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 for treating diffuse large B-cell lymphoma

Patent metadata

Field	Value
Publication number	US-10640509-B2
Application number	US-201816177927-A
Country	US
Kind code	B2
Filing date	Nov 1, 2018
Priority date	Jul 2, 2015
Publication date	May 5, 2020
Grant date	May 5, 2020

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 method for treating diffuse large B-cell lymphoma in a human, comprising administering to said human a therapeutically effective amount of 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 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 method of claim 1 , wherein the method further comprises orally administering to said human twice daily a solid pharmaceutical composition comprising 95 mg to 105 mg of the 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.

3. The method of claim 2 , 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-Kα radiation.

4. The method of claim 2 , 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.

5. The method of claim 2 , 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.

6. The method of claim 5 , 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.

7. The method of claim 2 , wherein the reflection X-ray powder diffraction pattern is the same as the representative reflection X-ray powder diffraction pattern shown in FIG. 1 .

8. The method of claim 2 , wherein the crystal form is further characterized by a Raman spectrum comprising peaks at 1620 cm −1 ±4 cm −1 , 1609 cm −1 ±4 cm −1 , 1547 cm −1 ±4 cm −1 , 1514 cm −1 ±4 cm −1 , and 1495 cm −1 ±4 cm −1 .

9. The method of claim 8 , wherein the Raman spectrum of the crystal form further comprises one or more peaks selected from the group consisting of 1680 cm −1 ±4 cm −1 , 1574 cm −1 ±4 cm −1 , 1454 cm −1 ±4 cm −1 , 1433 cm −1 +4 cm −1 , 1351 cm −1 +4 cm −1 , 1312 cm −1 +4 cm −1 , 1255 cm −1 +4 cm −1 , 1232 cm −1 +4 cm −1 , 1187 cm −1 +4 cm −1 , 1046 cm −1 ±4 cm −1 , 995 cm −1 ±4 cm −1 , 706 cm −1 ±4 cm −1 , 406 cm −1 ±4 cm −1 ±4 cm −1 , and 280 cm −1 ±4 cm −1 .

10. The method of claim 8 , wherein the Raman spectrum is the same as the representative Raman spectrum shown in FIG. 2 .

11. The method of claim 2 , wherein the crystal form is further characterized by an infrared spectrum comprising peaks at 1621 cm −1 ±4 cm −1 , 1608 cm −1 ±4 cm −1 , 1403 cm −1 ±4 cm −1 , 1303 cm −1 +4 cm −1 , and 764 cm −1 ±4 cm −1 .

12. The method of claim 11 , wherein the infrared spectrum of the crystal form further comprises one or more peaks selected from the group consisting of 3367 cm −1 ±4 cm −1 , 3089 cm −1 ±4 cm −1 , 2246 cm −1 ±4 cm −1 , 1682 cm −1 ±4 cm −1 , 1574 cm −1 ±4 cm −1 , 1514 cm −1 ±4 cm −1 , 1504 cm −1 ±4 cm −1 , 1454 cm −1 ±4 cm −1 , 1428 cm −1 ±4 cm −1 , 1345 cm −1 ±4 cm −1 , 1248 cm −1 ±4 cm −1 , 1194 cm −1 ±4 cm −1 , 1177 cm −1 ±4 cm −1 , 1149 cm −1 ±4 cm −1 , 1109 cm −1 ±4 cm −1 , 1049 cm −1 ±4 cm −1 , 1023 cm −1 ±4 cm −1 , 1003 cm −1 ±4 cm −1 , 947 cm −1 ±4 cm −1 , 900 cm −1 +4 cm −1 , 858 cm −1 +4 cm −1 , 842 cm −1 +4 cm −1 , 816 cm −1 +4 cm −1 , 734 cm −1 +4 cm −1 , 729 cm −1 +4 cm −1 , 701 cm −1 ±4 cm −1 , 689 cm −1 ±4 cm −1 , 665 cm −1 ±4 cm −1 , 623 cm −1 ±4 cm −1 , and 612 cm −1 ±4 cm −1 .

13. The method of claim 11 , wherein the infrared spectrum is the same as the representative infrared spectrum shown in FIG. 3 .

14. The method of claim 2 , wherein the crystal form is further characterized by a Raman spectrum comprising peaks at 1620 cm −1 ±4 cm −1 , 1609 cm −1 ±4 cm −1 , 1547 cm −1 ±4 cm −1 , 1514 cm −1 ±4 cm −1 , and 1495 cm −1 ±4 cm −1 and an infrared spectrum comprising peaks at 1621 cm −1 ±4 cm −1 , 1608 cm −1 ±4 cm −1 , 1403 cm −1 ±4 cm −1 , 1303 cm −1 ±4 cm −1 , and 764 cm −1 ±4 cm −1 .

15. The method of claim 2 , wherein the solid pharmaceutical composition comprises 100 mg of the 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.

16. The method of claim 15 , 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.

17. The method of claim 16 , 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.

18. The method of claim 2 , wherein the solid pharmaceutical composition is a capsule.

19. The method of claim 2 , wherein the solid pharmaceutical composition further comprises an extragranular acidulant.

20. The method of claim 19 , wherein the extragranular acidulant is selected from the group consisting of fumaric acid, succinic acid, D-tartaric acid, L-tartaric acid, (±)-tartaric acid, ascorbic acid, isoascorbic acid, alginic acid, a salt of alginic acid, Protacid F 120 NM, Protacid AR 1112, and Carbopol 971P, or a combination thereof.

Assignees

• Acerta Pharma Bv

Inventors

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

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61P31/04

  Antibacterial agents · CPC title