Polymorphic and other crystalline forms cis-FTC

• US 6,723,728 B2
• Filed: 03/01/2002
• Issued: 04/20/2004
• Est. Priority Date: 03/01/2001
• Status: Expired due to Term

• Current Assignee: Abbvie Incorporated
• Original Assignee: Abbott Laboratories Incorporated, Gilead Sciences Inc.
• Inventors: Law, Devalina, Hu, Yuerong, Phares, Kenneth R.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): MCKENZIE, THOMAS C
• Application Number:
  US10/086,830
• Publication Number:
  US 20030060645A1
• Time in Patent Office: 781 Days
• Field of Search: 514/274, 544/317
• US Class Current: 514/274
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: C07D 411/04 directly linked by a ring-member-to-ring-member bond

Abstract

Solid phases of (−)-cis-FTC, which are designated herein as amorphous (−)-FTC and Forms II and III (−)-cis-FTC) are provided that can be distinguished from Form I (−)-cis-FTC by X-ray powder diffraction patterns, thermal properties, and methods of manufacture. A hydrated crystalline form of (±)-cis-FTC (i.e. racemic cis-FTC), and a dehydrated form of the hydrate, are also provided, and can similarly be distinguished from other forms of FTC by X-ray powder diffraction patterns, thermal properties, and methods of manufacture. These FTC forms can be used in the manufacture of other forms of FTC, or in pharmaceutical compositions. Particularly preferred uses of these forms are in the treatment of HIV or hepatitis B.

Claims

1. A polymorphic compound of (−

)-cis-FTC, wherein the compound displays the following angular positions (two theta) of characteristic peaks in a powder X-ray diffraction pattern;

a. 14.7°

.1°

±

0.1°

, 16.7°

±

0.1°

, 19.6°

±

0.1°

, 21.1°

±

0.1°

, 21.8°

±

0.1°

, 24.6°

±

0.1°

, and 25.6°

±

0.1°

(Form II (−

)-cis-FTC);

or

b. 14.5°

±

0.1°

, 16.7°

±

0.1°

, 19.6°

±

0.1°

, 20.4°

±

0.1°

, 21.4°

±

0.1°

, 21.7°

±

0.1°

, 25.2°

±

0.1°

, and 26.2°

±

0.1°

(Form III (−

)-cis-FTC).

2. The compound of claim 1 which is Form II (−

)-cis-FTC.

3. The compound of claim 1 which is Form III (−

)-cis-FTC.

4. The compound of claim 1 which is substantially pure Form II (−

)-cis-FTC.

5. The compound of claim 4 which is at least 97% pure.

6. The compound of claim 1 which is substantially pure Form III (−

)-cis-FTC.

7. The compound of claim 6 which is at least 97% pure.

25. A method of treating a HIV or HBV comprising administering to a patient afflicted with the disease a treatment effective amount of the compound of claim 1.

8. A polymorphic form of (−

)-cis-FTC prepared by a method comprising;

a. melting Form I (−

)-cis-FTC, and

b. recrystallizing the melted (−

)-cis-FTC,

wherein the Form I (−

)-cis-FTC displays the following angular positions (two theta) of characteristic peaks in a powder X-ray diffraction pattern;

14.1°

±

0.1°

, 19.9°

±

0.1°

, 20.2°

±

0.1°

, 20.6°

±

0.1°

, 21.0°

±

0.1°

, 22.4°

±

0.1°

, 28.5°

±

0.1°

, 29.5°

±

0.1°

, and 32.6°

±

0.1°

.

9. The polymorphic form of (−

)-cis-FTC of claim 8 wherein the method further comprises cooling the recrystallized FTC to below about 96°

C.

10. A polymorphic form of (−

)-cis-FTC prepared by a method comprising cooling a Form II polymorph of (−

)-cis-FTC to below about 96°

C, wherein the Form II polymorph displays the following angular positions (two theta) of characteristic peaks in a powder X-ray diffraction pattern;

14.7°

±

0.1°

, 16.7°

±

0.1°

, 19.6°

±

0.1°

, 21.1°

±

0.1°

, 21.8°

±

0.1°

, 24.6°

±

0.1°

, and 25.6°

±

0.1°

.

11. A polymorphic form of (−

)-cis-FTC prepared by a method comprising heating a Form III polymorph of (−

)-cis-FTC to above about 112°

C., wherein the Form III polymorph displays the following angular positions (two theta) of characteristic peaks in a powder X-ray diffraction pattern;

14.5°

±

0.1°

, 16.7°

±

0.1°

, 19.6°

±

0.1°

, 20.4°

±

0.1°

, 21.4°

±

0.1°

, 21.7°

±

0.1°

, 25.2°

±

0.1°

, and 26.2°

±

0.1°

.

12. A hydrated crystalline form of (±

)-cis-FTC prepared by a method comprising;

a. dissolving a first crystalline form of (±

)-cis-FTC in water, and

b. recrystallizing the dissolved (±

)-cis-FTC.

20. The crystalline form of (±

)-cis-FTC of claim 12 wherein the first crystalline form of (±

)-cis-FTC is present in a composition of cis-FTC that comprises up to 98% of the (−

) or (+) enantiomer.

13. A compound selected from:

a. (±

)-cis-FTC sesquihydrate; and

b. amorphous (±

)-cis-FTC.

14. The compound of claim 13 in substantially pure form.

15. The compound of claim 13 in a purity of at least 97%.

16. A crystalline form of (±

)-cis-FTC that displays the following angular positions (two theta) of characteristic peaks in a powder X-ray diffraction pattern;

a. 11.5°

±

0.1°

, 13.4°

±

0.1°

, 19.1°

±

0.1°

, 20.3°

±

0.1°

, 20.8°

±

0.1°

, 21.5°

±

0.1°

, 21.9°

±

0.1°

, and 30.9°

±

0.1°

;

or

b. 12.3°

±

0.1°

, 14.0°

±

0.1°

, 20.7°

±

0.1°

, 22.6°

±

0.1°

, 23.3°

±

0.1°

, and 25.5°

±

0.1°

.

17. The crystalline form of claim 16 in substantially pure form.

18. The crystalline form of claim 16 in a purity of at least 97%.

19. A pharmaceutical composition comprising a polymorphic compound of (−

)-cis-FTC, wherein the compound displays the following angular positions (two theta) of characteristic peaks in a powder X-ray diffraction pattern;

a. 14.7°

±

0.1°

, 16.7°

±

0.1°

, 19.6°

±

0.1°

, 21.1°

±

0.1°

, 21.8°

±

0.1°

, 24.6°

±

0.1°

, and 25.6°

±

0.1°

(Form II (−

)-cis-FTC);

or

b. 14.5°

±

0.1°

, 16.7°

±

0.1°

, 19.6°

±

0.1°

, 20.4°

±

0.1°

, 21.4°

±

0.1°

, 21.7°

±

0.1°

, 25.2 °

±

0.1°

, and 26.2°

±

0.1°

(Form III (−

)-cis-FTC)

and a pharmaceutically acceptable carrier;

wherein the pharmaceutical composition is in a solid form.

22. The pharmaceutical composition of claim 19 or 21 wherein the composition is in a unit dosage form.

23. The pharmaceutical composition of claim 22 wherein the dosage form is suitable for oral administration.

24. The pharmaceutical composition of claim 22 wherein the dosage form is a tablet.

21. A pharmaceutical composition comprising a compound selected from:

a. (±

)-cis-FTC sesquihydrate; and

b. amorphous (±

)-cis-FTC;

wherein the pharmaceutical composition is in a solid form.

26. A method of treating HIV or HBV comprising administering to a patient afflicted with the disease a treatment effective amount of (±

)-cis-FTC sesquihydrate, or amorphous (−

)-cis-FTC.

27. A method of preparing a polymorphic form of (−

)-cis-FTC comprising;

a. melting Form I (−

)-cis-FTC, and

b. recrystallizing the melted (−

)-cis-ETC,

wherein the Form I (−

)-cis-FTC displays the following angular positions (two theta) of characteristic peaks in a powder X-ray diffraction pattern;

14.1°

±

0.1°

, 19.9°

±

0.1°

, 20.2°

±

0.1°

, 20.6°

±

0.1°

, 21.0°

±

0.1°

, 22.4°

±

0.1°

, 28.5°

±

0.1°

, 29.5°

±

0.1°

, and 32.60°

±

0.1°

.

28. The method of claim 27 wherein the method further comprises cooling the recrystallized FTC to below about 96°

C.

29. A method of preparing a polymorphic form of (−

)-cis-FTC comprising cooling a Form II polymorph of (−

)-cis-FTC to below about 96°

C., wherein the Form II polymorph displays the following angular positions (two theta) of characteristic peaks in a powder X-ray diffraction pattern;

14.7°

±

0.1°

, 16.7°

±

0.1°

, 19.6°

±

0.1°

, 21.1°

±

0.1°

, 21.8°

±

0.1°

, 24.6°

±

0.1°

, and 25.6°

±

0.1°

.

30. A method of preparing a polymorphic form of (−

)-cis-FTC comprising heating a Form III polymorph of (−

)-cis-FTC to above about 112°

C., wherein the Form III polymorph displays the following angular positions (two theta) of characteristic peaks in a powder X-ray diffraction pattern;

14.5°

±

0.1°

, 16.7°

±

0.1°

, 19.6°

±

0.1°

, 20.4°

±

0.1°

, 21.4°

, 0.1°

, 21.7°

±

0.1°

, 25.2°

±

0.1°

, and 26.2°

±

0.1°

.

31. A method of preparing a crystalline form of (±

)-cis-FTC comprising;

a. dissolving a first crystalline form of (±

)-cis-FTC in water, and

b. recrystallizing the dissolved (±

)-cis-FTC.

32. The method of claim 31 further comprising dehydrating the recrystallized (±

)−

cis-FTC.

33. The method of claim 31 wherein the first crystalline form of (±

)-cis-FTC is present in a composition of cis-FTC that comprises up to 98% of the (−

) or (+) enantiomer.

34. A method of preparing amorphous (−

)-cis-FTC comprising;

a. melting a (−

)-cis-FTC, and

b. quench cooling the melt to avoid recrystallization.

35. The method of claim 34 further comprising cooling the amorphous (−

)-cis-FTC to below about 96°

C.