FENOFIBRIC ACID POLYMORPHS; METHODS OF MAKING; AND METHODS OF USE THEREOF

• US 20090187040A1
• Filed: 01/15/2009
• Published: 07/23/2009
• Est. Priority Date: 01/18/2008
• Status: Abandoned Application

• Current Assignee: Mutual Pharmaceutical Company (Takeda Pharmaceutical Company Limited)
• Original Assignee: Mutual Pharmaceutical Company (Takeda Pharmaceutical Company Limited)
• Inventors: Hall, Michael L., Sun, Tong, Whitehead, Brent R., Isbester, Paul K.
• Application Number:
  US12/354,043
• Publication Number:
  US 20090187040A1
• Time in Patent Office: Days
• US Class Current: 560/52
• CPC Class Codes: C07C 51/43 by change of the physical state, e.g. crystallisation
• CPC Class Codes: C07C 59/90 containing singly bound oxygen-containing groups

Abstract

Disclosed are new methods of making the fenofibric acid polymorphs as well as formulations prepared therefrom and uses thereof.

Claims

1. A method of preparing fenofibric acid Form B, comprising:

crystallizing fenofibric acid from a crystallization solution comprising fenofibric acid and a solvent system comprising

i) ethyl acetate;

ii) methyl ethyl ketone;

iii) ethyl acetate as a primary solvent and water as an anti-solvent;

iv) dioxane as a primary solvent and heptane as an anti-solvent;

or

v) tert-amyl alcohol.

2. The method of claim 1, wherein the solvent system is methyl ethyl ketone.

3. The method of claim 1, wherein the crystallization solution during crystallization is about −

10 to about 30°

C.

4. The method of claim 1, wherein the crystallization solution has an initial temperature when prepared that is greater than the crystallization solution during crystallization.

5. The method of claim 4, wherein the crystallization solution is allowed to cool from the initial temperature to a final temperature during crystallization at a rate of about 1 to about 30°

C. per hour.

6. The method of claim 4, wherein the crystallization solution is prepared with heating and subsequently subjected to a temperature that is the final temperature during crystallization without allowing for the crystallization solution to cool gradually.

7. The method of claim 1, wherein fenofibric acid Form B is substantially free of fenofibric acid Form A.

8. A method of preparing fenofibric acid Form A, comprising:

crystallizing fenofibric acid from a crystallization solution comprising fenofibric acid and a solvent system comprising

i) dichloromethane;

ii) methanol;

iii) acetone;

iv) dichloromethane as a primary solvent and water, heptane, or c-hexane as an anti-solvent;

v) benzene, toluene, or xylenes as a primary solvent and heptane or c-hexane as an anti-solvent;

v) 1,2-dimethoxyethane, isopropanol, dioxane, dimethylacetamide, methanol, ethanol, or acetonitrile as a primary solvent and water as an anti-solvent;

or

vi) methanol, dimethyl sulfoxide, or dimethylacetamide as a primary solvent and heptane as an anti-solvent.

9. The method of claim 8, wherein the solvent system is dichloromethane.

10. The method of claim 9, wherein the crystallization solution during crystallization is about −

10 to about 30°

C.

11. The method of claim 9, wherein the crystallization solution has an initial temperature when prepared that is greater than the crystallization solution during crystallization.

12. The method of claim 11, wherein the crystallization solution is allowed to cool from the initial temperature to a final temperature during crystallization at a rate of about 1 to about 30°

C. per hour.

13. The method of claim 11, wherein the crystallization solution is prepared with heating and subsequently subjected to a temperature that is the final temperature during crystallization without allowing for the crystallization solution to cool gradually.

14. The method of claim 8, wherein fenofibric acid Form A is substantially free of fenofibric acid Form B.

15. A method of preparing fenofibric acid Form B, comprising:

slurrying fenofibric acid Form A seeded with fenofibric acid Form B in acetonitrile at about 15°

C. to about 40°

C.;

or

slurrying a mixture of Form A and Form B in water, toluene, water/isopropyl alcohol, dichloromethane, or acetonitrile at about 15°

C. to about 40°

C.

16. The method of claim 15, wherein the ratio of total fenofibric acid to acetonitrile is about 100 to about 300 mg fenofibric acid per milliliter of acetonitrile.

17. The method of claim 15, wherein fenofibric acid Form B is substantially free of fenofibric acid Form A.

18. A method of preparing fenofibric acid Form A, comprising:

slurrying fenofibric acid Form B in water, acetonitrile, or 1;

1 water/isopropyl alcohol at about 30°

C. to about 50°

C.;

or

slurrying a mixture of Form A and Form B in water, toluene, 1;

1 water/isopropyl alcohol, dichloromethane, or acetonitrile at about 30°

C. to about 50°

C.

19. The method of claim 18, wherein fenofibric acid Form A is substantially free of fenofibric acid Form B.

20. A method of preparing fenofibric acid Form A, comprising:

lyophilizing a mixture of fenofibric acid and water or a mixture of fenofibric acid, water and methanol.

21. The method of claim 20, wherein fenofibric acid Form A is substantially free of fenofibric acid Form B.

22. A method of preparing fenofibric acid Form B, comprising:

lyophilizing a mixture of fenofibric acid, water, and acetonitrile.

23. The method of claim 22, wherein fenofibric acid Form B is substantially free of fenofibric acid Form A.

24. A method of preparing fenofibric acid Form A, comprising:

grinding fenofibric acid Form B or a combination comprising fenofibric acid Form B and Form A under high shear conditions.

25. The method of claim 24, wherein the grinding is performed in a ball mill.

26. A method of preparing fenofibric acid Form A or Form B, comprising:

preparing fenofibric acid Form A or Form B by vapor diffusion.