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

• US 10,640,509 B2
• Filed: 11/01/2018
• Issued: 05/05/2020
• Est. Priority Date: 07/02/2015
• Status: Active Grant

• Current Assignee: Acerta Pharma B.V. (Astrazeneca PLC)
• Original Assignee: Acerta Pharma B.V. (Astrazeneca PLC)
• Inventors: Blatter, Fritz, Ingallinera, Tim, Barf, Tjeerd, Aret, Edwin, Krejsa, Cecile, Evarts, Jerry
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US16/177,927
• Publication Number:
  US 20190337949A1
• Time in Patent Office: 551 Days
• Field of Search: 514249, 544350
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07B 2200/13 : Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

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.

Claims

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<sup>−

1</sup>, 1609 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1547 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1514 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, and 1495 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>.

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<sup>−

1</sup>, 1574 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1454 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1433 cm<sup>−

1</sup>+4 cm<sup>−

1</sup>, 1351 cm<sup>−

1</sup>+4 cm<sup>−

1</sup>, 1312 cm<sup>−

1</sup>+4 cm<sup>−

1</sup>, 1255 cm<sup>−

1</sup>+4 cm<sup>−

1</sup>, 1232 cm<sup>−

1</sup>+4 cm<sup>−

1</sup>, 1187 cm<sup>−

1</sup>+4 cm<sup>−

1</sup>, 1046 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 995 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 706 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 406 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, and 280 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>.

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<sup>−

1</sup>, 1608 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1403 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1303 cm<sup>−

1</sup>+4 cm<sup>−

1</sup>, and 764 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>.

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<sup>−

1</sup>, 3089 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 2246 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1682 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1574 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1514 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1504 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1454 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1428 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1345 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1248 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1194 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1177 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1149 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1109 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1049 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1023 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1003 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 947 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 900 cm<sup>−

1</sup>+4 cm<sup>−

1</sup>, 858 cm<sup>−

1</sup>+4 cm<sup>−

1</sup>, 842 cm<sup>−

1</sup>+4 cm<sup>−

1</sup>, 816 cm<sup>−

1</sup>+4 cm<sup>−

1</sup>, 734 cm<sup>−

1</sup>+4 cm<sup>−

1</sup>, 729 cm<sup>−

1</sup>+4 cm<sup>−

1</sup>, 701 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 689 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 665 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 623 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, and 612 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>.

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<sup>−

1</sup>, 1609 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1547 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1514 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, and 1495 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup> and an infrared spectrum comprising peaks at 1621 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1608 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1403 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, 1303 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>, and 764 cm<sup>−

1</sup>±

4 cm<sup>−

1</sup>.

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.