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

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.