Solid forms of treprostinil

Patent metadata

Field	Value
Publication number	US-9822057-B2
Application number	US-201414200575-A
Country	US
Kind code	B2
Filing date	Mar 7, 2014
Priority date	Mar 14, 2013
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

There is provided individual polymorphic forms of treprostinil and pharmaceutical formulations comprising the same, methods of making and using the same.

First claim

What is claimed is:

1. A crystalline treprostinil monohydrate Form A, having an X-ray powder diffractogram comprising the following peaks: 11.6, 16.2, and 20.0 °2θ±0.2 °2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54059 Å, and having a purity of at least 90% aside from residual solvents, wherein said Form A is free of any other form of crystalline treprostinil.

2. The crystalline treprostinil monohydrate Form A according to claim 1 , wherein the diffractogram further comprises peaks at 5.2, 21.7, and 27.7 °2θ±0.2 °2θ.

3. The crystalline treprostinil monohydrate Form A according to claim 1 , wherein the diffractogram is as shown in FIG. 2 .

4. The crystalline treprostinil monohydrate Form A according to claim 1 , wherein the crystalline treprostinil monohydrate form A has a differential scanning calorimetry (DSC) curve that comprises a minor endotherm at about 78.3° C. and a major endotherm at about 126.3° C.

5. The crystalline treprostinil monohydrate Form A according to claim 4 , wherein the DSC curve is as shown in FIG. 3 .

6. The crystalline treprostinil monohydrate Form A according to claim 1 having a purity of at least 95% aside from residual solvents.

7. A method of making the crystalline treprostinil monohydrate Form A according to claim 1 comprising agitating anhydrous or wet treprostinil in an aprotic organic solvent and water to form a slurry followed by removal of the solvent by air-drying the slurry at a temperature from about 15° C. to about 35° C. until at least as long as no additional solvent evaporates.

8. The method of claim 7 , wherein the aprotic organic solvent is acetone or 1,4-dioxane.

9. A crystalline treprostinil monohydrate Form B, having an X-ray powder diffractogram comprising the following peaks: 5.9, 12.1, and 24.4 °2θ±0.2 °2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54059 Å, and having a purity of at least 90% aside from residual solvents, wherein said Form B is free of any other form of crystalline treprostinil.

10. The crystalline treprostinil monohydrate Form B according to claim 9 , wherein the diffractogram further comprises peaks at 10.7, 20.6, and 22.3 °2θ±0.2 °2θ.

11. The crystalline treprostinil Form B according to claim 9 , wherein the diffractogram is as shown in FIG. 9 .

12. The crystalline treprostinil monohydrate Form B according to claim 9 , wherein the crystalline treprostinil monohydrate Form B has a differential scanning calorimetry (DSC) curve that comprises a minor endotherm at about 74.8° C. and a major endotherm at about 125.2° C.

13. The crystalline treprostinil monohydrate Form B according to claim 12 , wherein the DSC curve is as shown in FIG. 10 .

14. The crystalline treprostinil monohydrate Form B according to claim 9 having a purity of at least 95% aside from residual solvents.

15. A method of making the crystalline treprostinil monohydrate Form B according to claim 9 comprising agitating anhydrous or wet treprostinil in a protic organic solvent and water to form a slurry followed by removal of the solvent by air-drying the slurry at a temperature from about 15° C. to about 35° C. until at least as long as no additional solvent evaporates.

16. The method of claim 15 , wherein the protic organic solvent is methanol.

17. A treprostinil Form C, having an X-ray powder diffractogram comprising the following peak: 6.55 °2θ±0.2 °2θ, as determined on a diffractometer using Cu-Kα radiation at a wavelength of 1.54059 Å, and having a purity of at least 90% aside from residual solvents, wherein said Form C is free of any other form of crystalline treprostinil.

18. The treprostinil Form C according to claim 17 , wherein the diffractogram is as shown in FIG. 16 .

19. The crystalline treprostinil monohydrate Form A according to claim 1 having a purity of at least 98% aside from residual solvents.

20. The crystalline treprostinil monohydrate Form A according to claim 19 in an amount of 1 gram to 50 kg.

21. The crystalline treprostinil monohydrate Form A according to claim 1 having a purity of at least 99% aside from residual solvents.

22. The crystalline treprostinil monohydrate Form A according to claim 21 in an amount of 1 gram to 50 kg.

23. The crystalline treprostinil monohydrate Form A according to claim 1 having a purity of at least 99.9% aside from residual solvents.

24. The crystalline treprostinil monohydrate Form A according to claim 23 in an amount of 1 gram to 50 kg.

25. The crystalline treprostinil monohydrate Form A according to claim 1 in an amount of 1 gram to 50 kg.

26. The crystalline treprostinil monohydrate Form A according to claim 6 in an amount of 1 gram to 50 kg.

27. The crystalline treprostinil monohydrate Form B according to claim 9 having a purity of at least 98% aside from residual solvents.

28. The crystalline treprostinil monohydrate Form B according to claim 27 in an amount of 1 gram to 50 kg.

29. The crystalline treprostinil monohydrate Form B according to claim 9 having a purity of at least 99% aside from residual solvents.

30. The crystalline treprostinil monohydrate Form B according to claim 29 in an amount of 1 gram to 50 kg.

31. The crystalline treprostinil monohydrate Form B according to claim 9 having a purity of at least 99.9% aside from residual solvents.

32. The crystalline treprostinil monohydrate Form B according to claim 31 in an amount of 1 gram to 50 kg.

33. The crystalline treprostinil monohydrate Form B according to claim 9 in an amount of 1 gram to 50 kg.

34. The crystalline treprostinil monohydrate Form B according to claim 33 in an amount of 1 gram to 50 kg.

35. The treprostinil Form C according to claim 17 having a purity of at least 95% aside from residual solvents.

36. The treprostinil Form C according to claim 35 in an amount of 1 gram to 50 kg.

37. The treprostinil Form C according to claim 17 having a purity of at least 98% aside from residual solvents.

38. The treprostinil Form C according to claim 37 in an amount of 1 gram to 50 kg.

39. The treprostinil Form C according to claim 17 having a purity of at least 99% aside from residual solvents.

40. The treprostinil Form C according to claim 39 in an amount of 1 gram to 50 kg.

41. The treprostinil Form C according to claim 17 having a purity of at least 99.9% aside from residual solvents.

42. The treprostinil Form C according to claim 41 in an amount of 1 gram to 50 kg.

43. The treprostinil Form C according to claim 17 in an amount of 1 gram to 50 kg.

44. A solid dosage form comprising the treprostinil Form C according to claim 17 and a pharmaceutically acceptable carrier.

Assignees

• United Therapeutics Corp

Inventors

• Phares Ken
• Scannell Michael

Classifications

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P37/02

  Immunomodulators · CPC title