Crystalline Form of (R)-7-Chloro-N-(Quinuclidin-3-yl)benzo[B]thiophene-2-Carboxamide Hydrochloride Monohydrate

• US 20130183380A1
• Filed: 05/17/2011
• Published: 07/18/2013
• Est. Priority Date: 05/17/2010
• Status: Active Grant

• Current Assignee: Forum Pharmaceuticals Inc.
• Original Assignee: Envivo Pharmaceuticals, Inc.
• Inventors: Oliver-Shaffer, Patricia, Shapiro, Gideon, Chesworth, Richard, Kishida, Muneki, Ishige, Takayuki
• Granted Patent: US 8,710,227 B2
• Time in Patent Office: Days
• US Class Current: 424/451
• 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 I 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 2⊖

at one or both of 17.48 and 20.58±

0.20 degrees when measured against an internal silicon standard.

2. The crystalline Form I of claim 1, characterized by an x-ray powder diffraction pattern further having at least one peak expressed as 2⊖

at 4.50, 9.04, 14.60, 15.14, 15.80, 16.60, 18.16, 18.44, 19.48, 21.74, and 25.46±

0.20 degrees when measured against an internal silicon standard.

3. The crystalline Form I of claim 2, characterized by an x-ray powder diffraction pattern further having at least two peaks expressed as 2⊖

at 4.50, 9.04, 14.60, 15.14, 15.80, 16.60, 18.16, 18.44, 19.48, 21.74 and 25.46±

0.20 degrees when measured against an internal silicon standard.

4. The crystalline Form I of claim 2, characterized by an x-ray powder diffraction pattern further having at least four peaks expressed as 2⊖

at 4.50, 9.04, 14.60, 15.14, 15.80, 16.60, 18.16, 18.44, 19.48, 21.74 and 25.46±

0.20 degrees when measured against an internal silicon standard.

5. The crystalline Form I of claim 2, characterized by an x-ray powder diffraction pattern further having at least six peaks expressed as 2⊖

at 4.50, 9.04, 14.60, 15.14, 15.80, 16.60, 18.16, 18.44, 19.48, 21.74 and 25.46±

0.20 degrees when measured against an internal silicon standard.

6. The crystalline Form I of claim 2, characterized by an x-ray powder diffraction pattern further having at least eight peaks expressed as 2⊖

at 4.50, 9.04, 14.60, 15.14, 15.80, 16.60, 18.16, 18.44, 19.48, 21.74 and 25.46±

0.20 degrees when measured against an internal silicon standard.

7. The crystalline Form I of claim 2, characterized by an x-ray powder diffraction pattern further having peaks expressed as 2⊖

at 4.50, 9.04, 14.60, 15.14, 15.80, 16.60, 18.16, 18.44, 19.48, 21.74 and 25.46±

0.20 degrees when measured against an internal silicon standard.

15. A pharmaceutical composition comprising the crystalline form of claim 1.

17. The crystalline form of claim 1 for the treatment and/or prophylaxis of a disease which can be treated or prevented by alpha-7 receptor activation.

19. A method of treating or preventing a disease which can be treated or prevented by alpha-7 receptor activation comprising administering to a subject the crystalline form of claim 1.

21. A method for improving cognition or treating cognitive loss in a subject comprising administering to a subject the crystalline form of claim 1.

22. The method of claim 21 wherein the subject is suffering from a disorder selected from:

attention deficit disorder, attention deficit hyperactivity disorder, and Parkinson'"'"'s Disease.

23. The method of claim 21 wherein the subject is suffering from a disorder selected from Alzheimer'"'"'s Disease and schizophrenia.

24. A method of treating a disorder selected from attention deficit disorder, attention deficit hyperactivity disorder, Parkinson'"'"'s Disease, Alzheimer'"'"'s Disease and schizophrenia, the method comprising administering to a subject the crystalline form of claim 1.

25. A method of treating a subject that is at risk for developing a disorder selected from:

Alzheimer'"'"'s disease, Parkinson'"'"'s Disease and schizophrenia, the method comprising administering to the subject the crystalline form of claim 1.

26. A method of treating a subject over age 60, comprising administering to the subject the crystalline form of claim 1.

27. A method of treating a subject for age-related memory loss, comprising administering to the subject the crystalline form of claim 1.

28. The method of claim 27 wherein the subject is over age 60.

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

30. The method according to claim 29, the method comprising combining the crystalline form of claim 1 with a liquid.

31. A method for preparing a pharmaceutical composition, the method comprising filling a capsule with a composition comprising the crystalline form of claim 1.

43. A method of manufacturing a crystalline Form I of claim 1, which comprises:

(1) stirring (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride in an aqueous organic solvent within the temperature-water activity range I, if required with decreasing the temperature and/or water activity thereof, to form a substantially pure crystalline Form I, and

(2) isolating the resulting crystalline Form I,

wherein the temperature-water activity range I is defined by the following relationship of the temperature and the water activity of the aqueous organic solvent, the water activity (x) of the aqueous organic solvent is from 0.16 to 0.73; and

the temperature (T) of the aqueous organic solvent is higher than (183x−

64.2) and lower than the boiling temperature of the aqueous organic solvent.

44. The method of claim 43, wherein in step (1) the initial state of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride in an aqueous organic solvent is a solution, and the solution is stirred within the temperature-water activity range I with decreasing the temperature and/or water activity thereof.

45. The method of claim 43, wherein in step (1) the initial state of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride in an aqueous organic solvent is a suspension, and the suspension is stirred within the temperature-water activity range I, if required with decreasing the temperature and/or water activity thereof.

46. The method of claim 44 wherein in step (1) the seed crystals of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride is added to the solution.

47. The method of claim 46 wherein the seed crystals are Form I of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate.

48. The method of claim 43, wherein the water activity is from 0.29 to 0.59.

49. The method of claim 43, wherein the temperature is between −

10°

C. and 60°

C. and higher than the following T;

T=183x−

57.6

wherein x is water activity of the aqueous organic solvent and T is a temperature (°

C.).

50. The method of claim 49, wherein the end point temperature in step (1) is between 0°

C. and 35°

C.

51. The method of claim 43, wherein the aqueous organic solvent is mixture of water and one or more of organic solvents which are miscible with water and are selected from alcohols, ketones, nitriles and ethers.

52. The method of claim 43, wherein the aqueous organic solvent is mixture of water and one or more of organic solvents which are miscible with water and are selected from propanol, butanol, butanone and acetonitrile.

63. A method for preparing the crystalline Form I of claim 1, the method comprising:

(a) heating 10-30% by weight of (R)-7-chloro-N-(quinuclidin-3-yl)benzo [b]thiophene-2-carboxamide hydrochloride in acetonitrile or an aqueous acetonitrile to between 60°

C. and the boiling point of the solution

(b) optionally adding water to the mixture to fully dissolve the (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride;

(c) cooling the solution until crystals are just visible;

(d) if the water content is greater than 3% volume/volume when crystals are just visible, adding acetonitrile to the mixture so that the water content is less than 3% volume/volume;

(e) cooling the resulting mixture to below 15°

C.; and

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

64. The method of claim 63 wherein the water added in step (a) does not bring the water content of the mixture above 30% volume/volume.

65. The method of claim 63 wherein (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride is present at 15-25% by weight in step (a).

66. The method of claim 63 wherein (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride is present at 16-20% by weight in step (a).

67. The method of claim 63 wherein (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride is present at 17-19% by weight in step (a).

68. The method of claim 63 further comprising adding Form I (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate to the mixture after crystals are just visible.

69. The method of claim 63 wherein step (c) comprises cooling the solution to below 55°

C.

70. The method of claim 63 wherein step (c) comprises cooling the solution to below 50°

C.

8. 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 2⊖

at one or both of 21.16 and 21.38±

0.20 degrees when measured against an internal silicon standard.

9. The crystalline Form II of claim 8, characterized by an x-ray powder diffraction pattern further having at least one peak expressed as 2⊖

at 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.

10. The crystalline Form II of claim 9, characterized by an x-ray powder diffraction pattern further having at least two peaks expressed as 2⊖

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

0.2 degrees when measured against an internal silicon standard.

11. The crystalline Form II of claim 9, characterized by an x-ray powder diffraction pattern further having at least four peaks expressed as 2⊖

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

0.2 degrees when measured against an internal silicon standard.

12. The crystalline Form II of claim 9, characterized by an x-ray powder diffraction pattern further having at least six peaks expressed as 2⊖

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

0.2 degrees when measured against an internal silicon standard.

13. The crystalline Form II of claim 9, characterized by an x-ray powder diffraction pattern further having at least eight peaks expressed as 2⊖

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

0.2 degrees when measured against an internal silicon standard.

14. The crystalline Form II of claim 9, characterized by an x-ray powder diffraction pattern further having peaks expressed as 2⊖

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

0.2 degrees when measured against an internal silicon standard.

16. A pharmaceutical composition comprising the crystalline form of claim 8.

18. The crystalline form of claim 8 for the treatment and/or prophylaxis of a disease which can be treated or prevented by alpha-7 receptor activation.

20. A method of treating or preventing a disease which can be treated or prevented by alpha-7 receptor activation comprising administering to a subject the crystalline form of claim 8.

32. A method for improving cognition or treating cognitive loss in a subject comprising administering to a subject the crystalline form of claim 8.

33. The method of claim 32 wherein the subject is suffering from a disorder selected from:

attention deficit disorder, attention deficit hyperactivity disorder, and Parkinson'"'"'s Disease.

34. The method of claim 32 wherein the subject is suffering from a disorder selected from Alzheimer'"'"'s Disease and schizophrenia.

35. A method of treating a disorder selected from attention deficit disorder, attention deficit hyperactivity disorder, Parkinson'"'"'s Disease, Alzheimer'"'"'s Disease and schizophrenia, the method comprising administering to a subject the crystalline form of claim 8.

36. A method of treating a subject that is at risk for developing a disorder selected from:

Alzheimer'"'"'s disease, Parkinson'"'"'s Disease and schizophrenia, the method comprising administering to the subject the crystalline form of claim 8.

37. A method of treating a subject over age 60, comprising administering to the subject the crystalline form of claim 8.

38. A method of treating a subject for age-related memory loss, comprising administering to the subject the crystalline form of claim 8.

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

40. A method for preparing a pharmaceutical composition, the method comprising combining the crystalline form of claim 8 with an excipient or pharmaceutically acceptable carrier

41. The method according to claim 40, the method comprising combining the 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 2⊖

at one or both of 21.16 and 21.38±

0.20 degrees when measured against an internal silicon standard, with a liquid.

42. A method for preparing a pharmaceutical composition, the method comprising filling a capsule with a composition comprising the crystalline form of claim 8.

53. A method of manufacturing a crystalline Form II of claim 8, which comprises:

(1) stirring (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride in an aqueous organic solvent within the temperature-water activity range II, if required with decreasing the temperature and/or water activity thereof, to form a crystalline Form II, and

(2) isolating the resulting crystalline Form II,

wherein the temperature-water activity range II is defined by the following relationship of the temperature and the water activity of the aqueous organic solvent, the water activity (x) of the aqueous organic solvent is from 0.16 to 0.73; and

the temperature (T) of the aqueous organic solvent is lower than (183x−

64.2) and higher than the freezing-point temperature of the aqueous organic solvent.

54. The method of claim 53, wherein in step (1) the initial state of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride in an aqueous organic solvent is a solution, and the solution is stirred within the temperature-water activity range II with decreasing the temperature and/or water activity thereof.

55. The method of claim 53, wherein in step (1) the initial state of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride in an aqueous organic solvent is a suspension, and the suspension is stirred within the temperature-water activity range II, optionally decreasing the temperature and/or water activity thereof.

56. The method of claim 54 wherein in step (1) the seed crystals of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride is added to the solution.

57. The method of claim 56 wherein the seed crystals are Form II of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate.

58. The method of claim 53, wherein the water activity is from 0.29 to 0.59.

59. The method of claim 53, wherein the temperature is between −

10°

C. and 60°

C. and lower than the following T;

T=183x−

70.8

wherein x is water activity of the aqueous organic solvent and T is a temperature (°

C.).

60. The method of claim 59, wherein the end point temperature in step (1) is between 0°

C. and 35°

C.

61. The method of claim 53, wherein the aqueous organic solvent is mixture of water and one or more of organic solvents which are miscible with water and are selected from alcohols, ketones, nitriles and ethers.

62. The method of claim 53, wherein the aqueous organic solvent is mixture of water and one or more of organic solvents which are miscible with water and are selected from propanol, butanol, butanone and acetonitrile.

71. A method for preparing the crystalline Form II of claim 8, the method comprising:

(a) heating 5-15% by weight of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride in 2-butanol or an aqueous 2-butanol to between 60°

C. and the boiling point of the solution;

(b) if the water content is less than 5% volume/volume, adding water to the mixture so that the water content is not less than 5% volume/volume;

(c) cooling the solution to below 10°

C.;

(d) keeping the resulting mixture at below 10°

C.; and

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

72. A method for preparing the crystalline Form II of claim 8, the method comprising:

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