Crystallization and purification of macrolides

• US 20060169199A1
• Filed: 01/05/2006
• Published: 08/03/2006
• Est. Priority Date: 03/31/2003
• Status: Abandoned Application

• Current Assignee: Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag (Teva Pharmaceutical Industries Limited)
• Original Assignee: Teva Pharmaceuticals USA, Inc. (Teva Pharmaceutical Industries Limited)
• Inventors: Keri, Vilmos, Kovacsne-Mezei, Adrienne, Melczer, Istvan, Csorvasi, Andrea
• Application Number:
  US11/326,723
• Publication Number:
  US 20060169199A1
• Time in Patent Office: Days
• US Class Current: 117/23
• CPC Class Codes: C30B 29/58 Macromolecular compounds
• CPC Class Codes: C30B 7/00 Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions from molten solvents C30B9/00; by normal or gradient freezing C30B11/00; under a protective fluid C30B27/00

Abstract

The invention provides a method for crystallization and purification of tacrolimus that includes the step of providing a combination of a macrolide and a polar solvent, dopolar aprotic solvent, or hydrocarbon solvent at pH of 7 or above. The invention also provides a novel crystalline form of tacrolimus.

Claims

1. Crystalline Tacrolimus.

2. A crystalline form of tacrolimus characterized by a powder X-ray diffraction pattern, having peaks at about 10.5, 11.3 and 13.8±

0.2 degrees 2θ

.

3. The crystalline form of claim 2, wherein the crystalline form is further characterized by an XRD peak at about 14.2±

0.2 degrees 2θ

.

4. The crystalline form of claim 3, wherein the crystalline form is further characterized by XRD peaks at about 8.7, 15.4 and 19.1±

0.2 degrees 2θ

.

5. The crystalline form of claim 4, further characterized by a powder X-ray diffraction pattern, substantially as depicted in any of FIGS. 1, 2, 3, 5, 7, and 9.

6. The crystalline form of claim 2, wherein the crystalline form is characterized by a TGA, showing a weight loss of about 1.9-2.2% over a temperature range of up to 120°

C.

7. The crystalline form of claim 6, further characterized by TGA curves substantially as depicted in FIGS. 4, 6, 8, and 10.

8. The crystalline form of claim 2, wherein the crystalline form is monohydrate.

9. The crystalline form of claim 2, having a maximum particle size of 500 μ

m.

10. The crystalline form of claim 9, having a maximum particle size of 300 μ

m.

11. The crystalline form of claim 10, having a maximum particle size of less than 200 μ

m

12. The crystalline form of claim 11, having a maximum particle size of less than 100 μ

m.

13. The crystalline form of claim 12, having a maximum particle size of less than 50 μ

m.

14. The crystalline form of claim 2, wherein the crystalline form contains less than about 10% (by weight) of other crystalline or amorphous forms of Tacrolimus.

15. The crystalline form of claim 14, wherein the crystalline form contains less than about 5% (by weight) of other crystalline or amorphous forms of Tacrolimus.

16. The crystalline form of claim 15, wherein the crystalline form contains less than about 1% (by weight) of other crystalline or amorphous forms of Tacrolimus.

17. A method for crystallizing the crystalline form of tacrolimus of claim 2 from a tacrolimus starting material, comprising the steps of:

a) combining a tacrolimus starting material, a polar solvent, a hydrocarbon solvent, and water, whereby at least two phases are formed, at least one of which is a water-rich phase, and wherein the pH of the water-rich phase is at least about 7,

b) maintaining the combination at for at least 1 hour, whereby a tacrolimus-rich phase is formed from which the crystalline form of tacrolimus of claim 2 crystallizes.

18. The method of claim 17, further comprising the step of isolating the crystalline form of tacrolimus that crystallizes.

19. The method of claim 17, wherein the combination of step b) is maintained at a temperature of from about −

15°

C. to about 50°

C.

20. The method of claim 19, wherein the combination of step b is maintained at a temperature of from about −

5°

C. to about 40°

C.

21. The method of claim 20, wherein the combination of step b is maintained at a temperature of from about −

2°

C. to about 35°

C.

22. The method of claim 17, wherein the combination of step b is maintained for between 48 and 100 hours.

23. The method of claim 17, wherein the polar solvent is selected from the group consisting of alcohols, esters, nitriles and ethers.

24. The method of claim 23, wherein the polar solvent is selected from the group consisting of ethyl acetate, acetonitrile, methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, acetone, diisopropyl ether, dimethyl formamide, and dimethyl acetamide.

25. The method of claim 24, wherein the polar solvent is ethyl acetate.

26. The method of claim 17, wherein the hydrocarbon solvent is selected from the group consisting of n-hexane, n-heptane, octane, iso-octane cyclohexane, methylcyclohexane, benzene, toluene, and xylene.

27. The method of claim 26, wherein the hydrocarbon solvent is n-hexane.

28. The method of claim 17, wherein the pH of the water-rich phase is about 8 or higher.

29. The method of claim 17, wherein the water comprises a base selected from NaOH, KOH, Ca(OH)₂, NH₃, Et₃N, diethylamine and pyridine.

30. A method of crystallizing the crystalline form of tacrolimus of claim 2 from a tacrolimus starting material comprising the steps of:

a) combining a concentrate residue from whole-broth extraction of tacrolimus-containing biomatter in a polar solvent with a hydrocarbon solvent, and water, whereby at least two phases are formed, at least one of which is a water-rich phase, and wherein the pH of the water-rich phase is at least about 7,

b) maintaining the combination at for at least 1 hour, whereby a tacrolimus-rich phase is formed from which the crystalline form of tacrolimus of claim 2 crystallizes.

31. The method of claim 30, further comprising the step of isolating the crystalline form of tacrolimus that crystallizes.

32. The method of claim 30, wherein the combination of step b is maintained at a temperature of from about −

15°

C. to about 50°

C.

33. The method of claim 32, wherein the combination of step b is maintained at a temperature of from about −

5°

C. to about 40°

C.

34. The method of claim 33, wherein the combination of step b is maintained at a temperature of from about −

2°

C. and about 35°

C.

35. The method of claim 30, wherein the combination of step b is maintained for between 48 and 100 hours.

36. The method of claim 30, wherein the polar solvent is selected from the group consisting of alcohols, esters, nitrites and ethers.

37. The method of claim 36, wherein the polar solvent is selected from the group consisting of ethyl acetate, acetonitrile, methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, acetone, diisopropyl ether, dimethyl formamide, and dimethyl acetamide.

38. The method of claim 37, wherein the polar solvent is ethyl acetate.

39. The method of claim 30, wherein the hydrocarbon solvent is selected from the group consisting of n-hexane, n-heptane, octane, iso-octane cyclohexane, methylcyclohexane, benzene, toluene, and xylene.

40. The method of claim 39, wherein the hydrocarbon solvent is n-hexane.

41. The method of claim 30, wherein the pH of the water-rich phase is about 8 or higher.

42. The method of claim 30, wherein the water comprises a base selected from NaOH, KOH, Ca(OH)₂, NH₃, Et₃N, diethylamine and pyridine.

43. A method of crystallizing the crystalline form of tacrolimus of claim 2 from a tacrolimus starting material comprising the steps of:

a) combining, at a temperature of about 20°

to about 25°

C., tacrolimus starting material, ethyl acetate, n-hexane, and a water solution of a base selected from the group consisting of NaOH, KOH, Ca(OH)₂, NH₃, (C₂H₅)₃N, diethylamine and pyridine, whereby at least two phases are formed, one of which is a water-rich phase, wherein the pH of the water-rich phase is greater than about 7,

b) maintaining the combination at a temperature of about 20°

C. to about 25°

C. for at least 1 hour, whereby a tacrolimus-rich phase is formed from which the crystalline form of tacrolimus of claim 2 crystallizes,

c) maintaining the combination at a temperature of about 0°

C. to about 20°

C. for at least 1 hour, and

d) recovering the crystalline form of tacrolimus of claim 2 that crystallizes.

44. The method of claim 43, wherein the pH of the water-rich phase is about 8 or higher.

45. A method of crystallizing the crystalline form of tacrolimus of claim 2 from a tacrolimus starting material comprising the steps of:

a) combining, at a temperature of about 20°

to about 25°

C., a concentrate residue from whole-broth extraction of tacrolimus-containing biomatter in ethyl acetate, n-hexane, and a water solution of a base selected from NaOH, KOH, Ca(OH)₂, NH₃, (C₂H₅)₃N, diethylamine and pyridine whereby at least two phases are formed, one of which is a water-rich phase, wherein the pH of the water-rich phase is greater than about 7,

b) maintaining the combination at a temperature of about 20°

C. to about 25°

C. for at least 1 hour, whereby a tacrolimus-rich phase is formed from which the crystalline form of tacrolimus of claim 2 crystallizes,

c) maintaining the combination at a temperature of about 0°

C. to about 20°

C. for at least 1 hour, and

d) recovering the crystalline form of tacrolimus of claim 2 that crystallizes.

46. The method of claim 45, wherein the pH of the water-rich phase is about 8 or higher.

47. In a method for crystallizing the crystalline form of tacrolimus of claim 2 from a tacrolimus starting material, the step of combining the tacrolimus starting material, a polar solvent, a hydrocarbon solvent, and water, whereby at least two phases are formed, at least one of which is water rich, wherein the pH of the water-rich phase is at least about 7.

48. In a method for crystallizing the crystalline form of tacrolimus of claim 2 from a concentrate residue from whole-broth extraction of tacrolimus-containing biomatter in a polar solvent, the step of combining the tacrolimus concentrate in the polar solvent, a hydrocarbon solvent, and water, whereby at least two phases are formed, at least one of which is water rich, wherein the pH of the water-rich phase is at least about 7.