Solid Forms and Formulations of Imidazopyrazine Compound

Patent metadata

Field	Value
Publication number	US-2018208596-A1
Application number	US-201715707508-A
Country	US
Kind code	A1
Filing date	Sep 18, 2017
Priority date	Jul 2, 2015
Publication date	Jul 26, 2018
Grant date	—

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

1 - 18 . (canceled)

19 . A solid pharmaceutical composition for oral administration comprising about 100 mg of 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; and at least one pharmaceutically-acceptable excipient.

20 . The composition of claim 19 , 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.

21 . The composition of claim 20 , 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.

22 . The composition of claim 19 , wherein the crystal form is characterized by a Raman spectrum comprising peaks at 1620, 1609, 1547, 1514, and 1495 cm −1 ±4 cm −1 .

23 . The composition of claim 22 , wherein the Raman spectrum of the crystal form further comprises one or more peaks selected from the group consisting of 1680, 1574, 1454, 1433, 1351, 1312, 1255, 1232, 1187, 1046, 995, 706, 406, and 280 cm −1 ±4 cm −1 .

24 . The composition of claim 18 , wherein the crystal form is characterized by an infrared (IR) spectrum comprising peaks at 1621, 1608, 1403, 1303, and 764 cm −1 ±4 cm −1 .

25 . The composition of claim 24 , wherein the IR spectrum of the crystal form further comprises one or more peaks selected from the group consisting of 3367, 3089, 2246, 1682, 1574, 1514, 1504, 1454, 1428, 1345, 1248, 1194, 1177, 1149, 1109, 1049, 1023, 1003, 947, 900, 858, 842, 816, 734, 729, 701, 689, 665, 623, and 612 cm −1 ±4 cm −1 .

26 . The composition of claim 19 , wherein the crystal form is characterized by a Raman spectrum comprising peaks at 1620, 1609, 1547, 1514, and 1495 cm −1 ±2 cm −1 ; and by an infrared (IR) spectrum comprising peaks at 1621, 1608, 1403, 1303, and 764 cm −1 ±4 cm −1 .

27 . The composition of claim 26 , wherein the crystal form is a crystalline anhydrate.

28 . The composition of claim 27 , wherein the composition is a capsule.

29 . The composition of claim 28 , wherein the peaks are present when the reflection X-ray powder diffraction is carried out using Cu—K a radiation.

30 . The composition of claim 29 , 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, sample rotation of 0.5 rps, and a step time of 37 seconds.

31 . A method of treating a hyperproliferative disease, comprising the step of orally administering to a human twice daily a solid pharmaceutical composition comprising about 100 mg of 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° 20, 10.5±0.2° 2θ, 11.6±0.2° 2θ, and 15.7±0.2° 2θ; and at least one pharmaceutically-acceptable excipient.

32 . The method of claim 31 , 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° 20, 14.3±0.2° 2θ, 14.9±0.2° 2θ, and 18.2±0.2° 2θ.

33 . The method of claim 32 , 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° 2 θ, 19 . 8 ± 0 . 2 ° 2 θ, 20 . 7 ± 0 . 2 ° 2 θ, 21 . 1 ± 0 . 2 ° 2 θ, 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° 20, 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.

34 . The method of claim 31 , wherein the crystal form is characterized by a Raman spectrum comprising peaks at 1620, 1609, 1547, 1514, and 1495 cm −1 ±4 cm −1 .

35 . The method of claim 34 , wherein the Raman spectrum of the crystal form further comprises one or more peaks selected from the group consisting of 1680, 1574, 1454, 1433, 1351, 1312, 1255, 1232, 1187, 1046, 995, 706, 406, and 280 cm −1 ±4 cm −1 .

36 . The method of claim 31 , wherein the crystal form is characterized by an infrared (IR) spectrum comprising peaks at 1621, 1608, 1403, 1303, and 764 cm −1 ±4 cm −1 .

37 . The method of claim 36 , wherein the IR spectrum of the crystal form further comprises one or more peaks selected from the group consisting of 3367, 3089, 2246, 1682, 1574, 1514, 1504, 1454, 1428, 1345, 1248, 1194, 1177, 1149, 1109, 1049, 1023, 1003, 947, 900, 858, 842, 816, 734, 729, 701, 689, 665, 623, and 612 cm −1 ±4 cm −1 .

38 . The method of claim 31 , wherein the crystal form is characterized by a Raman spectrum comprising peaks at 1620, 1609, 1547, 1514, and 1495 cm −1 ±4 cm −1 ; and by an infrared (IR) spectrum comprising peaks at 1621, 1608, 1403, 1303, and 764 cm −1 ±4 cm −1 .

39 . The method of claim 31 , wherein the composition is a capsule.

40 . The method of claim 31 , wherein the hyperproliferative disease is chronic lymphocytic leukemia.

41 . The method of claim 31 , wherein the hyperproliferative disease is small lymphocytic leukemia.

42 . The method of claim 31 , wherein the hyperproliferative disease is mantle cell lymphoma.

43 . The method of claim 31 , wherein the hyperproliferative disease is Waldennström's macroglobulinemia.

Assignees

• Acerta Pharma Bv

Inventors

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

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P31/04

  Antibacterial agents · CPC title