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.

1 - 13 . (canceled) 
     
     
         14 . A pharmaceutical formulation for oral administration comprising one or more pharmaceutically acceptable excipients and 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 an X-ray powder diffraction (XRPD) pattern comprising 2-Theta peaks at 5.7±0.1°, 18.9±0.1°, and 21.3±0.1°. 
     
     
         15 . The pharmaceutical formulation of  claim 14 , wherein the X-ray powder diffraction (XRPD) pattern further comprises a 2-Theta peak at 16.1±0.1°. 
     
     
         16 . The pharmaceutical formulation of  claim 14 , wherein the X-ray powder diffraction (XRPD) pattern further comprises a 2-Theta peak at 13.6±0.1°. 
     
     
         17 . The pharmaceutical formulation of  claim 14 , wherein the X-ray powder diffraction (XRPD) pattern further comprises a 2-Theta peak at 21.6±0.1°. 
     
     
         18 . The pharmaceutical formulation of  claim 14 , wherein the X-ray powder diffraction (XRPD) pattern further comprises 2-Theta peaks at 13.6±0.1° and 16.1±0.1°. 
     
     
         19 . The pharmaceutical formulation of  claim 14 , wherein the X-ray powder diffraction (XRPD) pattern further comprises 2-Theta peaks at 13.6±0.1° and 21.6±0.1°. 
     
     
         20 . The pharmaceutical formulation of  claim 14 , wherein the X-ray powder diffraction (XRPD) pattern further comprises 2-Theta peaks at 16.1±0.1° and 21.6±0.1°. 
     
     
         21 . The pharmaceutical formulation of  claim 14 , wherein the X-ray powder diffraction (XRPD) pattern further comprises 2-Theta peaks at 13.6±0.1°, 16.1±0.1°, and 21.6±0.1°. 
     
     
         22 . The pharmaceutical formulation of  claim 14 , wherein the crystalline form has 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 . 
     
     
         23 . The pharmaceutical formulation of  claim 14 , wherein the crystalline Form A has a melting temperature of about 155-156° C. 
     
     
         24 . The pharmaceutical formulation of  claim 14 , wherein the crystalline Form A has 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. 
     
     
         25 . The pharmaceutical formulation of  claim 14 , wherein the crystalline Form A is non-hygroscopic. 
     
     
         26 . A pharmaceutical formulation for oral administration comprising
 (a) about 40 mgs to about 200 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 that has an X-ray powder diffraction (XRPD) pattern comprising 2-Theta peaks at 5.7±0.1°, 18.9±0.1°, and 21.3±0.1°;   (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.   
     
     
         27 . The pharmaceutical formulation of  claim 26 , 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. 
     
     
         28 . The pharmaceutical formulation of  claim 26 , wherein the diluent is microcrystalline cellulose. 
     
     
         29 . The pharmaceutical formulation of  claim 26 , 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, cross-linked polymer, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, and a gum. 
     
     
         30 . The pharmaceutical formulation of  claim 26 , wherein the disintegrating agent is croscarmellose sodium. 
     
     
         31 . The pharmaceutical formulation of  claim 26 , wherein the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide. 
     
     
         32 . The pharmaceutical formulation of  claim 26 , wherein the surfactant is sodium lauryl sulfate. 
     
     
         33 . The pharmaceutical formulation of  claim 26 , wherein the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, sodium stearates, magnesium stearate, zinc stearate, and waxes. 
     
     
         34 . The pharmaceutical formulation of  claim 26 , wherein the lubricant is magnesium stearate. 
     
     
         35 . The pharmaceutical formulation of  claim 26 , 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;   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, cross-linked polymer, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, and a gum;   the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide; and   the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, sodium stearates, magnesium stearate, zinc stearate, and waxes.   
     
     
         36 . The pharmaceutical formulation of  claim 26 , wherein:
 the diluent is selected from the group consisting of lactose, sucrose, mannitol, calcium phosphate, starches, modified starches, and microcrystalline cellulose;   the disintegrating agent is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, and crospovidone;   the surfactant is selected from the group consisting of sodium lauryl sulfate, poloxamers, copolymers of ethylene oxide and propylene oxide; and   the lubricant is selected from the group consisting of stearic acid, talc, sodium stearyl fumarate, and magnesium stearate.   
     
     
         37 . The pharmaceutical formulation of  claim 26 , wherein the formulation comprises:
 (a) about 40 mgs to about 200 mgs of the crystalline Form A;   (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.   
     
     
         38 . The pharmaceutical formulation of  claim 26 , wherein the formulation comprises:
 (a) 140 mgs of the crystalline Form A;   (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.   
     
     
         39 . The pharmaceutical formulation of  claim 26 , which is in a hard gelatin capsule. 
     
     
         40 . A pharmaceutical formulation comprising:
 (a) about 40 wt % to about 50 wt % 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 that has an X-ray powder diffraction (XRPD) pattern comprising 2-Theta peaks at 5.7±0.1°, 18.9±0.1°, and 21.3±0.1°;   (b) about 40 wt % to about 50 wt % of microcrystalline cellulose;   (c) about 3 wt % to about 10 wt % of croscarmellose sodium;   (d) about 2 wt % to about 7 wt % of sodium lauryl sulfate; and   (e) about 0.2 wt % to about 1.0 wt % of magnesium stearate.   
     
     
         41 . The pharmaceutical formulation of  claim 40 , which is in a hard gelatin capsule. 
     
     
         42 . A pharmaceutical formulation 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 that has an X-ray powder diffraction (XRPD) pattern comprising 2-Theta peaks at 5.7±0.1°, 18.9±0.1°, and 21.3±0.1°;   (b) 151.4 mgs of microcrystalline cellulose;   (c) 23.0 mgs of croscarmellose sodium;   (d) 14.0 mgs of sodium lauryl sulfate; and   (e) 1.6 mgs of magnesium stearate.   
     
     
         43 . The pharmaceutical formulation of  claim 42 , which is in a hard gelatin capsule.