Crystalline forms of a bruton's tyrosine kinase inhibitor

Abstract

Described herein is the Bruton's tyrosine kinase (Btk) inhibitor 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one, including crystalline forms, solvates and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical compositions that include the Btk inhibitor, as well as methods of using the Btk inhibitor, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

What is claimed is: 
     
         1 . A pharmaceutical formulation for oral administration comprising:
 (a) about 40 mgs to about 200 mgs of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;   (b) about 40 wt % to about 50 wt % of a diluent;   (c) about 3 wt % to about 10 wt % of a disintegrating agent;   (d) about 2 wt % to about 7 wt % of a surfactant; and   (e) about 0.2 wt % to about 1.0 wt % of a lubricant.   
     
     
         2 . The pharmaceutical formulation of  claim 1 , wherein the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. 
     
     
         3 . The pharmaceutical formulation of  claim 2 , wherein the diluent is microcrystalline cellulose. 
     
     
         4 . The pharmaceutical formulation of  claim 1 , wherein the disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, and a gum. 
     
     
         5 . The pharmaceutical formulation of  claim 4 , wherein the disintegrating agent is croscarmellose sodium. 
     
     
         6 . The pharmaceutical formulation of  claim 1 , wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide. 
     
     
         7 . The pharmaceutical formulation of  claim 6 , wherein the surfactant is sodium lauryl sulfate. 
     
     
         8 . The pharmaceutical formulation of  claim 1 , wherein the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes. 
     
     
         9 . The pharmaceutical formulation of  claim 8 , wherein the lubricant is magnesium stearate. 
     
     
         10 . The pharmaceutical formulation of  claim 1  comprising:
 (a) 140 mgs of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one; 
 (b) 45.9 wt % of microcrystalline cellulose; 
 (c) 7.0 wt % of croscarmellose sodium; 
 (d) 4.2 wt % of sodium lauryl sulfate; and 
 (e) 0.5 wt % of magnesium stearate. 
 
     
     
         11 . The pharmaceutical formulation of  claim 10 , wherein the dosage form is a hard gelatin capsule. 
     
     
         12 . A crystalline Form A of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one that has at least one of the following properties:
 (a) an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in  FIG. 1 ;   (b) an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.7±0.1° 2-Theta, 13.6±0.1° 2-Theta, 16.1±0.1° 2-Theta, 18.9±0.1° 2-Theta, 21.3±0.1° 2-Theta, and 21.6±0.1° 2-Theta;   (c) substantially the same X-ray powder diffraction (XRPD) pattern post storage at 40° C. and 75% relative humidity (RH) for at least a week;   (d) substantially the same X-ray powder diffraction (XRPD) pattern post storage at 25° C. and 97% relative humidity (RH) for at least a week;   (e) Infrared (IR) spectrum substantially similar to the one set forth in  FIG. 2 ;   (f) Infrared (IR) spectrum weak peaks at about 1584 cm −1 , about 1240 cm −1 , about 1147 cm −1 , about 1134 cm −1 , about 1099 cm −1 , and about 1067 cm −1 ;   (g) a differential scanning calorimetry (DSC) thermogram substantially similar to the one set forth in  FIG. 3 ;   (h) a thermo-gravimetric analysis (TGA) thermogram substantially similar to the one set forth in  FIG. 4 ;   (i) a DSC thermogram with an endotherm having an onset at about 154° C. and a peak at about 157° C. and an exotherm at about 159° C.;   (j) non-hygroscopicity;   (k) an observed aqueous solubility of about 0.013 mg/mL at about pH 8; or   (l) combinations thereof.   
     
     
         13 . The crystalline form of  claim 12 , wherein the crystalline form has an X-Ray powder diffraction (XRPD) pattern substantially the same as shown in  FIG. 1 . 
     
     
         14 . The crystalline form of  claim 12 , wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.7±0.1° 2-Theta, 13.6±0.1° 2-Theta, 16.1±0.1° 2-Theta, 18.9±0.1° 2-Theta, 21.3±0.1° 2-Theta, and 21.6±0.1° 2-Theta. 
     
     
         15 . The crystalline form of  claim 12 , wherein the crystalline form has substantially the same X-ray powder diffraction (XRPD) pattern post storage at 40° C. and 75% relative humidity (RH) for at least a week. 
     
     
         16 . The crystalline form of  claim 12 , wherein the crystalline form has substantially the same X-ray powder diffraction (XRPD) pattern post storage at 25° C. and 97% relative humidity (RH) for at least a week. 
     
     
         17 . The crystalline form of  claim 12 , wherein the crystalline form has a differential scanning calorimetry (DSC) thermogram substantially similar to the one set forth in  FIG. 3 . 
     
     
         18 . The crystalline form of  claim 12 , wherein the crystalline form is unsolvated. 
     
     
         19 . The crystalline form of  claim 12 , wherein the crystalline form is anhydrous. 
     
     
         20 . The pharmaceutical formulation of  claim 12 , wherein 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is crystalline Form A. 
     
     
         21 . A pharmaceutical formulation for oral administration comprising:
 (a) 140 mgs of crystalline Form A of 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one;   (b) 45.9 wt % of microcrystalline cellulose;   (c) 7.0 wt % of croscarmellose sodium;   (d) 4.2 wt % of sodium lauryl sulfate; and   (e) 0.5 wt % of magnesium stearate.