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

Patent metadata

Field	Value
Publication number	US-11059829-B2
Application number	US-202016863033-A
Country	US
Kind code	B2
Filing date	Apr 30, 2020
Priority date	Jul 2, 2015
Publication date	Jul 13, 2021
Grant date	Jul 13, 2021

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 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°±0.2° 2θ, 9.8°±0.2° 2θ, 10.6°±0.2° 2θ, 11.6°±0.2° 2θ, 13.5°±0.2° 2θ, 13.8°±0.2° 2θ, 13.9°±0.2° 2θ, 14.3°±0.2° 2θ, 15.3°±0.2° 2θ, 15.6°±0.2° 2θ, 15.8°±0.2° 2θ, 15.9°±0.2° 2θ, 16.6°±0.2° 2θ, 17.4°±0.2° 2θ, 17.5°±0.2° 2θ, 18.7°±0.2° 2θ, 19.3°±0.2° 2θ, 19.6°±0.2° 2θ, 19.8°±0.2° 2θ, 20.0°±0.2° 2θ, 20.9°±0.2° 2θ, 21.3°±0.2° 2θ, 22.1°±0.2° 2θ, 22.3°±0.2° 2θ, 22.7°±0.2° 2θ, 23.2°±0.2° 2θ, 23.4°±0.2° 2θ, 23.7°±0.2° 2θ, 23.9°±0.2° 2θ, 24.5°±0.2° 2θ, 24.8°±0.2° 2θ, 25.2°±0.2° 2θ, 25.6°±0.2° 2θ, 26.1°±0.2° 2θ, 26.4°±0.2° 2θ, 26.7°±0.2° 2θ, 26.9°±0.2° 2θ, 27.1°±0.2° 2θ, 27.6°±0.2° 2θ, 28.8°±0.2° 2θ, 29.5°±0.2° 2θ, 30.0°±0.2° 2θ, 30.3°±0.2° 2θ, 30.9°±0.2° 2θ, 31.5°±0.2° 2θ, 31.9°±0.2° 2θ, 32.5°±0.2° 2θ, 34.0°±0.2° 2θ, and 35.1°±0.2° 2θ.

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°±0.2° 2θ, 9.8°±0.2° 2θ, 10.6°±0.2° 2θ, 11.6°±0.2° 2θ, and 19.3°±0.2° 2θ.

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-Kα 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° 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 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° 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° 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 μm to 100 μm.

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 μm to 100 μm.

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°±0.2° 2θ, 9.8°±0.2° 2θ, 10.6°±0.2° 2θ, 11.6°±0.2° 2θ, 13.5°±0.2° 2θ, 13.8°±0.2° 2θ, 13.9°±0.2° 2θ, 14.3°±0.2° 2θ, 15.3°±0.2° 2θ, 15.6°±0.2° 2θ, 15.8°±0.2° 2θ, 15.9°±0.2° 2θ, 16.6°±0.2° 2θ, 17.4°±0.2° 2θ, 17.5°±0.2° 2θ, 18.7°±0.2° 2θ, 19.3°±0.2° 2θ, 19.6°±0.2° 2θ, 19.8°±0.2° 2θ, 20.0°±0.2° 2θ, 20.9°±0.2° 2θ, 21.3°±0.2° 2θ, 22.1°±0.2 2θ, 22.3°±0.2° 2θ, 22.7°±0.2° 2θ, 23.2°±0.2° 2θ, 23.4°±0.2° 2θ, 23.7°±0.2° 2θ, 23.9°±0.2° 2θ, 24.5°±0.2° 2θ, 24.8°±0.2° 2θ, 25.2°±0.2° 2θ, 25.6°±0.2° 2θ, 26.1°±0.2° 2θ, 26.4°±0.2° 2θ, 26.7°±0.2° 2θ, 26.9°±0.2° 2θ, 27.1°±0.2° 2θ, 27.6°±0.2° 2θ, 28.8°±0.2° 2θ, 29.5°±0.2° 2θ, 30.0°±0.2° 2θ, 30.3°±0.2° 2θ, 30.9°±0.2° 2θ, 31.5°±0.2° 2θ, 31.9°±0.2° 2θ, 32.5°±0.2° 2θ, 34.0°±0.2° 2θ, and 35.1°±0.2° 2θ.

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 μm to 100 μm.

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°±0.2° 2θ, 9.8°±0.2° 2θ, 10.6°±0.2° 2θ, 11.6°±0.2° 2θ, and 19.3°±0.2° 2θ.

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-Kα 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° window, a step size of 0.02° 2θ, 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° 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.

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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title