Solid Forms and Formulations of Imidazopyrazine Compound

• US 20190337949A1
• Filed: 11/01/2018
• Published: 11/07/2019
• 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
• Granted Patent: US 10,640,509 B2
• Time in Patent Office: Days
• 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

1-18. -18. (canceled)

19. A method of treating diffuse large B-cell lymphoma (DLBCL) 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

.

20. The method of claim 19, wherein the pharmaceutical composition is a solid pharmaceutical composition comprising 95-105 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;

and wherein the method comprises orally administering the solid pharmaceutical composition to said human twice daily.

21. The method of claim 20, 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.

22. The method of claim 20, 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

.

23. The method of claim 21, 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

.

24. The method of claim 22, 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

.

25. The method of claim 23, 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

.

26. The method of claim 20, 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.

27. The method of claim 26, 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.

28. The method of claim 26, wherein the Raman spectrum is substantially the same as the representative Raman spectrum shown in FIG. 2.

29. The method of claim 20, 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.

30. The method of claim 29, 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.

31. The method of claim 29, wherein the infrared spectrum is substantially the same as the representative infrared spectrum shown in FIG. 3.

32. The method of claim 20, 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.

33. The method of claim 20, wherein the solid pharmaceutical composition is a capsule.

34. The method of claim 20, wherein the solid pharmaceutical composition further comprises an extragranular acidulant.

35. The method of claim 34, 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, and a combination thereof.

36. The method of claim 20, 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.

37. The method of claim 20, 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.

38. The method of claim 20, wherein the reflection X-ray powder diffraction pattern is substantially same as the representative X-ray powder diffraction pattern shown in FIG. 1.

39. 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 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

.

40. The method of claim 39, 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

.