Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate

• US 9,273,044 B2
• Filed: 07/09/2015
• Issued: 03/01/2016
• Est. Priority Date: 05/17/2010
• Status: Active Grant

• Current Assignee: Forum Pharmaceuticals Inc.
• Original Assignee: Forum Pharmaceuticals Inc.
• Inventors: Oliver-Shaffer, Patricia, Shapiro, Gideon, Chesworth, Richard, Kishida, Muneki, Ishige, Takayuki
• Primary Examiner(s): REESE, HEIDI L
• Application Number:
  US14/795,595
• Publication Number:
  US 20160009707A1
• Time in Patent Office: 236 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 9/4833 Encapsulating processes; Filling of capsules mechanical aspects A61J3/07
• CPC Class Codes: A61K 9/4841 Filling excipients; Inactive ingredients
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 453/02 containing not further condensed quinuclidine ring systems
• CPC Class Codes: C30B 29/54 Organic compounds
• CPC Class Codes: C30B 7/08 by cooling of the solution

Abstract

Crystalline Forms I and II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate and compositions, methods of manufacture and therapeutic uses thereof are described.

Claims

1. A crystalline Form II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate, characterized by an x-ray powder diffraction pattern having peaks expressed as 2Θ

at;

i) one or both of 21.16 and 21.38±

0.20 degrees when measured against an internal silicon standard; and

ii) at least four peaks selected from a group of peaks consisting of;

4.48, 9.00, 13.58, 15.62, 16.48, 19.02, 19.44, 22.46, and 25.00+0.20 degrees when measured against an internal silicon standard.

2. The crystalline Form II of claim 1, characterized by an x-ray powder diffraction pattern, wherein at least six peaks are selected from the group of peaks.

3. The crystalline Form II of claim 1, characterized by an x-ray powder diffraction pattern, wherein at least eight peaks are selected from the group of peaks.

4. The crystalline Form II of claim 1, characterized by an x-ray powder diffraction pattern, wherein all of the peaks are selected from the group of peaks.

5. A pharmaceutical composition comprising the crystalline Form II of claim 1.

6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is for the treatment of cognitive loss in a subject suffering from Alzheimer'"'"'s disease.

7. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is for the treatment of cognitive loss in a subject suffering from Schizophrenia.

8. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is for the improvement of cognition in a subject suffering from Alzheimer'"'"'s disease.

9. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is for the improvement of cognition in a subject suffering from Schizophrenia.

10. A pharmaceutical composition comprising the crystalline Form II of claim 2.

11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is for the treatment of cognitive loss in a subject suffering from Alzheimer'"'"'s disease.

12. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is for the treatment of cognitive loss in a subject suffering from Schizophrenia.

13. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is for the improvement of cognition in a subject suffering from Alzheimer'"'"'s disease.

14. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is for the improvement of cognition in a subject suffering from Schizophrenia.

15. A pharmaceutical composition comprising the crystalline Form II of claim 3.

16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is for the treatment of cognitive loss in a subject suffering from Alzheimer'"'"'s disease.

17. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is for the treatment of cognitive loss in a subject suffering from Schizophrenia.

18. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is for the improvement of cognition in a subject suffering from Alzheimer'"'"'s disease.

19. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is for the improvement of cognition in a subject suffering from Schizophrenia.

20. A pharmaceutical composition comprising the crystalline Form II of claim 4.

21. The pharmaceutical composition of claim 20, wherein the pharmaceutical composition is for the treatment of cognitive loss in a subject suffering from Alzheimer'"'"'s disease.

22. The pharmaceutical composition of claim 20, wherein the pharmaceutical composition is for the treatment of cognitive loss in a subject suffering from Schizophrenia.

23. The pharmaceutical composition of claim 20, wherein the pharmaceutical composition is for the improvement of cognition in a subject suffering from Alzheimer'"'"'s disease.

24. The pharmaceutical composition of claim 20, wherein the pharmaceutical composition is for the improvement of cognition in a subject suffering from Schizophrenia.

41. A method for preparing a pharmaceutical composition, the method comprising combining the crystalline Form II of claim 1 with an excipient or pharmaceutically acceptable carrier.

42. The method according to claim 41, the method comprising combining the crystalline Form II of claim 1 with a liquid.

43. A method for preparing a pharmaceutical composition, the method comprising filling a capsule with a composition comprising the crystalline Form II of claim 1.

44. A method for preparing the crystalline Form II of claim 1, the method comprising:

a) adding (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride to acetonitrile or an aqueous acetonitrile to create a composition that is 10-20 wt. % of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride;

b) optionally adding water to the composition to make the water content 6-10%;

c) optionally cooling the solution at below 10°

C.;

d) allowing crystals to form; and

e) isolating crystalline (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate.

25. A method of improving cognition in a patient suffering from Schizophrenia, comprising administering to the patient a crystalline Form II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate.

26. The method of claim 25, wherein the crystalline Form II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate is characterized by an x-ray powder diffraction pattern having peaks expressed as 2Θ

at;

i) one or both of 21.16 and 21.38±

0.20 degrees when measured against an internal silicon standard; and

ii) at least four peaks selected from a group of peaks consisting of;

4.48, 9.00, 13.58, 15.62, 16.48, 19.02, 19.44, 22.46, and 25.00±

0.20 degrees when measured against an internal silicon standard.

27. The method of claim 26, wherein the crystalline Form II is characterized by an x-ray powder diffraction pattern with at least six peaks selected from the group of peaks.

28. The method of claim 26, wherein the crystalline Form II is characterized by an x-ray powder diffraction pattern with at least eight peaks selected from the group of peaks.

29. The method of claim 26, wherein the crystalline Form II is characterized by an x-ray powder diffraction pattern with all of the peaks selected from the group of peaks.

30. The method of claim 25, wherein the method further treats cognitive loss in the patient.

31. The method of claim 30, wherein the patient is over age 60.

32. The method of claim 30, wherein the patient further suffers from age-related memory loss.

33. A method of improving cognition in a patient suffering from Alzheimer'"'"'s Disease, comprising administering to the patient a pharmaceutical composition comprising a crystalline Form II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate.

34. The method of claim 33, wherein the crystalline Form II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate is characterized by an x-ray powder diffraction pattern having peaks expressed as 2Θ

at;

i) one or both of 21.16 and 21.38±

0.20 degrees when measured against an internal silicon standard; and

ii) at least four peaks selected from a group of peaks consisting of;

4.48, 9.00, 13.58, 15.62, 16.48, 19.02, 19.44, 22.46, and 25.00±

0.20 degrees when measured against an internal silicon standard.

35. The method of claim 34, wherein the crystalline Form II is characterized by an x-ray powder diffraction pattern with at least six peaks selected from the group of peaks.

36. The method of claim 34, wherein the crystalline Form II is characterized by an x-ray powder diffraction pattern with at least eight peaks selected from the group of peaks.

37. The method of claim 34, wherein the crystalline Form II is characterized by an x-ray powder diffraction pattern with all of the peaks selected from the group of peaks.

38. The method of claim 33, wherein the method further treats cognitive loss in the patient.

39. The method of claim 38, wherein the patient is over age 60.

40. The method of claim 38, wherein the patient further suffers from age-related memory loss.