 a flow aid (e.g., colloidal silica); (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); Thus, the total is 100% (w / w) of the composition.

[0235] In some embodiments, the composition comprises: (a) Crystalline form A of compound of formula (I) in approximately 39% (w / w) to 41% (w / w); (b) about 53% (w / w) to 55% (w / w) of fillers, such as microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 2% (w / w) of a flow aid (e.g., colloidal silica); (d) Approximately 3% (w / w) of a disintegrant (e.g., croscarmellose sodium); (e) Approximately 1.5% (w / w) of lubricant (e.g., magnesium stearate); Thus, the total is 100% (w / w) of the composition.

[0236] In some embodiments, the composition comprises: (a) Crystalline form A of approximately 40% (w / w) of compound (I); (b) Approximately 54% (w / w) of filler, such as microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 2% (w / w) of a flow aid (e.g., colloidal silica); (d) Approximately 3% (w / w) of a disintegrant (e.g., croscarmellose sodium); (e) Approximately 1.5% (w / w) of lubricant (e.g., magnesium stearate); Thus, the total is 100% (w / w) of the composition.

[0237] In some embodiments, the composition comprises: (a) Crystalline form A of compound (I) comprising approximately 39.8% (w / w); (b) Approximately 53.7% (w / w) of filler, such as microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 2% (w / w) of a flow aid (e.g., colloidal silica); (d) Approximately 3% (w / w) of a disintegrant (e.g., croscarmellose sodium); (e) Approximately 1.5% (w / w) of lubricant (e.g., magnesium stearate); Thus, the total is 100% (w / w) of the composition.

[0238] In some embodiments, the composition comprises: (a) Crystalline form A of approximately 40% (w / w) of compound (I); (b) Approximately 54% (w / w) of filler, such as microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 2% (w / w) of a flow aid (e.g., colloidal silica); (d) Approximately 3% (w / w) of a disintegrant (e.g., croscarmellose sodium); (e) Approximately 1% (w / w) of a lubricant (e.g., magnesium stearate); Thus, the total is 100% (w / w) of the composition.

[0239] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of the compound of formula (I) as described herein (I); (b) Microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Colloidal silica; (d) Crosslinked sodium carboxymethyl cellulose; and (e) Magnesium stearate.

[0240] In some embodiments, the composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 50% (w / w); (b) Approximately 40% (w / w) to approximately 60% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Colloidal silica of about 1% (w / w) to about 3% (w / w); (d) Approximately 2% (w / w) to approximately 4% (w / w) of croscarmellose sodium; (e) Magnesium stearate of about 1.0% (w / w) to about 2.0% (w / w); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0241] In some embodiments, the composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 50% (w / w); (b) Approximately 40% (w / w) to approximately 60% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Colloidal silica of about 1% (w / w) to about 3% (w / w); (d) Approximately 2% (w / w) to approximately 4% (w / w) of croscarmellose sodium; (e) Magnesium stearate of about 0.5% (w / w) to about 1.5% (w / w); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0242] In some embodiments, the composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 45% (w / w); (b) Approximately 50% (w / w) to approximately 60% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Colloidal silica of about 1% (w / w) to about 3% (w / w); (d) Approximately 2% (w / w) to approximately 4% (w / w) of croscarmellose sodium; (e) Magnesium stearate of about 1.0% (w / w) to about 2.0% (w / w); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0243] In some embodiments, the composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 45% (w / w); (b) Approximately 50% (w / w) to approximately 60% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Colloidal silica of about 1% (w / w) to about 3% (w / w); (d) Approximately 2% (w / w) to approximately 4% (w / w) of croscarmellose sodium; (e) Magnesium stearate of about 0.5% (w / w) to about 1.5% (w / w); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0244] In some embodiments, the composition comprises: (a) Crystalline form A of the compound of formula (I) in approximately 37% (w / w) to approximately 43% (w / w); (b) Approximately 52% (w / w) to approximately 56% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Colloidal silica of about 1.5% (w / w) to about 2.5% (w / w); (d) Approximately 2.5% (w / w) to approximately 3.5% (w / w) of croscarmellose sodium; (e) Magnesium stearate of about 1.25% (w / w) to about 1.75% (w / w); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0245] In some embodiments, the composition comprises: (a) Crystalline form A of the compound of formula (I) in approximately 37% (w / w) to approximately 43% (w / w); (b) Approximately 52% (w / w) to approximately 56% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Colloidal silica of about 1.5% (w / w) to about 2.5% (w / w); (d) Approximately 2.5% (w / w) to approximately 3.5% (w / w) of croscarmellose sodium; (e) Magnesium stearate of about 0.75% (w / w) to about 1.25% (w / w); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0246] In some embodiments, the composition comprises: (a) Crystalline form A of compound of formula (I) in 39% (w / w) to 41% (w / w); (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 silica; (d) 2.9% (w / w) to 3.1% (w / w) of croscarmellose sodium; (e) 1.4% (w / w) to 1.6% (w / w) magnesium stearate; Thus, the total is 100% (w / w) of the composition.

[0247] In some embodiments, the composition comprises: (a) Crystalline form A of the compound of formula (I) in approximately 39% (w / w) to 41% (w / w); (b) Approximately 53% (w / w) to 55% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 2% (w / w) of colloidal silica; (d) Approximately 3% (w / w) of croscarmellose sodium; (e) Approximately 1.5% (w / w) magnesium stearate; Thus, the total is 100% (w / w) of the composition.

[0248] In some embodiments, the composition comprises: (a) Crystalline form A of approximately 40% (w / w) of compound (I); (b) Approximately 54% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 2% (w / w) of colloidal silica; (d) Approximately 3% (w / w) of croscarmellose sodium; (e) Approximately 1.5% (w / w) magnesium stearate; Thus, the total is 100% (w / w) of the composition.

[0249] In some embodiments, the composition comprises: (a) Crystalline form A of compound of formula (I) comprising approximately 39.8% (w / w); (b) Approximately 53.7% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 2% (w / w) of colloidal silica; (d) Approximately 3% (w / w) of croscarmellose sodium; (e) Approximately 1.5% (w / w) magnesium stearate; Thus, the total is 100% (w / w) of the composition.

[0250] In some embodiments, the composition comprises: (a) Crystalline form A of approximately 40% (w / w) of compound (I); (b) Approximately 54% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 2% (w / w) of colloidal silica; (d) Approximately 3% (w / w) of croscarmellose sodium; (e) Approximately 1% (w / w) magnesium stearate; Thus, the total is 100% (w / w) of the composition.

[0251] Pharmaceutically acceptable excipients can be present in the in-particle or extra-particle components of a pharmaceutical composition. In some embodiments, one or more pharmaceutically acceptable excipients are present in both the in-particle and extra-particle components.

[0252] In some embodiments, the pharmaceutical composition contains an in-particle filler selected from the fillers described herein. In some embodiments, the in-particle filler comprises microcrystalline cellulose (e.g., Avicel). ® In some implementations, the in-particle filler is essentially composed of microcrystalline cellulose (e.g., Avicel). ® The composition of microcrystalline cellulose is as follows. The average particle size of microcrystalline cellulose affects its binding with the active ingredient and additional excipients, and a closer match between the API particle size and the microcrystalline cellulose particle size is considered to contribute to better binding and better manufacturability. The median particle sizes of microcrystalline cellulose PH 101 and PH 102 are ~50 μm and ~100 μm, respectively, and the smaller particle size of PH 101 is a better match to the average particle size of the API. Therefore, in some embodiments, the in-particle filler comprises microcrystalline cellulose PH 101 (e.g., Avicel). ® PH 101). In some embodiments, the in-particle filler is essentially composed of microcrystalline cellulose PH 101 (e.g., Avicel). ® Composition of PH 101).

[0253] The ratio of API to granular filler can affect the homogeneity of API in the mixture; a lower API to granular filler ratio may make it more difficult to achieve acceptable API homogeneity. In some embodiments, the API to granular filler w / w ratio is between 0.9 and 1.6. In some embodiments, the API to granular filler w / w ratio is between 0.9 and 1.4. In some embodiments, the API to granular filler w / w ratio is between 0.9 and 1.2. In some embodiments, the API to granular filler w / w ratio is between 0.9 and 1.1. In some embodiments, the API to granular filler w / w ratio is between 0.9 and 1.05. In some embodiments, the API to granular filler w / w ratio is between 0.9 and 1.0. In some embodiments, the API to granular filler w / w ratio is between 0.95 and 1.05. In some embodiments, the API to granular filler w / w ratio is between 0.95 and 1.0. In some implementations, the w / w ratio of API to in-particle filler is approximately 0.95.

[0254] In some embodiments, the pharmaceutical composition comprises about 20% (w / w) to about 50% (w / w) of an in-particle filler. In some embodiments, the pharmaceutical composition comprises about 25% (w / w) to about 50% (w / w) of an in-particle filler. In some embodiments, the pharmaceutical composition comprises about 30% (w / w) to about 50% (w / w) of an in-particle filler. In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 50% (w / w) of an in-particle filler. In some embodiments, the pharmaceutical composition comprises about 38% (w / w) to about 46% (w / w) of an in-particle filler. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 44% (w / w) of an in-particle filler. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) to about 43% (w / w) of an in-particle filler. In some embodiments, the pharmaceutical composition comprises about 41.5% (w / w) to about 42.5% (w / w) of an in-particle 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) In-particle filler.

[0255] 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 an in-particle 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) of an in-particle filler.

[0256] In some embodiments, the pharmaceutical composition comprises about 25% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 26% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 27% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 28% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 29% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 30% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 31% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 32% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 33% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 34% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 35% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 36% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 37% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 38% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 39% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 41.8% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 42% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 43% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 44% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 45% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 46% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 47% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 48% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 49% (w / w) of in-particle filler. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) of in-particle filler.

[0257] In some embodiments, the pharmaceutical composition comprises about 20% (w / w) to about 50% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 25% (w / w) to about 50% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 30% (w / w) to about 50% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 35% (w / w) to about 50% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 38% (w / w) to about 46% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) to about 44% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) to about 43% (w / w) of in-particle microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 41.5% (w / w) to about 42.5% (w / w) of 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) Microcrystalline cellulose within particles, pH 101.

[0258] 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 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) of in-particle microcrystalline cellulose PH 101.

[0259] In some embodiments, the pharmaceutical composition comprises about 25% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 26% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 27% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 28% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 29% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 30% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 31% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 32% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 33% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 34% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 35% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 36% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 37% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 38% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 39% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 40% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 41% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 41.8% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 42% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 43% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 44% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 45% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 46% (w / w) of intragranular microcrystalline cellulose PH 101.In some embodiments, the pharmaceutical composition comprises about 47% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 48% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 49% (w / w) of intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 50% (w / w) of intragranular microcrystalline cellulose PH 101.

[0260] In some embodiments, the pharmaceutical composition contains an extragranular filler selected from the fillers described herein. The addition of an extragranular filler results in better compressibility compared to high-API compositions lacking an extragranular filler. In some embodiments, the extragranular filler comprises microcrystalline cellulose (e.g., Avicel). ® In some implementations, the ex-particle filler is essentially composed of microcrystalline cellulose (e.g., Avicel). ® The composition is as follows. Since the internal phase represents a large proportion of the final composition, the properties of the external filler (e.g., filler particle size distribution, flowability, etc.) should be selected to match the behavior of the particles and avoid negatively impacting the flowability and compressibility of the final mixture. In some embodiments, the external filler comprises microcrystalline cellulose PH 102 (e.g., Avicel). ® PH 102). In some embodiments, the ex-particle filler is essentially composed of microcrystalline cellulose PH 102 (e.g., Avicel). ® Composition of PH 102).

[0261] In some embodiments, the pharmaceutical composition comprises about 5% (w / w) to about 20% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 8% (w / w) to about 16% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 10% (w / w) to about 14% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 11% (w / w) to about 13% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 11.5% (w / w) to about 12.5% ​​(w / w) of an exfoliating filler.

[0262] 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) of an extraparticle filler.

[0263] 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) of an explant filler.

[0264] In some embodiments, the pharmaceutical composition comprises about 5% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 6% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 7% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 8% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 9% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 10% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 11% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 12% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 13% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 14% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 15% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 16% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 17% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 18% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 19% (w / w) of an exfoliating filler. In some embodiments, the pharmaceutical composition comprises about 20% (w / w) of an exfoliating filler.

[0265] In some embodiments, the pharmaceutical composition comprises about 5% (w / w) to about 20% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 8% (w / w) to about 16% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 10% (w / w) to about 14% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 11% (w / w) to about 13% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 11.5% (w / w) to about 12.5% ​​(w / w) of exomeric microcrystalline cellulose PH 102.

[0266] 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) of exogranular microcrystalline cellulose PH 102.

[0267] 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) of exogranular microcrystalline cellulose PH 102.

[0268] In some embodiments, the pharmaceutical composition comprises about 5% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 6% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 7% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 8% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 9% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 10% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 11% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 12% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 13% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 14% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 15% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 16% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 17% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 18% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 19% (w / w) of exomeric microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 20% (w / w) of exomeric microcrystalline cellulose PH 102.

[0269] In some embodiments, the pharmaceutical composition comprises an intraparticle flow aid selected from the flow aids described herein. In some embodiments, the intraparticle flow aid is substantially composed of colloidal silica (e.g., Aerosil). ® 200, CAB-O-SIL ® The composition is M-5P. The amount of in-granule gliding agent affects the flowability of the mixture, and the selected amount of in-granule gliding agent helps to make the in-granule mixture suitable for dry granulation.

[0270] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) to about 1.2% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) of an intragranular flow aid.

[0271] 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) of an intraparticle flow aid. 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) of an intraparticle flow aid.

[0272] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 0.6% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 0.7% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 0.85% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 1.15% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) of an intragranular flow aid. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) of an intragranular flow aid.

[0273] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) to about 1.2% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) of intraparticle colloidal silica.

[0274] 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) of intraparticle colloidal silica. 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) of intraparticle colloidal silica.

[0275] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.6% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.7% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.85% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.15% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) of intraparticle colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) of intraparticle colloidal silica.

[0276] In some embodiments, the pharmaceutical composition comprises an extraparticle flow aid selected from the flow aids described herein. In some embodiments, the extraparticle flow aid is substantially composed of colloidal silica (e.g., Aerosil). ® 200, CAB-O-SIL ® Composition (M-5P). The amount of extraparticle flow aid in the composition affects the flowability and compressibility of the mixture, and the amount of flow aid selected in the pharmaceutical composition described herein contributes to improved flowability and compressibility of the extraparticle mixture.

[0277] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) of an external aspiration agent. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) to about 1.2% (w / w) of an external aspiration agent. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) of an external aspiration agent. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) of an external aspiration agent.

[0278] 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) of an extraparticle flow aid. 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) of an extraparticle flow aid.

[0279] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) of an external duct flow aid. In some embodiments, the pharmaceutical composition comprises about 0.6% (w / w) of an external duct flow aid. In some embodiments, the pharmaceutical composition comprises about 0.7% (w / w) of an external duct flow aid. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) of an external duct flow aid. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) of an external duct flow aid. In some embodiments, the pharmaceutical composition comprises about 0.85% (w / w) of an external duct flow aid. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) of an external duct flow aid. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) of an external duct flow aid. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) of an external duct flow aid. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w) of an external duct flow aid. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) of an external aspiration agent. In some embodiments, the pharmaceutical composition comprises about 1.15% (w / w) of an external aspiration agent. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) of an external aspiration agent. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) of an external aspiration agent. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) of an external aspiration agent. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) of an external aspiration agent. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) of an external aspiration agent.

[0280] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.5% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) to about 1.2% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) of extrapartic colloidal silica.

[0281] 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) of exomeric colloidal silica. 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) of exomeric colloidal silica.

[0282] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.6% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.7% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.8% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.85% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.05% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.1% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.15% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.2% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) of extrapartic colloidal silica. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) of extrapartic colloidal silica.

[0283] In some embodiments, the pharmaceutical composition comprises an intragranular disintegrant selected from the disintegrants described herein. In some embodiments, the intragranular disintegrant is substantially composed of croscarmellose sodium.

[0284] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 2.5% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 2.0% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) to about 1.75% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) to about 1.55% (w / w) of an intragranular disintegrant.

[0285] 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) of an intraparticle 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) of an intraparticle disintegrant.

[0286] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.35% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.55% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.6% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.65% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.7% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) of an intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) of an intragranular disintegrant.

[0287] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 2.5% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 2.0% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) to about 1.75% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) to about 1.55% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose.

[0288] 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) of intraparticle crosslinked sodium carboxymethyl cellulose. 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) of intraparticle crosslinked sodium carboxymethyl cellulose.

[0289] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1.35% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1.35% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1.55% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1.6% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1.65% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1.7% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose.

[0290] In some embodiments, the pharmaceutical composition comprises an extraparticle disintegrant selected from the disintegrants described herein. In some embodiments, the extraparticle disintegrant is substantially composed of croscarmellose sodium.

[0291] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 2.5% (w / w) of an extraparticle disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 2.0% (w / w) of an extraparticle disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) to about 1.75% (w / w) of an extraparticle disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) of an extraparticle disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) to about 1.55% (w / w) of an extraparticle disintegrant.

[0292] 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) of an exodisintegrant. 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) of an ex-particle disintegrant.

[0293] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) of an externally disintegrant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) of an externally disintegrant. In some embodiments, the pharmaceutical composition comprises about 1% (w / w) of an externally disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) of an externally disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) of an externally disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.35% (w / w) of an externally disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) of an externally disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) of an externally disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) of an externally disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.55% (w / w) of an externally disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.6% (w / w) of an extraparticle disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.65% (w / w) of an extraparticle disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.7% (w / w) of an extraparticle disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) of an extraparticle disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) of an extraparticle disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) of an extraparticle disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) of an extraparticle disintegrant.

[0294] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 2.5% (w / w) of externally crosslinked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) to about 2.0% (w / w) of externally crosslinked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) to about 1.75% (w / w) of externally crosslinked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) to about 1.6% (w / w) of externally crosslinked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) to about 1.55% (w / w) of externally crosslinked carboxymethyl cellulose sodium.

[0295] 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) of extraparticle crosslinked sodium carboxymethyl cellulose. 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) of extraparticle crosslinked sodium carboxymethyl cellulose.

[0296] In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) of externally crosslinked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) of externally crosslinked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1% (w / w) of externally crosslinked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1.25% (w / w) of externally crosslinked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1.3% (w / w) of externally crosslinked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1.35% (w / w) of externally crosslinked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1.35% (w / w) of externally crosslinked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1.4% (w / w) of externally crosslinked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1.45% (w / w) of externally crosslinked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1.5% (w / w) of externally crosslinked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1.55% (w / w) of externally cross-linked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1.6% (w / w) of externally cross-linked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1.65% (w / w) of externally cross-linked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1.7% (w / w) of externally cross-linked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 1.75% (w / w) of externally cross-linked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 2.0% (w / w) of externally cross-linked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 2.25% (w / w) of externally cross-linked carboxymethyl cellulose sodium. In some embodiments, the pharmaceutical composition comprises about 2.5% (w / w) of externally cross-linked carboxymethyl cellulose sodium.

[0297] In some embodiments, the pharmaceutical composition comprises an in-particle lubricant selected from the lubricants described herein. In some embodiments, the in-particle lubricant is substantially composed of magnesium stearate.

[0298] In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) of an in-particle lubricant. In some embodiments, the pharmaceutical composition comprises about 0.3% (w / w) to about 0.7% (w / w) of an in-particle lubricant.

[0299] In some embodiments, the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) of an in-particle lubricant. In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) to about 0.55% (w / w) of an in-particle lubricant.

[0300] 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) of an in-particle 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) of an in-particle lubricant.

[0301] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) of an in-particle lubricant. In some embodiments, the pharmaceutical composition comprises about 0.46% (w / w) of an in-particle lubricant. In some embodiments, the pharmaceutical composition comprises about 0.47% (w / w) of an in-particle lubricant. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w) of an in-particle lubricant. In some embodiments, the pharmaceutical composition comprises about 0.49% (w / w) of an in-particle lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) of an in-particle lubricant. In some embodiments, the pharmaceutical composition comprises about 0.51% (w / w) of an in-particle lubricant. In some embodiments, the pharmaceutical composition comprises about 0.52% (w / w) of an in-particle lubricant. In some embodiments, the pharmaceutical composition comprises about 0.53% (w / w) of an in-particle lubricant. In some embodiments, the pharmaceutical composition comprises about 0.54% (w / w) of an in-particle lubricant. In some embodiments, the pharmaceutical composition comprises about 0.55% (w / w) of an in-particle lubricant.

[0302] In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) of intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.3% (w / w) to about 0.7% (w / w) of intragranular magnesium stearate.

[0303] In some embodiments, the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) of intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) to about 0.55% (w / w) of intragranular magnesium stearate.

[0304] 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) of 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) of intragranular magnesium stearate.

[0305] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) of intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.46% (w / w) of intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.47% (w / w) of intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w) of intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.49% (w / w) of intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) of intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.51% (w / w) of intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.52% (w / w) of intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.53% (w / w) of intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.54% (w / w) of intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.55% (w / w) of intragranular magnesium stearate.

[0306] In some embodiments, the pharmaceutical composition comprises an external lubricant selected from the lubricants described herein. In some embodiments, the external lubricant is substantially composed of magnesium stearate.

[0307] In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 1.5% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 1.25% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.25% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) to about 1.25% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.3% (w / w) to about 0.7% (w / w) of an external particulate lubricant.

[0308] In some embodiments, the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) to about 0.55% (w / w) of an external particulate lubricant.

[0309] 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) of an external particulate 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) of an external particulate lubricant.

[0310] 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) of an external particulate 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) of an external particulate lubricant.

[0311] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.46% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.47% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.49% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.51% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.52% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.53% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.54% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.55% (w / w) of an external particulate lubricant.

[0312] In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.96% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.97% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.98% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.99% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 1.01% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 1.02% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 1.03% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 1.04% (w / w) or about 1.05% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.98% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 0.99% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) of an external particulate lubricant. In some embodiments, the pharmaceutical composition comprises about 1.01% (w / w) or about 1.02% (w / w) of an external particulate lubricant.

[0313] In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 1.5% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 1.25% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) to about 1.25% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.75% (w / w) to about 1.25% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.9% (w / w) to about 1.1% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) to about 1.05% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.25% (w / w) to about 0.75% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.3% (w / w) to about 0.7% (w / w) of extragranular magnesium stearate.

[0314] In some embodiments, the pharmaceutical composition comprises about 0.4% (w / w) to about 0.6% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) to about 0.55% (w / w) of extragranular magnesium stearate.

[0315] 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) of exfoliated 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) of exfoliated magnesium stearate.

[0316] 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) of exfoliated 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) of exfoliated magnesium stearate.

[0317] In some embodiments, the pharmaceutical composition comprises about 0.45% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.46% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.47% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.48% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.49% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.5% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.51% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.52% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.53% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.54% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.55% (w / w) of extragranular magnesium stearate.

[0318] In some embodiments, the pharmaceutical composition comprises about 0.95% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.96% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.97% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.98% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.99% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.01% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.02% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.03% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.04% (w / w) or about 1.05% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.98% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.99% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.0% (w / w) of extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.01% (w / w) or about 1.02% (w / w) of extragranular magnesium stearate.

[0319] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) (I); (b) An in-particle filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients. In some embodiments, the compound of formula (I), the in-particle filler, and the additional excipients are present in the w / w percentages described in any of the embodiments herein.

[0320] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) in approximately 35% (w / w) to approximately 50% (w / w) (I); (b) An in-particle filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients.

[0321] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) (I); (b) In-particle filler containing microcrystalline cellulose PH 101; (c) In-particle flow aids (e.g., colloidal silica); (d) Intraparticle disintegrants (e.g., croscarmellose sodium carboxymethyl cellulose); (e) External lubricants (e.g., magnesium stearate); (f) Extragranular fillers (e.g., microcrystalline cellulose PH 102); (g) Particulate flow aids (e.g., colloidal silica); (h) Extraparticle disintegrants (e.g., croscarmellose sodium); and (i) External lubricant (e.g., magnesium stearate).

[0322] In some embodiments, the compound of formula (I), the in-particle filler, the out-of-particle filler, the in-particle flow aid, the out-of-particle flow aid, the in-particle disintegrant, the out-of-particle disintegrant, the in-particle lubricant, and the out-of-particle lubricant are present in the w / w percentages described in any of the embodiments herein.

[0323] In some embodiments, a pharmaceutical composition is provided comprising: (a) Crystalline form A of compound of formula (I) (I); (b) Microcrystalline cellulose within the particles, pH 101; (c) Colloidal silica within particles; (d) Intragranular cross-linked sodium carboxymethyl cellulose; (e) Magnesium stearate outside the particles; (f) Microcrystalline cellulose outside the particles, pH 102; (g) Colloidal silica particles; (h) cross-linked sodium carboxymethyl cellulose particles; and (i) Magnesium stearate outside the particles.

[0324] In some embodiments, the compound of formula (I), the microcrystalline cellulose within the particle, the microcrystalline cellulose outside the particle, the silica within the particle, the silica outside the particle, the sodium cross-linked carboxymethyl cellulose within the particle, the sodium cross-linked carboxymethyl cellulose outside the particle, the magnesium stearate within the particle, and the magnesium stearate outside the particle are present in the w / w percentages described in any of the embodiments herein.

[0325] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 60% (w / w); (b) Approximately 20% (w / w) to approximately 50% (w / w) of an in-particle filler comprising microcrystalline cellulose PH 101; (c) About 0.5% (w / w) to about 1.5% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) About 0.5% (w / w) to about 2.5% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) about 0.25% (w / w) to about 0.75% (w / w) of an in-particle lubricant (e.g., magnesium stearate); (f) Approximately 5% (w / w) to approximately 20% (w / w) of ex-particle fillers (e.g., microcrystalline cellulose PH 102); (g) about 0.5% (w / w) to about 1.5% (w / w) of particulate flow aid (e.g., colloidal silica); (h) about 0.5% (w / w) to about 2.5% (w / w) of an external disintegrant (e.g., croscarmellose sodium); and (i) about 0.25% (w / w) to about 0.75% (w / w) of an external particulate lubricant (e.g., magnesium stearate); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0326] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 50% (w / w); (b) Approximately 30% (w / w) to approximately 50% (w / w) of an in-particle filler comprising microcrystalline cellulose PH 101; (c) About 0.5% (w / w) to about 1.5% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) About 0.5% (w / w) to about 2.5% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) about 0.25% (w / w) to about 0.75% (w / w) of an in-particle lubricant (e.g., magnesium stearate); (f) Approximately 5% (w / w) to approximately 20% (w / w) of ex-particle fillers (e.g., microcrystalline cellulose PH 102); (g) about 0.5% (w / w) to about 1.5% (w / w) of particulate flow aid (e.g., colloidal silica); (h) about 0.5% (w / w) to about 2.5% (w / w) of an external disintegrant (e.g., croscarmellose sodium); and (i) about 0.25% (w / w) to about 0.75% (w / w) of an external particulate lubricant (e.g., magnesium stearate); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0327] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 45% (w / w); (b) Approximately 35% (w / w) to approximately 50% (w / w) of an in-particle filler comprising microcrystalline cellulose PH 101; (c) About 0.5% (w / w) to about 1.5% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) About 0.5% (w / w) to about 2.5% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) about 0.25% (w / w) to about 0.75% (w / w) of an in-particle lubricant (e.g., magnesium stearate); (f) Approximately 5% (w / w) to approximately 20% (w / w) of ex-particle fillers (e.g., microcrystalline cellulose PH 102); (g) about 0.5% (w / w) to about 1.5% (w / w) of particulate flow aid (e.g., colloidal silica); (h) about 0.5% (w / w) to about 2.5% (w / w) of an external disintegrant (e.g., croscarmellose sodium); and (i) about 0.25% (w / w) to about 0.75% (w / w) of an external particulate lubricant (e.g., magnesium stearate); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0328] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in approximately 37% (w / w) to approximately 43% (w / w); (b) Approximately 38% (w / w) to approximately 46% (w / w) of an in-particle filler comprising microcrystalline cellulose PH 101; (c) Approximately 0.8% (w / w) to approximately 1.2% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) About 1.25% (w / w) to about 1.75% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) about 0.3% (w / w) to about 0.7% (w / w) of an in-particle lubricant (e.g., magnesium stearate); (f) Approximately 8% (w / w) to approximately 16% (w / w) of ex-particle fillers (e.g., microcrystalline cellulose PH 102); (g) about 0.8% (w / w) to about 1.2% (w / w) of particulate flow aid (e.g., colloidal silica); (h) about 1.25% (w / w) to about 1.75% (w / w) of an external disintegrant (e.g., croscarmellose sodium); and (i) about 0.3% (w / w) to about 0.7% (w / w) of an external particulate lubricant (e.g., magnesium stearate); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0329] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in approximately 38% (w / w) to approximately 42% (w / w); (b) Approximately 40% (w / w) to approximately 44% (w / w) of an in-particle filler comprising microcrystalline cellulose PH 101; (c) Approximately 0.9% (w / w) to approximately 1.1% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) About 1.4% (w / w) to about 1.6% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) about 0.4% (w / w) to about 0.6% (w / w) of an in-particle lubricant (e.g., magnesium stearate); (f) Approximately 10% (w / w) to approximately 14% (w / w) of ex-particle fillers (e.g., microcrystalline cellulose PH 102); (g) about 0.9% (w / w) to about 1.1% (w / w) of particulate flow aid (e.g., colloidal silica); (h) about 1.4% (w / w) to about 1.6% (w / w) of an external disintegrant (e.g., croscarmellose sodium); and (i) about 0.4% (w / w) to about 0.6% (w / w) of an external particulate lubricant (e.g., magnesium stearate); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0330] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in approximately 39% (w / w) to approximately 41% (w / w); (b) Approximately 41% (w / w) to approximately 43% (w / w) of an in-particle filler comprising microcrystalline cellulose PH 101; (c) Approximately 0.95% (w / w) to approximately 1.05% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) About 1.45% (w / w) to about 1.55% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) about 0.45% (w / w) to about 0.55% (w / w) of an in-particle lubricant (e.g., magnesium stearate); (f) Approximately 11% (w / w) to approximately 13% (w / w) of ex-particle filler (e.g., microcrystalline cellulose PH 102); (g) about 0.95% (w / w) to about 1.05% (w / w) of particulate flow aid (e.g., colloidal silica); (h) about 1.45% (w / w) to about 1.55% (w / w) of an external disintegrant (e.g., croscarmellose sodium); and (i) about 0.45% (w / w) to about 0.55% (w / w) of an external particulate lubricant (e.g., magnesium stearate); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0331] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of approximately 40% (w / w) of compound (I); (b) Approximately 42% (w / w) of in-particle filler containing microcrystalline cellulose PH 101; (c) Approximately 1.0% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) Approximately 1.5% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) Approximately 0.5% (w / w) of in-particle lubricant (e.g., magnesium stearate); (f) Approximately 12% (w / w) of ex-particle filler (e.g., microcrystalline cellulose PH 102); (g) Approximately 1.0% (w / w) of particulate flow aid (e.g., colloidal silica); (h) Approximately 1.5% (w / w) of an external disintegrant (e.g., croscarmellose sodium); and (i) Approximately 0.5% (w / w) of an external particulate lubricant (e.g., magnesium stearate).

[0332] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) at approximately 45% (w / w); (b) Approximately 37% (w / w) of in-particle filler containing microcrystalline cellulose PH 101; (c) Approximately 1.0% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) Approximately 1.5% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) Approximately 0.5% (w / w) of in-particle lubricant (e.g., magnesium stearate); (f) Approximately 12% (w / w) of ex-particle filler (e.g., microcrystalline cellulose PH 102); (g) Approximately 1.0% (w / w) of particulate flow aid (e.g., colloidal silica); (h) Approximately 1.5% (w / w) of an external disintegrant (e.g., croscarmellose sodium); and (i) Approximately 0.5% (w / w) of an external particulate lubricant (e.g., magnesium stearate).

[0333] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of approximately 50% (w / w) of compound (I); (b) Approximately 32% (w / w) of in-particle filler containing microcrystalline cellulose PH 101; (c) Approximately 1.0% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) Approximately 1.5% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) Approximately 0.5% (w / w) of in-particle lubricant (e.g., magnesium stearate); (f) Approximately 12% (w / w) of ex-particle filler (e.g., microcrystalline cellulose PH 102); (g) Approximately 1.0% (w / w) of particulate flow aid (e.g., colloidal silica); (h) Approximately 1.5% (w / w) of an external disintegrant (e.g., croscarmellose sodium); and (i) Approximately 0.5% (w / w) of an external particulate lubricant (e.g., magnesium stearate).

[0334] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) at approximately 55% (w / w); (b) Approximately 27% (w / w) of in-particle filler containing microcrystalline cellulose PH 101; (c) Approximately 1.0% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) Approximately 1.5% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) Approximately 0.5% (w / w) of in-particle lubricant (e.g., magnesium stearate); (f) Approximately 12% (w / w) of ex-particle filler (e.g., microcrystalline cellulose PH 102); (g) Approximately 1.0% (w / w) of particulate flow aid (e.g., colloidal silica); (h) Approximately 1.5% (w / w) of an external disintegrant (e.g., croscarmellose sodium); and (i) Approximately 0.5% (w / w) of an external particulate lubricant (e.g., magnesium stearate).

[0335] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of approximately 60% (w / w) of compound (I); (b) Approximately 22% (w / w) of in-particle filler containing microcrystalline cellulose PH 101; (c) Approximately 1.0% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) Approximately 1.5% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) Approximately 0.5% (w / w) of in-particle lubricant (e.g., magnesium stearate); (f) Approximately 12% (w / w) of ex-particle filler (e.g., microcrystalline cellulose PH 102); (g) Approximately 1.0% (w / w) of particulate flow aid (e.g., colloidal silica); (h) Approximately 1.5% (w / w) of an external disintegrant (e.g., croscarmellose sodium); and (i) Approximately 0.5% (w / w) of an external particulate lubricant (e.g., magnesium stearate).

[0336] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 50% (w / w); (b) Microcrystalline cellulose PH 101 with approximately 30% (w / w) to approximately 50% (w / w) of granular material; (c) In-particle colloidal silica of about 0.5% (w / w) to about 1.5% (w / w); (d) Intragranular crosslinked sodium carboxymethyl cellulose, approximately 0.5% (w / w) to approximately 2.5% (w / w); (e) Magnesium stearate in particles, from about 0.25% (w / w) to about 0.75% (w / w); (f) Approximately 5% (w / w) to approximately 20% (w / w) of exogranular microcrystalline cellulose pH 102; (g) Approximately 0.5% (w / w) to approximately 1.5% (w / w) of particulate colloidal silica; (h) approximately 0.5% (w / w) to approximately 2.5% (w / w) of externally cross-linked sodium carboxymethyl cellulose; and (i) Magnesium stearate in particulate form, from about 0.25% (w / w) to about 0.75% (w / w); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0337] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 45% (w / w); (b) Microcrystalline cellulose PH 101 with approximately 35% (w / w) to approximately 50% (w / w) of granular cellulose; (c) In-particle colloidal silica of about 0.5% (w / w) to about 1.5% (w / w); (d) Intragranular crosslinked sodium carboxymethyl cellulose, approximately 0.5% (w / w) to approximately 2.5% (w / w); (e) Magnesium stearate in particles, from about 0.25% (w / w) to about 0.75% (w / w); (f) Approximately 5% (w / w) to approximately 20% (w / w) of exogranular microcrystalline cellulose pH 102; (g) Approximately 0.5% (w / w) to approximately 1.5% (w / w) of particulate colloidal silica; (h) approximately 0.5% (w / w) to approximately 2.5% (w / w) of externally cross-linked sodium carboxymethyl cellulose; and (i) Magnesium stearate in particulate form, from about 0.25% (w / w) to about 0.75% (w / w); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0338] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in approximately 37% (w / w) to approximately 43% (w / w); (b) Microcrystalline cellulose within particles, pH 101, comprising approximately 38% (w / w) to approximately 46% (w / w); (c) In-particle colloidal silica of about 0.8% (w / w) to about 1.2% (w / w); (d) Intragranular crosslinked sodium carboxymethyl cellulose, approximately 1.25% (w / w) to approximately 1.75% (w / w); (e) Magnesium stearate in particles, approximately 0.3% (w / w) to approximately 0.7% (w / w); (f) Per-particle microcrystalline cellulose pH 102, approximately 8% (w / w) to approximately 16% (w / w); (g) about 0.8% (w / w) to about 1.2% (w / w) of particulate colloidal silica; (h) approximately 1.25% (w / w) to approximately 1.75% (w / w) of externally cross-linked sodium carboxymethyl cellulose; and (i) Magnesium stearate in particulate form, ranging from about 0.3% (w / w) to about 0.7% (w / w); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0339] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in approximately 38% (w / w) to approximately 42% (w / w); (b) Microcrystalline cellulose within particles of pH 101, comprising approximately 40% (w / w) to approximately 44% (w / w); (c) In-particle colloidal silica of about 0.9% (w / w) to about 1.1% (w / w); (d) Intragranular crosslinked sodium carboxymethyl cellulose, approximately 1.4% (w / w) to approximately 1.6% (w / w); (e) Magnesium stearate in particles, approximately 0.4% (w / w) to approximately 0.6% (w / w); (f) Approximately 10% (w / w) to approximately 14% (w / w) of exogranular microcrystalline cellulose pH 102; (g) about 0.9% (w / w) to about 1.1% (w / w) of particulate colloidal silica; (h) approximately 1.4% (w / w) to approximately 1.6% (w / w) of externally cross-linked sodium carboxymethyl cellulose; and (i) Magnesium stearate in particulate form, ranging from about 0.4% (w / w) to about 0.6% (w / w); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0340] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in approximately 39% (w / w) to approximately 41% (w / w); (b) Microcrystalline cellulose within particles, pH 101, comprising approximately 41% (w / w) to approximately 43% (w / w); (c) In-particle colloidal silica of about 0.95% (w / w) to about 1.05% (w / w); (d) Intragranular crosslinked sodium carboxymethyl cellulose, approximately 1.45% (w / w) to approximately 1.55% (w / w); (e) Magnesium stearate in particles, approximately 0.45% (w / w) to approximately 0.55% (w / w); (f) Per-particle microcrystalline cellulose pH 102, approximately 11% (w / w) to approximately 13% (w / w); (g) approximately 0.95% (w / w) to approximately 1.05% (w / w) of particulate colloidal silica; (h) approximately 1.45% (w / w) to approximately 1.55% (w / w) of externally cross-linked sodium carboxymethyl cellulose; and (i) Magnesium stearate in particulate form, ranging from about 0.45% (w / w) to about 0.55% (w / w); Thus, the total amount does not exceed 100% (w / w) of the composition.

[0341] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of approximately 40% (w / w) of compound (I); (b) Approximately 42% (w / w) of microcrystalline cellulose within the granules at pH 101; (c) Approximately 1.0% (w / w) of intraparticle colloidal silica; (d) Approximately 1.5% (w / w) of intraparticle cross-linked sodium carboxymethyl cellulose; (e) Approximately 0.5% (w / w) of magnesium stearate within the particles; (f) Approximately 12% (w / w) of exogranular microcrystalline cellulose at pH 102; (g) Approximately 1.0% (w / w) of particulate colloidal silica; (h) Approximately 1.5% (w / w) of externally cross-linked sodium carboxymethyl cellulose; and (i) Approximately 0.5% (w / w) of particulate magnesium stearate.

[0342] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) at approximately 45% (w / w); (b) Approximately 37% (w / w) of microcrystalline cellulose within the granules at pH 101; (c) Approximately 1.0% (w / w) of intraparticle colloidal silica; (d) Approximately 1.5% (w / w) of intraparticle cross-linked sodium carboxymethyl cellulose; (e) Approximately 0.5% (w / w) of magnesium stearate within the particles; (f) Approximately 12% (w / w) of exogranular microcrystalline cellulose at pH 102; (g) Approximately 1.0% (w / w) of particulate colloidal silica; (h) Approximately 1.5% (w / w) of externally cross-linked sodium carboxymethyl cellulose; and (i) Approximately 0.5% (w / w) of particulate magnesium stearate.

[0343] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of approximately 50% (w / w) of compound (I); (b) Approximately 32% (w / w) of microcrystalline cellulose within the granules at pH 101; (c) Approximately 1.0% (w / w) of intraparticle colloidal silica; (d) Approximately 1.5% (w / w) of intraparticle cross-linked sodium carboxymethyl cellulose; (e) Approximately 0.5% (w / w) of magnesium stearate within the particles; (f) Approximately 12% (w / w) of exogranular microcrystalline cellulose at pH 102; (g) Approximately 1.0% (w / w) of particulate colloidal silica; (h) Approximately 1.5% (w / w) of externally cross-linked sodium carboxymethyl cellulose; and (i) Approximately 0.5% (w / w) of particulate magnesium stearate.

[0344] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) at approximately 55% (w / w); (b) Approximately 27% (w / w) of microcrystalline cellulose within the granules at pH 101; (c) Approximately 1.0% (w / w) of intraparticle colloidal silica; (d) Approximately 1.5% (w / w) of intraparticle cross-linked sodium carboxymethyl cellulose; (e) Approximately 0.5% (w / w) of magnesium stearate within the particles; (f) Approximately 12% (w / w) of exogranular microcrystalline cellulose at pH 102; (g) Approximately 1.0% (w / w) of particulate colloidal silica; (h) Approximately 1.5% (w / w) of externally cross-linked sodium carboxymethyl cellulose; and (i) Approximately 0.5% (w / w) of particulate magnesium stearate.

[0345] In some embodiments, the pharmaceutical composition comprises: (a) Crystalline form A of approximately 60% (w / w) of compound (I); (b) Approximately 22% (w / w) of microcrystalline cellulose within the granules at pH 101; (c) Approximately 1.0% (w / w) of intraparticle colloidal silica; (d) Approximately 1.5% (w / w) of intraparticle cross-linked sodium carboxymethyl cellulose; (e) Approximately 0.5% (w / w) of magnesium stearate within the particles; (f) Approximately 12% (w / w) of exogranular microcrystalline cellulose at pH 102; (g) Approximately 1.0% (w / w) of particulate colloidal silica; (h) Approximately 1.5% (w / w) of externally cross-linked sodium carboxymethyl cellulose; and (i) Approximately 0.5% (w / w) of particulate magnesium stearate.

[0346] Dosage form

[0347] In some embodiments, a dosage form comprising the pharmaceutical composition described herein is provided.

[0348] In some embodiments, dosage forms comprising the pharmaceutical compositions described herein are provided for oral administration.

[0349] In some embodiments, the dosage form is selected from powder, sachets, strips, capsules, microtablets, and tablets.

[0350] In some implementations, the dosage form is a tablet.

[0351] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 200 mg to 1000 mg.

[0352] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is about 200 mg to 750 mg.

[0353] In some embodiments, the total weight of the pharmaceutical composition in the dosage form is approximately 225 mg to 650 mg.

[0354] 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.

[0355] 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.

[0356] In some embodiments, the dosage form comprises about 50 mg to about 350 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises about 100 mg to about 300 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises about 100 mg to about 250 mg of crystalline form A of compound (I).

[0357] In some embodiments, the dosage form comprises crystalline form A of a compound of formula (I) in the form of 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.

[0358] In some embodiments, the dosage form comprises crystalline form A of a compound of formula (I) in the amounts of 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.

[0359] In some embodiments, the dosage form comprises crystalline form A of a compound of formula (I) in the form of about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg.

[0360] In some embodiments, 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 compound (I). In some embodiments, the dosage form comprises about 150 mg, about 200 mg, or about 250 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises about 150 mg or about 250 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises about 200 mg or about 250 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises about 100 mg, about 200 mg, or about 300 mg of crystalline form A of compound (I).

[0361] In some embodiments, the dosage form comprises about 100 mg or about 200 mg of the crystalline form A of the compound of formula (I).

[0362] In some embodiments, the dosage form comprises about 50 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises 75 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises 100 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises 125 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises 150 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises 175 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises 200 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises 225 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises 250 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises 275 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises 300 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises 325 mg of crystalline form A of compound (I). In some embodiments, the dosage form comprises 350 mg of crystalline form A of compound (I).

[0363] In some embodiments, the dosage form comprises 100 mg of compound (I), 105 mg of intragranular microcrystalline cellulose PH 101, and 2.5 mg of intragranular colloidal silica (e.g., Aerosil). ® 200, CAB-O-SIL ® M-5P), 3.7 mg intragranular cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) ® ), 1.3 mg intragranular magnesium stearate, 29.9 mg extragranular microcrystalline cellulose pH 102, 2.5 mg extragranular colloidal silica (e.g., Aerosil) ® 200, CAB-O-SIL ® M-5P), 3.7 mg externally cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) ® ) and 2.5 mg of magnesium stearate outside the particles.

[0364] In some embodiments, the dosage form comprises 100 mg of compound (I), 105 mg of intragranular microcrystalline cellulose PH 101, and 2.5 mg of intragranular colloidal silica (e.g., Aerosil). ® 200, CAB-O-SIL ®M-5P), 3.75 mg intragranular cross-linked carboxymethyl cellulose sodium (Ac-Di-Sol) ® ), 1.25 mg intragranular magnesium stearate, 30 mg extragranular microcrystalline cellulose pH 102, 2.5 mg extragranular colloidal silica (e.g., Aerosil) ® 200, CAB-O-SIL ® M-5P), 3.75 mg of externally cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) ® ) and 1.25 mg of magnesium stearate outside the particles.

[0365] In some embodiments, the dosage form comprises 125 mg of compound (I), 131 mg of intragranular microcrystalline cellulose PH 101, and 3.2 mg of intragranular colloidal silica (e.g., Aerosil). ® 200, CAB-O-SIL ® M-5P), 4.7 mg intragranular cross-linked carboxymethyl cellulose sodium (Ac-Di-Sol) ® ), 1.6 mg intragranular magnesium stearate, 37.4 mg extragranular microcrystalline cellulose pH 102, 3.2 mg extragranular colloidal silica (e.g., Aerosil) ® 200, CAB-O-SIL ® M-5P), 4.7 mg externally cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) ® ) and 3.2 mg of magnesium stearate outside the particles.

[0366] In some embodiments, the dosage form comprises 125 mg of compound (I), 131.25 mg of intragranular microcrystalline cellulose PH 101, and 3.13 mg of intragranular colloidal silica (e.g., Aerosil). ® 200, CAB-O-SIL ® M-5P), 4.69 mg intragranular cross-linked carboxymethyl cellulose sodium (Ac-Di-Sol) ® ), 1.56 mg intragranular magnesium stearate, 37.50 mg extragranular microcrystalline cellulose pH 102, 3.13 mg extragranular colloidal silica (e.g., Aerosil) ® 200, CAB-O-SIL ® M-5P), 4.69 mg of externally cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) ® ) and 1.56 mg of magnesium stearate outside the particles.

[0367] In some embodiments, the dosage form comprises 150 mg of compound (I), 157.5 mg of intragranular microcrystalline cellulose PH 101, and 3.8 mg of intragranular colloidal silica (e.g., Aerosil). ® 200, CAB-O-SIL ® M-5P), 5.6 mg intragranular cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) ® ), 1.9 mg intragranular magnesium stearate, 44.9 mg extragranular microcrystalline cellulose pH 102, 3.8 mg extragranular colloidal silica (e.g., Aerosil) ® 200, CAB-O-SIL ® M-5P), 5.6mg of externally cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) ® ) and 3.8 mg of magnesium stearate outside the particles.

[0368] In some embodiments, the dosage form comprises 150 mg of compound (I), 157 mg of intragranular microcrystalline cellulose PH 101, and 3.75 mg of intragranular colloidal silica (e.g., Aerosil). ® 200, CAB-O-SIL ® M-5P), 5.63 mg intragranular cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) ® ), 1.88 mg intragranular magnesium stearate, 45 mg extragranular microcrystalline cellulose pH 102, 3.75 mg extragranular colloidal silica (e.g., Aerosil) ® 200, CAB-O-SIL ® M-5P), 5.63 mg of externally cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) ® ) and 1.88 mg of magnesium stearate outside the particles.

[0369] In some embodiments, the dosage form comprises 200 mg of compound (I), 210 mg of intragranular microcrystalline cellulose PH 101, and 5.1 mg of intragranular colloidal silica (e.g., Aerosil). ® 200, CAB-O-SIL ® M-5P), 7.5 mg intragranular cross-linked carboxymethyl cellulose sodium (Ac-Di-Sol) ® ), 2.5 mg intragranular magnesium stearate, 59.9 mg extragranular microcrystalline cellulose pH 102, 5.1 mg extragranular colloidal silica (e.g., Aerosil) ® 200, CAB-O-SIL ®M-5P), 7.5 mg externally cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) ® ) and 5.1 mg of magnesium stearate outside the particles.

[0370] In some embodiments, the dosage form comprises 200 mg of compound (I), 210 mg of intragranular microcrystalline cellulose PH 101, and 5.0 mg of intragranular colloidal silica (e.g., Aerosil). ® 200, CAB-O-SIL ® M-5P), 7.5 mg intragranular cross-linked carboxymethyl cellulose sodium (Ac-Di-Sol) ® ), 2.5 mg intragranular magnesium stearate, 60 mg extragranular microcrystalline cellulose pH 102, 5.0 mg extragranular colloidal silica (e.g., Aerosil) ® 200, CAB-O-SIL ® M-5P), 7.5 mg externally cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) ® ) and 2.5 mg of magnesium stearate outside the particles.

[0371] In some embodiments, the dosage form comprises 250 mg of compound (I), 262.5 mg of intragranular microcrystalline cellulose PH 101, and 6.3 mg of intragranular colloidal silica (e.g., Aerosil). ® 200, CAB-O-SIL ® M-5P), 9.3 mg intragranular cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) ® ), 3.2 mg intragranular magnesium stearate, 74.8 mg extragranular microcrystalline cellulose pH 102, 6.3 mg extragranular colloidal silica (e.g., Aerosil) ® 200, CAB-O-SIL ® M-5P), 9.3mg of externally cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) ® ) and 6.3 mg of magnesium stearate outside the particles.

[0372] In some embodiments, the dosage form comprises 250 mg of compound (I), 262.5 mg of intragranular microcrystalline cellulose PH 101, and 6.25 mg of intragranular colloidal silica (e.g., Aerosil). ® 200, CAB-O-SIL ® M-5P), 9.38 mg intragranular cross-linked carboxymethyl cellulose sodium (Ac-Di-Sol) ®), 3.13 mg intragranular magnesium stearate, 75 mg extragranular microcrystalline cellulose pH 102, 6.25 mg extragranular colloidal silica (e.g., Aerosil) ® 200, CAB-O-SIL ® M-5P), 9.38 mg of externally cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol) ® ) and 3.13 mg of magnesium stearate outside the particles.

[0373] In some implementations, the dosage form is a tablet.

[0374] In some embodiments, the tablet further comprises a coating. In some embodiments, the coating is selected from film-forming polymers, plasticizers, and combinations thereof. In some embodiments, the film-forming polymer is selected from hydroxypropyl methylcellulose, ethylcellulose, cellulose acetate, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylate, and combinations thereof. In some embodiments, the plasticizer is selected from triacetin, polyethylene glycol, propylene glycol, and combinations thereof. In some embodiments, the coating comprises polyvinyl alcohol.

[0375] In some embodiments, the coating comprises a colorant selected from titanium dioxide, aluminum lake, iron oxide, carbon black, and combinations thereof. In some embodiments, the colorant is titanium dioxide.

[0376] Preparation method

[0377] In some embodiments, methods for preparing the pharmaceutical compositions described herein are provided.

[0378] In some embodiments, a method is provided for preparing a pharmaceutical composition comprising crystalline form A of a compound of formula (I) as described in any of the embodiments herein, comprising: (a) Add and mix the crystalline form A of compound (I), the in-particle filler, the in-particle flow aid and the in-particle disintegrant, and mix to obtain a pre-lubricated in-particle mixture; (b) Adding a lubricant to the pre-lubricated intragranular mixture and mixing to obtain a lubricated intragranular mixture; (c) Granulating the mixture within the particles to obtain particles; (d) Grinding the particles to obtain ground particles; (e) Add the ground particles, external filler, external disintegrant and external flow aid, and mix to obtain a pre-lubricated external mixture; (f) Adding a lubricant to the pre-lubricated extragranular mixture and mixing to obtain the pharmaceutical composition; On the other hand, a method is provided for preparing a dosage form of the crystalline form A of the compound of formula (I) as described in any embodiment herein, comprising, for example: (a) Add and mix the crystalline form A of compound (I), the in-particle filler, the in-particle flow aid and the in-particle disintegrant, and mix to obtain a pre-lubricated in-particle mixture; (b) Adding a lubricant to the pre-lubricated intragranular mixture and mixing to obtain a lubricated intragranular mixture; (c) Granulating the mixture within the particles to obtain particles; (d) Grinding the particles to obtain ground particles; (e) Add the ground particles, external filler, external disintegrant and external flow aid, and mix to obtain a pre-lubricated external mixture; (f) Adding a lubricant to the pre-lubricated extragranular mixture and mixing to obtain the pharmaceutical composition; (g) Compressing the pharmaceutical composition into a dosage form; and, optionally... (h) Coating the dosage form.

[0379] The pharmaceutical compositions and dosage forms described herein are suitable for manufacture using simplified manufacturing processes. An illustrative process flow for preparing the dosage forms described herein is as follows: Figure 14 As shown.

[0380] The order in which components are added during the mixing step affects the homogeneity of the API in the mixture and the distribution of low-content components within the mixture. Uniform distribution of low-content components within the intragranular mixture is crucial for successful dry granulation of the intragranular mixture. For example, uneven distribution of the glidant within the granules can lead to suboptimal granulation, resulting in a wide particle size distribution, which negatively impacts extragranular mixing and ultimately affects the compressibility of the final mixture. In some embodiments, the order of addition is shown in Table 5.

[0381] Table 5. Order of Addition of Ingredients

[0382] MCC – Microcrystalline Cellulose

[0383] CCS – Crosslinked Sodium Carboxymethyl Cellulose

[0384] API – Formula (I) Compound

[0385] In some embodiments, a method for preparing the pharmaceutical composition described herein is provided, for example, comprising: (a) The following shall be added in sequence: i. 50% of the total required amount of in-particle filler; ii. The required total amount of the crystalline form A of the compound of formula (I) as described herein; iii. The required total amount of intraparticle disintegrant; iv. The required total amount of in-particle flow aid; and v. 50% of the total required amount of in-particle filler; (b) The components added in step (a) are premixed and sieved to obtain a premixed intragranular mixture; (c) Mix the premixed intraparticle mixture to obtain a pre-lubricated intraparticle mixture; (d) The following shall be added in sequence: i. 50% of the pre-lubricated intragranular mixture; ii. The required amount of 100% intragranular lubricant is added by sieving; iii. 50% of the pre-lubricated intraparticle mixture; to obtain a lubricated intraparticle mixture; (e) Mix the lubricated intraparticle mixture to obtain an intraparticle mixture; (f) Granulating the intragranular mixture to obtain granules; (g) Grinding the particles to obtain ground particles; (h) The following shall be added in sequence: i. 50% of the required amount of particulate filler; ii. The ground particles obtained in step (g); iii. The required amount of external disintegrant; iv. The required amount of particulate effusion aid; v. 50% of the required amount of particulate filler; (i) The components added in step (h) are premixed and sieved to obtain a premixed non-particle mixture; (j) Mix the premixed off-particle mixture to obtain a pre-lubricated off-particle mixture; (k) The following shall be added in sequence: i. 50% of the pre-lubricated extra-particle mixture; ii. The required amount of particulate external lubricant is added by sieving; iii. 50% of the pre-lubricated extra-particle mixture; to obtain a lubricated extra-particle mixture; (l) Mixing the lubricated intragranular mixture to obtain the pharmaceutical composition.

[0386] On the other hand, methods for preparing the dosage forms described herein are provided, for example, including: (a) The following shall be added in sequence: i. 50% of the total required amount of in-particle filler; ii. The required total amount of the crystalline form A of the compound of formula (I) as described herein; iii. The required total amount of intraparticle disintegrant; iv. The required total amount of in-particle flow aid; and v. 50% of the total required amount of in-particle filler; (b) The components added in step (a) are premixed and sieved to obtain a premixed intragranular mixture; (c) Mix the premixed intraparticle mixture to obtain a pre-lubricated intraparticle mixture; (d) The following shall be added in sequence: i. 50% of the pre-lubricated intragranular mixture; ii. The required amount of 100% intragranular lubricant is added by sieving; iii. 50% of the pre-lubricated intraparticle mixture; to obtain a lubricated intraparticle mixture; (e) Mix the lubricated intraparticle mixture to obtain an intraparticle mixture; (f) Granulating the intragranular mixture to obtain granules; (g) Grinding the particles to obtain ground particles; (h) The following shall be added in sequence: i. 50% of the required amount of particulate filler; ii. The ground particles obtained in step (g); iii. The required amount of external disintegrant; iv. The required amount of particulate effusion aid; v. 50% of the required amount of particulate filler; (i) The components added in step (h) are premixed and sieved to obtain a premixed non-particle mixture; (j) Mix the premixed off-particle mixture to obtain a pre-lubricated off-particle mixture; (k) The following shall be added in sequence: i. 50% of the pre-lubricated extra-particle mixture; ii. The required amount of particulate external lubricant is added by sieving; iii. 50% of the pre-lubricated extra-particle mixture; to obtain a lubricated extra-particle mixture; (l) Mixing the lubricated intragranular mixture to obtain the pharmaceutical composition.

[0387] (m) compressing the pharmaceutical composition into a dosage form; and, optionally...

[0388] (n) Coating the dosage form.

[0389] The choice of sieve size during the grinding step affects the particle size distribution of the resulting particles. In some embodiments, a 3.15 mm sieve size is used in the grinding step, followed by a 1 mm sieve size, to produce a distribution of ground particles with an acceptable particle size distribution (including a low level of fine powder), suitable for processing during tablet compression, which is often difficult to achieve for crystalline drug formulations with high drug loading.

[0390] In some implementations, the in-particle filler consists primarily of microcrystalline cellulose PH 101.

[0391] In some implementations, the in-particle disintegrant is essentially composed of croscarmellose sodium.

[0392] In some implementations, the flow aid within the particles is essentially composed of colloidal silica.

[0393] In some implementations, the in-particle lubricant consists primarily of magnesium stearate.

[0394] In some implementations, the exfoliant consists primarily of microcrystalline cellulose PH 102.

[0395] In some implementations, the exodisintegrant is essentially composed of croscarmellose sodium.

[0396] In some implementations, the particulate flow aid is essentially composed of colloidal silica.

[0397] In some implementations, the particulate external lubricant is essentially composed of magnesium stearate.

[0398] In some embodiments, the desired amounts of the crystalline form A of the compound of formula (I), the in-particle filler, the in-particle disintegrant, the in-particle flow aid, the in-particle lubricant, the out-of-particle filler, the out-of-particle disintegrant, the out-of-particle flow aid, and the out-of-particle lubricant are selected to obtain a pharmaceutical composition having the components described in the "Pharmaceutical Composition" section in w / w percentage.

[0399] In some embodiments, granulating the intragranular mixture to obtain particles includes a dry granulation process step. In some embodiments, granulating the intragranular mixture to obtain particles includes a wet granulation process step.

[0400] In some embodiments, the tablet comprises a coating. In some embodiments, the coating comprises one or more film-forming polymers selected from hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, polyacrylate, plasticizers, and combinations thereof. In some embodiments, the coating comprises polyvinyl alcohol.

[0401] In some embodiments, the coating comprises a colorant selected from titanium dioxide, aluminum lake, iron oxide, carbon black, and combinations thereof. In some embodiments, the colorant is titanium dioxide.

[0402] In some embodiments, the pharmaceutical compositions or dosage forms described herein are provided and prepared by the methods described herein.

[0403] Use and treatment methods

[0404] Treatment of MTAP deficiency and / or MTA cumulative proliferative disorders

[0405] 5-Methionine phosphorylase (MTAP) catalyzes the reversible phosphorylation of S-methyl-5'-thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. MTAP deficiency is a common genetic event in human cancers. The frequency of MTAP deficiency in some human cancers is described in Cerami et al., Cancer Discov. (2012); 2(5):401-4; Gao et al., Sci Signal. (2013); 6(269):p11; and Lee et al., Nat. Gen. (2014) 46(11):1227-32. For example, more than 50% of malignant peripheral nerve sheath tumors (MPNSTs) have MTAP deficiency (Lee et al., Nat. Gen. (2014)). Other cancers with high MTAP deficiency frequencies include glioblastoma (GBM), mesothelioma, bladder cancer, pancreatic cancer, esophageal cancer, squamous cell lung cancer, melanoma, diffuse large B-cell lymphoma (DLBCL), head and neck cancer, cholangiocarcinoma, lung adenoma, sarcoma, gastric cancer, glioma, adrenal cancer, thymoma, breast cancer, liver cancer, ovarian cancer, papillary renal carcinoma, uterine cancer, prostate cancer, and clear cell renal carcinoma. MTAP deficiency in cells is one of the mechanisms leading to MTAP deficiency, increased intracellular MTA accumulation, and conferring enhanced dependence of cancer cells on protein arginine methyltransferase 5 (PRMT5). Other mechanisms leading to MTAP deficiency include, among others, MTAP translocation and MTAP epigenetic silencing, which may also result in MTAP-deficient and / or MTAP-deficient tumors. PRMT5 mediates the formation of symmetric dimethylarginine (SDMA); therefore, PRMT5 activity can be assessed by measuring SDMA levels using antibodies against SDMA or SDMA-modified peptides.

[0406] In some embodiments, methods are provided for treating human or animal subjects who have or have been diagnosed with MTAP deficiency-related and / or MTA cumulative proliferative disorders (e.g., cancer), including administering to the subject in need a therapeutically effective amount of the disclosed compound (e.g., a crystalline form of compound (I), crystalline form A of compound (I), a pharmaceutical composition comprising compound (I) as described herein, or a dosage form as described herein. In some cases, MTAP deficiency is MTAP absence.

[0407] In some embodiments, the disclosed compound (e.g., crystalline form of compound (I), crystalline form A of compound (I)) or a pharmaceutical composition comprising compound (I) is provided in a method of treating a human or animal subject suffering from or diagnosed with MTAP deficiency-related and / or MTA cumulative proliferative disorders (e.g., cancer). In some embodiments, the compound or composition is provided in a therapeutically effective amount.

[0408] In some embodiments, the disclosed compounds (e.g., crystalline forms of compounds of formula (I), crystalline form A of compounds of formula (I)) or pharmaceutical compositions comprising compounds of formula (I) are provided for the preparation of a medicament for treating human or animal subjects who have or have been diagnosed with MTAP deficiency-related and / or MTA cumulative proliferative disorders (e.g., cancer). In some embodiments, the compounds or compositions are provided in a therapeutically effective amount.

[0409] In some embodiments, use is provided in methods of treating human or animal subjects who have or have been diagnosed with MTAP deficiency-related and / or MTA cumulative proliferative disorders (e.g., cancer). In some embodiments, said use is the use of a therapeutically effective amount of the compound or composition.

[0410] In some embodiments, use is provided in the preparation of a medicament for treating human or animal subjects suffering from or diagnosed with MTAP deficiency-related and / or MTA cumulative proliferative disorders (e.g., cancer). In some embodiments, said use is the use of a therapeutically effective amount of the compound or composition.

[0411] In some embodiments, methods are provided for treating subjects with MTAP deficiency-related and / or MTA cumulative proliferative disorders (e.g., cancer) in need of treatment, 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 compound (I), crystalline form A of compound (I), a pharmaceutical composition comprising a compound of formula (I) as described herein, or a dosage form as described herein.

[0412] In some embodiments, a method is provided for treating human or animal subjects who have or have been diagnosed with MTAP deficiency-related and / or MTA cumulative proliferative disorders (e.g., cancer), comprising administering a therapeutically effective amount of the disclosed pharmaceutical composition to the subject in need. In some embodiments, the method comprises administering a dosage form of the disclosed composition to the subject. In one embodiment, the compound or composition is administered in combination with a second therapeutic agent.

[0413] In some embodiments, a method is provided for treating MTAP deficiency-related and / or MTA cumulative proliferative disorders (e.g., cancer) in subjects with this need, comprising administering a therapeutically effective amount of the disclosed pharmaceutical composition to the subject. In some embodiments, the method comprises administering a dosage form of the disclosed composition to the subject. In one embodiment, the compound or composition is administered in combination with a second therapeutic agent.

[0414] In some implementations, the subjects are humans.

[0415] In some embodiments, the disease is MTAP deficiency and / or MTA-cumulative cancer. In some embodiments, the cancer is MTAP-deficient cancer.

[0416] In some implementations, 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., lung squamous cell carcinoma or lung adenocarcinoma), undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleural cancer, colorectal cancer, or sarcoma.

[0417] In some implementations, 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 cell carcinoma or lung adenocarcinoma), undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleural cancer, colorectal cancer, or sarcoma.

[0418] In some implementations, the cancer is 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 cell carcinoma or lung adenocarcinoma), undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleural cancer, colorectal cancer, or sarcoma.

[0419] In some embodiments of any of the methods, uses, compounds for use, or compositions for use described herein, the cancer is selected from the group consisting of malignant peripheral nerve sheath tumor (MPNST), pancreatic cancer, NSCLC, mesothelioma, and sarcoma.

[0420] In some embodiments of any of the methods, uses, compounds for use, or compositions for use described herein, the cancer is selected from pancreatic cancer, NSCLC, mesothelioma, and sarcoma.

[0421] In some embodiments of any of the methods, uses, compounds used for use, or compositions used 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 histologically unknown (i.e., any MTAP-deficient and / or MTA-cumulative cancer), regardless of histology. In some embodiments, the cancer described herein is MTAP-deficient cancer.

[0422] In some embodiments, the cancer is selected from cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous cell carcinoma), bladder cancer, and DLBCL. In some embodiments, the cancer is selected from non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), 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 cell carcinoma). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL. In some embodiments, the cancer is MPNST.

[0423] In some implementations, the cancer is selected from non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, and urothelial carcinoma.

[0424] In some embodiments, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)) and a dosage form thereof may be used to inhibit the proliferation of MTAP-deficient cells in a subject in need of such treatment. The method includes administering to the subject an amount of a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)) or a dosage form thereof that effectively inhibits the proliferation of MTAP-deficient cells. In one implementation, the subject in need of this treatment has 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 cell carcinoma or lung adenocarcinoma), undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleural cancer, colorectal cancer, or sarcoma.

[0425] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous cell carcinoma), bladder cancer, and DLBCL. In some embodiments, the cancer is selected from the group consisting of non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), 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 cell carcinoma). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0426] In some implementations, the cancer is selected from the group consisting of non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, and urothelial carcinoma.

[0427] In some embodiments, a method for inhibiting the proliferation of MTA-accumulating cells in a subject who requires such inhibition may be used with a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form thereof. The method includes administering to the subject an amount of a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form thereof that effectively inhibits the proliferation of MTA-accumulating cells. In one implementation, the subject in need of this treatment has 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 cell carcinoma or lung adenocarcinoma), undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleural cancer, colorectal cancer, or sarcoma.

[0428] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous cell carcinoma), bladder cancer, and DLBCL. In some embodiments, the cancer is selected from the group consisting of non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), 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 cell carcinoma). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0429] In some implementations, the cancer is selected from the group consisting of non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, and urothelial carcinoma.

[0430] In some embodiments, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)) or a dosage form thereof may be used to inhibit the proliferation of MTAP-deficient and / or MTA-accumulating cells in a subject in need of such treatment. The method includes administering to the subject an amount of a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)) or a dosage form thereof that effectively inhibits the proliferation of MTAP-deficient and / or MTA-accumulating cells. In one implementation, the subject in need of this treatment has 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 cell carcinoma or lung adenocarcinoma), undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleural cancer, colorectal cancer, or sarcoma.

[0431] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous cell carcinoma), bladder cancer, and DLBCL. In some embodiments, the cancer is selected from the group consisting of non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), 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 cell carcinoma). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0432] In some implementations, the cancer is selected from the group consisting of non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, and urothelial carcinoma.

[0433] combination therapy

[0434] In some embodiments, methods are provided for treating MTAP deficiency and / or MTA cumulative proliferative disorders (e.g., cancer) in combination with one or more therapeutic agents using a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form thereof.

[0435] In some embodiments, methods are provided for treating MTAP deficiency and / or MTA cumulative proliferative disorders (e.g., cancer) in combination with a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing compound (I)), or a dosage form thereof, in combination with a second therapeutic agent. In some embodiments, methods are provided for treating MTAP deficiency and / or MTA cumulative proliferative disorders (e.g., cancer) in combination with a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing compound (I)), or a dosage form thereof, in combination with a second therapeutic agent and a third therapeutic agent. In some embodiments, methods are provided for treating MTAP deficiency and / or MTA cumulative proliferative disorders (e.g., cancer) in combination with a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing compound (I)), or a dosage form thereof, in combination with a second therapeutic agent, a third therapeutic agent, and a fourth therapeutic agent.

[0436] The term “combination” refers to a fixed combination in the same dosage unit form, or administered in combination, wherein a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)) or a dosage form thereof, and a combination partner (e.g., another drug as explained below, also referred to as a “therapeutic agent” or “co-agent”) can be administered independently, simultaneously or separately at time intervals, particularly when these time intervals allow the combination partner to exhibit a synergistic effect, such as a cooperative effect. The components may be packaged in a kit or individually. One or two components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose prior to administration. As used herein, the terms “co-administered” or “combined administration” are intended to cover administration of selected combination partners to a single subject (e.g., a patient) with this need, and are intended to include treatment regimens in which the agents are not necessarily administered via the same route of administration or simultaneously. As used herein, the term “drug combination” refers to a product resulting from mixing or combining more than one therapeutic agent, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" refers to a therapeutic agent, such as a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form thereof and its combination partners, administered simultaneously to a patient as a single entity or dosage form. The term "non-fixed combination" refers to a therapeutic agent, such as a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form thereof and its combination partners, administered simultaneously, in parallel, or sequentially to a patient as a single entity without a specific time limit, wherein such administration provides therapeutically effective levels of two compounds in the patient's body. The latter also applies to cocktail therapy, such as the administration of three or more therapeutic agents.

[0437] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat the therapeutic condition or disorder described in this disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed proportion of active ingredients. Alternatively, such administration encompasses the co-administration of each active ingredient in multiple or separate containers (e.g., tablets, capsules, powders, and liquids). Powders and / or liquids may be reconstituted or diluted to the desired dose prior to administration. Furthermore, such administration also encompasses the sequential use of each type of therapeutic agent, approximately simultaneously or at different times.

[0438] In some embodiments, compounds of formula (I) as described herein, crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., containing compounds of formula (I)) or dosage forms thereof are combined with other therapeutic agents, including but not limited to other anticancer agents, anti-allergic agents, anti-nausea agents (or antiemetics), analgesics, cytoprotective agents, and combinations thereof.

[0439] In some embodiments, a method of treating a disease or disorder (e.g., cancer) is provided, comprising administering, in any order or in combination, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form thereof, and a common chemotherapeutic agent selected from anastrozole (Arimidex) to a patient in need. ® ), Bicalutamide (Casodex) ® ), Blenoxane sulfate ® Myleran ® Busulfex injection ® ), capecitabine (Xeloda) ® N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin ® ), carmustine (BiCNU) ® ), chlorambucil (Leukeran) ® ), cisplatin ® Leustatin ® ), Cytoxamide ® Or Neosar ® ), cytarabine, cytosine arabinoside (Cytosar-U) ® ), Cytarabine liposome injection (DepoCyt) ® ), Dacarbazine (DTIC-Dome) ®), Actinomycin D (Cosmegan), Cerubidine hydrochloride ® ), DaunoXome citrate liposome injection ® ), dexamethasone, docetaxel (Taxotere ® Doxorubicin hydrochloride (Adriamycin) ® Rubex ® ), etoposide (Vepesid) ® Fludara phosphate ® 5-Fluorouracil (Adrucil) ® Efudex ® ), flutamide (Eulexin) ® ), tezatitabine, gemcitabine (difluorodeoxycytidine), hydroxyurea (Hydrea) ® Idamycin ® ), ifosfamide (IFEX) ® ), Irinotecan (Camptosar) ® L-Asparaginase (ELSPAR) ® ), calcium leucovorin, and melphalan (Alkeran) ® ), 6-mercaptopurine (Purinethol) ® ), methotrexate (Folex) ® Novantrone ® ), mylotarg, paclitaxel (Taxol) ® ), nab-paclitaxel (Abraxane) ® Phoenix (Yttrium 90 / MX-DTPA), Pentostatin, and Polifeprosan 20 with carmustine implants (Gliadel) ® ), Tamoxifen Citrate (Nolvadex) ® ), teniposide (Vumon) ® ), 6-thioguanine, thiotepa, tirazone ® Hycamptin hydrochloride for injection ® ), Vinpocetine (Velban ® Oncovin ® ) and Changchun Ruibin (Navelbine) ® ).

[0440] In some embodiments, a method for treating a disease or disorder (e.g., cancer) is provided, the method comprising administering, in any order, or co-administering to a patient in need a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing compound (I)), or a dosage form thereof, and an EGFR inhibitor (e.g., cetuximab, panitumumab, erlotinib, gefitinib, osimertinib, and EGFRi NOS). In some embodiments, a method for treating a disease or disorder (e.g., cancer) is provided, the method comprising administering, in any order, or co-administering to a patient in need a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing compound (I)), or a dosage form thereof, and an MAPK pathway inhibitor (e.g., BRAFi, panRAFi, MEKi, ERKi; PI3K-mTOR pathway inhibitors, such as α-specific PI3Ki, pan-I PI3Ki, and mTOR / PI3Ki, particularly everolimus and its analogues).

[0441] MTAP deficiency can occur concurrently with KRAS gene mutations (e.g., KRASG12C). In some embodiments, a method of treating a disease or disorder (e.g., cancer) is provided, the method comprising administering, in any order, to a patient in need, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., a compound containing formula (I)), or a dosage form thereof, and a KRAS inhibitor (e.g., pan-KRAS or specific G12C, G12D, G13C inhibitors, such as adagraxibu, sotoprazib, LY3537982, RMC-6236, RMC-6291, RMC-9805, RMC-8839).

[0442] In some embodiments, a method for treating a disease or disorder (e.g., cancer) is provided, the method comprising administering, in any order, to a patient in need, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)) or a dosage form thereof, and a spliceosome inhibitor (e.g., an SF3b1 inhibitor; e.g., E7107).

[0443] In some embodiments, a method of treating a disease or disorder (e.g., cancer) is provided, the method comprising administering, in any order, to a patient in need, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form thereof, and an HDAC inhibitor or a DNA methyltransferase inhibitor. In some embodiments, the HDAC inhibitor is trichostatin A. In some embodiments, the DNA methyltransferase inhibitor is 5-azacytidine.

[0444] In some embodiments, a method for treating a disease or disorder (e.g., cancer) is provided, the method comprising administering, in any order, to a patient in need, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)) or a dosage form thereof, and a MAT2A inhibitor (e.g., AG-270, IDE397, S95035).

[0445] In some embodiments, a method for treating a disease or disorder (e.g., cancer) is provided, the method comprising administering, in any order to a patient in need, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)) or a dosage form thereof, and an inhibitor of a protein that interacts with or is required for PRMT5 function, including but not limited to pICIN, WDR77, or RIOK1.

[0446] In some embodiments, a method for treating a disease or disorder (e.g., cancer) is provided, the method comprising administering, in any order, to a patient in need, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)) or a dosage form thereof, and an HDM2 inhibitor and / or 5-FU or other purine analogues (e.g., 6-thioguanine, 6-mercaptopurine).

[0447] In some embodiments, a method for treating a disease or disorder (e.g., cancer) is provided, the method comprising administering, in any order, to a patient in need, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)) or a dosage form thereof, and a CDK4 inhibitor, including but not limited to LEE011 or CDK 4 / 6 inhibitors (e.g., palbociclib (Ibrance)). ® Kisqali ® ) and Verzenio ® ).

[0448] In some embodiments, a method for treating a disease or disorder (e.g., cancer) is provided, the method comprising administering, in any order, to a patient in need, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)) or a dosage form thereof, and targeted therapy dependent on the individual target tumor’s dependence on relevant pathways (determined by appropriate predictive biomarkers), including but not limited to: HDM2i, PI3K / mTOR-I, MAPKi, RTKi (EGFRi, FGFRi, METi, IGFiRi, JAKi, and WNTi) inhibitors.

[0449] In some embodiments, a method for treating a disease or disorder (e.g., cancer) is provided, the method comprising administering, in any order, to a patient in need, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I) or a dosage form thereof), and immunotherapy.

[0450] In some implementations, a method for treating a disease or disorder (e.g., cancer) is provided, the method comprising administering or co-administering cancer immunotherapy (e.g., checkpoint blocking antibody) to a patient in need in any order to treat a subject (e.g., a human subject), such as a subject suffering from the disease or disorder described herein (e.g., the cancer described herein).

[0451] In some implementations, the immunotherapy agent is an anti-CTLA-4 antibody (e.g., ipilimumab, trimemumab).

[0452] In some implementations, the immunotherapy agent is an anti-PD-1 antibody (e.g., anti-PD-1 or anti-PD-L1). In some implementations, the immunotherapy agent is an anti-PD-1 agent (e.g., anti-PD-1 antibodies, such as nivolumab (i.e., MDX-1106, BMS-936558, ONO-4538); CT-011; AMP-224; pembrolizumab (MK-3475); pildizumab; cimiprizumab; dostalimumab; prologizumab; spartazumab; camrelizumab; sazalinumab; sintilimab; tislelizumab; toripalimab; rivanil; MEDI0680; budigamumab; geptanomab). In some implementations, the immunotherapeutic agent is an anti-PD-L1 agent (e.g., an anti-PD-L1 antibody, such as BMS936559 (i.e., MDX-1105); durvalumab (MEDI4736); avelumab (MSB0010718C); envorimab; cosibelimab; sugemalimab, AUNP-12 or atezolizumab (MPDL-3280A) or an anti-PD-L1 small molecule (e.g., CA-170)).

[0453] In some implementations, the immunotherapeutic agent is a checkpoint blocking antibody (e.g., anti-TIM3, anti-LAG3, anti-TIGIT, including IMP321 and MGA271).

[0454] In some implementations, immunotherapeutic agents are cell-based therapies. In some implementations, the cell-based therapy is CAR-T therapy.

[0455] In some implementations, the immunotherapeutic agent is a co-stimulatory antibody (e.g., anti-4-1BB, anti-OX40, anti-GITR, anti-CD27, anti-CD40).

[0456] In some implementations, immunotherapeutic agents are cancer vaccines, such as neoantigens. These vaccines can be developed using peptides or RNA.

[0457] In some implementation schemes, the immunotherapy agent is an oncolytic virus.

[0458] In some implementations, the immunotherapeutic agent is a STING pathway agonist. Exemplary STING agonists include MK-1454 and ADU-S100.

[0459] In some embodiments, a method for treating a disease or disorder (e.g., cancer) is provided, the method comprising administering, in any order, to a patient in need, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)) or a dosage form thereof, and a disease-specific huMAB (e.g., anti-HER3 huMAB).

[0460] In some embodiments, a method for treating a disease or disorder (e.g., cancer) is provided, the method comprising administering, in any order, to a patient in need, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)) or a dosage form thereof, and an ADC / ADCC dependent on the expression of an associated surface target on the target tumor.

[0461] In some embodiments, a method of treating a disease or disorder (e.g., cancer) is provided, the method comprising administering, in any order, to a patient in need, a compound of formula (I) as described herein, a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form thereof, and one or more DNA damage pathway inhibitors. In some embodiments, the DNA damage pathway inhibitor is selected from the group consisting of bleomycin, ATM inhibitors (e.g., AZD1390), USP1 inhibitors, WEE1 inhibitors (e.g., AZD1775), and Chk1 inhibitors (e.g., AZD7762). In some embodiments, the DNA damage pathway inhibitor is a DNA alkylating agent.

[0462] In some embodiments, a method of treating a disease or condition (e.g., cancer) is provided, the method comprising administering, in any order, to a patient in need, a compound of formula (I) as described herein, its crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form, and a PARP inhibitor. In some embodiments, the PARP inhibitor is selected from the group consisting of olaparib, rucaparib, niraparib, taprazoparib, veriparib, pamiparib, CEP 9722, E7016, iniparib, and 3-aminobenzamide.

[0463] Some patients may experience allergic reactions to the PRMT5 inhibitors and / or other anticancer agents described herein during or after administration; therefore, antihistamines are often administered to minimize the risk of allergic reactions. In some embodiments, a method of treating a disease or condition (e.g., cancer) is provided, the method comprising administering, in any order, to a patient in need, a compound of formula (I) as described herein, its crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form, and an antihistamine (e.g., a corticosteroid, 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 traded under the name Ala-Cort) ® Hydrocortisone phosphate, Solu-Cortef ® Hydrocort Acetate ® and Lanacort ® For sale), prednisolone (under the trade name Delta-Cortel) ® Orapred ® Pediapred ® and Prelone ® For Sale), Prednisone (under the brand name Deltasone) ® Liquid Red ® Meticorten ® and Orasone ® Methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, sodium methylprednisolone succinate, under the trade name Duralone) is available for sale. ® Medralone ® Medrol ® M-Prednisol ® and Solu-Medrol ® (for sale); antihistamines, such as diphenhydramine (e.g., Benadryl). ® ), hydroxyzine and cyproheptadine; and bronchodilators, such as β-adrenergic receptor agonists, salbutamol (e.g., Proventil). ® ) and terbutaline (Brethine) ® )).

[0464] Some patients may experience nausea during and after administration of the PRMT5 inhibitors and / or other anticancer agents described herein; therefore, antiemetics are used to prevent nausea (upper gastric nausea) and vomiting. In some embodiments, a method of treating a disease or condition (e.g., cancer) is provided, the method comprising administering, in any order, to a patient in need, a compound of formula (I) as described herein, its crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form, and an antiemetic (e.g., aprepitant, Emend). ® Zofran ® ), granisetron HCl (Kytril) ® ), Laurazepam (Ativan) ® Dexamethasone ® Compazine ® ), Cassopithin (Rezonic ® and Zunrisa ® (and their combinations).

[0465] Medications are often prescribed to relieve pain experienced during treatment to make patients more comfortable. In some embodiments, a method of treating a disease or condition (e.g., cancer) is provided, the method comprising administering, in any order, to a patient in need, a compound of formula (I) as described herein, its crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form, and an analgesic (e.g., an over-the-counter analgesic (e.g., Tylenol)). ® ), opioid analgesics (e.g., hydrocodone / paracetamol or hydrocodone / acetaminophen (e.g., Vicodin) ® ), morphine (e.g., Astramorphine) ® Or Avinza ® ), oxycodone (e.g., OxyContin) ® Or Percocet ® ), hydroxymorphone hydrochloride (Opana) ® ) and fentanyl (e.g., Duragesic ® ))).

[0466] To protect normal cells from therapeutic toxicity and limit organ toxicity, cell protectants (such as neuroprotectants, free radical scavengers, cardioprotectants, anthracycline extravasation neutralizers, nutrients, etc.) can be used as adjunctive therapy. In some embodiments, a method of treating a disease or condition (e.g., cancer) is provided, the method comprising administering, in any order, to a patient in need, a compound of formula (I) as described herein, its crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form, and a cell protectant (e.g., ethymol). ® ), glutamine, demestral sodium (Tavocept) ® Mesnex ® ), Right Lei Zuosheng (Zinecard) ® Or Totect ® ), Xaprila ® ) and folinic acid (also known as calcium folinic acid, citrovorum factor, and tetrahydrofolate).

[0467] The structure of an active compound identified by its code name, generic name, or trade name can be taken from the current version of the standard compilation "The Merck Index" or from databases such as international patents (e.g., IMS World Publications).

[0468] The above-mentioned compounds can be used in combination with PRMT5 inhibitors as described herein, and can be prepared and administered as described in the art (including but not limited to the literature cited above).

[0469] In one embodiment, a pharmaceutical composition is provided comprising at least one compound disclosed herein (e.g., a crystalline form of a compound of formula (I), such as crystalline form A) and a pharmaceutically acceptable carrier suitable for administration alone or together with other anticancer agents to human or animal subjects.

[0470] Specifically, the compositions will be formulated together as a combination therapy or administered alone.

[0471] In combination therapy, PRMT5 inhibitors, as described herein, can be administered simultaneously, concurrently, or sequentially with other anticancer agents without specific time restrictions, wherein such administration provides a therapeutically effective level of the two compounds in the patient.

[0472] In a preferred embodiment, the disclosed compounds (such as compounds of formula (I) described herein, their crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., containing compounds of formula (I)) or dosage forms) and other anticancer agents are generally administered sequentially by infusion or oral administration in any order. Dosing regimens may vary depending on the stage of the disease, the patient's physical condition, the safety profile and tolerability of the individual drugs, and other criteria known to the attending physician and practitioner administering the combination. PRMT5 inhibitors and other anticancer agents described herein may be administered at intervals of minutes, hours, days, or even weeks, depending on the specific cycle of treatment. Additionally, a cycle may include one drug being administered more frequently than another during a treatment cycle and the dosage of the drug varying with each administration.

[0473] In another aspect, a kit is provided comprising one or more PRMT5 inhibitors as described herein (a compound of formula (I), its crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form) and a second therapeutic agent as disclosed herein. A representative kit comprises (a) a PRMT5 inhibitor as described herein (a compound of formula (I), its crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form), and (b) at least one other therapeutic agent, such as those indicated above, thereby such a kit may include a packaging insert or other label, including instructions for use.

[0474] Compounds of formula (I) as described herein, their crystalline forms (e.g., crystalline form A), pharmaceutical compositions (e.g., containing compound (I)), or dosage forms may also be used in combination with known treatment procedures (e.g., administration of hormones or, in particular, radiation). The disclosed compounds can be used specifically as radiosensitizers, especially for treating tumors that exhibit poor sensitivity to radiation therapy. In some embodiments, a method of treating a disease or condition (e.g., cancer) is provided, the method comprising administering, or co-administering with, a compound of formula (I) as described herein, its crystalline form (e.g., crystalline form A), pharmaceutical compositions (e.g., containing compound (I)), or dosage forms, to a patient in need in any order, and radiation.

[0475] Patient selection and monitoring

[0476] In some embodiments, a method is provided for determining whether a subject with or diagnosed with cancer (e.g., a cancer patient) will respond to therapeutic treatment using a PRMT5 inhibitor (e.g., an MTA-free PRMT5 inhibitor, such as a compound of formula (I) as described herein, its crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form), said method comprising the steps of: a) Contacting the test sample obtained from the subject with a reagent capable of detecting human cancer cells with MTAP deficiency and / or MTA accumulation; and b) Compare the test sample with a reference (e.g., a reference sample taken from a non-cancerous or normal control subject). The presence of MTAP deficiency and / or MTA accumulation in the test sample indicates that the subject will respond to therapeutic treatment using a PRMT5 inhibitor (e.g., an MTA-noncompetitive, noncompetitive, or mixed-mode PRMT5 inhibitor or an MTA synergistic binder, such as a compound of formula (I) as described herein, its crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)) or a dosage form).

[0477] In some embodiments, a method is provided for determining whether cancer will respond to therapeutic treatment using a PRMT5 inhibitor (e.g., an MTA-noncompetitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA synergistic binder, such as a compound of formula (I) as described herein, its crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form), said method comprising the following steps: a) Contacting a test sample obtained from a subject who has or has been diagnosed with the said cancer with a reagent capable of detecting human cancer cells exhibiting MTAP deficiency and / or MTA accumulation; and b) Compare the test sample with a reference (e.g., a reference sample taken from a non-cancerous or normal control subject). The presence of MTAP deficiency and / or MTA accumulation in the test sample indicates that the cancer will respond to therapeutic treatment with a PRMT5 inhibitor (e.g., an MTA-non-competitive, non-competitive, or mixed-mode PRMT5 inhibitor or an MTA synergistic binder, such as a compound of formula (I), a crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)) or a dosage form thereof, as described herein). In some implementations, 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 cell carcinoma or lung adenocarcinoma), undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleural cancer, colorectal cancer, or sarcoma.

[0478] In some embodiments, the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (squamous cell carcinoma), bladder cancer, and DLBCL. In some embodiments, the cancer is selected from the group consisting of non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), 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 cell carcinoma). In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is DLBCL.

[0479] In some implementations, the cancer is selected from the group consisting of non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma), mesothelioma, cholangiocarcinoma, and urothelial carcinoma.

[0480] In some implementations, the method further includes the step of determining PRMT5 levels in cancer cells. PRMT5 expression levels can be considered when determining an effective therapeutic dose of a PRMT5 inhibitor.

[0481] On the one hand, a method is provided for determining the sensitivity of cancer cells to PRMT5 inhibition (e.g., inhibition using an MTA-free PRMT5 inhibitor, such as a compound of formula (I) as described herein, its crystalline form (e.g., crystalline form A), a pharmaceutical composition (e.g., containing a compound of formula (I)), or a dosage form), said method comprising the steps of: a) Determine the production, level, activity, expression, or presence of MTAP in the cancer cells; b) Compare the production, level, activity, expression, or presence of MTAP in the cancer cells with the production, level, activity, expression, or presence of MTAP in non-cancerous or normal control cells. The reduced level, activity, or expression of said cancer cells indicates MTAP deficiency, and the MTAP deficiency indicates that said cancer cells are sensitive to said PRMT5 inhibitor.

[0482] In some implementations, 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 cell carcinoma or lung adenocarcinoma), undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleural...

Claims

1. A pharmaceutical composition comprising a compound of formula (I) in crystalline form A. (I)； and at least one pharmaceutically acceptable excipient; Crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four, or five) characteristic peaks selected from the following, represented by 2θ: 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 The pharmaceutically acceptable excipients mentioned herein include microcrystalline cellulose PH 101.

2. A pharmaceutical composition comprising: (a) Crystalline form A of compound of formula (I) in approximately 35% (w / w) to approximately 50% (w / w) (I); and (b) A filler containing microcrystalline cellulose PH 101; Crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four, or five) characteristic peaks selected from the following, represented by 2θ: 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) Crystalline form A of compound of formula (I) in approximately 35% (w / w) to approximately 50% (w / w) (I); Japanese (b) A filler containing microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102; Crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four, or five) characteristic peaks selected from the following, represented by 2θ: 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 the 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 the 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 for the intragranular mixture is substantially composed of microcrystalline cellulose PH 101, and the filler for the extragranular mixture is substantially composed 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) of a 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) of a filler.

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

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

12. The pharmaceutical composition of claim 11, wherein the gliding agent is substantially composed of colloidal silica.

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) of a gliding agent.

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) of a gliding agent.

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

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

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 is substantially composed of croscarmellose sodium (e.g., Ac-Di-Sol). ® )composition.

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) of a 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) of a disintegrant.

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

22. The pharmaceutical composition of any one of claims 1-18, wherein the pharmaceutical composition comprises about 3% (w / w) of 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 is substantially composed 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) of a 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) of a lubricant.

27. The pharmaceutical composition of any one of claims 1-24, wherein the pharmaceutical composition comprises about 1.0% (w / w) of a 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 compound of formula (I) (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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 containing microcrystalline cellulose PH 101; (c) Flow aids (e.g., colloidal silica); (d) Disintegrants (e.g., croscarmellose sodium); and (e) Lubricants (e.g., magnesium stearate).

30. A pharmaceutical composition comprising: (a) Crystalline form A of compound of formula (I) in approximately 35% (w / w) to approximately 50% (w / w) (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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) Flow aids (e.g., colloidal silica); (d) Disintegrants (e.g., croscarmellose sodium); and (e) Lubricants (e.g., magnesium stearate).

31. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 60% (w / w); (b) about 30% (w / w) to about 60% (w / w) of a filler containing microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 1% (w / w) to approximately 3% (w / w) of a flow aid (e.g., colloidal silica); (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); Thus, the total amount does not exceed 100% (w / w) of the pharmaceutical composition.

32. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 50% (w / w); (b) about 40% (w / w) to about 60% (w / w) of a filler containing microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 1% (w / w) to approximately 3% (w / w) of a flow aid (e.g., colloidal silica); (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); Thus, the total amount does not exceed 100% (w / w) of the pharmaceutical composition.

33. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 45% (w / w); (b) About 50% (w / w) to about 60% (w / w) of a filler containing microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 1% (w / w) to approximately 3% (w / w) of a flow aid (e.g., colloidal silica); (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); Thus, the total amount does not exceed 100% (w / w) of the pharmaceutical composition.

34. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition comprises: (a) Crystalline form A of approximately 40% (w / w) of compound (I); (b) Approximately 54% (w / w) of filler, such as microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 2% (w / w) of a flow aid (e.g., colloidal silica); (d) Approximately 3% (w / w) of a disintegrant (e.g., croscarmellose sodium); (e) Approximately 1% (w / w) of lubricant (e.g., magnesium stearate); Thus, the total is 100% (w / w) of the pharmaceutical composition.

35. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 50% (w / w); (b) Approximately 40% (w / w) to approximately 60% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Colloidal silica of about 1% (w / w) to about 3% (w / w); (d) Approximately 2% (w / w) to approximately 4% (w / w) of croscarmellose sodium; (e) Magnesium stearate of about 0.5% (w / w) to about 1.5% (w / w); Thus, the total amount does not exceed 100% (w / w) of the pharmaceutical composition.

36. The pharmaceutical composition of claim 29, wherein the pharmaceutical composition comprises: (a) Crystalline form A of approximately 40% (w / w) of compound (I); (b) Approximately 54% (w / w) of microcrystalline cellulose PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102; (c) Approximately 2% (w / w) of colloidal silica; (d) Approximately 3% (w / w) of croscarmellose sodium; (e) Approximately 1% (w / w) magnesium stearate; Thus, the total is 100% (w / w) of the pharmaceutical composition.

37. The pharmaceutical composition of any one of claims 1-36, wherein the pharmaceutical composition comprises an in-particle filler.

38. The pharmaceutical composition of claim 37, wherein the in-particle filler is substantially composed of microcrystalline cellulose PH101 (e.g., Avicel). ® Composition of PH 101).

39. The pharmaceutical composition of any one of claims 37-38, wherein the w / w ratio of API to in-particle 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 in-particle 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 in-particle 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) of an in-particle 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) of an in-particle filler.

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

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

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

47. The pharmaceutical composition of claim 46, wherein the exfoliating agent is substantially composed of microcrystalline cellulose PH102 (e.g., Avicel). ® Composition of 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) of an explant 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) of an explant 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) of an explant filler.

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

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

53. The pharmaceutical composition of any one of claims 1-52, wherein the pharmaceutical composition comprises an intraparticle flow aid.

54. The pharmaceutical composition of claim 53, wherein the intraparticle flow aid is substantially composed of colloidal silica (e.g., Aerosil). ® 200, CAB-O-SIL ® Composed of 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) of an intraparticle flow aid.

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) of an intraparticle flow aid.

57. The pharmaceutical composition of claim 53 or 54, wherein the pharmaceutical composition comprises about 1.0% (w / w) of an intraparticle flow aid.

58. The pharmaceutical composition of any one of claims 1-57, wherein the pharmaceutical composition comprises an extraparticle flow aid.

59. The pharmaceutical composition of claim 58, wherein the particulate flow aid is substantially composed of colloidal silica (e.g., Aerosil). ® 200, CAB-O-SIL ® Composed of 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) of an extraparticle flow aid.

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) of an extraparticle flow aid.

62. The pharmaceutical composition of claim 58 or 59, wherein the pharmaceutical composition comprises about 1.0% (w / w) of an extraparticle flow aid.

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

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 intraparticle disintegrant is substantially composed 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) of an intraparticle 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) of an intraparticle disintegrant.

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

69. The pharmaceutical composition of claim 64 or 65, wherein the pharmaceutical composition comprises about 1.5% (w / w) of intraparticle crosslinked sodium carboxymethyl cellulose.

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

71. The pharmaceutical composition of claim 70, wherein the exodisintegrant is substantially composed 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) of an ex-particle 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) of an ex-particle disintegrant.

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

75. The pharmaceutical composition of claim 70 or 71, wherein the pharmaceutical composition comprises about 1.5% (w / w) of extraparticle crosslinked sodium carboxymethyl cellulose.

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

77. The pharmaceutical composition of claim 76, wherein the intraparticle lubricant is substantially composed 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) of an in-particle 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) of an in-particle lubricant.

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

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

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

83. The pharmaceutical composition of claim 82, wherein the external lubricant is substantially composed 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) of an external particulate 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) of an external particulate lubricant.

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

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

88. A pharmaceutical composition comprising: (a) Crystalline form A of compound of formula (I) (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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 in-particle 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 compound of formula (I) (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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) In-particle filler containing microcrystalline cellulose PH 101; (c) In-particle flow aids (e.g., colloidal silica); (d) Intraparticle disintegrants (e.g., croscarmellose sodium carboxymethyl cellulose); (e) External lubricants (e.g., magnesium stearate); (f) Extragranular fillers (e.g., microcrystalline cellulose PH 102); (g) Particulate flow aids (e.g., colloidal silica); (h) Extraparticle disintegrants (e.g., croscarmellose sodium); and (i) External lubricant (e.g., magnesium stearate).

90. A pharmaceutical composition comprising: (a) Crystalline form A of compound of formula (I) (I); wherein crystalline form A has an X-ray powder diffraction (XRPD) pattern containing one or more (e.g., one, two, three, four or five) characteristic peaks selected from the following, represented by 2θ: 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 within the particles, pH 101; (c) Colloidal silica within particles; (d) Intragranular cross-linked sodium carboxymethyl cellulose; (e) Magnesium stearate outside the particles; (f) Microcrystalline cellulose outside the particles, pH 102; (g) Colloidal silica particles; (h) cross-linked sodium carboxymethyl cellulose particles; and (i) Magnesium stearate outside the particles.

91. The pharmaceutical composition of claim 89, wherein the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in about 35% (w / w) to about 50% (w / w); (b) Approximately 30% (w / w) to approximately 50% (w / w) of an in-particle filler comprising microcrystalline cellulose PH 101; (c) About 0.5% (w / w) to about 1.5% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) About 0.5% (w / w) to about 2.5% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) about 0.25% (w / w) to about 0.75% (w / w) of an in-particle lubricant (e.g., magnesium stearate); (f) Approximately 5% (w / w) to approximately 20% (w / w) of ex-particle fillers (e.g., microcrystalline cellulose PH 102); (g) about 0.5% (w / w) to about 1.5% (w / w) of particulate flow aid (e.g., colloidal silica); (h) about 0.5% (w / w) to about 2.5% (w / w) of an external disintegrant (e.g., croscarmellose sodium); and (i) about 0.25% (w / w) to about 0.75% (w / w) of an external particulate lubricant (e.g., magnesium stearate); Thus, the total amount does not exceed 100% (w / w) of the pharmaceutical composition.

92. The pharmaceutical composition of claim 89, wherein the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in approximately 37% (w / w) to approximately 43% (w / w); (b) Approximately 38% (w / w) to approximately 46% (w / w) of an in-particle filler comprising microcrystalline cellulose PH 101; (c) Approximately 0.8% (w / w) to approximately 1.2% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) About 1.25% (w / w) to about 1.75% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) about 0.3% (w / w) to about 0.7% (w / w) of an in-particle lubricant (e.g., magnesium stearate); (f) Approximately 8% (w / w) to approximately 16% (w / w) of ex-particle fillers (e.g., microcrystalline cellulose PH 102); (g) about 0.8% (w / w) to about 1.2% (w / w) of particulate flow aid (e.g., colloidal silica); (h) about 1.25% (w / w) to about 1.75% (w / w) of an ex-particle disintegrant (e.g., croscarmellose sodium); and (i) about 0.3% (w / w) to about 0.7% (w / w) of an external particulate lubricant (e.g., magnesium stearate); Thus, the total amount does not exceed 100% (w / w) of the pharmaceutical composition.

93. The pharmaceutical composition of claim 89, wherein the pharmaceutical composition comprises: (a) Crystalline form A of approximately 40% (w / w) of compound (I); (b) Approximately 42% (w / w) of in-particle filler containing microcrystalline cellulose PH 101; (c) Approximately 1.0% (w / w) of an in-particle flow aid (e.g., colloidal silica); (d) Approximately 1.5% (w / w) of an intraparticle disintegrant (e.g., croscarmellose sodium); (e) Approximately 0.5% (w / w) of in-particle lubricant (e.g., magnesium stearate); (f) Approximately 12% (w / w) of ex-particle filler (e.g., microcrystalline cellulose PH 102); (g) Approximately 1.0% (w / w) of particulate flow aid (e.g., colloidal silica); (h) Approximately 1.5% (w / w) of an external disintegrant (e.g., croscarmellose sodium); and (i) Approximately 0.5% (w / w) of an external particulate lubricant (e.g., magnesium stearate).

94. The pharmaceutical composition of claim 89, wherein the pharmaceutical composition comprises: (a) Crystalline form A of the compound of formula (I) in approximately 37% (w / w) to approximately 43% (w / w); (b) Microcrystalline cellulose within particles, pH 101, comprising approximately 38% (w / w) to approximately 46% (w / w); (c) In-particle colloidal silica of about 0.8% (w / w) to about 1.2% (w / w); (d) Intragranular crosslinked sodium carboxymethyl cellulose, approximately 1.25% (w / w) to approximately 1.75% (w / w); (e) Magnesium stearate in particles, approximately 0.3% (w / w) to approximately 0.7% (w / w); (f) Approximately 8% (w / w) to approximately 16% (w / w) of exogranular microcrystalline cellulose pH 102; (g) about 0.8% (w / w) to about 1.2% (w / w) of particulate colloidal silica; (h) approximately 1.25% (w / w) to approximately 1.75% (w / w) of externally cross-linked sodium carboxymethyl cellulose; and (i) Magnesium stearate in particulate form, ranging from about 0.3% (w / w) to about 0.7% (w / w); Thus, the total amount does not exceed 100% (w / w) of the pharmaceutical composition.

95. The pharmaceutical composition of claim 89, wherein the pharmaceutical composition comprises: (a) Crystalline form A of approximately 40% (w / w) of compound (I); (b) Approximately 42% (w / w) of microcrystalline cellulose within the granules at pH 101; (c) Approximately 1.0% (w / w) of intraparticle colloidal silica; (d) Approximately 1.5% (w / w) of intraparticle cross-linked sodium carboxymethyl cellulose; (e) Approximately 0.5% (w / w) of magnesium stearate within the particles; (f) Approximately 12% (w / w) of exogranular microcrystalline cellulose at pH 102; (g) Approximately 1.0% (w / w) of particulate colloidal silica; (h) Approximately 1.5% (w / w) of externally cross-linked sodium carboxymethyl cellulose; and (i) Approximately 0.5% (w / w) of particulate magnesium stearate.

96. A dosage form intended for oral administration, comprising the 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 from 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 crystalline form A of the compound of formula (I) in the form of about 100 mg, about 125 mg, about 150 mg, about 200 mg, or about 250 mg.

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 method for preparing the pharmaceutical composition according to any one of claims 1-95, comprising: (a) Add and mix the crystalline form A of compound (I), the in-particle filler, the in-particle flow aid and the in-particle disintegrant, and mix to obtain a pre-lubricated in-particle mixture; (b) Adding a lubricant to the pre-lubricated intragranular mixture and mixing to obtain a lubricated intragranular mixture; (c) Granulating the mixture within the particles to obtain particles; (d) Grinding the particles to obtain ground particles; (e) Add the ground particles, external filler, external disintegrant and external flow aid, and mix to obtain a pre-lubricated external mixture; (f) Adding a lubricant to the pre-lubricated extragranular mixture and mixing to obtain the pharmaceutical composition.

105. A method for preparing the pharmaceutical composition according to any one of claims 1-95, comprising: (a) Premix, sieve and add the crystalline form A of compound of formula (I), the in-particle filler, the in-particle flow aid and the in-particle disintegrant, and mix to obtain a pre-lubricated in-particle mixture. (b) Adding a lubricant to the pre-lubricated intragranular mixture and mixing to obtain a lubricated intragranular mixture; (c) Granulating the mixture within the particles to obtain particles; (d) Grinding the particles to obtain ground particles; (e) The ground particles are premixed with the external filler, external disintegrant and external flow aid, sieved, added and mixed to obtain a pre-lubricated external mixture; (f) Adding a lubricant to the pre-lubricated extragranular mixture and mixing to obtain the pharmaceutical composition.

106. A method for preparing the dosage form according to any one of claims 96-103, comprising: (a) Add and mix the crystalline form A of compound (I), the in-particle filler, the in-particle flow aid and the in-particle disintegrant, and mix to obtain a pre-lubricated in-particle mixture; (b) Adding a lubricant to the pre-lubricated intragranular mixture and mixing to obtain a lubricated intragranular mixture; (c) Granulating the mixture within the particles to obtain particles; (d) Grinding the particles to obtain ground particles; (e) Add and mix the ground particles, external filler, external disintegrant and external flow aid to obtain a pre-lubricated external mixture; (f) Adding a lubricant to the pre-lubricated extragranular mixture and mixing to obtain the pharmaceutical composition; (g) Compressing the pharmaceutical composition into a dosage form; and, optionally... (h) Coating the dosage form.

107. A method for preparing the dosage form according to any one of claims 96-103, comprising: (a) Premix, sieve and add the crystalline form A of compound of formula (I), the in-particle filler, the in-particle flow aid and the in-particle disintegrant, and mix to obtain a pre-lubricated in-particle mixture. (b) Adding a lubricant to the pre-lubricated intragranular mixture and mixing to obtain a lubricated intragranular mixture; (c) Granulating the mixture within the particles to obtain particles; (d) Grinding the particles to obtain ground particles; (e) The ground particles are premixed with the external filler, external disintegrant and external flow aid, sieved, added and mixed to obtain a pre-lubricated external mixture; (f) Adding a lubricant to the pre-lubricated extragranular mixture and mixing to obtain the pharmaceutical composition; (g) Compressing the pharmaceutical composition into a dosage form; and, optionally... (h) Coating the dosage form.

108. A method for preparing the pharmaceutical composition according to any one of claims 1-95, comprising: (a) The following shall be added in sequence: i. 50% of the total required amount of in-particle filler; ii. The required total amount of the crystalline form A of compound of formula (I); iii. The required total amount of intraparticle disintegrant; iv. The required total amount of in-particle flow aid; and v. 50% of the total required amount of in-particle filler; (b) The components added in step (a) are premixed and sieved to obtain a premixed intragranular mixture; (c) Mix the premixed intraparticle mixture to obtain a pre-lubricated intraparticle mixture; (d) The following shall be added in sequence: i. 50% of the pre-lubricated intragranular mixture; ii. 100% of the required amount of in-granular lubricant, added through sieving; iii. 50% of the pre-lubricated intraparticle mixture; to obtain a lubricated intraparticle mixture; (e) Mix the lubricated intraparticle mixture to obtain an intraparticle mixture; (f) Granulating the intragranular mixture to obtain granules; (g) Grinding the particles to obtain ground particles; (h) The following shall be added in sequence: i. 50% of the required amount of particulate filler; ii. The ground particles obtained in step (g); iii. The required amount of external disintegrant; iv. The required amount of particulate effusion aid; v. 50% of the required amount of particulate filler; (i) The components added in step (h) are premixed and sieved to obtain a premixed non-particle mixture; (j) Mix the premixed off-particle mixture to obtain a pre-lubricated off-particle mixture; (k) The following shall be added in sequence: i. 50% of the pre-lubricated extra-particle mixture; ii. The required amount of particulate external lubricant is added by sieving; iii. 50% of the pre-lubricated extra-particle mixture; to obtain a lubricated extra-particle mixture; (l) Mixing the lubricated intragranular mixture to obtain the pharmaceutical composition.

109. A method for preparing the dosage form according to any one of claims 96-103, comprising: (a) The following shall be added in sequence: i. 50% of the total required amount of in-particle filler; ii. The required total amount of the crystalline form A of compound of formula (I); iii. The required total amount of intraparticle disintegrant; iv. The required total amount of in-particle flow aid; and v. 50% of the total required amount of in-particle filler; (b) The components added in step (a) are premixed and sieved to obtain a premixed intragranular mixture; (c) Mix the premixed intraparticle mixture to obtain a pre-lubricated intraparticle mixture; (d) The following shall be added in sequence: i. 50% of the pre-lubricated intragranular mixture; ii. The required amount of 100% intragranular lubricant is added by sieving; iii. 50% of the pre-lubricated intraparticle mixture; to obtain a lubricated intraparticle mixture; (e) Mix the lubricated intraparticle mixture to obtain an intraparticle mixture; (f) Granulating the intragranular mixture to obtain granules; (g) Grinding the particles to obtain ground particles; (h) Input in sequence: i. 50% of the required amount of particulate filler; ii. The ground particles obtained in step (g); iii. The required amount of external disintegrant; iv. The required amount of particulate effusion aid; v. 50% of the required amount of particulate filler; (i) The components added in step (h) are premixed and sieved to obtain a premixed non-particle mixture; (j) Mix the premixed off-particle mixture to obtain a pre-lubricated off-particle mixture; (k) Input in sequence: i. 50% of the pre-lubricated extra-particle mixture; ii. The required amount of particulate external lubricant is added by sieving; iii. 50% of the pre-lubricated extra-particle mixture; to obtain a lubricated extra-particle mixture; (l) Mixing 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 dosage form prepared by any one of claims 104-109.

111. A pharmaceutical composition of any one of claims 1 to 95 or a dosage form of any one of claims 96 to 103 containing a therapeutically effective amount of a compound of formula (I), in a method of treating a subject with MTAP deficiency and / or MTA cumulative disease, wherein the method comprises administering to the subject the pharmaceutical composition of any one of claims 1 to 95 or the dosage form of any one of claims 96 to 103.

112. The pharmaceutical composition or dosage form for use according to claim 111, wherein the disease is MTAP deficiency and / or MTA-accumulating cancer.

113. The pharmaceutical composition or dosage form for use according to claim 112, wherein the cancer is histologically unknown.

114. The pharmaceutical composition or dosage form for use according to 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 cell carcinoma or lung adenocarcinoma), undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleural cancer, colorectal cancer, or sarcoma.

115. The pharmaceutical composition or dosage form for use according to claim 112, wherein the cancer is selected from the group consisting of cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (non-squamous carcinoma), bladder cancer, and DLBCL.

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

117. The pharmaceutical composition or dosage form for use according to claim 112, wherein the cancer is histologically unknown MTAP-deficient cancer.

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

119. The pharmaceutical composition or dosage form for use according to any one of claims 111-117, wherein the pharmaceutical composition 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 or dosage form for use according to any one of claims 111-117, wherein the pharmaceutical composition 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 or dosage form for use according to any one of claims 111-117, wherein the pharmaceutical composition 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 according to 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. Compound of formula (I) (I), in a method for treating MTAP deficiency and / or MTA accumulation in a subject with such need, wherein the method comprises administering to the subject a dose of about 100 mg to about 1000 mg of a compound of formula (I) once or twice daily.

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

125. The compound of claim 124 for use, 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 cell carcinoma or lung adenocarcinoma), undifferentiated pleomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, gastric adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, gastric cancer, kidney cancer, breast cancer, endometrial cancer, urinary tract cancer, liver cancer, soft tissue cancer, pleural cancer, colorectal cancer, or sarcoma.

126. The compound of claim 124 for use, wherein the cancer is selected from cholangiocarcinoma, NSCLC (adenocarcinoma), NSCLC (non-squamous carcinoma), bladder cancer, and DLBCL.

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

128. The compound of claim 124 for use, wherein the cancer is a histologically unknown MTAP-deficient cancer.

129. The compound for use according to 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 according to any one of claims 123-128, wherein the dosage 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 according to any one of claims 123-128, wherein the dosage 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 according to 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 according to any one of claims 123-128, wherein the dose is administered once daily.

134. The compound for use according to any one of claims 123-128, wherein the 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) once daily.

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

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