Pure paliperidone and processes for preparing thereof

• US 20080171876A1
• Filed: 08/14/2007
• Published: 07/17/2008
• Est. Priority Date: 05/10/2007
• Status: Abandoned Application

• Current Assignee: Teva Pharmaceuticals USA, Inc. (Teva Pharmaceutical Industries Limited)
• Original Assignee: Teva Pharmaceuticals USA, Inc. (Teva Pharmaceutical Industries Limited)
• Inventors: Chasid, Naama, Ini, Santiago, Chen, Kobi, Porter-Kleks, Osnat
• Application Number:
  US11/889,558
• Publication Number:
  US 20080171876A1
• Time in Patent Office: Days
• US Class Current: 544/282
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention provides pure paliperidone as well as purification processes to obtain thereof.

Claims

1. Paliperidone comprising less than about 0.2% of the impurity PLP-NO.

2. Paliperidone of claim 1 comprising less than about 0.02% of the impurity PLP-NO.

3. Paliperidone of claim 1 comprising PLP-NO at less than about 0.2%.

4. Paliperidone of claim 3, comprising PLP-NO at less than about 0.1%.

5. Paliperidone of claim 4, comprising PLP-NO at less than about 0.05%.

6. Paliperidone of claim 5 comprising PLP-NO at less than about 0.02%.

7. Paliperidone of anyone of claims 3-6, further comprising PLP-Car at less than about 0.2%.

8. Paliperidone of anyone of claims 3-6, further comprising PLP-Car at less than about 0.1%.

9. Paliperidone of anyone of claims 3-6, further comprising PLP-Car at less than about 0.05%.

10. Paliperidone of anyone of claims 3-6, further comprising PLP-Car at less than about 0.02%.

11. Paliperidone having a total purity of at least about 98%.

12. Paliperidone of claim 11 having a total purity of at least about 99%.

13. Paliperidone of claim 12 having a total purity of at least about 99.9%.

14. Paliperidone of claim 11 having a total purity of about 98% to about 99.9%.

15. Paliperidone of claim 14 having a total purity of about 99% to about 99.9%.

16. Paliperidone of claim 11 having a total purity of about 98% to about 99.99%.

17. Paliperidone of claim 16 having a total purity of about 99% to about 99.99%.

18. Paliperidone of anyone of claims 11-17, comprising PLP-NO at less than about 0.2%.

19. Paliperidone of anyone of claims 11-17, comprising PLP-NO at less than about 0.1%.

20. Paliperidone of anyone of claims 11-17, comprising PLP-NO at less than about 0.02%.

21. Paliperidone of claim 18, further comprising PLP-car at less than about 0.2%.

22. Paliperidone of claim 20, further comprising PLP-car at less than about 0.02%.

23. A process for purifying paliperidone, comprising

crystallizing paliperidone from at least one solvent selected from the group consisting of C_3-6 ketones, a mixture of a C_3-6 ketone and water, N-methylpyrrolidone, C_3-6 amides, halo-substituted C_6-12 aromatic hydrocarbons, propylene glycol, dimethyl sulfoxide, di-methyl carbonate, C_1-4 alkyl alcohols, a mixture of a C_1-4 alkyl alcohol and water, acetonitrile, a mixture of acetonitrile and water, C_2-6 alkyl acetates, a mixture of a C_2-6 alkyl acetate and water, cellosolve, dimethyl carbonate, polyethylene glycol methyl ether and C_2-8 ethers to obtain the purified paliperidone, wherein the total purity of the purified paliperidone is higher than the total purity of the starting paliperidone.

24. The process of claim 23, wherein the C_3-6 ketone(s) is selected from the group consisting of acetone, methyl ethyl ketone and methyl iso-butyl ketone;

the C_3-6 amides are selected from the group consisting of dimethylacetamide and dimethylformamide;

the halo-substituted C_6-12 aromatic hydrocarbons are selected from the group consisting of chlorobenzene and dichlorobenzene;

the C_1-4 alkyl alcohol(s) is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and 2-butanol;

the C_2-6 alkyl acetate(s) is selected from the group consisting of ethyl acetate and isobutyl acetate; and

the C_2-8 ethers are selected from the group consisting of dibutyl ether and polyethylene glycol.

25. The process of claim 23, wherein the at least one solvent is a mixture of acetone and water.

26. The process of claim 25, wherein the at least one solvent is a mixture of solvents at a volume ratio of between about 1:

1 to about 3;

1.

27. The process of claim 26, wherein the at least one solvent is a mixture of acetone and water, or a mixture of ethanol and water.

28. The process of claim 27, wherein the at least one solvent is a mixture of acetone and water.

29. The process of claim 28, wherein the at least one solvent is acetone/water at a volume ratio of about 3:

1.

30. The process of claim 23, wherein the crystallizing step comprises heating the at least one solvent and paliperidone to form a solution by complete dissolution, and thereafter precipitating paliperidone in the solution to obtain the purified paliperidone.

31. The process of claim 30, wherein the precipitating step is performed by cooling the solution to a temperature ranging from about 0°

C. to about 30°

C.

32. The process of claim 31, wherein the cooling is to a temperature of about 25°

C.

33. The process of claim 30, wherein the precipitating step is performed by solvent removal from the solution via evaporation.

58. The process of anyone of claims 23, 34, 46 and 52, wherein the total purity of the purified paliperidone is at least about 98%.

59. The process of claim 58, wherein the total purity of the purified paliperidone is at least about 99%.

60. The process of claim 59, wherein the total purity of the purified paliperidone is at least about 99.9%.

34. A process for purifying paliperidone, comprising crystallizing paliperidone from a solvent, wherein the crystallizing step comprises

dissolving the paliperidone in the solvent to obtain a solution;

mixing the solution with an anti-solvent to form a mixture in order to induce crystallization of paliperidone as purified paliperidone, wherein the total purity of the purified paliperidone is higher than the total purity of the starting paliperidone.

35. The process of claim 34, wherein the dissolving step is performed at reflux and thereafter the solution is cooled.

36. The process of claim 35, wherein the solution is cooled to a temperature of about 0°

C. to about 30°

C.

37. The process of claim 36, wherein the solution is cooled to a temperature of about 20°

C. to about 30°

C.

38. The process of claim 37, wherein the solution is cooled to a temperature of about 25°

C.

39. The process of claim 34, wherein the mixture is maintained for at least about 5 minutes.

40. The process of claim 39, wherein the mixture is stirred.

41. The process of claim 34, wherein the solvent is selected from the group consisting of dichloromethane, dioxane and C_1-4 alkyl alcohols.

42. The process of claim 41, wherein the solvent is selected from the group consisting of dichloromethane, dioxane, n-propanol and butanol.

43. The process of claim 34, wherein the anti-solvent is selected from the group consisting of methyl t-butyl ether (MTBE), methyl ethyl ketone (MEK), acetone, methyl iso-butyl ketone (MIBK), acetonitrile, cyclohexane, hexane, heptane, toluene, benzene, xylene and water.

44. The process of claim 43, wherein the anti-solvent is selected from the group consisting of MTBE, MEK, acetonitrile, cyclohexane, heptane, toluene and water.

45. The process of claim 44, wherein the anti-solvent is selected from the group consisting of MTBE, MEK, acetonitrile and toluene.

46. A process for purifying paliperidone, comprising slurrying paliperidone in an organic solvent to obtain purified paliperidone, wherein the total purity of the purified paliperidone is higher than the total purity of the starting paliperidone.

47. The process of claim 46, wherein the organic solvent is selected from the group consisting of C_1-4 alkyl alcohols, C_3-5 ketones and water.

48. The process of claim 47, wherein the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone and water.

49. The process of claim 46, wherein the slurrying is performed at a temperature of about 20°

C. to about 70°

C.

50. The process of claim 46 wherein the slurrying is performed for about 30 minutes to about 24 hours.

51. The process of claim 50, wherein the slurrying is performed for about 35 minutes to about 1 hour.

52. A process for purifying paliperidone, comprising

(a) providing a paliperidone solution containing more than about 0.1% PLP-NO;

(b) admixing the solution with finely powdered carbon; and

(c) filtrating the admixture obtained from step (b) to obtain purified paliperidone, wherein the total purity of the purified paliperidone is higher than the total purity of the starting paliperidone.

53. The process of claim 52, wherein the paliperidone solution in step (a) is obtained by dissolving paliperidone in at least one organic solvent.

54. The process of claim 53, wherein the at least one organic solvent is a mixture of acetone and water.

55. The process of claim 54, wherein the finely powdered carbon is an active carbon.

56. The process of claim 55, wherein the active carbon is selected from the group consisting of HB ultra, CGP super, GBG, SX plus, ROX 0.8 and A super eur.

57. The process of claim 52, wherein the filtration is done through hi-flow.