Polymorphic and other crystalline forms of cis-FTC
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.
1. A pharmaceutical composition comprising a polymorphic compound of (−)-cis-FTC prepared by a method comprising:
a) melting Form I (−)-cis-FTC, and
b) recrystallizing the melted (−)-cis-FTC, and a pharmaceutically acceptable carrier.
2. The pharmaceutical composition of claim 1 wherein the compound is Form II (−)-cis-FTC.
3. The pharmaceutical composition of claim 1 wherein the compound is Form III (−)-cis-FTC.
4. The pharmaceutical composition of claim 2 wherein the compound is at least 97% pure.
5. The pharmaceutical composition of claim 3 wherein the compound is at least 97% pure.
6. The pharmaceutical composition of claim 1 wherein the method further comprises cooling the recrystallized FTC to below about 96° C.
7. The pharmaceutical composition of claim 6 wherein the method further comprises the (−)-cis-FTC to above about 112° C., wherein the 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°, in a pharmaceutically acceptable carrier.
8. The pharmaceutical composition of claim 1 , wherein the composition is in the form of a capsule.
9. A method of treating HIV or HBV comprising administering to a patient afflicted with the disease a treatment effective amount of the pharmaceutical composition of claim 1 .
10. A pharmaceutical composition comprising a (±)-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, in a pharmaceutically acceptable carrier.
11. The composition of claim 10 wherein the method further comprises dehydrating the recrystallized (±)-cis-FTC.
12. The composition of claim 10 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;
b) dehydrated (±)-cis-FTC sesquihydrate; and
c) 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 polymorphic form of (−)-cis-FTC characterized by a solid state transition at about 96-112° C.
17. The polymorphic form of (−)-cis-FTC of claim 16 , which is further characterized by a melting point of about 162-167° C.
18. The polymorphic form of (−)-cis-FTC of any one of claims 16 , which is greater than 95% pure.
19. The polymorphic form of (−)cis-FTC of claim 16 , prepared by a method comprising:
a) heating (−)-cis-FTC to above about 151° C.; and
b) cooling the (−)-cis-FTC to about 112-151° C. to obtain polymorphic crystalline (−)-cis-FTC;
wherein the polymorphic (−)-cis-FTC is characterized by a melting point of about 162-167° C.
20. The polymorphic form of (−)cis-FTC of claim 16 , prepared by a method comprising:
a) heating (−)-cis-FTC to above about 151° C.; and
b) cooling the (−)-cis-FTC to below 96° C. to obtain polymorphic crystalline (−)-cis-FTC.
21. The polymorphic form of (−)-cis-FTC of claim 19 , wherein the (−)-cis-FTC of step
(a) has a melting temperature of about 148-153° C.
22. The polymorphic form of (−)-cis-FTC of claim 20 , wherein the (−)-cis-FTC of step
(a) has a melting temperature of about 148-153° C.
23. The polymorphic form of (−)-cis-FTC of claim 20 , wherein step (a) comprises heating (−)-cis-FTC to above 160° C.; and step (b) comprises cooling the compound to about 25° C.
24. The polymorphic form of (−)-cis-FTC of claim 16 , wherein the solid state transition temperature is 102° C.