Claims for Patent: 11,059,829

Summary for Patent: 11,059,829

Title:	Crystal forms of (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-- yl)-N-(pyridin-2-yl)benzamide maleate
Abstract:	In some embodiments, the invention relates to crystalline solid forms, including hydrates, polymorphs, and salt forms, of (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-- yl)-N-(pyridin-2-yl)benzamide. In some embodiments, the invention relates to amorphous solid forms of (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-- yl)-N-(pyridin-2-yl)benzamide. In some embodiments, the invention also relates to pharmaceutical compositions containing the solid forms, and methods for treating conditions or disorders by administering to a subject a pharmaceutical composition that includes the forms, including pharmaceutical compositions and methods for overcoming the effects of acid reducing agents.
Inventor(s):	Blatter; Fritz (Reinach, CH), Ingallinera; Tim (San Francisco, CA), Barf; Tjeerd (Ravenstein, NL), Aret; Edwin (Almere, NL), Krejsa; Cecile (Seattle, WA), Evarts; Jerry (Bellevue, WA)
Assignee:	Acerta Pharma B.V. (Oss, NL)
Application Number:	16/863,033
Patent Claims:	1. A crystal form of (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-- yl)-N-(pyridin-2-yl)benzamide maleate, or hydrate thereof, characterized by a reflection X-ray powder diffraction pattern comprising at least five peaks selected from the group consisting of 5.3.degree..+-.0.2.degree. 2.theta., 9.8.degree..+-.0.2.degree. 2.theta., 10.6.degree..+-.0.2.degree. 2.theta., 11.6.degree..+-.0.2.degree. 2.theta., 13.5.degree..+-.0.2.degree. 2.theta., 13.8.degree..+-.0.2.degree. 2.theta., 13.9.degree..+-.0.2.degree. 2.theta., 14.3.degree..+-.0.2.degree. 2.theta., 15.3.degree..+-.0.2.degree. 2.theta., 15.6.degree..+-.0.2.degree. 2.theta., 15.8.degree..+-.0.2.degree. 2.theta., 15.9.degree..+-.0.2.degree. 2.theta., 16.6.degree..+-.0.2.degree. 2.theta., 17.4.degree..+-.0.2.degree. 2.theta., 17.5.degree..+-.0.2.degree. 2.theta., 18.7.degree..+-.0.2.degree. 2.theta., 19.3.degree..+-.0.2.degree. 2.theta., 19.6.degree..+-.0.2.degree. 2.theta., 19.8.degree..+-.0.2.degree. 2.theta., 20.0.degree..+-.0.2.degree. 2.theta., 20.9.degree..+-.0.2.degree. 2.theta., 21.3.degree..+-.0.2.degree. 2.theta., 22.1.degree..+-.0.2.degree. 2.theta., 22.3.degree..+-.0.2.degree. 2.theta., 22.7.degree..+-.0.2.degree. 2.theta., 23.2.degree..+-.0.2.degree. 2.theta., 23.4.degree..+-.0.2.degree. 2.theta., 23.7.degree..+-.0.2.degree. 2.theta., 23.9.degree..+-.0.2.degree. 2.theta., 24.5.degree..+-.0.2.degree. 2.theta., 24.8.degree..+-.0.2.degree. 2.theta., 25.2.degree..+-.0.2.degree. 2.theta., 25.6.degree..+-.0.2.degree. 2.theta., 26.1.degree..+-.0.2.degree. 2.theta., 26.4.degree..+-.0.2.degree. 2.theta., 26.7.degree..+-.0.2.degree. 2.theta., 26.9.degree..+-.0.2.degree. 2.theta., 27.1.degree..+-.0.2.degree. 2.theta., 27.6.degree..+-.0.2.degree. 2.theta., 28.8.degree..+-.0.2.degree. 2.theta., 29.5.degree..+-.0.2.degree. 2.theta., 30.0.degree..+-.0.2.degree. 2.theta., 30.3.degree..+-.0.2.degree. 2.theta., 30.9.degree..+-.0.2.degree. 2.theta., 31.5.degree..+-.0.2.degree. 2.theta., 31.9.degree..+-.0.2.degree. 2.theta., 32.5.degree..+-.0.2.degree. 2.theta., 34.0.degree..+-.0.2.degree. 2.theta., and 35.1.degree..+-.0.2.degree. 2.theta.. 2. The crystal form of claim 1, or hydrate thereof, wherein the reflection X-ray powder diffraction pattern of the crystal form, or hydrate thereof, comprises peaks at 5.3.degree..+-.0.2.degree. 2.theta., 9.8.degree..+-.0.2.degree. 2.theta., 10.6.degree..+-.0.2.degree. 2.theta., 11.6.degree..+-.0.2.degree. 2.theta., and 19.3.degree..+-.0.2.degree. 2.theta.. 3. The crystal form of claim 2, or hydrate thereof, wherein the peaks are present when the reflection X-ray powder diffraction is carried out using Cu-K.alpha. radiation. 4. The crystal form of claim 2, or hydrate thereof, wherein the peaks are present when the reflection X-ray powder diffraction is carried out using a Bruker D8 Advance powder X-ray diffractometer equipped with a LynxEye detector and operating in Bragg-Brentano reflection geometry mode, a tube voltage of 40 kV and current of 40 mA, a variable divergence slit with a 3.degree. window, a step size of 0.02.degree. 2.theta., a sample rotation of 0.5 revolution per second, and a step time of 37 seconds. 5. The crystal form of claim 2, or hydrate thereof, wherein the crystal form, or hydrate thereof, is further characterized by a differential scanning calorimetry thermogram comprising an endothermic peak at 174.degree. C. 6. The crystal form of claim 2, or hydrate thereof, wherein the crystal form, or hydrate thereof, is further characterized by a dynamic vapor sorption isotherm exhibiting a water content change of 0.5% between 20% relative humidity and 80% relative humidity. 7. The crystal form of claim 2, or hydrate thereof, wherein the crystal form, or hydrate thereof, is further characterized by a differential scanning calorimetry thermogram comprising an endothermic peak at 174.degree. C. and a dynamic vapor sorption isotherm exhibiting a water content change of 0.5% between 20% relative humidity and 80% relative humidity. 8. The crystal form of claim 2, or hydrate thereof, wherein the crystal form, or hydrate thereof, is micronized. 9. The crystal form of claim 8, or hydrate thereof, wherein the micronized crystal form, or hydrate thereof, has a particle size distribution ranging from 10 .mu.m to 100 .mu.m. 10. The crystal form of claim 2, or hydrate thereof, wherein the crystal form is a crystal hydrate. 11. The crystal form of claim 10, wherein the crystal hydrate is a monohydrate. 12. The crystal form of claim 11, wherein the crystal monohydrate is micronized. 13. The crystal form of claim 12, wherein the micronized crystal monohydrate has a particle size distribution ranging from 10 .mu.m to 100 .mu.m. 14. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a crystal form of (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-- yl)-N-(pyridin-2-yl)benzamide maleate, or hydrate thereof, characterized by a reflection X-ray powder diffraction pattern comprising at least five peaks selected from the group consisting of 5.3.degree..+-.0.2.degree. 2.theta., 9.8.degree..+-.0.2.degree. 2.theta., 10.6.degree..+-.0.2.degree. 2.theta., 11.6.degree..+-.0.2.degree. 2.theta., 13.5.degree..+-.0.2.degree. 2.theta., 13.8.degree..+-.0.2.degree. 2.theta., 13.9.degree..+-.0.2.degree. 2.theta., 14.3.degree..+-.0.2.degree. 2.theta., 15.3.degree..+-.0.2.degree. 2.theta., 15.6.degree..+-.0.2.degree. 2.theta., 15.8.degree..+-.0.2.degree. 2.theta., 15.9.degree..+-.0.2.degree. 2.theta., 16.6.degree..+-.0.2.degree. 2.theta., 17.4.degree..+-.0.2.degree. 2.theta., 17.5.degree..+-.0.2.degree. 2.theta., 18.7.degree..+-.0.2.degree. 2.theta., 19.3.degree..+-.0.2.degree. 2.theta., 19.6.degree..+-.0.2.degree. 2.theta., 19.8.degree..+-.0.2.degree. 2.theta., 20.0.degree..+-.0.2.degree. 2.theta., 20.9.degree..+-.0.2.degree. 2.theta., 21.3.degree..+-.0.2.degree. 2.theta., 22.1.degree..+-.0.2 2.theta., 22.3.degree..+-.0.2.degree. 2.theta., 22.7.degree..+-.0.2.degree. 2.theta., 23.2.degree..+-.0.2.degree. 2.theta., 23.4.degree..+-.0.2.degree. 2.theta., 23.7.degree..+-.0.2.degree. 2.theta., 23.9.degree..+-.0.2.degree. 2.theta., 24.5.degree..+-.0.2.degree. 2.theta., 24.8.degree..+-.0.2.degree. 2.theta., 25.2.degree..+-.0.2.degree. 2.theta., 25.6.degree..+-.0.2.degree. 2.theta., 26.1.degree..+-.0.2.degree. 2.theta., 26.4.degree..+-.0.2.degree. 2.theta., 26.7.degree..+-.0.2.degree. 2.theta., 26.9.degree..+-.0.2.degree. 2.theta., 27.1.degree..+-.0.2.degree. 2.theta., 27.6.degree..+-.0.2.degree. 2.theta., 28.8.degree..+-.0.2.degree. 2.theta., 29.5.degree..+-.0.2.degree. 2.theta., 30.0.degree..+-.0.2.degree. 2.theta., 30.3.degree..+-.0.2.degree. 2.theta., 30.9.degree..+-.0.2.degree. 2.theta., 31.5.degree..+-.0.2.degree. 2.theta., 31.9.degree..+-.0.2.degree. 2.theta., 32.5.degree..+-.0.2.degree. 2.theta., 34.0.degree..+-.0.2.degree. 2.theta., and 35.1.degree..+-.0.2.degree. 2.theta.. 15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is a tablet. 16. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is a solid pharmaceutical composition for oral administration. 17. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is a tablet. 18. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is a solid pharmaceutical composition for oral administration comprising 100 mg free base equivalent weight of the crystalline maleate. 19. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition is a tablet. 20. The pharmaceutical composition of claim 14, wherein the crystal form, or hydrate thereof, is micronized. 21. The pharmaceutical composition of claim 20, wherein the micronized crystal form, or hydrate thereof, has a particle size distribution ranging from 10 .mu.m to 100 .mu.m. 22. The pharmaceutical composition of claim 14, wherein the reflection X-ray powder diffraction pattern of the crystal form, or hydrate thereof, comprises peaks at 5.3.degree..+-.0.2.degree. 2.theta., 9.8.degree..+-.0.2.degree. 2.theta., 10.6.degree..+-.0.2.degree. 2.theta., 11.6.degree..+-.0.2.degree. 2.theta., and 19.3.degree..+-.0.2.degree. 2.theta.. 23. The pharmaceutical composition of claim 22, wherein the pharmaceutical composition is a solid pharmaceutical composition for oral administration. 24. The pharmaceutical composition of claim 23, wherein the solid pharmaceutical composition for oral administration is a tablet. 25. The pharmaceutical composition of claim 22, wherein the pharmaceutical composition is a solid pharmaceutical composition for oral administration comprising 100 mg free base equivalent weight of the crystalline maleate. 26. The pharmaceutical composition of claim 22, wherein the peaks are present when the reflection X-ray powder diffraction is carried out using Cu-K.alpha. radiation. 27. The pharmaceutical composition of claim 22, wherein the peaks are present when the reflection X-ray powder diffraction is carried out using a Bruker D8 Advance powder X-ray diffractometer equipped with a LynxEye detector and operating in Bragg-Brentano reflection geometry mode, a tube voltage of 40 kV and current of 40 mA, a variable divergence slit with a 3.degree. window, a step size of 0.02.degree. 2.theta., a sample rotation of 0.5 revolution per second, and a step time of 37 seconds. 28. The pharmaceutical composition of claim 22, wherein the crystal form, or a hydrate thereof, is further characterized by a differential scanning calorimetry thermogram comprising an endothermic peak at 174.degree. C. 29. The pharmaceutical composition of claim 22, wherein the crystal form, or hydrate thereof, is further characterized by a dynamic vapor sorption isotherm exhibiting a water content change of 0.5% between 20% relative humidity and 80% relative humidity. 30. The pharmaceutical composition of claim 22, wherein the crystal form, or hydrate thereof, is further characterized by a differential scanning calorimetry thermogram comprising an endothermic peak at 174.degree. C. and a dynamic vapor sorption isotherm exhibiting a water content change of 0.5% between 20% relative humidity and 80% relative humidity. 31. The pharmaceutical composition of claim 22, wherein the crystal form, or hydrate thereof, is micronized. 32. The pharmaceutical composition of claim 31, wherein the micronized crystal form, or hydrate thereof, has a particle size distribution ranging from 10 .mu.m to 100 .mu.m. 33. The pharmaceutical composition of claim 22, wherein the crystal form is a crystal hydrate. 34. The pharmaceutical composition of claim 33, wherein the crystal hydrate is a monohydrate. 35. A method for inhibiting Bruton's tyrosine kinase activity in a human, comprising orally administering to the human a solid pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a crystal form of (S)-4-(8-amino-3-(1-(but-2-ynoyl)pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-- yl)-N-(pyridin-2-yl)benzamide maleate, or hydrate thereof, characterized by a reflection X-ray powder diffraction pattern comprising at least five peaks selected from the group consisting of 5.3.degree..+-.0.2.degree. 2.theta., 9.8.degree..+-.0.2.degree. 2.theta., 10.6.degree..+-.0.2.degree. 2.theta., 11.6.degree..+-.0.2.degree. 2.theta., 13.5.degree..+-.0.2.degree. 2.theta., 13.8.degree..+-.0.2.degree. 2.theta., 13.9.degree..+-.0.2.degree. 2.theta., 14.3.degree..+-.0.2.degree. 2.theta., 15.3.degree..+-.0.2.degree. 2.theta., 15.6.degree..+-.0.2.degree. 2.theta., 15.8.degree..+-.0.2.degree. 2.theta., 15.9.degree..+-.0.2.degree. 2.theta., 16.6.degree..+-.0.2.degree. 2.theta., 17.4.degree..+-.0.2.degree. 2.theta., 17.5.degree..+-.0.2.degree. 2.theta., 18.7.degree..+-.0.2.degree. 2.theta., 19.3.degree..+-.0.2.degree. 2.theta., 19.6.degree..+-.0.2.degree. 2.theta., 19.8.degree..+-.0.2.degree. 2.theta., 20.0.degree..+-.0.2.degree. 2.theta., 20.9.degree..+-.0.2.degree. 2.theta., 21.3.degree..+-.0.2.degree. 2.theta., 22.1.degree..+-.0.2.degree. 2.theta., 22.3.degree..+-.0.2.degree. 2.theta., 22.7.degree..+-.0.2.degree. 2.theta., 23.2.degree..+-.0.2.degree. 2.theta., 23.4.degree..+-.0.2.degree. 2.theta., 23.7.degree..+-.0.2.degree. 2.theta., 23.9.degree..+-.0.2.degree. 2.theta., 24.5.degree..+-.0.2.degree. 2.theta., 24.8.degree..+-.0.2.degree. 2.theta., 25.2.degree..+-.0.2.degree. 2.theta., 25.6.degree..+-.0.2.degree. 2.theta., 26.1.degree..+-.0.2.degree. 2.theta., 26.4.degree..+-.0.2.degree. 2.theta., 26.7.degree..+-.0.2.degree. 2.theta., 26.9.degree..+-.0.2.degree. 2.theta., 27.1.degree..+-.0.2.degree. 2.theta., 27.6.degree..+-.0.2.degree. 2.theta., 28.8.degree..+-.0.2.degree. 2.theta., 29.5.degree..+-.0.2.degree. 2.theta., 30.0.degree..+-.0.2.degree. 2.theta., 30.3.degree..+-.0.2.degree. 2.theta., 30.9.degree..+-.0.2.degree. 2.theta., 31.5.degree..+-.0.2.degree. 2.theta., 31.9.degree..+-.0.2.degree. 2.theta., 32.5.degree..+-.0.2.degree. 2.theta., 34.0.degree..+-.0.2.degree. 2.theta., and 35.1.degree..+-.0.2.degree. 2.theta.. 36. The method of claim 35, wherein the reflection X-ray powder diffraction pattern of the crystal form, or hydrate thereof, comprises peaks at 5.3.degree..+-.0.2.degree. 2.theta., 9.8.degree..+-.0.2.degree. 2.theta., 10.6.degree..+-.0.2.degree. 2.theta., 11.6.degree..+-.0.2.degree. 2.theta., and 19.3.degree..+-.0.2.degree. 2.theta.. 37. The method of claim 36, wherein the human suffers from a hyperproliferative disease. 38. The method of claim 37, wherein the hyperproliferative disease is Waldenstrom's macroglobulinemia. 39. The method of claim 37, wherein the hyperproliferative disease is mantle cell lymphoma. 40. The method of claim 37, wherein the hyperproliferative disease is small lymphocytic lymphoma. 41. The method of claim 37, wherein the hyperproliferative disease is chronic lymphocytic leukemia. 42. The method of claim 37, wherein the hyperproliferative disease is diffuse large B cell lymphoma.