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WO2025166308A1 - Formes cristallines, compositions pharmaceutiques et leurs méthodes d'utilisation - Google Patents

Formes cristallines, compositions pharmaceutiques et leurs méthodes d'utilisation

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Publication number
WO2025166308A1
WO2025166308A1 PCT/US2025/014214 US2025014214W WO2025166308A1 WO 2025166308 A1 WO2025166308 A1 WO 2025166308A1 US 2025014214 W US2025014214 W US 2025014214W WO 2025166308 A1 WO2025166308 A1 WO 2025166308A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
intragranular
extragranular
composition comprises
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/014214
Other languages
English (en)
Inventor
Meghna ISRANI
Adam Samuel CRYSTAL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tango Therapeutics Inc
Original Assignee
Tango Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tango Therapeutics Inc filed Critical Tango Therapeutics Inc
Publication of WO2025166308A1 publication Critical patent/WO2025166308A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • compositions comprising one or more novel active ingredients requires a variety of considerations, such as route of administration (e.g., enteral, parenteral, topical, etc.), dosage form (e.g., solid - tablet, capsule, etc.; liquid - solution, suspension, syrup, etc.), strength of active ingredient(s) (e.g., 1 mg - 1,000 mg), non-therapeutic component(s) (e.g., excipients) and their respective amounts, and each of these considerations may involve additional considerations such as stability, degradation, sensitivity to light, solubility, taste if administered enterally, palatability, pH, skin irritability, microbial growth, etc.
  • Advancing a novel active ingredient e.g., a PRMT5 inhibitor
  • rigorous regulatory entities requires discovering and developing a pharmaceutical composition that addresses these, or other, considerations.
  • thiazol-5-yl )pi peridin- 1 -yl)-2-oxoacetamide (TNG462) has been disclosed in WO 2022/026892.
  • First-generation pharmaceutical compositions and dosage forms of the compound have been disclosed in WO2024091551.
  • compositions described in WO2024091551 are relatively low-drug load compositions, and the dosage forms disclosed therein comprise up to 100 mg of active ingredient (the exemplary dosage forms described in Example 7 therein contain 10 mg and 50 mg of active ingredient, at a drug load of 10%).
  • a pharmaceutical composition comprising crystalline Form A of A r -(6-amino-5-ethylpyridin-3-yl)-2-((2R,5S)-5-methyl-2-(2-(l -methylpiperidin-4- yl)benzo[ ⁇ 7]thiazol-5-yl)piperidin-l-yl)-2-oxoacetamide (a compound of formula (I)) and at least one pharmaceutically acceptable excipient, wherein crystalline Form A has an X- Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6 ⁇ 0.2. 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.5 ⁇ 0.2 degrees and wherein the phannaceutically acceptable excipient comprises microcrystalline cellulose PH 101.
  • XRPD X- Ray Powder Diffraction
  • composition comprising:
  • a filler comprising microcrystalline cellulose PH 101; wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.5 ⁇ 0.2 degrees.
  • XRPD X-Ray Powder Diffraction
  • composition comprising:
  • a filler comprising microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102; wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.5 ⁇ 0.2 degrees.
  • XRPD X-Ray Powder Diffraction
  • composition comprising:
  • XRPD X-Ray Powder Diffraction
  • a glidant e.g., colloidal silicon dioxide
  • a disintegrant e.g., croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • composition comprising:
  • XRPD X-Ray Powder Diffraction
  • a glidant e.g., colloidal silicon dioxide
  • a disintegrant e.g., croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • composition comprising:
  • crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.5 ⁇ 0.2 degrees;
  • XRPD X-Ray Powder Diffraction
  • a glidant e.g., colloidal silicon dioxide
  • a disintegrant e.g., croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • composition comprising:
  • XRPD X-Ray Powder Diffraction
  • composition comprising:
  • XRPD X-Ray Powder Diffraction
  • an intragranular filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients.
  • composition comprising:
  • crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.5 ⁇ 0.2 degrees;
  • XRPD X-Ray Powder Diffraction
  • an intragranular filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients.
  • composition comprising:
  • XRPD X-Ray Powder Diffraction
  • an intragranular glidant e.g. colloidal silicon dioxide
  • an intragranular disintegrant e.g, croscarmellose sodium
  • an extragranular lubricant e.g., magnesium stearate
  • an extragranular filler e.g., microcrystalline cellulose PH 102
  • an extragranular glidant e.g., colloidal silicon dioxide
  • an extragranular disintegrant e.g, croscarmellose sodium
  • an extragranular lubricant e.g., magnesium stearate
  • composition comprising:
  • XRPD X-Ray Powder Diffraction
  • composition comprising:
  • crystalline Form A of a compound of formula (I) wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.5 ⁇ 0.2 degrees;
  • XRPD X-Ray Powder Diffraction
  • an intragranular glidant e.g, colloidal silicon dioxide
  • an intragranular disintegrant e.g., croscarmellose sodium
  • an intragranular lubricant e.g., magnesium stearate
  • an extragranular glidant e.g., colloidal silicon dioxide
  • an extragranular lubricant e.g, magnesium stearate
  • composition comprising:
  • crystalline Form A of a compound of formula (I) wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2. 16.8 ⁇ 0.2, 18.6 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2.
  • XRPD X-Ray Powder Diffraction
  • an intragranular glidant e.g, colloidal silicon dioxide
  • an intragranular disintegrant e.g, croscarmellose sodium
  • an intragranular lubricant e.g, magnesium stearate
  • an extragranular glidant e.g, colloidal silicon dioxide
  • an extragranular lubricant e.g. magnesium stearate
  • composition comprising:
  • crystalline Form A of a compound of formula (I) wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.5 ⁇ 0.2 degrees;
  • XRPD X-Ray Powder Diffraction
  • an intragranular glidant e.g., colloidal silicon dioxide
  • an intragranular disintegrant e.g., croscarmellose sodium
  • an intragranular lubricant e.g. magnesium stearate
  • an extragranular glidant e.g, colloidal silicon dioxide
  • an extragranular lubricant e.g., magnesium stearate
  • composition comprising:
  • crystalline Form A of a compound of formula (I) wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.5 ⁇ 0.2 degrees;
  • XRPD X-Ray Powder Diffraction
  • an intragranular glidant e.g., colloidal silicon dioxide
  • an intragranular disintegrant e.g, croscarmellose sodium
  • an intragranular lubricant e.g., magnesium stearate
  • an extragranular filler e.g., microcrystallinc cellulose PH 102
  • an extragranular glidant e.g., colloidal silicon dioxide
  • an extragranular lubricant e.g., magnesium stearate
  • composition comprising:
  • cry stalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 29, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2. 16.8 ⁇ 0.2, 18.6 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2.
  • XRPD X-Ray Powder Diffraction
  • composition comprising:
  • composition comprising:
  • crystalline Form A of a compound of formula (I) wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.5 ⁇ 0.2 degrees;
  • XRPD X-Ray Powder Diffraction
  • composition comprising:
  • crystalline Form A of a compound of formula (I) wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g., one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.5 ⁇ 0.2 degrees;
  • XRPD X-Ray Powder Diffraction
  • composition comprising:
  • crystalline Form A of a compound of formula (I) wherein crystalline Form A has an X-Ray Powder Diffraction (XRPD) pattern comprising one or more (e.g, one, two, three, four or five) characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.5 ⁇ 0.2 degrees;
  • XRPD X-Ray Powder Diffraction
  • a dosage form comprising a pharmaceutical composition as described herein.
  • a dosage form intended for oral administration comprising a pharmaceutical composition as described herein.
  • a process for preparing a pharmaceutical composition as described herein comprising:
  • a process for preparing a dosage form of as described herein comprising:
  • a process for preparing a pharmaceutical composition as described herein comprising:
  • a process for preparing a dosage form of as described herein comprising:
  • a processes for preparing a pharmaceutical composition as described herein comprising:
  • step (b) pre-blending and sieving the components charged at step (a) to obtain a pre-blending intragranular mixture
  • a process for preparing a dosage form as described herein comprising:
  • step (b) pre-blending and sieving the components charged at step (a) to obtain a pre-blending intragranular mixture
  • a pharmaceutical composition or a dosage form prepared by any of the processes described herein.
  • a method for treating an MTAP-deficient and/or an MTA-accumulating disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or dosage form described herein.
  • a method of treating a cancer in a subject in need thereof comprising the steps of: a) assessing the level of MTAP and/or MTA in a test sample obtained from said subject, wherein the MTA level can be assessed directly (e.g, by ELISA or LC- MS/MS) or indirectly (e.g., by SDMA-modified protein ELISA or IHC, or by RNA splicing); b) comparing the test sample with a reference, wherein MTAP deficiency and/or MTA accumulation in said test sample compared to the reference indicates the cancer in said subject will respond to therapeutic treatment with a PRMT5 inhibitor; and c) administering an effective amount (e.g., a therapeutically effective amount) of a pharmaceutical composition or dosage form as described herein to the subject identified in step b).
  • an effective amount e.g., a therapeutically effective amount
  • a pharmaceutical composition or dosage form described herein in a method for treating an MT AP -deficient and/or an MTA-accumulating disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or dosage form described herein.
  • a pharmaceutical composition or dosage form described herein in the manufacture of a medicament for treating an MTAP-deficient and/or an MTA-accumulating disease in a subject in need thereof.
  • a pharmaceutical composition or dosage form described herein for use in a method for treating an MTAP-deficient and/or an MTA- accumulating disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or dosage form described herein.
  • a pharmaceutical composition or dosage form described herein for use in the manufacture of a medicament for treating an MTAP-deficient and/or an MTA- accumulating disease in a subject in need thereof.
  • FIG. 1 is an exemplary X-ray powder diffraction pattern of crystalline Form A of the compound of Formula (I).
  • FIG. 2A shows an exemplary thermogravimetric analysis (TGA) thermogram of the compound of Formula (I).
  • FIG. 2B shows a differential scanning calorimetry (DSC) thermogram for crystalline Form A the compound of Formula (I), under a heat-cool -heat protocol, show ing a melt peak at about 145.8 °C.
  • DSC differential scanning calorimetry
  • FIG. 3A shows the change of water content (solid curve) and relative humidity (hashed curve) as a function of time in an exemplary DVS experiment for the compound of Formula (I) (Crystalline form A).
  • FIG. 3B show s the change of w ater content as a function of relative humidity in an exemplary DVS experiment for the compound of Formula (I) (Crystalline form A).
  • FIG. 4A shows the antiproliferative activity (viability at different concentrations) of the compound of Formula (I) in an MT AP -isogenic cell line pair engineered by CRISPR-mediated MTAP gene knockout of the HAP1 chronic myeloid leukemia cell line.
  • FIG. 4B shows the antiproliferative activity (viability 7 at different concentrations) of the compound of Formula (I) in an MT AP -isogenic cell line pair engineered by CRISPR-mediated MTAP gene knockout of the HCT116 colorectal cancer cell line.
  • FIG. 4C shows the antiproliferative activity (viability at different concentrations) of the compound of Formula (I) in an MTAP -isogenic cell line pair engineered by reconstituting exogenous MTAP in an endogenous MTAP-deleted LU99 non-small cell lung cancer cell line.
  • FIG. 4D shows the antiproliferative activity (viability at different concentrations) of the compound of Formula (I) in an MTAP -isogenic cell line pair engineered by reconstituting exogenous MTAP in an endogenous MTAP-deleted LN18 glioblastoma cell line.
  • FIG. 5 A shows the pharmacodynamic activity of the compound of Formula (I) against PRMT5, by showing a graph of a normalized single SDMA-modified protein level at various concentrations of PRMT5 inhibitor of Formula (I) in a HAP 1 MTAP-isogenic cell line pair. Normalized to a DMSO control for each cell tine and represented as mean ⁇ SD.
  • FIG. 5B shows the pharmacodynamic activity of the compound of Formula (I) against Type I PRMTs, by showing a graph of a normalized single ADMA-modified protein level at various concentrations of PRMT5 inhibitor of Formula (I) in a HAP 1 MTAP-isogenic cell line pair. Normalized to a DMSO control for each cell tine and represented as mean ⁇ SD.
  • FIG. 5C shows a dendrogram of biochemical selectivity 7 of the compound of formula (I) for PRMT5 in a histone methyltransferase panel.
  • FIG. 6 shows the pharmacokinetic profile in cynomolgus monkey of the compound of Formula (I), depicting the free plasma exposures following 3 mg/kg oral gavage of the compound of Formula (I).
  • the GI50 for WT and MTAP -null cells is indicated by dotted lines.
  • FIG. 7 shows the results of a 7-day PK/PD study using a LU99 (lung giant cell carcinoma) MTAP -null xenograft model.
  • the compound of Formula (I) was dosed as indicated, and PK and tumor samples were harvested at the indicated timepoints; the SDMA-modified protein levels for each dose as a proportion of vehicle are shown.
  • N 4 tumors per group, and data are presented as mean ⁇ SEM.
  • FIG. 8A shows the dose-dependent antitumor activity of the compound of Formula (I) against an LN18 MTAP -null cell line-derived xenograft model. Data are presented as mean ⁇ SEM.
  • FIG. 8B shows the dose-dependent antitumor activity of the compound of Formula (I) against an OCI-LY19 MTAP -null cell line-derived xenograft model. Data are presented as mean ⁇ SEM.
  • FIG. 8C shows the dose-dependent antitumor activity of the compound of Formula (I) against an MT AP -null mesothelioma patient-derived xenograft model. Data are presented as mean ⁇ SEM.
  • FIG. 8D shows the dose-dependent antitumor activity of the compound of Formula (I) against an MT AP -null bladder cancer patient-derived xenograft model. Data are presented as mean ⁇ SEM.
  • FIG. 8E shows the dose-dependent antitumor activity of the compound of Formula (I) against an MTAP-null cholangiocarcinoma patient-derived xenograft model. Data are presented as mean ⁇ SEM.
  • FIG. 8F shows the dose-dependent antitumor activity 7 of the compound of Formula (I) against an MTAP-null NSCLC (squamous) patient-derived xenograft model. Data are presented as mean ⁇ SEM.
  • FIG. 8G shows the dose-dependent antitumor activity of the compound of Formula (I) (40 mg/kg BID and 100 mg/kg QD) against a LU-99 NSCLC MTAP-null cell line-derived xenograft model.
  • the dotted line is the regression line, which is defined as final mean tumor volume that is 30% less than the initial mean tumor volume. Data are presented as mean ⁇ SEM.
  • FIG. 8H shows the dose-dependent antitumor activity of 30 mg/kg BID and 60 mg/kg BID of the compound of Formula (I) against a LU-99 NSCLC MTAP-null cell line-derived xenograft model.
  • FIG. 9A shows the antitumor activity of the compound of Formula (I) in patient-derived xenograft models obtained from bladder cancer, cholangiocarcinoma, mesothelioma, non-small cell lung cancer (e.g, adenocarcinoma and squamous cell carcinoma), and pancreatic cancer (e.g., pancreatic ductal adenocarcinoma).
  • the final mean tumor volume for the PRMT5 inhibitor-treated mice was greater than the initial mean tumor volume, the data are presented in relation to vehicle-treated tumors (greater than 0). If the final mean tumor volume for the PRMT5 inhibitor-treated mice was less than the initial mean tumor volume, then the data are presented relative to mean tumor volume (less than 0).
  • FIG. 9B shows an updated representation of the data from 9A with an additional 3 datapoints for cholangiocarcinoma (1), bladder (1) and lung (1) cancer xenografts.
  • the data for adenocarcinoma and squamous carcinoma of the lung is consolidated in a single category.
  • the graph represents final tumor volume as a percentage of initial tumor volume - the 100 line represents no change in tumor volume, values between 0-100% of initial tumor represent reductions in tumor volume, and values above 100 represent increases in tumor volume.
  • FIG. 10A shows the ability of compound of Formula (I) to overcome resistance to the MTA-cooperative PRMT5 inhibitor in a diffuse large B cell lymphoma cell line-derived xenograft model. Data are presented as mean ⁇ SEM.
  • FIG. 10B shows the enlarged portion of FIG. 10A with broken y-axis to highlight the region of interest.
  • FIG. 11 shows waterfall plots of 180 cancer cell lines representing multiple cancer lineages including NSCLC, PDAC, bladder, CNS, and heme malignancies, which were profiled with PRMT5 inhibitor of Formula (I) in a 7-day CellTiter-Glo assay.
  • FIG. 12 shows the antitumor activity of the compound of Formula (I), at 30 mg/kg BID, alone or in combination with 1 mg/kg QD osimertinib, against an NCI-H1650 NSCLC MTAP- null cell line-derived xenograft model. Data are presented as mean ⁇ SEM.
  • FIG. 13 shows the antitumor activity of the compound of Formula (I), at 30 and 60 mg/kg BID alone and at 30 mg/kg BID in combination with 10 mg/kg BID AGI-41998, against an NCI-H838 NSCLC MTAP -null cell line-derived xenograft model. Data are presented as mean ⁇ SEM.
  • FIG. 14 shows a schematic representation of the process for manufacturing the pharmaceutical compositions and dosage forms of the present disclosure.
  • FIG. 15 shows a schematic representation of the original clinical trial design described in Example 20.
  • SD standard deviations
  • FIG. 18 shows the Mean AUC on cycle 1, day 15 for all cohorts (20 mg QD, 40 mg QD, 80 mg QD, 160 mg QD, 300 mg QD and 600 mg QD.
  • a dashed line represents the in vitro HAP1 MTAP Del GI90 and a dotted line represents the non-human primates no observed adverse effect level/highest non-severely toxic dose (NHP NOAEL)/HNSTD.
  • FIG. 19 shows the compaction profile for the crystalline form A of the compound of Formula (I), two different batches.
  • FIG. 20 shows the compaction profile for dosage forms containing 10 mg and 50 mg of crystalline form A of the compound of Formula (I) at 10% drug-load formulation as described in WO2024091551 and a dosage form containing 150 mg crystalline form A of the compound of Fonnula (I) at 40% drug-load formulation as described in the instant application.
  • FIG. 21 shows the particle size distribution for two lots of milled granules of a formulation as described in the instant application containing 40% drug-load of crystalline form A of the compound of Fonnula (I).
  • compositions and dosage forms containing crystalline form A of a compound of formula (1) methods of making the pharmaceutical compositions and dosage forms, and methods of using the pharmaceutical compositions to treat medical conditions, diseases, and disorders e.g., proliferation diseases such as cancers.
  • compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • an element means one element and/or in certain contexts more than one element.
  • a filler means one filler and/or in certain contexts more than one filler (e.g, a mixture of two or more fillers).
  • variables or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges.
  • an integer in the range of 0 to 40 is specifically intended to individually disclose 0. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22. 23. 24. 25. 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40
  • an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.
  • compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.
  • XRPD refers to X-ray powder diffraction.
  • An XRPD pattern is an x-y graph with 20 (diffraction angle) plotted on the x-axis and intensity plotted on the y-axis. These are the diffraction peaks which may be used to characterize a crystalline material.
  • the diffraction peaks are usually represented and referred to by their position on the x-axis rather than the intensity of the diffraction peaks on the y-axis because diffraction peak intensity can be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee & Web, pp. 255- 257 (2003)). Thus, intensity is not typically used by those of skill in the art to characterize a crystalline material.
  • variability 7 in XRPD data there may be variability 7 in XRPD data.
  • variability 7 in diffraction peak intensity there may also be variability in the position of the diffraction peaks on the x-axis. This variability can, however, typically be accounted for when reporting the positions of diffraction peaks for purposes of characterization.
  • Such variability in the position of diffraction peaks along the x-axis may be derived from several sources.
  • One such source can be sample preparation. Samples of the same cry stalline material prepared under different conditions may yield slightly different diffractograms. Factors such as particle size, moisture content, solvent content, temperature, and orientation may all affect how a sample diffracts X-rays. Another source of variability comes from instrument parameters.
  • Crystalline forms such as crystalline forms of a compound of formula (I) are readily analyzed by XRPD.
  • the data from x-ray powder diffraction may be used in multiple ways to characterize cry stalline forms.
  • the entire x-ray powder diffraction pattern output from a diffractometer may be used to characterize a crystalline form (e.g., of a compound of formula (I).
  • a smaller subset of such data may also be suitable and used for characterizing such cry stalline forms. Indeed, often even a single x-ray powder diffraction peak may be used to characterize such a cry stalline form.
  • any one or more of the peaks in the x-ray powder diffraction pattern of FIG. 1 may be used to characterize the crystalline form of a compound of formula (I) disclosed herein.
  • characteristic peaks when referring to the peaks in an XRPD pattern of a crystalline form of a given chemical entity (e.g., a crystalline form of a compound of formula (I)) refers to a collection of specific diffraction peaks whose values span a range of 20 values (e.g., 0°-40°) that are, as a whole, unique to that specific cry stalline form.
  • crystalline refers to a solid phase of a given chemical entity having well-defined 3 -dimensional structural order.
  • the atoms, ions, and/or molecules are arranged in a regular, periodic manner within a repeating 3-dimensional lattice.
  • a crystalline material may comprise one or more discreet crystalline forms.
  • crystalline form,’ 7 “crystalline solid form,” “crystal form,” “solid form,” and related terms herein refer to crystalline modifications comprising a given substance (e.g, the compound of formula (I)), including single-component crystal forms and multiple-component crystal forms, and including, but not limited to, polymorphs, solvates, hydrates, and salts.
  • substantially crystalline refers to solid forms that may be at least a particular weight percent crystalline. Particular weight percentages may include 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 70% and 100%.
  • the particular weight percent of crystallinity is at least 90%.
  • the particular weight percent of crystallinity is at least 95%.
  • the compound of formula (I) can be a substantially crystalline sample of any of the cry stalline solid forms described herein (e.g, a crystalline form with the XRPD pattern shown in FIG. 1).
  • the term “substantially pure” relates to the composition of a specific crystalline solid form (e.g., a crystalline form of the compound of formula (I)) that may be at least a particular weight percent free of impurities and/or other solid forms. Particular weight percentages may include 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%.
  • the compound of formula (I) can be a substantially pure sample of any of the crystalline solid forms described herein, (e.g., a crystalline form with the XRPD pattern show n in FIG. 1 (Form A)).
  • the compound of formula (I) can be a substantially pure cry stalline form with the XRPD pattern shown in FIG. 1 (Form A).
  • anhydrous or “anhydrate” when referring to a crystalline form means that no water molecules form a portion of the unit cell of the crystalline form.
  • An anhydrous crystalline form may nonetheless contain water molecules that do not form part of the unit cell of the anhydrous crystalline form (e.g., , as residual solvent molecule left behind from the production of the crystalline form).
  • water can make up about 0.5% by weight of the total composition of a sample of an anhydrous form. In a more preferred embodiment, water can make up about 0.2% by weight of the total composition of a sample of an anhydrous form.
  • a sample of an anhydrous cry stalline form of the compound of formula (I) contains no water molecules, e.g, no detectable amount of water.
  • the term “desolvated” or “unsolvated” when referring to a crystalline form means that no solvent molecules form a portion of the unit cell of the crystalline form.
  • An unsolvated crystalline form may nonetheless contain solvent molecules that do not form part of the unit cell of the unsolvated crystalline form (e.g, as residual solvent molecule left behind from the production of the crystalline form).
  • the solvent can make up 0.5% by weight of the total composition of a sample of an unsolvated form.
  • solvent can make up 0.2% by weight of the total composition of a sample of an unsolvated form.
  • a sample of an unsolvated crystalline form of the compound of formula (I) contains no solvent molecules, e.g, no detectable amount of solvent.
  • polymorph As used herein, the terms “polymorph.” “polymorphic form,” “polymorphs,” “polymorphic forms” and related terms herein refer to two or more crystal forms that consist essentially of the same molecule, molecules, or ions (e g., the compound of formula (I)). Different polymorphs may exhibit different physicochemical properties including, but not limited to, melting temperatures, solubilities, dissolution rates, and physical stabilities as a result of differences in the arrangement or conformation of the molecules or ions in the crystal lattice.
  • solvate when referring to a crystalline form of the compound of formula (I) means that solvent molecules (e.g., organic solvents and water), form a portion of the unit cell of the crystalline form. Solvates that contain water as the solvent are also referred to herein as “hydrates.”
  • dissolution profile refers to dissolution testing of a drug substance or drug product at multiple time points.
  • Dissolution profiles for drug substances e.g., the compound of formula (I)
  • drug products e.g., the pharmaceutical compositions described herein
  • dissolution testing may be predictive of or give insight into in vivo bioavailability of the drug substance.
  • Dissolution testing may be performed using USP testing protocols and dissolution apparatus.
  • granulation refers to a process of forming granules from a powdered or particulate material.
  • “Dry granulation” refers to a process in which granules are formed without the presence of a liquid solution and may be useful in the preparation of granules of materials sensitive to heat, moisture, or solvents.
  • roller compaction is a dry granulation process.
  • “Wet granulation” refers to the formation of granules wherein the particles are bound together using a binder or a liquid solution. Examples of wet granulation are high shear granulation and fluid bed granulation.
  • composition or “pharmaceutical formulation” refer to the combination of a therapeutically active agent with a pharmaceutically acceptable excipient, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • “Pharmaceutically acceptable” refers to compounds, molecular entities, compositions, materials and/or dosage forms that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or human, as appropriate; or means approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • pharmaceutically acceptable salt refers to any salt of an acidic or a basic group that may be present in a compound of the present disclosure (e.g., the compound of formula (I)), which salt is compatible with pharmaceutical administration.
  • salts of compounds may be derived from inorganic or organic acids and bases.
  • acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acid.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.
  • bases include, but are not limited to, alkali metal (e.g.. sodium and potassium) hydroxides, alkaline earth metal (e.g, magnesium and calcium) hydroxides, ammonia, and compounds of formula NW 4+ , wherein W is Ci-4 alkyl, and the like.
  • salts include, but are not limited, to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,
  • salts include anions of the compounds of the present disclosure compounded with a suitable cation such as Na + . K + . Ca 2+ . NH 4+ , and NW 4+ (where W can be a Ci-4 alkyl group), and the like.
  • salts of the compounds of the present disclosure are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • compositions of the present disclosure refers to a substance that aids the administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient.
  • Non-limiting examples of pharmaceutically acceptable excipients include binders, diluents, carriers, adjuvants, fillers (e.g., brittle diluents or fillers and ductile diluents or fillers), disintegrants, lubricants, coatings, sweeteners, flavors, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxypropyl methylcellulose, polyvinyl pyrrolidine, and colors, and the like.
  • fillers e.g., brittle diluents or fillers and ductile diluents or fillers
  • disintegrants e.g., brittle diluents or fillers and ductile diluents or fillers
  • lubricants e.g., g., g., g., brittle diluents or fillers and ductile diluents or fillers
  • diluents or fillers include, but are not limited to, a sugar (e.g., mannitol, lactose, sorbitol, lactitol, erythritol, sucrose, fructose, glucose, agarose, maltose, isomalt, poly dextrose, and combinations thereof), an inorganic material (e.g., dibasic calcium phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium sulfate, magnesium carbonate, magnesium oxide, bentonite, kaolin), calcium lactate, a starch (e.g., a pregelatinized starch), a microcrystalline cellulose, a silicified microcrystalline cellulose, a polysacchande, a
  • a sugar e.g., mannitol, lactose, sorbitol, lactitol, erythritol, sucrose, fructose, glucose
  • a hydroxypropyl cellulose a hypromellose, a carboxymethylcellulose, a methylcellulose, a hydroxypropyl methylcellulose, a hydroxy ethylcellulose), a dextrin, a maltodextrin, an alginate, a collagen, a polyvinylpyrrolidone, a polyvinyl acrylate, polyethylene oxide, and polyethylene glycol.
  • Sugar is defined herein to include sugar alcohols.
  • disintegrants include, but are not limited to, alginic acid, an alginate, primogel, a cellulose (e.g., hydroxypropyl cellulose), polacrillin potassium, sodium starch glycolate, sodium croscarmellose, a polyplasdone (e.g., a crospovidone), and a starch (e.g., com starch, pregelatinized starch, hydroxypropyl starch, and carboxymethyl starch).
  • a cellulose e.g., hydroxypropyl cellulose
  • polacrillin potassium sodium starch glycolate
  • sodium croscarmellose e.g., a crospovidone
  • a starch e.g., com starch, pregelatinized starch, hydroxypropyl starch, and carboxymethyl starch.
  • binders include, but are not limited to, a hydroxypropyl cellulose, hydroxyethylcellulose, a hydroxypropyl methylcellulose (e.g., a low viscosity' hydroxypropyl methylcellulose), a sugar, a polyvinylpyrrolidone, a polyvinyl alcohol, a polyvinyl acetate, a poly dextrose, a chitosan, a carrageenan, carbophil, a microcrystalline cellulose, gum tragacanth, guar gum, gellan gum, gelatin, and a starch (e.g., com starch).
  • a hydroxypropyl cellulose hydroxyethylcellulose
  • a hydroxypropyl methylcellulose e.g., a low viscosity' hydroxypropyl methylcellulose
  • a sugar e.g., a polyvinylpyrrolidone, a polyvinyl alcohol, a polyvinyl
  • wetting agents include, but are not limited to, a poloxamer (e.g., poloxamer 407), sodium dodecyl sulfate, sodium lauryl sulfate (SLS), sodium stearyl fumarate (SSF), a poly dimethylsiloxane, a polysorbate (e.g., polyoxyethylene 20 sorbitan mono-oleate (Tween® 20)), sorbitan monooleate, sorbitan trioleate, sorbitan laurate, sorbitan stearate, sorbitan monopalmitate, lecithin, sodium taurocholate, ursodeoxy cholate, poly ethoxylated castor oil, cetyl trimethylammonium bromide, nonoxynol, a-tocopherol polyethylene glycol 1000 succinate, and docusate sodium.
  • a poloxamer e.g., poloxamer 407
  • lubricants and glidants include, but are not limited to, a wax, a glyceride, a light mineral oil, a polyethylene glycol, sodium steary l fumarate, magnesium stearate, stearic acid, hydrogenated oil (e.g., hydrogenated vegetable oil), an alkyl sulfate, sodium benzoate, sodium acetate, glyceryl behenate, palmitic acid, and coconut oil.
  • glidants include, but are not limited to, colloidal silicon dioxide, colloidal silicon dioxide, talc, kaolin, bentonite, and activated carbon/charcoal.
  • colorants include, but are not limited to, titanium dioxide, aluminum lakes, iron oxides and carbon black.
  • coatings include but are not limited to, a film forming polymer (e.g., a hypromellose, a methyl cellulose, an ethylcellulose, cellulose acetate, a hydroxypropyl methyl cellulose, a hydroxypropyl cellulose, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, a polyvinylpyrrolidone, polyvinyl alcohol, a Eudragit/acrylate) and a plasticizer (e.g, triacetin, polyethylene glycol, propylene glycol).
  • a film forming polymer e.g., a hypromellose, a methyl cellulose, an ethylcellulose, cellulose acetate, a hydroxypropyl methyl cellulose, a hydroxypropyl cellulose, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, a polyvinylpyrrolidone, polyvin
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pills, tablets, capsules or the like in the case of solid compositions.
  • a “subject’' to which administration is contemplated includes, but is not limited to, humans (i.e.
  • a male or female of any age group e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a nonhuman animal, e.g., a mammal such as primates (e.g, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is anon-human animal.
  • solid dosage form means a pharmaceutical dose(s) in solid form, e.g., tablets, capsules, granules, powders, minitabs, sachets, stickpacks, reconstitutable powders, dry powder inhalers, lozenges, and chewables.
  • administering means oral administration, administration as a pulmonary, suppository, intramuscular administration, intrathecal administration, intranasal administration or subcutaneous administration, or the implantation of a slow-release device, e.g, a mini-osmotic pump, to a subject.
  • Administration is by any route, including transmucosal (e.g. , buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or).
  • Parenteral administration includes, e.g., intramuscular and subcutaneous. Other modes of delivery' include, but are not limited to, the use of liposomal formulations, etc.
  • co-administer it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., anti-cancer agent, chemotherapeutic, or treatment for a neurodegenerative disease).
  • additional therapies e.g., anti-cancer agent, chemotherapeutic, or treatment for a neurodegenerative disease.
  • the compound of formula (I) can be administered alone or can be co-administered to the patient.
  • Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent).
  • the preparations can also be combined, when desired, with other active substances (e.g, to reduce metabolic degradation).
  • disease As used herein, and unless otherwise specified, the terms “treat.” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment'’), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic treatment”).
  • the compounds provided herein are contemplated to be used in methods of therapeutic treatment wherein the action occurs while a subject is suffering from the specified disease, disorder or condition and results in a reduction in the severity of the disease, disorder or condition, or retardation or slowing of the progression of the disease, disorder or condition.
  • the compounds provided herein are contemplated to be used in methods of prophylactic treatment wherein the action occurs before a subject begins to suffer from the specified disease, disorder or condition and results in preventing a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or preventing the recurrence of the disease, disorder or condition.
  • the "effective amount” of a compound refers to an amount sufficient to elicit the desired biological response e.g, to treat a disease or disorder described herein.
  • the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment (z.e., encompasses a “therapeutically effective amount” and a “prophylactically effective amount”).
  • a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the therapeutic treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the therapeutic treatment of the disease, disorder or condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • HPLC high-pressure liquid chromatography
  • the “enantiomeric excess” (“e.e.”) or “% enantiomeric excess” (“%e.e.”) of a composition as used herein refers to an excess of one enantiomer relative to the other enantiomer present in the composition.
  • composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%.
  • the “diastereomeric excess” (“d.e.”) or “% diastereomeric excess” (“%d.e.”) of a composition as used herein refers to an excess of one diastereomer relative to one or more different diastereomers present in the composition.
  • composition containing 90% of one diastereomers and 10% of one or more different diastereomers is said to have a diastereomeric excess of 80%.
  • jV-(6-amino-5-ethylpyridin-3-yl)-2-((2 ?,5S)-5- methyl-2-(2-(l-methylpiperidin-4-yl)benzo[ ⁇ 7]thiazol-5-yl)piperidin-l-yl)-2-oxoacetamide a PRMT5 inhibitor (e.g.. an MTA-uncompetitive PRMT5 inhibitor) compound of formula (I).
  • the compound of formula (I) is also known as TNG462.
  • the compound of formula (I) is a crystalline form of the compound of formula (I).
  • the compound of formula (I) can also be referred to as “Compound I.”
  • Form A has an XRPD pattern with one or more (e.g, one, two, three or four) characteristic peaks between and including the following values of 20 in degrees: 4.2 to 4.6 (e.g, 4.4 ⁇ 0.2), 9.4 to 9.8 (e.g., 9.6 ⁇ 0.2), 16.6 to 17.0 (e.g, 16.8 ⁇ 0.2) and 24.3 to 24.7 (e.g, 24.5 ⁇ 0.2).
  • Form A has an XRPD pattern comprising characteristic peaks between and including the following values of 20 in degrees: 4.2 to 4.6 (e.g. 4.4 ⁇ 0.2). 9.4 to 9.8 (e.g.. 9.6 ⁇ 0.2), 16.6 to 17.0 (e.g., 16.8 ⁇ 0.2) and 24.3 to 24.7 (e.g., 24.5 ⁇ 0.2).
  • Form A has an XRPD pattern with one or more (e.g., one, two, three, four, five, six, seven or eight) characteristic peaks between and including the following values of 20 in degrees: 4.2 to 4.6 (e.g., 4.4 ⁇ 0.2), 9.4 to 9.8 (e.g., 9.6 ⁇ 0.2), 16.6 to 17.0 (e.g., 16.8 ⁇ 0.2), 18.4 to 18.8 (e.g.. 18.6 ⁇ 0.2), 19.2 to 19.6 (e.g.. 19.4 ⁇ 0.2), 20.7 to 21. l(e.g., 20.9 ⁇ 0.2), 23.5 to 23.9 (e.g., 23.7 ⁇ 0.2) and 24.3 to 24.7 (e.g., 24.5 ⁇ 0.2).
  • one or more e.g., one, two, three, four, five, six, seven or eight
  • Form A has an XRPD pattern comprising characteristic peaks between and including the following values of 20 in degrees: 4.2 to 4.6 (e.g., 4.4 ⁇ 0.2), 9.4 to 9.8 (e.g, 9.6 ⁇ 0.2), 16.6 to 17.0 (e.g, 16.8 ⁇ 0.2) and 24.3 to 24.7 (e.g, 24.5 ⁇ 0.2) and at least one additional characteristic peak selected from peaks between and including the following values of 20 in degrees: 18.4 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).
  • 18.4 to 18.8 e.g, 18.6 ⁇ 0.2
  • 19.2 to 19.6 e.g., 19.4 ⁇ 0.2
  • 23.5 to 23.9 e.g., 23.7 ⁇ 0.2
  • Form A has an XRPD pattern comprising characteristic peaks between and including the following values of 29 in degrees: 4.2 to 4.6 (e.g., 4.4 ⁇ 0.2), 9.4 to 9.8 (e.g, 9.6 ⁇ 0.2), 16.6 to 17.0 (e.g, 16.8 ⁇ 0.2), 18.4 to 18.8 (e.g, 18.6 ⁇ 0.2), 19.2 to 19.6 (e.g, 19.4 ⁇ 0.2), 20.7 to 21.1(e.g, 20.9 ⁇ 0.2), 23.5 to 23.9 (e.g., 23.7 ⁇ 0.2) and 24.3 to 24.7 (e.g., 24.5 ⁇ 0.2).
  • 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
  • 23.5 to 23.9 e.g., 23.7 ⁇ 0.2
  • 24.3 to 24.7
  • Form A has an XRPD pattern with one or more (e.g, one, two, three, four, five, six, seven, eight, nine or ten) characteristic peaks between and including the following values of 20 in degrees: 4.2 to 4.6 (e.g., 4.4 ⁇ 0.2), 9.4 to 9.8 (e.g., 9.6 ⁇ 0.2), 15.7 to 16.1 (e.g, 15.9 ⁇ 0.2). 16.6 to 17.0 (e.g, 16.8 ⁇ 0.2).
  • one or more e.g, one, two, three, four, five, six, seven, eight, nine or ten
  • 18.4 to 18.8 e.g, 18.6 ⁇ 0.2
  • 19.1 to 19.5 e.g, 19.3 ⁇ 0.2
  • 19.2 to 19.6 e.g, 19.4 ⁇ 0.2
  • 20.7 to 21.1 e.g., 20.9 ⁇ 0.2
  • 20.8 to 21.2 e.g, 21.0 ⁇ 0.2
  • 23.5 to 23.9 e.g., 23.7 ⁇ 0.2
  • 24.3 to 24.5 e.g., 24.5 ⁇ 0.2
  • 25.5 to 25.9 e.g., 25.7 ⁇ 0.2
  • 33.8 to 34.2 e.g, 34.0 ⁇ 0.2
  • the X-ray powder diffraction pattern for Form A may comprise one or more (e.g, one. two, three or four) characteristic peaks, in terms of 20, selected from the peaks at degrees: 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.8 ⁇ 0.2 and 24.5 ⁇ 0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least one characteristic peak, in terms of 20, selected from the peaks at degrees: 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.8 ⁇ 0.2 and 24.5 ⁇ 0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least two characteristic peaks, in terms of 20, selected from the peaks at degrees: 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.8 ⁇ 0.2 and 24.5 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least three characteristic peaks, in terms of 29, selected from the peaks at degrees: 4.4 ⁇ 0.2, 9.6 ⁇ 0.2. 16.8 ⁇ 0.2 and 24.5 ⁇ 0.2.
  • Form A has an XRPD pattern comprising characteristic peaks at the following values of 20 in degrees: 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.8 ⁇ 0.2 and 24.5 ⁇ 0.2.
  • the X-ray powder diffraction pattern for Form A may comprise one or more (e.g., one, two. three, four, five, six, seven or eight) characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2. 9.6 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6 ⁇ 0.2. 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.5 ⁇ 0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least one characteristic peak, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 16.8 ⁇ 0.2. 18.6 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.5 ⁇ 0.2.
  • the X- ray powder diffraction pattern for Form A comprises at least two characteristic peaks, in terms of 20, selected from the peaks at 4.4+0.2. 9.6+0.2, 16.8 ⁇ 0.2, 18.6 ⁇ 0.2. 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 23.7+0.2 and 24.5+0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least three characteristic peaks, in terms of 29, selected from the peaks at 4.4+0.2, 9.6+0.2, 16.8+0.2, 18.6+0.2, 19.4+0.2, 20.9+0.2, 23.7+0.2 and 24.5+0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least four characteristic peaks, in terms of 20, selected from the peaks at 4.4+0.2, 9.6+0.2, 16.8+0.2, 18.6+0.2, 19.4+0.2, 20.9+0.2, 23.7 ⁇ 0.2 and 24.5 ⁇ 0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least five characteristic peaks, in terms of 20, selected from the peaks at 4.4+0.2, 9.6+0.2, 16.8+0.2, 18.6+0.2, 19.4+0.2, 20.9+0.2, 23.7+0.2 and 24.5 ⁇ 0.2. In certain embodiments, the X-ray powder diffraction pattern for Form A comprises at least six characteristic peaks, in terms of 20, selected from the peaks at 4.4+0.2, 9.6+0.2, 16.8+0.2, 18.6+0.2, 19.4+0.2, 20.9 ⁇ 0.2, 23.7+0.2 and 24.5+0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least seven characteristic peaks, in terms of 20, selected from the peaks at 4.4+0.2, 9.6+0.2, 16.8+0.2, 18.6+0.2. 19.4+0.2, 20.9+0.2, 23.7 ⁇ 0.2 and 24.5 ⁇ 0.2.
  • Form A has an XRPD pattern comprising characteristic peaks at the following values of 20 in degrees :4.4 ⁇ 0.2, 9.6+0.2, 16.8+0.2, 19.3+0.2, 19.4+0.2, 20.9+0.2, 23.7+0.2, 24.5+0.2 and at least one additional characteristic peak at a value of 20 in degrees selected from: 19.3 ⁇ 0.2, 19.4 ⁇ 0.2. 20.9 ⁇ 0.2 and 23.7 ⁇ 0.2. In certain embodiments.
  • Form A has an XRPD pattern comprising characteristic peaks at the following values of 20 in degrees :4.4 ⁇ 0.2, 9.6+0.2, 16.8+0.2, 19.3+0.2, 19.4+0.2, 20.9+0.2, 23.7+0.2, 24.5+0.2 and at least two additional characteristic peaks at a value of 20 in degrees selected from: 19.3+0.2, 19.4+0.2, 20.9+0.2 and 23.7+0.2. In certain embodiments.
  • Form A has an XRPD pattern comprising characteristic peaks at the following values of 20 in degrees :4.4 ⁇ 0.2. 9.6+0.2, 16.8+0.2.
  • Form A has an XRPD pattern comprising characteristic peaks at the following values of 20 in degrees :4.4 ⁇ 0.2, 9.6+0.2, 16.8+0.2. 18.6+0.2, 19.4+0.2, 20.9+0.2, 23.7+0.2, 24.5+0.2.
  • the X-ray powder diffraction pattern for Form A may comprise one or more (e.g., one, tw o, three, four, five, six, seven, eight, nine, or ten) characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6 ⁇ 0.2, 19.3 ⁇ 0.2. 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 21.0 ⁇ 0.2, 23.7 ⁇ 0.2, 24.5 ⁇ 0.2, 25.7 ⁇ 0.2 and 34.0 ⁇ 0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least one characteristic peak, in terms of 29, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6 ⁇ 0.2, 19.3 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 21.0 ⁇ 0.2, 23.7 ⁇ 0.2, 24.5 ⁇ 0.2, 25.7 ⁇ 0.2 and 34.0 ⁇ 0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least two characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6, 19.3 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 21.0 ⁇ 0.2, 23.7 ⁇ 0.2, 24.5 ⁇ 0.2, 25.7 ⁇ 0.2 and 34.0 ⁇ 0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least three characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6, 19.3 ⁇ 0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least four characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6, 19.3 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 21.0 ⁇ 0.2, 23.7 ⁇ 0.2, 24.5 ⁇ 0.2, 25.7 ⁇ 0.2 and 34.0 ⁇ 0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least five characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6, 19.3 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 21.0 ⁇ 0.2, 23.7 ⁇ 0.2, 24.5 ⁇ 0.2, 25.7 ⁇ 0.2 and 34.0 ⁇ 0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least six characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6, 19.3 ⁇ 0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least seven characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6, 19.3 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 21.0 ⁇ 0.2, 23.7 ⁇ 0.2, 24.5 ⁇ 0.2, 25.7 ⁇ 0.2 and 34.0 ⁇ 0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least eight characteristic peaks, in terms of 20. selected from the peaks at 4.4 ⁇ 0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least nine characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6, 19.3 ⁇ 0.2. 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 21.0 ⁇ 0.2, 23.7 ⁇ 0.2. 24.5 ⁇ 0.2, 25.7 ⁇ 0.2 and 34.0 ⁇ 0.2.
  • the X-ray powder diffraction pattern for Form A comprises at least ten characteristic peaks, in terms of 20, selected from the peaks at 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.8 ⁇ 0.2, 18.6, 19.3 ⁇ 0.2, 19.4 ⁇ 0.2, 20.9 ⁇ 0.2, 21.0 ⁇ 0.2, 23.7 ⁇ 0.2, 24.5 ⁇ 0.2. 25.7 ⁇ 0.2 and 34.0 ⁇ 0.2.
  • Form A has an XRPD pattern comprising characteristic peaks at the following values of 20 in degrees: 4.4 ⁇ 0.2, 9.6 ⁇ 0.2, 15.9 ⁇ 0.2. 16.8 ⁇ 0.2, 18.6, 19.3 ⁇ 0.2, 19.4 ⁇ 0.2. 20.9 ⁇ 0.2, 21.0 ⁇ 0.2, 23.7 ⁇ 0.2, 24.5 ⁇ 0.2 and 25.7 ⁇ 0.2. 34.0 ⁇ 0.2.
  • Form A has an XRPD pattern (obtained using CuKa radiation) with characteristic peaks comprising one, two, three, four, five, six. seven, eight, nine, or ten characteristic peaks, in terms of 20 values in degrees shown in Table 1 ( ⁇ 0.2 degrees).
  • Form A is substantially characterized by the thermal gravimetric analysis (TGA) as shown in FIG. 2A.
  • Form A is substantially characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 2B. In some embodiments. Form A can be characterized by the differential scanning calorimetry profile (DSC) shown in FIG. 2B, showing a melt peak at about 145.8 °C.
  • Form A is substantially characterized by the DVS profile as shown in FIG. 3A and FIG. 3B.
  • the crystalline form of the compound of formula (I) comprises a mixture of two or more crystalline forms. In some embodiments, the crystalline form of the compound of formula (I) is substantially pure crystalline Form A.
  • the crystalline form A of the compound of formula (I) has a DIO of between 2-4 pm.
  • the API comprising crystalline form A of the compound of formula (I) has a D50 of betw een 6-10 pm.
  • the API comprising crystalline form A of the compound of formula (I) has a D90 of between 18-35 pm.
  • the API comprising crystalline form A of the compound of formula (I) D90 of between 25-30 pm.
  • the API comprising crystalline form A of the compound of formula (I) has a D90 of less than 30 pm.
  • API comprising cry stalline form A of the compound of formula (I) is subjected to wet milling prior to incorporation in the pharmaceutical compositions and dosage forms described herein to optimize particle size.
  • the crystalline Form A of the compound of Formula (I) is partly plastic (not highly compressible) as shown in FIG. 19.
  • a change in compression force from 2-5 kN and from 4-8 kN, respectively only resulted in an increase in hardness from 60-80 N to 130-140N, with signs of plateauing at the higher compression forces.
  • the compressibility index for the API is -43-49% (for the same two batches used for the data shown in FIG. 19), which is considered extremely poor under United States Pharmacopeia (USP) guidelines (see Table. 2).
  • the compressibility index is calculated as: lOO(Vo-Vf)/Vo where Vf is the tapped volume and Vo is the untapped volume of a given amount of compound.
  • the Hausner ratio for the API was found to be in the range of 1.76-1.95 for the two batches, which is also considered extremely poor under USP guidelines.
  • the Hausner ratio is the ratio of bulk density to tapped density, also expressed as Vf/Vo (where Vf is the tapped volume and Vo is the untapped volume of a given amount of compound). Vo and Vf can be determined, for example, as described in USP ⁇ 616>.
  • the first-generation formulation containing 10% drug load resulted in an improvement in compressibility compared to API alone, as seen in FIG. 20. but due to the poor compressibility' of the API it would not be expected that the improvement in compressibility would be maintained for higher API loads without additional changes to the formulation. Simply increasing the drug load in the first-generation formulation would result in poorer flowability' of the powder blend, which in turn would lead to manufacturability issues such as inadequate blend uniformity, insufficient compressibility and sticking to equipment.
  • compositions comprising API’s with poor compressibility (“plastic” APIs)
  • a combination of fillers including “brittle” fillers such as lactose or mannitol is recommended in the intragranular blend to achieve high drug loads (See, e.g., Teng, et al.. “Systematical approach of formulation and process development using roller compaction”, European Journal of Pharmaceutics and Biopharmaceutics, 73 (2009) 219-229, Section 2.1.2).
  • binders are generally required for intragranular blends to be used in dry granulation processes to ensure granules that have adequate strength, can be deformed, and can be mixed homogenously with extragranular components (See Teng, section 2.2).
  • the high API-load pharmaceutical compositions described herein in which granules represent -85% of the formulation achieve higher compressibility (FIG. 20) and granule density (Table. 3) than the first-generation low API-load compositions.
  • higher granule density corelates with better compressibility.
  • the granules obtained with the instant formulations can be milled to obtain a favorable and reproducible mix of small and large particles (FIG. 21).
  • the pharmaceutical compositions disclosed herein achieve high API loads (e.g.. 40%) and adequate properties such as tablet strength, particle size distribution, density and flow while using a single intragranular filler, a glidant, a disintegrant and a lubricant only, with no addition of binders.
  • the instant formulations display consistent performance for small and large scale production (Table. 3) with equal or better properties compared to the low API-load formulations previously disclosed.
  • compositions comprising crystalline Form A of a compound of formula (I) and at least one pharmaceutically acceptable excipient, wherein cry stalline Form A is as described herein.
  • compositions comprising as the pharmaceutically active ingredient a compound of formula (I) and at least one pharmaceutically acceptable excipient, wherein the compound of formula (I) is present as cry stalline Form A as described herein.
  • pharmaceutical compositions comprising crystalline Form A of a compound of formula (I) and at least one pharmaceutically acceptable excipient, wherein crystalline Form A is as described herein and the pharmaceutically acceptable excipient comprises microcrystal line cellulose PH 101.
  • compositions comprising as the pharmaceutically active ingredient a compound of formula (I) and at least one pharmaceutically acceptable excipient, wherein the compound of formula (I) is present as crystalline Form A as described herein and the pharmaceutically acceptable excipient comprises microcrystalline cellulose PH 101.
  • composition comprising:
  • composition compnsing a pharmaceutical composition compnsing:
  • composition comprising:
  • a filler comprising microcrystalline cellulose PH 101 and microcrystalline cellulose PH 102.
  • a pharmaceutical composition comprising:
  • composition comprises one or more additional pharmaceutically acceptable excipients.
  • compositions and dosage forms described herein are characterized by relatively high API loads, which are beneficial for minimizing dosage form (e g., tablet) size, thus improving patient dosing convenience.
  • High API loads particularly in the case of crystalline APIs such as the instant case can result in blends with sub-optimal manufacturability properties (e.g., uniformity, flow, compressibility, API release profiles) requiring careful optimization of the pharmaceutical excipients.
  • the pharmaceutical composition comprises about 35% (w/w) to about 60% (w/w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 35% (w/w) to about 55% (w/w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 35% (w/w) to about 50% (w/w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 40% (w/w) to about 50% (w/w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 40% (w/w) to about 60% (w/w) of a compound of formula (I).
  • the pharmaceutical composition comprises about 40% (w/w) to about 55% (w/w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 40% (w/w) to about 50% (w/w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 40% (w/w) to about 45% (w/w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 35% (w/w) to about 45% (w/w) of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 37% (w/w) to about 43% (w/w) of a compound of formula (I).
  • the pharmaceutical composition comprises about 38% (w/w) to about 42% (w/w) of crystalline form A of a compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 39% (w/w) to about 41% (w/w) of a compound of formula (I).
  • the pharmaceutical composition comprises about 35% (w/w), about 36% (w/w), about 37% (w/w), about 38% (w/w), about 39% (w/w), about 40% (w/w), about 41% (w/w), about 42% (w/w), about 43% (w/w), about 44% (w/w), about 45% (w/w), about 46% (w/w), about 47% (w/w), about 48% (w/w), about 49% (w/w) or about 50% (w/w) of the compound of formula (I).
  • the pharmaceutical composition comprises about 35% (w/w), about 36% (w/w), about 37% (w/w), about 38% (w/w), about 39% (w/w), about 40% (w/w), about 41% (w/w), about 42% (w/w), about 43% (w/w), about 44% (w/w) or about 45% (w/w) of the compound of formula (I).
  • the pharmaceutical composition comprises about 35% (w/w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 36% (w/w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 37% (w/w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 38% (w/w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 39% (w/w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 39.8% (w/w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 40% (w/w) of the compound of formula (I).
  • the pharmaceutical composition comprises about 41% (w/w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 42% (w/w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 43% (w/w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 44% (w/w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 45% (w/w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 46% (w/w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 47% (w/w) of the compound of formula (I).
  • the pharmaceutical composition comprises about 48% (w/w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 49% (w/w). In some embodiments, the pharmaceutical composition comprises about 50% (w/w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 55% (w/w) of the compound of formula (I). In some embodiments, the pharmaceutical composition comprises about 60% (w/w) of the compound of formula (I).
  • the filler comprises a sugar, an inorganic material, a microcry stalline cellulose, a starch, a polysaccharide, a cellulose, a polyvinylpyrrolidone, a polyvinyl acrylate or combinations thereof.
  • the filler comprises a sugar, an inorganic material, and combinations thereof.
  • the sugar is selected from the group consisting of mannitol, lactose, sucrose, fructose, glucose, maltose, and combinations thereof.
  • the inorganic material is selected from the group consisting of dibasic calcium phosphate, hydroxyapatite, sodium carbonate, sodium bicarbonate, calcium carbonate, bentonite, kaolin, and combinations thereof.
  • the filler comprises a microcrystalline cellulose, a starch, a polysaccharide, a cellulose, a polyvinylpyrrolidone, a polyvinyl acrylate, and combinations thereof.
  • the cellulose is selected from the group consisting of a hydroxypropyl cellulose, ahypromellose, a carboxymethylcellulose, a methylcellulose, a hydroxypropyl methylcellulose, or combinations thereof.
  • the filler comprises microcrystalline cellulose (e.g, Avicel®).
  • the microcrystalline cellulose filler can be of different grades.
  • the filler comprises microcrystalline cellulose PH 101, PH 102 or a mixture thereof.
  • the filler comprises microcry stalline cellulose PH 101 (e.g., Avicel® PH 101).
  • a portion of the filler comprises microcrystalline cellulose PH 101 (e.g. Avicel® PH 101) and another portion of the filler comprises microcrystalline cellulose PH 102 (e.g, Avicel® PH 102).
  • the filler used in the intragranular blend comprises microcrystalline cellulose PH 101 and the filler used in the extragranular blend comprises microcrystalline cellulose PH 102. In some embodiments, the filler used in the intragranular blend consists substantially of microcrystalline cellulose PH 101 and the filler used in the extragranular blend consists substantially of microcrystalline cellulose PH 102.
  • the pharmaceutical composition comprises about 30% (w/w) to about 60% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 40% (w/w) to about 60% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 50% (w/w) to about 60% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 52% (w/w) to about 58% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 52% (w/w) to about 56% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 53% (w/w) to about 54% (w/w) filler.
  • the pharmaceutical composition comprises about 40% (w/w), about 41% (w/w), about 42% (w/w), about 43% (w/w), about 44% (w/w), about 45% (w/w), about 46% (w/w), about 47% (w/w). about 48% (w/w), about 49% (w/w), about 50% (w/w), about 51% (w/w), about 52% (w/w), about 53% (w/w), about 54% (w/w), about 55% (w/w), about 56% (w/w), about 57% (w/w). about 58% (w/w) filler or about 60% (w/w) filler.
  • the pharmaceutical composition comprises about 50% (w/w), about 51% (w/w). about 52% (w/w), about 53% (w/w), about 54% (w/w), about 55% (w/w), about 56% (w/w), about 57% (w/w), about 58% (w/w) filler or about 60% (w/w) filler.
  • the pharmaceutical composition comprises about 40% (w/w) filler.
  • the pharmaceutical composition comprises about 41% (w/w) filler.
  • the pharmaceutical composition comprises about 42% (w/w) filler.
  • the pharmaceutical composition comprises about 43% (w/w) filler.
  • the pharmaceutical composition comprises about 44% (w/w) filler.
  • the pharmaceutical composition comprises about 45% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 46% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 47% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 48% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 49% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 50% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 51 % (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 52% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 53% (w/w) filler.
  • the pharmaceutical composition comprises about 53.7% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 54% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 55% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 56% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 57% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 58% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 59% (w/w) filler. In some embodiments, the pharmaceutical composition comprises about 60% (w/w) filler.
  • the pharmaceutical composition comprises about 30% (w/w) to about 60% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 40% (w/w) to about 60% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 50% (w/w) to about 60% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 52% (w/w) to about 58% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 52% (w/w) to about 56% (w/w) microcry stallinc cellulose.
  • the pharmaceutical composition comprises about 40% (w/w), about 41% (w/w), about 42% (w/w), about 43% (w/w), about 44% (w/w), about 45% (w/w), about 46% (w/w), about 47% (w/w), about 48% (w/w), about 49% (w/w), about 50% (w/w), about 51% (w/w), about 52% (w/w), about 53% (w/w), about 54% (w/w), about 55% (w/w), about 56% (w/w), about 57% (w/w). about 58% (w/w) or about 60% (w/w) microcrystalline cellulose.
  • the pharmaceutical composition comprises about 50% (w/w), about 51% (w/w), about 52% (w/w), about 53% (w/w), about 54% (w/w), about 55% (w/w), about 56% (w/w), about 57% (w/w), about 58% (w/w) microcrystalline cellulose or about 60% (w/w) microcrystalline cellulose.
  • the pharmaceutical composition comprises about 40% (w/w) microcrystalline cellulose.
  • the pharmaceutical composition comprises about 41% (w/w) microcrystalline cellulose.
  • the pharmaceutical composition comprises about 42% (w/w) microcry stalline cellulose.
  • the pharmaceutical composition comprises about 43% (w/w) microcrystalline cellulose.
  • the pharmaceutical composition comprises about 44% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 45% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 46% (w/w) microcry stalline cellulose. In some embodiments, the pharmaceutical composition comprises about 47% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 48% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 49% (w/w) microcry stalline cellulose. In some embodiments, the pharmaceutical composition comprises about 50% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 51% (w/w) microcrystalline cellulose.
  • the pharmaceutical composition comprises about 52% (w/w) microcry stalline cellulose. In some embodiments, the pharmaceutical composition comprises about 53% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 53.7% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 54% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 55% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 56% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 57% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 58% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 59% (w/w) microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises about 60% (w/w) microcrystalline cellulose.
  • the pharmaceutical composition comprises a glidant.
  • the glidant comprises colloidal silicon dioxide, talc, kaolin, bentonite, or combinations thereof.
  • the glidant comprises colloidal silicon dioxide.
  • the glidant consists substantially of colloidal silicon dioxide.
  • the colloidal silicon dioxide is prepared through a process involving flame hydrolysis of silicon tetrachloride in an oxy -hydrogen flame and is referred to as “fumed silica” or “untreated fumed silica” (e.g., Aerosil® 200, CAB-O-SIL® M-5P).
  • the amount of glidant in the composition influences blend flow and compressibility, and the selected amounts of glidant in the pharmaceutical compositions described herein result in improved blend flow, contributing to adequate granulation for the intragranular blend and improved compressibility for the extragranular blend.
  • the pharmaceutical composition comprises about 1.0% (w/w) to about 3.0% (w/w) glidant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w/w) to about 2.5% (w/w) glidant. In some embodiments, the pharmaceutical composition comprises about 1.75% (w/w) to about 2.25% (w/w) glidant. In some embodiments, the pharmaceutical composition comprises about 1.9% (w/w) to about 2. 1% (w/w) glidant.
  • the pharmaceutical composition comprises about 1.5% (w/w), about 1.75% (w/w), about 1.9% (w/w), about 2% (w/w), about 2.1% (w/w), about 2.25% (w/w), about 2.5% (w/w) or about 3% (w/w) glidant.
  • the pharmaceutical composition comprises about 1.5% (w/w) glidant.
  • the pharmaceutical composition comprises about 1.75% (w/w) glidant.
  • the pharmaceutical composition comprises about 1.9% (w/w) glidant.
  • the pharmaceutical composition comprises about 2.0% (w/w) glidant.
  • the pharmaceutical composition comprises about 2.1% (w/w) glidant. In some embodiments, the pharmaceutical composition comprises about 2.25% (w/w) glidant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w/w) glidant. In some embodiments, the pharmaceutical composition comprises about 3% (w/w) glidant. [0198] In some embodiments, the pharmaceutical composition comprises about 1.0% (w/w) to about 3.0% (w/w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.5% (w/w) to about 2.5% (w/w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.75% (w/w) to about 2.25% (w/w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.9% (w/w) to about 2.1% (w/w) colloidal silicon dioxide.
  • the pharmaceutical composition comprises about 1.5% (w/w). about 1.75% (w/w), about 1.9% (w/w), about 2.0% (w/w), about 2.1% (w/w), about 2.25% (w/w), about 2.5% (w/w) or about 3% (w/w) colloidal silicon dioxide.
  • the pharmaceutical composition comprises about 1.5% (w/w) colloidal silicon dioxide.
  • the pharmaceutical composition comprises about 1.75% (w/w) colloidal silicon dioxide.
  • the pharmaceutical composition comprises about 1.9% (w/w) colloidal silicon dioxide.
  • the pharmaceutical composition comprises about 2.0% (w/w) colloidal silicon dioxide.
  • the pharmaceutical composition comprises about 2.1% (w/w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 2.25% (w/w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 2.5% (w/w) colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 3% (w/w) colloidal silicon dioxide.
  • the pharmaceutical composition comprises a disintegrant.
  • the disintegrant comprises sodium starch glycolate, a crospovidone, croscarmellose sodium, or combinations thereof.
  • the disintegrant comprises croscarmellose sodium (e.g., Ac-Di-Sol®).
  • the disintegrant consists substantially of croscarmellose sodium (e.g, Ac-Di-Sol®).
  • the pharmaceutical composition comprises about 2% (w/w) to about 4% (w/w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w/w) to about 3.5% (w/w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.75% (w/w) to about 3.25% (w/w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.9% (w/w) to about 3. 1% (w/w) disintegrant.
  • the pharmaceutical composition comprises about 2.0% (w/w), about 2.25% (w/w), about 2.5% (w/w), about 2.75% (w/w), about 2.9% (w/w), about 3% (w/w), about 3.1% (w/w), about 3.25% (w/w), about 3.5% (w/w), about 3.75% (w/w) or about 4.0% (w/w) disintegrant.
  • the pharmaceutical composition comprises about 2.0% (w/w) disintegrant.
  • the pharmaceutical composition comprises about 2.25% (w/w) disintegrant.
  • the pharmaceutical composition comprises about 2.5% (w/w) disintegrant.
  • the pharmaceutical composition comprises about 2.75% (w/w) disintegrant.
  • the pharmaceutical composition comprises about 2.9% (w/w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 3% (w/w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.1% (w/w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.25% (w/w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.5% (w/w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 3.75% (w/w) disintegrant. In some embodiments, the pharmaceutical composition comprises about 4.0% (w/w) disintegrant.
  • the pharmaceutical composition comprises about 2% (w/w) to about 4% (w/w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.5% (w/w) to about 3.5% (w/w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.75% (w/w) to about 3.25% (w/w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.9% (w/w) to about 3.1% (w/w) croscarmellose sodium.
  • the pharmaceutical composition comprises about 2.0% (w/w), about 2.25% (w/w), about 2.5% (w/w), about 2.75% (w/w), about 2.9% (w/w). about 3% (w/w). about 3. 1% (w/w). about 3.25% (w/w), about 3.5% (w/w), about 3.75% (w/w) or about 4.0% (w/w) croscarmellose sodium.
  • the pharmaceutical composition comprises about 2.0% (w/w) croscarmellose sodium.
  • the pharmaceutical composition comprises about 2.25% (w/w) croscarmellose sodium.
  • the pharmaceutical composition comprises about 2.5% (w/w) croscarmellose sodium.
  • the pharmaceutical composition comprises about 2.75% (w/w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.9% (w/w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3% (w/w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.1% (w/w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.25% (w/w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.5% (w/w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 3.75% (w/w) croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 4.0% (w/w) croscarmellose sodium.
  • the pharmaceutical composition comprises a lubricant.
  • the lubricant comprises sodium stearyl fumarate, magnesium stearate, stearic acid, glyceryl behenate, or combinations thereof.
  • the lubricant comprises magnesium stearate. In some embodiments, the lubricant consists substantially of magnesium stearate.
  • the pharmaceutical composition comprises about 0.5% (w/w) to about 2.0% (w/w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% (w/w) to about 1.5% (w/w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w/w) to about 1.25% (w/w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w/w) to about 1.1% (w/w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w/w) to about 1.05% (w/w) lubricant.
  • the pharmaceutical composition comprises about 1.25% (w/w) to about 1.75% (w/w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w/w) to about 1.6% (w/w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1 .45% (w/w) to about 1.55% (w/w) lubricant.
  • 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.
  • the pharmaceutical composition comprises about 0.5% (w/w) lubricant.
  • the pharmaceutical composition comprises about 0.75% (w/w) lubricant.
  • the pharmaceutical composition comprises about 0.8% (w/w) lubricant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w/w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w/w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.05% (w/w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.1% (w/w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.2% (w/w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w/w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w/w) lubricant. In some embodiments, the pharmaceutical composition comprises about 1.75% (w/w) lubricant. In some embodiments, the pharmaceutical composition comprises about 2.0% (w/w) lubricant.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition comprises about 0.5% (w/w) magnesium stearate.
  • the pharmaceutical composition comprises about 0.75% (w/w) magnesium stearate.
  • the pharmaceutical composition comprises about 0.8% (w/w) magnesium stearate.
  • 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.
  • a pharmaceutical composition comprising: (a) cry stalline form A of a compound of formula (I) as described herein
  • a glidant e.g., colloidal silicon dioxide
  • a disintegrant e.g.. croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • the compound of formula (I), the filler, the glidant, the disintegrant and the lubricant are present in the amounts described herein.
  • composition comprising:
  • a glidant e.g., colloidal silicon dioxide
  • a disintegrant e.g., croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • the compound of formula (I), the filler, the glidant. the disintegrant and the lubricant are present in the amounts described herein.
  • composition comprising:
  • a glidant e.g., colloidal silicon dioxide
  • a disintegrant e.g., croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • composition comprising:
  • a glidant e.g., colloidal silicon dioxide
  • a disintegrant e.g., croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • the composition comprises:
  • a glidant e.g., colloidal silicon dioxide
  • a disintegrant e.g., croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • the composition comprises:
  • a glidant e.g., colloidal silicon dioxide
  • a lubricant e.g, magnesium stearate
  • the composition comprises:
  • a glidant e.g, colloidal silicon dioxide
  • a disintegrant e.g, croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • the composition comprises:
  • a glidant e.g., colloidal silicon dioxide
  • a disintegrant e.g., croscarmellose sodium
  • the composition comprises:
  • a glidant e.g., colloidal silicon dioxide
  • a disintegrant e.g., croscarmellose sodium
  • the composition comprises:
  • a glidant e.g., colloidal silicon dioxide
  • a disintegrant e.g., croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • the composition comprises:
  • a glidant e.g., colloidal silicon dioxide
  • a disintegrant e.g, croscarmellose sodium
  • a lubricant e.g, magnesium stearate
  • the composition comprises:
  • a glidant e.g, colloidal silicon dioxide
  • a disintegrant e.g, croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • a glidant e.g, colloidal silicon dioxide
  • a lubricant e.g, magnesium stearate
  • the composition comprises: (a) about 39% (w/w) to 41% (w/w) of the cry stalline form A of compound of formula (I) ;
  • a glidant e.g., colloidal silicon dioxide
  • a disintegrant e.g., croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • the composition comprises:
  • a filler e.g., microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;
  • a glidant e.g, colloidal silicon dioxide
  • a disintegrant e.g., croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • the composition comprises:
  • a filler e.g., microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;
  • a glidant e.g, colloidal silicon dioxide
  • a disintegrant e.g., croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • the composition comprises:
  • a filler e.g., microcrystalline PH 101 or a combination of microcrystalline cellulose PH 101 and PH 102;
  • a glidant e.g., colloidal silicon dioxide
  • a disintegrant e.g, croscarmellose sodium
  • a lubricant e.g., magnesium stearate
  • composition comprising:
  • the composition comprises:
  • the composition comprises:
  • the composition comprises:
  • the composition comprises:
  • the composition comprises:
  • the composition comprises:
  • the composition comprises:
  • the composition comprises:
  • the composition comprises:
  • the composition comprises:
  • the pharmaceutically acceptable excipients can be present in either the intragranular or the extragranular components of the pharmaceutical composition. In some embodiments, one or more pharmaceutically acceptable excipients are present in both the intragranular and the extragranular components.
  • the pharmaceutical composition contains an intragranular filler is selected from the fillers described herein.
  • the intragranular filler comprises microcrystalline cellulose (e.g. Avicel*).
  • the intragranular filler consists substantially of a microcrystalline cellulose (e.g., Avicel®). The average particle size of the microcrystalline cellulose affects binding to the active ingredient and additional excipients and a closer match between the particle size of the API and the particle size of the microcrystalline cellulose is believed to contribute to better binding and better manufacturability.
  • the intragranular filler comprises a microcrystalline cellulose PH 101 (e.g., Avicel® PH 101). In some embodiments, the intragranular filler consists substantially of a microcrystalline cellulose PH 101 (e.g.. Avicel® PH 101).
  • the ratio of API to intragranular filler can influence the uniformity of API in the blend and lower ratios of API to intragranular filler can make it more difficult to achieve acceptable API uniformity.
  • the w/w ratio of API to intragranular filler is between 0.9 and 1.6. In some embodiments, the w/w ratio of API to intragranular filler is between 0.9 and 1.4. In some embodiments, the w/w ratio of API to intragranular filler is between 0.9 and 1.2. In some embodiments, the w/w ratio of API to intragranular filler is between 0.9 and 1. 1. In some embodiments, the w/w ratio of API to intragranular filler is between 0.9 and 1.05.
  • the w/w ratio of API to intragranular filler is between 0.9 and 1.0. In some embodiments, the w/w ratio of API to intragranular filler is between 0.95 and 1.05. In some embodiments, the w/w ratio of API to intragranular filler is between 0.95 and 1.0. In some embodiments, the w/w ratio of API to intragranular filler is about 0.95.
  • the pharmaceutical composition comprises about 20% (w/w) to about 50% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 25% (w/w) to about 50% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 30% (w/w) to about 50% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 35% (w/w) to about 50% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 38% (w/w) to about 46% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 40% (w/w) to about 44% (w/w) intragranular filler.
  • the pharmaceutical composition comprises about 41% (w/w) to about 43% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 41.5% (w/w) to about 42.5% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 25% (w/w), about 26% (w/w), about 27% (w/w), about 28% (w/w), about 29% (w/w), about 30% (w/w), about 31% (w/w), about 32%
  • the pharmaceutical composition comprises about 35% (w/w), about 36% (w/w), about 37% (w/w), about 38% (w/w), about 39% (w/w), about 40% (w/w), about 41% (w/w), about 42% (w/w). about 43% (w/w), about 44% (w/w), about 45% (w/w), about 46% (w/w), about 47% (w/w). about 48% (w/w), about 49% (w/w), or about 50% (w/w) intragranular filler.
  • the pharmaceutical composition comprises about 38% (w/w), about 39% (w/w), about 40% (w/w), about 41% (w/w), about 42% (w/w), about 43% (w/w), about 44% (w/w), about 45% (w/w), about 46% (w/w) or about 47% (w/w) intragranular filler.
  • the pharmaceutical composition comprises about 25% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 26% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 27% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 28% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 29% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 30% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 31% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 32% (w/w) intragranular filler.
  • the pharmaceutical composition comprises about 33% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 34% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 35% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 36% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 37% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 38% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 39% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 40% (w/w) intragranular filler.
  • the pharmaceutical composition comprises about 41% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 41.8% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 42% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 43% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 44% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 45% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 46% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 47% (w/w) intragranular filler.
  • the pharmaceutical composition comprises about 48% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 49% (w/w) intragranular filler. In some embodiments, the pharmaceutical composition comprises about 50% (w/w) intragranular filler.
  • the pharmaceutical composition comprises about 20% (w/w) to about 50% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 25% (w/w) to about 50% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 30% (w/w) to about 50% (w/w) intragranular microcrystallinc cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 35% (w/w) to about 50% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 38% (w/w) to about 46% (w/w) intragranular microcrystalline cellulose PH 101.
  • the pharmaceutical composition comprises about 40% (w/w) to about 44% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 41% (w/w) to about 43% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 41.5% (w/w) to about 42.5% (w/w) microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 25% (w/w). about 26% (w/w), about 27% (w/w), about 28% (w/w), about 29% (w/w), about 30% (w/w), about 31% (w/w), about 32% (w/w), about 33% (w/w), about 34%
  • the pharmaceutical composition comprises about 35% (w/w), about 36% (w/w), about 37% (w/w). about 38% (w/w), about 39% (w/w), about 40% (w/w), about 41% (w/w), about 42% (w/w), about 43% (w/w), about 44% (w/w), about 45% (w/w), about 46% (w/w), about 47% (w/w), about 48% (w/w), about 49% (w/w), or about 50% (w/w) intragranular microcrystalline cellulose PH 101.
  • the pharmaceutical composition comprises about 38% (w/w), about 39% (w/w), about 40% (w/w), about 41% (w/w), about 42% (w/w), about 43% (w/w), about 44% (w/w), about 45% (w/w), about 46% (w/w) or about 47% (w/w) intragranular microcrystalline cellulose PH 101.
  • the pharmaceutical composition comprises about 25% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 26% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 27% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 28% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 29% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 30% (w/w) intragranular microcrystalline cellulose PH 101.
  • the pharmaceutical composition comprises about 31% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 32% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 33% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 34% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 35% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 36% (w/w) intragranular microcrystalline cellulose PH 101.
  • the pharmaceutical composition comprises about 37% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 38% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 39% (w/w) intragranular microcry stalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 40% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 41% (w/w) intragranular microcry stalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 41.8% (w/w) intragranular microcrystalline cellulose PH 101.
  • the pharmaceutical composition comprises about 42% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 43% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 44% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 45% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 46% (w/w) intragranular microcrystalline cellulose PH 101. In some embodiments, the pharmaceutical composition comprises about 47% (w/w) intragranular microcrystalline cellulose PH 101.
  • the pharmaceutical composition contains an extragranular filler selected from the fillers described herein. Addition of an extragranular filler results in better compression compared to high API compositions lacking an extragranular filler.
  • the extragranular filler comprises a microcrystalline cellulose (e.g, Avicel®).
  • the extragranular filler consists substantially of a microcrystalline cellulose (e.g., Avicel®). Because the intragranular phase represents a large proportion of the final composition, the properties of the extragranular filler (e.g. , filler particle size distribution, flow, etc.) should be selected to match the behavior of the granules and to avoid a negative impact on the flow and compressibility of the final mixture.
  • the extragranular filler comprises microcrystalline cellulose PH 102 (e.g., Avicel® PH 102). In some embodiments, the extragranular filler consists substantially of microcrystalline cellulose PH 102 (e.g., Avicel® PH 102). [0248] In some embodiments, the pharmaceutical composition comprises about 5% (w/w) to about 20% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 8% (w/w) to about 16% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 10% (w/w) to about 14% (w/w) extragranular filler.
  • the pharmaceutical composition comprises about 11% (w/w) to about 13% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 11.5% (w/w) to about 12.5% (w/w) extragranular filler.
  • the pharmaceutical composition comprises about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w), about 10% (w/w), about 11% (w/w), about 12% (w/w), about 13% (w/w), about 14% (w/w), about 15% (w/w), about 16% (w/w) , about 17% (w/w) , about 18% (w/w) , about 19% (w/w) or about 20% (w/w) extragranular filler.
  • the pharmaceutical composition comprises about 8% (w/w), about 9% (w/w), about 10% (w/w), about 11% (w/w), about 12% (w/w), about 13% (w/w), about 14% (w/w), about 15% (w/w) or about 16% (w/w) extragranular filler.
  • the pharmaceutical composition comprises about 5% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 6% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 7% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 8% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 9% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 10% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 11% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 12% (w/w) extragranular filler.
  • the pharmaceutical composition comprises about 13% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 14% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 15% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 16% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 17% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 18% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 19% (w/w) extragranular filler. In some embodiments, the pharmaceutical composition comprises about 20% (w/w) extragranular filler.
  • the pharmaceutical composition comprises about 5% (w/w) to about 20% (w/w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 8% (w/w) to about 16% (w/w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 10% (w/w) to about 14% (w/w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 1 1% (w/w) to about 13% (w/w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 11.5% (w/w) to about 12.5% (w/w) extragranular microcrystalline cellulose PH 102.
  • the pharmaceutical composition comprises about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w), about 10% (w/w), about 11% (w/w), about 12% (w/w), about 13% (w/w), about 14% (w/w), about 15% (w/w), about 16% (w/w) , about 17% (w/w) , about 18% (w/w) , about 19% (w/w) or about 20% (w/w) extragranular microcrystalline cellulose PH 102.
  • the pharmaceutical composition comprises about 8% (w/w), about 9% (w/w), about 10% (w/w), about 11% (w/w), about 12% (w/w), about 13% (w/w), about 14% (w/w), about 15% (w/w) or about 16% (w/w) extragranular microcry stalline cellulose PH 102.
  • the pharmaceutical composition comprises about 5% (w/w) extragranular microcrystalline cellulose PH 102.
  • the pharmaceutical composition comprises about 6% (w/w) extragranular microcrystalline cellulose PH 102.
  • the pharmaceutical composition comprises about 7% (w/w) extragranular microcrystalline cellulose PH 102.
  • the pharmaceutical composition comprises about 8% (w/w) extragranular microcrystalhne cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 9% (w/w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 10% (w/w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 11% (w/w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 12% (w/w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 13% (w/w) extragranular microcrystalline cellulose PH 102.
  • the pharmaceutical composition comprises about 14% (w/w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 15% (w/w) extragranular microcry stalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 16% (w/w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 17% (w/w) extragranular microcry stalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 18% (w/w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 19% (w/w) extragranular microcrystalline cellulose PH 102. In some embodiments, the pharmaceutical composition comprises about 20% (w/w) extragranular microcrystalline cellulose PH 102.
  • the pharmaceutical composition comprises an intragranular ghdant selected from the ghdants described herein.
  • the intragranular glidant consists substantially of colloidal silicon dioxide (e g., Aerosil® 200, CAB-O-SIL® M- 5P). The amount of intragranular glidant influences blend flow and the selected amounts of intragranular glidant contribute to rendering the intragranular blend amenable to dry granulation.
  • the pharmaceutical composition comprises about 0.5% (w/w) to about 1.5% (w/w) intragranular glidant.
  • the pharmaceutical composition comprises about 0.8% (w/w) to about 1.2% (w/w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w/w) to about 1.1% (w/w) intragranular ghdant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w/w) to about 1.05% (w/w) intragranular glidant.
  • the pharmaceutical composition comprises about 0.5% (w/w), about 0.6% (w/w), about 0.7% (w/w), about 0.8% (w/w), about 0.9% (w/w), about 0.95% (w/w), about 1.0% (w/w), about 1.05% (w/w), about 1.1% (w/w), about 1.2% (w/w), about 1.3% (w/w), about 1.4% (w/w) or about 1.5% (w/w) intragranular glidant.
  • the pharmaceutical composition comprises about 0.75% (w/w), about 0.8% (w/w), about 0.85 (w/w), about 0.9% (w/w), about 0.95% (w/w), about 1.0% (w/w), about 1.05% (w/w), about 1.1% (w/w), about 1.15% (w/w), about 1.2% (w/w) or about 1.25% (w/w) intragranular glidant.
  • the pharmaceutical composition comprises about 0.5% (w/w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.6% (w/w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.7% (w/w) intragranular ghdant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w/w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.8% (w/w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.85 (w/w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w/w) intragranular glidant.
  • the pharmaceutical composition comprises about 0.95% (w/w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w/w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.05% (w/w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.1% (w/w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.15% (w/w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.2% (w/w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w/w) intragranular glidant.
  • the pharmaceutical composition comprises about 1.3% (w/w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w/w) intragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w/w) intragranular glidant.
  • the pharmaceutical composition comprises about 0.5% (w/w) to about 1.5% (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.8% (w/w) to about 1.2% (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.9% (w/w) to about 1.1% (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.95% (w/w) to about 1.05% (w/w) intragranular colloidal silicon dioxide.
  • the pharmaceutical composition comprises about 0.5% (w/w), about 0.6% (w/w), about 0.7% (w/w), about 0.8% (w/w), about 0.9% (w/w), about 0.95% (w/w), about 1.0% (w/w), about 1.05% (w/w), about 1.1% (w/w), about 1.2% (w/w), about 1.3% (w/w). about 1.4% (w/w) or about 1.5% (w/w) intragranular colloidal silicon dioxide.
  • the pharmaceutical composition comprises about 0.75% (w/w), about 0.8% (w/w), about 0.85 (w/w), about 0.9% (w/w), about 0.95% (w/w), about 1.0% (w/w), about 1.05% (w/w), about 1.1% (w/w), about 1.15% (w/w), about 1.2% (w/w) or about 1.25% (w/w) intragranular colloidal silicon dioxide.
  • the pharmaceutical composition comprises about 0.5% (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.6% (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.7% (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.75% (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.8% (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.85 (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.9% (w/w) intragranular colloidal silicon dioxide.
  • the pharmaceutical composition comprises about 0.95% (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.0% (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.05% (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.1% (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.15% (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.2% (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.25% (w/w) intragranular colloidal silicon dioxide.
  • the pharmaceutical composition comprises about 1.3% (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.4% (w/w) intragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.5% (w/w) intragranular colloidal silicon dioxide.
  • the pharmaceutical composition comprises an extragranular glidant selected from the glidants described herein.
  • the extragranular glidant consists substantially of colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M- 5P).
  • the amount of extragranular glidant in the composition influences blend flow and compressibility, and the selected amounts of glidant in the pharmaceutical compositions described herein contribute to improved blend flow for the extragranular blend and improved compressibility.
  • the pharmaceutical composition comprises about 0.5% (w/w) to about 1.5% (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.8% (w/w) to about 1.2% (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w/w) to about 1.1% (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.95% (w/w) to about 1.05% (w/w) extragranular glidant.
  • the pharmaceutical composition comprises about 0.5% (w/w), about 0.6% (w/w), about 0.7% (w/w), about 0.8% (w/w), about 0.9% (w/w), about 0.95% (w/w), about 1.0% (w/w), about 1.05% (w/w), about 1.1% (w/w), about 1.2% (w/w), about 1.3% (w/w). about 1.4% (w/w) or about 1.5% (w/w) extragranular glidant.
  • the pharmaceutical composition comprises about 0.75% (w/w), about 0.8% (w/w), about 0.85 (w/w), about 0.9% (w/w), about 0.95% (w/w), about 1.0% (w/w), about 1.05% (w/w), about 1.1% (w/w), about 1.15% (w/w), about 1.2% (w/w) or about 1.25% (w/w) extragranular glidant.
  • the pharmaceutical composition comprises about 0.5% (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.6% (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.7% (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.8% (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.85 (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w/w) extragranular glidant.
  • the pharmaceutical composition comprises about 0.95% (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.05% (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.1% (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.15% (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.2% (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w/w) extragranular glidant.
  • the pharmaceutical composition comprises about 1.3% (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w/w) extragranular glidant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w/w) extragranular glidant.
  • the pharmaceutical composition comprises about 0.5% (w/w) to about 1.5% (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.8% (w/w) to about 1.2% (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.9% (w/w) to about 1.1% (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.95% (w/w) to about 1.05% (w/w) extragranular colloidal silicon dioxide.
  • the pharmaceutical composition comprises about 0.5% (w/w). about 0.6% (w/w), about 0.7% (w/w), about 0.8% (w/w), about 0.9% (w/w), about 0.95% (w/w), about 1.0% (w/w), about 1.05% (w/w), about 1.1% (w/w), about 1.2% (w/w), about 1.3% (w/w), about 1.4% (w/w) or about 1.5% (w/w) extragranular colloidal silicon dioxide.
  • the pharmaceutical composition comprises about 0.75% (w/w), about 0.8% (w/w), about 0.85 (w/w), about 0.9% (w/w), about 0.95% (w/w), about 1.0% (w/w), about 1.05% (w/w), about 1.1% (w/w), about 1.15% (w/w), about 1.2% (w/w) or about 1.25% (w/w) extragranular colloidal silicon dioxide.
  • the pharmaceutical composition comprises about 0.5% (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.6% (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.7% (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.75% (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.8% (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.85 (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 0.9% (w/w) extragranular colloidal silicon dioxide.
  • the pharmaceutical composition comprises about 0.95% (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.0% (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.05% (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.1% (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.15% (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.2% (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.25% (w/w) extragranular colloidal silicon dioxide.
  • the pharmaceutical composition comprises about 1.3% (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.4% (w/w) extragranular colloidal silicon dioxide. In some embodiments, the pharmaceutical composition comprises about 1.5% (w/w) extragranular colloidal silicon dioxide. [0270] In some embodiments, the pharmaceutical composition comprises an intragranular disintegrant selected from the disintegrants described herein. In some embodiments, the intragranular disintegrant consists substantially of croscarmellose sodium.
  • the pharmaceutical composition comprises about 0.5% (w/w) to about 2.5% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w/w) to about 2.0% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w/w) to about 1.75% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w/w) to about 1.6% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.45% (w/w) to about 1.55% (w/w) intragranular disintegrant.
  • the pharmaceutical composition comprises about 0.5% (w/w), about 0.75% (w/w), about 1% (w/w), about 1.25% (w/w), about 1.3% (w/w), about 1.35% (w/w), about 1.4% (w/w), about 1.45% (w/w), about 1.5% (w/w), about 1.55% (w/w), about 1.6% (w/w), about 1.65% (w/w), about 1.7% (w/w). about 1.75% (w/w), about 2.0% (w/w), about 2.25% (w/w) or about 2.5% (w/w) intragranular disintegrant.
  • the pharmaceutical composition comprises about 1% (w/w), about 1.25% (w/w), about 1.3% (w/w), about 1.35% (w/w), about 1.4% (w/w), about 1.45% (w/w), about 1.5% (w/w), about 1.55% (w/w), about 1.6% (w/w), about 1.65% (w/w), about 1.7% (w/w), about 1.75% (w/w) or about 2.0% (w/w) intragranular disintegrant.
  • the pharmaceutical composition comprises about 0.5% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.3% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.35% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w/w) intragranular disintegrant.
  • the pharmaceutical composition comprises about 1.45% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.55% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.6% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.65% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.7% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.75% (w/w) intragranular disintegrant.
  • the pharmaceutical composition comprises about 2.0% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.25% (w/w) intragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w/w) intragranular disintegrant.
  • the pharmaceutical composition comprises about 0.5% (w/w) to about 2.5% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.0% (w/w) to about 2.0% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.25% (w/w) to about 1.75% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.4% (w/w) to about 1.6% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1 .45% (w/w) to about 1 .55% (w/w) intragranular croscarmellose sodium.
  • the pharmaceutical composition comprises about 0.5% (w/w), about 0.75% (w/w), about 1% (w/w), about 1.25% (w/w), about 1.3% (w/w), about 1.35% (w/w), about 1.4% (w/w), about 1.45% (w/w). about 1.5% (w/w). about 1.55% (w/w), about 1.6% (w/w), about 1.65% (w/w), about 1.7% (w/w), about 1.75% (w/w), about 2.0% (w/w), about 2.25% (w/w) or about 2.5% (w/w) intragranular croscarmellose sodium.
  • the pharmaceutical composition comprises about 1% (w/w), about 1.25% (w/w), about 1.3% (w/w), about 1.35% (w/w), about 1.4% (w/w), about 1.45% (w/w), about 1.5% (w/w), about 1.55% (w/w), about 1.6% (w/w). about 1.65% (w/w), about 1.7% (w/w), about 1.75% (w/w) or about 2.0% (w/w) intragranular croscarmellose sodium.
  • the pharmaceutical composition comprises about 0.5% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 0.75% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.25% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.3% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.35% (w/w) intragranular croscarmellose sodium.
  • the pharmaceutical composition comprises about 1.4% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.45% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.5% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.55% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.6% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.65% (w/w) intragranular croscarmellose sodium.
  • the pharmaceutical composition comprises about 1.7% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.75% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.0% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.25% (w/w) intragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.5% (w/w) intragranular croscarmellose sodium.
  • the pharmaceutical composition comprises an extragranular disintegrant selected from the disintegrants described herein.
  • the extragranular disintegrant consists substantially of croscarmellose sodium.
  • the pharmaceutical composition comprises about 0.5% (w/w) to about 2.5% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w/w) to about 2.0% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w/w) to about 1.75% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w/w) to about 1.6% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.45% (w/w) to about 1.55% (w/w) extragranular disintegrant.
  • the pharmaceutical composition comprises about 0.5% (w/w). about 0.75% (w/w), about 1% (w/w), about 1.25% (w/w). about 1.3% (w/w), about 1.35% (w/w), about 1.4% (w/w), about 1.45% (w/w), about 1.5% (w/w), about 1.55% (w/w), about 1.6% (w/w), about 1.65% (w/w), about 1.7% (w/w), about 1.75% (w/w), about 2.0% (w/w), about 2.25% (w/w) or about 2.5% (w/w) extragranular disintegrant.
  • the pharmaceutical composition comprises about 1% (w/w), about 1.25% (w/w), about 1.3% (w/w), about 1.35% (w/w), about 1.4% (w/w), about 1.45% (w/w), about 1.5% (w/w), about 1.55% (w/w), about 1.6% (w/w), about 1.65% (w/w). about 1.7% (w/w). about 1.75% (w/w) or about 2.0% (w/w) extragranular disintegrant.
  • the pharmaceutical composition comprises about 0.5% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.25% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.3% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.35% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.4% (w/w) extragranular disintegrant.
  • the pharmaceutical composition comprises about 1.45% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.5% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.55% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.6% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.65% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.7% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 1.75% (w/w) extragranular disintegrant.
  • the pharmaceutical composition comprises about 2.0% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.25% (w/w) extragranular disintegrant. In some embodiments, the pharmaceutical composition comprises about 2.5% (w/w) extragranular disintegrant.
  • the pharmaceutical composition comprises about 0.5% (w/w) to about 2.5% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.0% (w/w) to about 2.0% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.25% (w/w) to about 1.75% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.4% (w/w) to about 1.6% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.45% (w/w) to about 1.55% (w/w) extragranular croscarmellose sodium.
  • the pharmaceutical composition comprises about 0.5% (w/w), about 0.75% (w/w), about 1% (w/w), about 1.25% (w/w), about 1.3% (w/w), about 1.35% (w/w), about 1.4% (w/w), about 1.45% (w/w). about 1.5% (w/w). about 1.55% (w/w), about 1.6% (w/w), about 1.65% (w/w), about 1.7% (w/w), about 1.75% (w/w), about 2.0% (w/w), about 2.25% (w/w) or about 2.5% (w/w) extragranular croscarmellose sodium.
  • the pharmaceutical composition comprises about 1% (w/w), about 1.25% (w/w), about 1.3% (w/w), about 1.35% (w/w), about 1.4% (w/w), about 1.45% (w/w), about 1.5% (w/w), about 1.55% (w/w), about 1.6% (w/w), about 1.65% (w/w), about 1.7% (w/w), about 1.75% (w/w) or about 2.0% (w/w) extragranular croscarmellose sodium.
  • the pharmaceutical composition comprises about 0.5% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 0.75% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.25% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.3% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.35% (w/w) extragranular croscarmellose sodium.
  • the pharmaceutical composition comprises about 1.4% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.45% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.5% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.55% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.6% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.65% (w/w) extragranular croscarmellose sodium.
  • the pharmaceutical composition comprises about 1.7% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 1.75% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.0% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.25% (w/w) extragranular croscarmellose sodium. In some embodiments, the pharmaceutical composition comprises about 2.5% (w/w) extragranular croscarmellose sodium. [0284] In some embodiments, the pharmaceutical composition comprises an intragranular lubricant selected from the lubricants described herein. In some embodiments, the intragranular lubricant consists substantially of magnesium stearate.
  • the pharmaceutical composition comprises about 0.25% (w/w) to about 0.75% (w/w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.3% (w/w) to about 0.7% (w/w) intragranular lubricant.
  • the pharmaceutical composition comprises about 0.4% (w/w) to about 0.6% (w/w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.45% (w/w) to about 0.55% (w/w) intragranular lubricant.
  • the pharmaceutical composition comprises about 0.45% (w/w), about 0.46% (w/w), about 0.47% (w/w). about 0.48% (w/w), about 0.49% (w/w), about 0.5% (w/w), about 0.51% (w/w), about 0.52% (w/w), about 0.53% (w/w), about 0.54% (w/w) or about 0.55% (w/w) intragranular lubricant.
  • the pharmaceutical composition comprises about 0.48% (w/w), about 0.49% (w/w), about 0.5% (w/w), about 0.51% (w/w) or about 0.52% (w/w) intragranular lubricant.
  • the pharmaceutical composition comprises about 0.45% (w/w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.46% (w/w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.47% (w/w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.48% (w/w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.49% (w/w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% (w/w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.51% (w/w) intragranular lubricant.
  • the pharmaceutical composition comprises about 0.52% (w/w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.53% (w/w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.54% (w/w) intragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.55% (w/w) intragranular lubricant.
  • the pharmaceutical composition comprises about 0.25% (w/w) to about 0.75% (w/w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.3% (w/w) to about 0.7% (w/w) intragranular magnesium stearate. [0290] In some embodiments, the pharmaceutical composition comprises about 0.4% (w/w) to about 0.6% (w/w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.45% (w/w) to about 0.55% (w/w) intragranular magnesium stearate.
  • the pharmaceutical composition comprises about 0.45% (w/w), about 0.46% (w/w), about 0.47% (w/w), about 0.48% (w/w), about 0.49% (w/w), about 0.5% (w/w), about 0.51% (w/w), about 0.52% (w/w), about 0.53% (w/w), about 0.54% (w/w) or about 0.55% (w/w) intragranular magnesium stearate.
  • the pharmaceutical composition comprises about 0.48% (w/w), about 0.49% (w/w), about 0.5% (w/w), about 0.51% (w/w) or about 0.52% (w/w) intragranular magnesium stearate.
  • the pharmaceutical composition comprises about 0.45% (w/w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.46% (w/w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.47% (w/w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.48% (w/w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.49% (w/w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.5% (w/w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.51% (w/w) intragranular magnesium stearate.
  • the pharmaceutical composition comprises about 0.52% (w/w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.53% (w/w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.54% (w/w) intragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.55% (w/w) intragranular magnesium stearate.
  • the pharmaceutical composition comprises an extragranular lubricant selected from the lubricants described herein.
  • the extragranular lubricant consists substantially of magnesium stearate.
  • the pharmaceutical composition comprises about 0.25% (w/w) to about 1.5% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.25% (w/w) to about 1.25% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% (w/w) to about 1.25% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.75% (w/w) to about 1.25% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.9% (w/w) to about 1.1% (w/w) extragranular lubricant.
  • the pharmaceutical composition comprises about 0.95% (w/w) to about 1.05% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.25% (w/w) to about 0.75% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.3% (w/w) to about 0.7% (w/w) extragranular lubricant.
  • the pharmaceutical composition comprises about 0.4% (w/w) to about 0.6% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.45% (w/w) to about 0.55% (w/w) extragranular lubricant.
  • the pharmaceutical composition comprises about 0.95% (w/w), about 0.96% (w/w), about 0.97% (w/w), about 0.98% (w/w), about 0.99% (w/w), about 1.0% (w/w), about 1.01% (w/w), about 1.02% (w/w), about 1.03% (w/w), about 1.0% (w/w) or about 1.05% (w/w) extragranular lubricant.
  • the pharmaceutical composition comprises about 0.98% (w/w), about 0.99% (w/w), about 1.0% (w/w), about 1.01% (w/w) or about 1.02% (w/w) extragranular lubricant.
  • the pharmaceutical composition comprises about 0.45% (w/w), about 0.46% (w/w), about 0.47% (w/w), about 0.48% (w/w), about 0.49% (w/w), about 0.5% (w/w), about 0.51% (w/w), about 0.52% (w/w), about 0.53% (w/w), about 0.54% (w/w) or about 0.55% (w/w) extragranular lubricant.
  • the pharmaceutical composition comprises about 0.48% (w/w), about 0.49% (w/w), about 0.5% (w/w), about 0.51% (w/w) or about 0.52% (w/w) extragranular lubricant.
  • the pharmaceutical composition comprises about 0.45% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.46% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.47% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.48% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.49% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.5% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.51% (w/w) extragranular lubricant.
  • the pharmaceutical composition comprises about 0.52% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.53% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.54% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.55% (w/w) extragranular lubricant.
  • the pharmaceutical composition comprises about 0.95% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.96% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.97% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.98% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.99% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 1.01% (w/w) extragranular lubricant.
  • the pharmaceutical composition comprises about 1.02% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 1.03% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 1.04% (w/w) or about 1.05% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.98% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 0.99% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 1.0% (w/w) extragranular lubricant. In some embodiments, the pharmaceutical composition comprises about 1.01% (w/w) or about 1.02% (w/w) extragranular lubricant.
  • the pharmaceutical composition comprises about 0.25% (w/w) to about 1.5% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.25% (w/w) to about 1.25% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.5% (w/w) to about 1.25% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.75% (w/w) to about 1.25% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.9% (w/w) to about 1.1% (w/w) extragranular magnesium stearate.
  • the pharmaceutical composition comprises about 0.95% (w/w) to about 1.05% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.25% (w/w) to about 0.75% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.3% (w/w) to about 0.7% (w/w) extragranular magnesium stearate. [0301] In some embodiments, the pharmaceutical composition comprises about 0.4% (w/w) to about 0.6% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.45% (w/w) to about 0.55% (w/w) extragranular magnesium stearate.
  • the pharmaceutical composition comprises about 0.95% (w/w), about 0.96% (w/w), about 0.97% (w/w), about 0.98% (w/w), about 0.99% (w/w), about 1.0% (w/w), about 1.01% (w/w), about 1.02% (w/w), about 1.03% (w/w), about 1.0% (w/w) or about 1.05% (w/w) extragranular magnesium stearate.
  • the pharmaceutical composition comprises about 0.98% (w/w), about 0.99% (w/w), about 1.0% (w/w), about 1.01% (w/w) or about 1.02% (w/w) extragranular magnesium stearate.
  • the pharmaceutical composition comprises about 0.45% (w/w), about 0.46% (w/w), about 0.47% (w/w), about 0.48% (w/w), about 0.49% (w/w), about 0.5% (w/w), about 0.51% (w/w), about 0.52% (w/w), about 0.53% (w/w), about 0.54% (w/w) or about 0.55% (w/w) extragranular magnesium stearate.
  • the pharmaceutical composition comprises about 0.48% (w/w), about 0.49% (w/w), about 0.5% (w/w), about 0.51% (w/w) or about 0.52% (w/w) extragranular magnesium stearate.
  • the pharmaceutical composition comprises about 0.45% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.46% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.47% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.48% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.49% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.5% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.51% (w/w) extragranular magnesium stearate.
  • the pharmaceutical composition comprises about 0.52% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.53% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.54% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.55% (w/w) extragranular magnesium stearate.
  • the pharmaceutical composition comprises about 0.95% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.96% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.97% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.98% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.99% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.0% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.01% (w/w) extragranular magnesium stearate.
  • the pharmaceutical composition comprises about 1.02% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.03% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.04% (w/w) or about 1.05% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.98% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 0.99% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.0% (w/w) extragranular magnesium stearate. In some embodiments, the pharmaceutical composition comprises about 1.01% (w/w) or about 1.02% (w/w) extragranular magnesium stearate.
  • an intragranular filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients.
  • the compound of formula (I), the intragranular filler and the additional excipients are present in the w/w percentages recited in any of the embodiments described herein.
  • composition comprising:
  • an intragranular filler comprising microcrystalline cellulose PH 101; and optionally one or more additional pharmaceutically acceptable excipients.
  • composition comprising:
  • an intragranular glidant e.g, colloidal silicon dioxide
  • an intragranular disintegrant e.g, croscarmellose sodium
  • an extragranular lubricant e.g, magnesium stearate
  • an extragranular filler e.g, microcrystalline cellulose PH 102
  • an extragranular glidant e.g, colloidal silicon dioxide
  • an extragranular disintegrant e.g, croscarmellose sodium
  • an extragranular lubricant e.g. magnesium stearate.
  • the compound of formula (I), the intragranular filler, the extragranular filler, the intragranular glidant, the extragranular glidant, the intragranular disintegrant, the extragranular disintegrant, the intragranular lubricant and the extragranular lubricant are present in the w/w percentages recited in any of the embodiments described herein.
  • composition comprising:
  • the compound of formula (I), the intragranular microcrystalline cellulose, the extragranular microcry stalline cellulose, the intragranular silicon dioxide, the extragranular silicon dioxide, the intragranular croscarmellose sodium, the extragranular croscarmellose sodium, the intragranular magnesium stearate and the extragranular magnesium stearate are present in the w/w percentages recited in any of the embodiments described herein.
  • the pharmaceutical composition comprises:
  • an intragranular lubricant e.g, magnesium stearate
  • the pharmaceutical composition comprises:
  • an intragranular lubricant e.g, magnesium stearate
  • an extragranular glidant e.g, colloidal silicon dioxide
  • an intragranular glidant e.g. colloidal silicon dioxide
  • an intragranular disintegrant e.g, croscarmellose sodium
  • an intragranular lubricant e.g, magnesium stearate
  • an extragranular glidant e.g, colloidal silicon dioxide
  • the pharmaceutical composition comprises:
  • an intragranular glidant e.g. colloidal silicon dioxide
  • an intragranular disintegrant e.g, croscarmellose sodium
  • an intragranular lubricant e.g, magnesium stearate
  • the pharmaceutical composition comprises:
  • an intragranular lubricant e.g. magnesium stearate
  • an extragranular glidant e.g., colloidal silicon dioxide
  • the pharmaceutical composition comprises:
  • an intragranular disintegrant e.g., croscarmellose sodium
  • an intragranular lubricant e.g., magnesium stearate
  • an extragranular filler e.g., microcrystalline cellulose PH 102
  • an extragranular glidant e.g., colloidal silicon dioxide
  • the pharmaceutical composition comprises:
  • an intragranular glidant e.g. colloidal silicon dioxide
  • an intragranular disintegrant e.g, croscarmellose sodium
  • an intragranular lubricant e.g, magnesium stearate
  • an extragranular filler e.g, microcrystalline cellulose PH 102
  • an extragranular glidant e.g, colloidal silicon dioxide
  • an extragranular lubricant e.g, magnesium stearate
  • the pharmaceutical composition comprises:
  • an intragranular glidant e.g, colloidal silicon dioxide
  • an intragranular disintegrant e.g, croscarmellose sodium
  • an intragranular lubricant e.g, magnesium stearate
  • an extragranular filler e.g, microcrystalline cellulose PH 102
  • an extragranular glidant e.g, colloidal silicon dioxide
  • an extragranular lubricant e.g, magnesium stearate
  • the pharmaceutical composition comprises:
  • an intragranular glidant e.g, colloidal silicon dioxide
  • an intragranular disintegrant e.g, croscarmellose sodium
  • an intragranular lubricant e.g. magnesium stearate
  • an extragranular glidant e.g, colloidal silicon dioxide
  • the pharmaceutical composition comprises:
  • an intragranular glidant e.g., colloidal silicon dioxide
  • an intragranular disintegrant e.g, croscarmellose sodium
  • an intragranular lubricant e.g., magnesium stearate
  • an extragranular glidant e.g, colloidal silicon dioxide
  • an extragranular lubricant e.g., magnesium stearate
  • the pharmaceutical composition comprises:
  • an intragranular glidant e.g., colloidal silicon dioxide
  • an intragranular disintegrant e.g, croscarmellose sodium
  • an intragranular lubricant e.g.. magnesium stearate
  • an extragranular glidant e.g., colloidal silicon dioxide
  • an extragranular lubricant e.g. magnesium stearate
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • dosage forms comprising a pharmaceutical composition described herein.
  • dosage forms intended for oral administration comprising a pharmaceutical composition described herein.
  • the dosage form is selected from the group consisting of a powder, a sachet, a stickpack, a capsule, a minitab, and a tablet.
  • the dosage form is a tablet.
  • the total weight of the pharmaceutical composition in the dosage form is about 200 mg to 1000 mg.
  • the total weight of the pharmaceutical composition in the dosage form is about 200 mg to 750 mg.
  • the total weight of the pharmaceutical composition in the dosage form is about 225 mg to 650 mg.
  • 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,.
  • 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.
  • the dosage form comprises about 50 mg to about 350 mg of the crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises about 100 mg to about 300 mg of the crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises about 100 mg to about 250 mg of the crystalline form A of the compound of formula (I).
  • the dosage form comprises about 50 mg. about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg or about 350 mg of crystalline form A of the compound of formula (I).
  • the dosage form comprises about 100 mg, about 125 mg, about 150 mg, about 175 mg. about 200 mg. about 225 mg, about 250 mg, about 275 mg or about 300 mg of crystalline form A of the compound of formula (I).
  • the dosage form comprises about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 250 mg or about 300 mg of crystalline form A of the compound of formula (I).
  • the dosage form comprises about 100 mg, about 125 mg, about 150 mg, about 200 mg or about 250 mg of cry stalline form A of the compound of formula (I). In some embodiments, the dosage form comprises about 150 mg, about 200 mg or about 250 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises about 150 mg or about 250 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises about 200 mg or about 250 mg of crystalline form A of the compound of formula (1). In some embodiments, the dosage form comprises about 100 mg, about 200 mg or about 300 mg of crystalline form A of the compound of formula (I). [0347] In some embodiments, the dosage form comprises about 100 mg or about 200 mg of crystalline form A of the compound of formula (I).
  • the dosage form comprises about 50 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 75 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 100 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 125 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 150 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 175 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 200 mg of crystalline form A of the compound of formula (I).
  • the dosage form comprises 225 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 250 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 275 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 300 mg of cry stalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 325 mg of crystalline form A of the compound of formula (I). In some embodiments, the dosage form comprises 350 mg of crystalline form A of the compound of formula (I).
  • the dosage form comprises 100 mg Compound of formula (I), 105 mg intragranular microcrystalline cellulose PH 101, 2.5 mg intragranular colloidal silicon dioxide (e.g.. Aerosil® 200, CAB-O-SIL® M-5P), 3.7 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.3 mg intragranular magnesium stearate, 29.9 mg extragranular microcrystalline cellulose PH 102, 2.5 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O- SIL® M-5P), 3.7 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 2.5 mg extragranular magnesium stearate.
  • 105 mg intragranular microcrystalline cellulose PH 101 e.g.. Aerosil® 200, CAB-O-SIL® M-5P
  • 3.7 mg intragranular croscarmellose sodium 1.3 mg intragranular magnesium stearate
  • the dosage form comprises 100 mg Compound of formula (I), 105 mg intragranular microcrystalline cellulose PH 101, 2.5 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 3.75 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.25 mg intragranular magnesium stearate, 30 mg extragranular microcrystalline cellulose PH 102, 2.5 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O- SIL® M-5P), 3.75 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 1.25 mg extragranular magnesium stearate.
  • 105 mg intragranular microcrystalline cellulose PH 101 2.5 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 3.75 mg intragranular croscarmellose sodium (Ac-Di-Sol®) and 1.25 mg
  • the dosage form comprises 125 mg Compound of formula (I), 131 mg intragranular microcrystalline cellulose PH 101, 3.2 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 4.7 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.6 mg intragranular magnesium stearate, 37.4 mg extragranular microcrystalline cellulose PH 102, 3.2 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O- SIL® M-5P), 4.7 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 3.2 mg extragranular magnesium stearate.
  • the dosage form comprises 125 mg Compound of formula (I). 131.25 mg intragranular microcrystalline cellulose PH 101, 3.13 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 4.69 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.56 mg intragranular magnesium stearate, 37.50 mg extragranular microcrystalline cellulose PH 102, 3.13 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 4.69 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 1.56 mg extragranular magnesium stearate.
  • intragranular microcrystalline cellulose PH 101 3.13 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 4.69 mg extragranular croscarmellose sodium (Ac-Di-Sol®)
  • the dosage form comprises 150 mg Compound of formula (I), 157.5 mg intragranular microcrystalline cellulose PH 101, 3.8 mg intragranular colloidal silicon dioxide (e.g. Aerosil® 200, CAB-O-SIL® M-5P), 5.6 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.9 mg intragranular magnesium stearate, 44.9 mg extragranular microcrystalline cellulose PH 102, 3.8 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O- SIL® M-5P), 5.6 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 3.8 mg extragranular magnesium stearate.
  • the dosage form comprises 150 mg Compound of formula (I). 157 mg intragranular microcrystalline cellulose PH 101, 3.75 mg intragranular colloidal silicon dioxide (e.g, Aerosil® 200, CAB-O-SIL® M-5P), 5.63 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 1.88 mg intragranular magnesium stearate, 45 mg extragranular microcrystalline cellulose PH 102, 3.75 mg extragranular colloidal silicon dioxide (e.g, Aerosil® 200, CAB-O- SIL® M-5P), 5.63 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 1.88 mg extragranular magnesium stearate.
  • Compound of formula (I) 157 mg intragranular microcrystalline cellulose PH 101, 3.75 mg intragranular colloidal silicon dioxide (e.g, Aerosil® 200, CAB-O-SIL® M-5P), 5.63 mg intragranular croscarmellose sodium (Ac-Di-
  • the dosage form comprises 200 mg Compound of formula (I), 210 mg intragranular microcrystalline cellulose PH 101. 5. 1 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 7.5 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 2.5 mg intragranular magnesium stearate, 59.9 mg extragranular microcrystalline cellulose PH 102, 5.1 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O- SIL® M-5P), 7.5 mg extragranular croscarmellose sodium (Ac-Di-Sol*) and 5.1 mg extragranular magnesium stearate.
  • intragranular colloidal silicon dioxide e.g., Aerosil® 200, CAB-O-SIL® M-5P
  • 7.5 mg extragranular croscarmellose sodium e.g., Aerosil® 200, CAB-O- SIL® M-5P
  • the dosage form comprises 200 mg Compound of formula (I). 210 mg intragranular microcrystalline cellulose PH 101. 5.0 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 7.5 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 2.5 mg intragranular magnesium stearate, 60 mg extragranular microcrystalline cellulose PH 102, 5.0 mg extragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O- SIL® M-5P), 7.5 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 2.5 mg extragranular magnesium stearate.
  • intragranular colloidal silicon dioxide e.g., Aerosil® 200, CAB-O-SIL® M-5P
  • 7.5 mg extragranular croscarmellose sodium Ac-Di-Sol®
  • 2.5 mg extragranular magnesium stearate 60 mg extragranular microcrystalline
  • the dosage form comprises 250 mg Compound of formula (I), 262.5 mg intragranular microcrystalline cellulose PH 101, 6.3 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P), 9.3 mg intragranular croscarmellose sodium (Ac-Di-Sol®), 3.2 mg intragranular magnesium stearate, 74.8 mg extragranular microcrystalline cellulose PH 102, 6.3 mg extragranular colloidal silicon dioxide (e.g., Aerosil* 200, CAB-O- SIL® M-5P), 9.3 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 6.3 mg extragranular magnesium stearate.
  • colloidal silicon dioxide e.g., Aerosil® 200, CAB-O-SIL® M-5P
  • 9.3 mg extragranular croscarmellose sodium e.g., Aerosil* 200, CAB-O- SIL® M-5P
  • the dosage form comprises 250 mg Compound of formula (I).
  • intragranular microcrystalline cellulose PH 101 6.25 mg intragranular colloidal silicon dioxide (e.g., Aerosil® 200, CAB-O-SIL® M-5P)
  • 9.38 mg extragranular croscarmellose sodium (Ac-Di-Sol®) and 3.13 mg extragranular magnesium stearate.
  • the dosage form is a tablet.
  • the tablet further comprises a coating.
  • the coating is selected from the group consisting of a film forming polymer, a plasticizer, and combinations thereof.
  • the film forming polymer is selected from the group consisting of a hypromellose, an ethylcellulose, cellulose acetate, a polyvinylpyrrolidone, a polyvinyl alcohol, a polyacrylate, and combinations thereof.
  • the plasticizer is selected from the group consisting of triacetin, polyethylene glycol, propylene glycol, and combinations thereof.
  • the coating comprises polyvinyl alcohol.
  • the coating compnses a colorant selected from the group consisting of titanium dioxide, an aluminum lake, an iron oxide, carbon black, and combinations thereof.
  • the colorant is titanium dioxide.
  • a process for preparing a pharmaceutical composition comprising cry stalline form A of a compound of formula (I) as described in any of the embodiments herein, comprising:
  • compositions and dosage forms described herein are amenable to manufacture using a streamlined manufacturing process.
  • a schematic process for preparing the dosage forms described herein is depicted in FIG. 14.
  • the order of addition of components for the blending steps influences the uniformity of API in the blend and impacts the distribution of low-level components in the blend. Uniform distribution of low-level components in the intragranular blend is important to successfully achieve dry granulation of the intragranular blend. For example, lack of uniform distribution of glidant in the intragranular blend can result in sub-optimal granulation with a wide particle size distribution, which would negatively impact extragranular blending and eventually compressibility of the final blend.
  • the order of addition is as show n in Table. 5.
  • step (b) pre-blending and sieving the components charged at step (a) to obtain a pre-blending intragranular mixture
  • step (b) pre-blending and sieving the components charged at step (a) to obtain a pre-blending intragranular mixture

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques et des formes posologiques de la forme cristalline A d'un inhibiteur de PRMT5 de formule (I), des procédés de production et des méthodes d'utilisation de celles-ci.
PCT/US2025/014214 2024-01-31 2025-01-31 Formes cristallines, compositions pharmaceutiques et leurs méthodes d'utilisation Pending WO2025166308A1 (fr)

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US63/658,373 2024-06-10
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WO1997010365A1 (fr) 1995-09-15 1997-03-20 Affymax Technologies N.V. Mesure de l'expression par l'hybridation avec des systemes tres denses d'oligonucleotides
WO2022026892A1 (fr) 2020-07-31 2022-02-03 Tango Therapeutics, Inc. Dérivés de pipéridin-1-yl-n-pyrydine-3-yl-2-oxo-acétamide utiles pour le traitement de cancers déficients en mtap et/ou accumulant mta
WO2022256806A1 (fr) * 2021-06-02 2022-12-08 Ideaya Biosciences, Inc. Polythérapie comprenant un inhibiteur de mat2a et un inhibiteur de prmt de type ii
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