Pharmaceutical composition comprising 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

Patent metadata

Field	Value
Publication number	US-10167291-B2
Application number	US-201715707508-A
Country	US
Kind code	B2
Filing date	Sep 18, 2017
Priority date	Jul 2, 2015
Publication date	Jan 1, 2019
Grant date	Jan 1, 2019

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.

First claim

We claim:

1. A solid pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and 95-105 mg of 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 characterized by a reflection X-ray powder diffraction pattern comprising peaks at 6.4° ±0.2° 2θ, 8.6°±0.2° 2θ, 10.5° ±0.2° 2θ, 11.6° ±0.2° 2θ and 15.7° ±0.2° 2θ.

2. The solid pharmaceutical composition of claim 1 , wherein the reflection X-ray powder diffraction pattern of the crystal form further comprises peaks at 10.9° ±0.2° 2θ, 12.7° ±0.2° 2θ, 13.4° ±0.2° 2θ, 14.3° ±0.2° 2θ, 14.9° ±0.2° 2θ and 18.2° ±0.2° 2θ.

3. The solid pharmaceutical composition of claim 2 , wherein the reflection X-ray powder diffraction pattern of the crystal form further comprises one or more peaks selected from the group consisting of 11.3° ±0.2° 2θ, 15.1° ±0.2° 2θ, 15.7° ±0.2° 2θ, 16.1° ±0.2° 2θ, 17.3° ±0.2° 2θ, 19.2° ±0.2° 2θ, 19.4° ±0.2° 2θ, 19.8° ±0.2° 2θ, 20.7° ±0.2° 2θ, 21.1° ±0.2° 2θ, 21.4° ±0.2° 2θ, 21.6° ±0.2° 2θ, 21.9° ±0.2° 2θ, 22.6° ±0.2° 2θ, 23.3° ±0.2° 2θ, 23.6° ±0.2° 2θ, 24.9° ±0.2° 2θ, 25.2° ±0.2° 2θ, 25.4° ±0.2° 2θ, 25.7° ±0.2° 2θ, 26.1° ±0.2° 2θ, 26.4° ±0.2° 2θ, 26.8° ±0.2° 2θ, 26.9° ±0.2° 2θ, 27.7° ±0.2° 2θ, 28.6° ±0.2° 2θ, 29.1° ±0.2° 2θ, 29.4° ±0.2° 2θ, 30.1° ±0.2° 2θ, 30.5° ±0.2° 2θ, 31.7° ±0.2° 2θ, 31.9° ±0.2° 2θ, 32.2° ±0.2° 2θ, 32.6° ±0.2° 2θ, 33.1° ±0.2° 2θ, 33.4° ±0.2° 2θ, 34.5° ±0.2° 2θ, 35.9° ±0.2° 2θ, 36.1° ±0.2° 2θ, 36.8° ±0.2° 2θ, 37.4° ±0.2° 2θ, 38.1° ±0.2° 2θ, 38.9° ±0.2° 2θ and 39.5° ±0.2° 2θ.

4. The solid pharmaceutical composition of claim 1 , wherein the crystal form is further characterized by a Raman spectrum comprising peaks at 1620 ±4 cm −1 , 1609 ±4 cm −1 , 1547 ±4 cm −1 , 1514 ±4 cm −1 and 1495 ±4 cm −1 .

5. The solid pharmaceutical composition of claim 4 , wherein the Raman spectrum of the crystal form further comprises one or more peaks selected from the group consisting of 1680 ±4 cm −1 , 1574 ±4 cm −1 , 1454 ±4 cm −1 , 1433 ±4 cm −1 , 1351 ±4 cm −1 , 1312 ±4 cm −1 , 1255 ±4 cm −1 , 1232 ±4 cm −1 , 1187 ±4 cm −1 , 1046 ±4 cm −1 , 995 ±4 cm −1 , 706 ±4 cm −1 , 406 ±4 cm −1 and 280 ±4 cm −1 .

6. The solid pharmaceutical composition of claim 1 , wherein the crystal form is further characterized by an infrared spectrum comprising peaks at 1621 ±4 cm −1 , 1608 ±4 cm −1 , 1403 ±4 cm −1 , 1303 ±4 cm −1 and 764 cm −1 ±4 cm −1 .

7. The solid pharmaceutical composition of claim 6 , wherein the infrared spectrum of the crystal form further comprises one or more peaks selected from the group consisting of 3367 ±4 cm −1 , 3089 ±4 cm −1 , 2246 ±4 cm −1 , 1682 ±4 cm −1 , 1574 ±4 cm −1 , 1514 ±4 cm −1 , 1504 ±4 cm −1 , 1454 ±4 cm −1 , 1428 ±4 cm −1 , 1345 ±4 cm −1 , 1248 ±4 cm −1 , 1194 ±4 cm −1 , 1177 ±4 cm −1 , 1149 ±4 cm −1 , 1109 ±4 cm −1 , 1049 ±4 cm −1 , 1023 ±4 cm −1 , 1003 ±4 cm −1 , 947 ±4 cm −1 , 900 ±4 cm −1 , 858 ±4 cm −1 , 842 ±4 cm −1 , 816 ±4 cm −1 , 734 ±4 cm −1 , 729 ±4 cm −1 , 701 ±4 cm −1 , 689 ±4 cm −1 , 665 ±4 cm −1 , 623 ±4 cm −1 and 612 ±4 cm −1 .

8. The solid pharmaceutical composition of claim 1 , wherein the crystal form is further characterized by a Raman spectrum comprising peaks at 1620 ±4 cm −1 , 1609 ±4 cm −1 , 1547 ±4 cm −1 , 1514 ±4 cm −1 and 1495 ±4 cm −1 ; and by an infrared spectrum comprising peaks at 1621 ±4 cm −1 , 1608 ±4 cm −1 , 1403 ±4 cm −1 , 1303 ±4 cm −1 and 764 ±4 cm −1 .

9. The solid pharmaceutical composition of claim 8 , wherein the crystal form is a crystalline anhydrate.

10. The solid pharmaceutical composition of claim 9 , wherein the solid pharmaceutical composition is a capsule.

11. The solid pharmaceutical composition of claim 10 , wherein the peaks of the reflection X-ray powder diffraction pattern are present when the reflection X-ray powder diffraction is carried out using Cu-K α radiation.

12. The solid pharmaceutical composition of claim 11 , wherein the peaks of the reflection X-ray powder diffraction pattern 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° window, a step size of 0.02° 2θ, a sample rotation of 0.5 revolution per second and a step time of 37 seconds.

13. The solid pharmaceutical composition of claim 1 , wherein the solid pharmaceutical composition comprises 100 mg of 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.

14. A method for inhibiting Bruton's tyrosine kinase activity in a human, comprising orally administering to said human twice daily a solid pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and 95-105 mg of 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 characterized by a reflection X-ray powder diffraction pattern comprising peaks at 6.4° ±0.2° 2θ, 8.6° ±0.2° 2θ, 10.5° ±0.2° 2θ, 11.6° ±0.2° 2θ and 15.7° ±0.2° 2θ.

15. The method of claim 14 , wherein the reflection X-ray powder diffraction pattern of the crystal form further comprises peaks at 10.9° ±0.2° 2θ, 12.7° ±0.2° 2θ, 13.4° ±0.2° 2θ, 14.3° ±0.2° 2θ, 14.9° ±0.2° 2θ and 18.2° ±0.2° 2θ.

16. The method of claim 15 , wherein the reflection X-ray powder diffraction pattern of the crystal form further comprises one or more peaks selected from the group consisting of 11.3° ±0.2° 2θ, 15.1° ±0.2° 2θ, 15.7° ±+0.2° 2θ, 16.1° ±0.2° 2θ, 17.3° ±0.2° 2θ, 19.2° ±0.2° 2θ, 19.4° ±0.2° 2θ, 19.8° ±0.2° 2θ, 20.7° ±+0.2° 2θ, 21.1° ±0.2° 2θ, 21.4° ±0.2° 2θ, 21.6° ±0.2° 2θ, 21.9° ±0.2° 2θ, 22.6° ±0.2° 2θ, 23.3° ±0.2° 2θ, 23.6° ±0.2° 2θ, 24.9° ±0.2° 2θ, 25.2° ±0.2° 2θ, 25.4° ±0.2° 2θ, 25.7° ±0.2° 2θ, 26.1° ±0.2° 2θ, 26.4° ±0.2° 2θ, 26.8° ±0.2° 2θ, 26.9° ±0.2° 2θ, 27.7° ±0.2° 2θ, 28.6° ±0.2° 2θ, 29.1° ±0.2° 2θ, 29.4° ±0.2° 2θ, 30.1° ±0.2° 2θ, 30.5° ±0.2° 2θ, 31.7° ±0.2° 2θ, 31.9° ±0.2° 2θ, 32.2° ±0.2° 2θ, 32.6° ±0.2° 2θ, 33.1° ±0.2° 2θ, 33.4° ±0.2° 2θ, 34.5° ±0.2° 2θ, 35.9° ±0.2° 2θ, 36.1° ±0.2° 2θ, 36.8° ±0.2° 2θ, 37.4° ±0.2° 2θ, 38.1° ±0.2° 2θ, 38.9° ±0.2° 2θ and 39.5° ±0.2° 2θ.

17. The method of claim 14 , wherein the crystal form is further characterized by a Raman spectrum comprising peaks at 1620 ±4 cm −1 , 1609 ±4 cm −1 , 1547 ±4 cm −1 , 1514 ±4 cm −1 and 1495 ±4 cm −1 .

18. The method of claim 17 , wherein the Raman spectrum of the crystal form further comprises one or more peaks selected from the group consisting of 1680 ±4 cm −1 , 1574 ±4 cm −1 , 1454 ±4 cm −1 , 1433 ±4 cm −1 , 1351 ±4 cm −1 , 1312 ±4 cm −1 , 1255 ±4 cm −1 , 1232 ±4 cm −1 , 1187 ±4 cm −1 , 1046 ±4 cm −1 , 995 ±4 cm −1 , 706 ±4 cm −1 , 406 ±4 cm −1 and 280 ±4 cm −1 .

19. The method of claim 14 , wherein the crystal form is further characterized by an infrared spectrum comprising peaks at 1621 ±4 cm −1 , 1608 ±4 cm −1 , 1403 ±4 cm −1 , 1303 ±4 cm −1 and 764 ±4 cm −1 .

20. The method of claim 19 , wherein the infrared spectrum of the crystal form further comprises one or more peaks selected from the group consisting of 3367 ±4 cm −1 , 3089 ±4 cm −1 , 2246 ±4 cm −1 , 1682 ±4 cm −1 , 1574 ±4 cm −1 , 1514 ±4 cm −1 , 1504 ±4 cm −1 , 1454 ±4 cm −1 , 1428 ±4 cm −1 , 1345 ±4 cm −1 , 1248 ±4 cm −1 , 1194 ±4 cm −1 , 1177 ±4 cm −1 , 1149 ±4 cm −1 , 1109 ±4 cm −1 , 1049 ±4 cm −1 , 1023 ±4 cm −1 , 1003 ±4 cm −1 , 947 ±4 cm −1 , 900 ±4 cm −1 , 858 ±4 cm −1 , 842 ±4 cm −1 , 816

Assignees

• Acerta Pharma Bv

Inventors

• Blatter Fritz
• Ingallinera Tim
• Barf Tjeerd
• Aret Edwin
• Krejsa Cecile
• Evarts Jerry

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/02

  specific for leukemia · CPC title