Crystalline forms of Tenofovir alafenamide
The present invention provides novel crystalline forms of tenofovir alafenamide comprising tenofovir alafenamide and two different pharmaceutically acceptable acids, compositions and processes for the preparation thereof, and their use in the treatment of a human immunodeficiency virus (HIV) infection or a hepatitis B virus (HBV) infection.
1. A crystalline form of tenofovir alafenamide succinate fumarate comprising tenofovir alafenamide, succinic acid, and fumaric acid.
2. The crystalline form of tenofovir alafenamide of claim 1 , wherein the molar ratio of tenofovir alafenamide to (succinic acid+fumaric acid) is approximately 1:1.
3. The crystalline form of claim 2 , wherein the crystalline form is represented by the following formula:
[TAF][succinic acid] 1-x [fumaric acid] x
wherein
TAF is tenofovir alafenamide; and
x is in the range of 0.05 to 0.95.
4. The crystalline form of claim 2 , wherein the molar ratio of tenofovir alafenamide to succinic acid to fumaric acid is approximately 1:0.25:0.75 and the crystalline form is characterized by a PXRD diffractogram comprising peaks, expressed in degrees 2θ (±0.2°), at 5.6°, 10.5° and 22.4°.
5. The crystalline form of claim 4 , further comprising at least three peaks in the PXRD diffractogram, expressed in degrees 2θ(±0.2°), selected from the group consisting of: 9.4°, 9.7°, 11.1°, 11.5°, 13.3°, 14.1°, 16.9°, 17.6°, 19.1° and 28.2°.
6. The crystalline form of claim 4 , characterized by a DSC thermogram comprising an endothermic peak with a peak onset at approximately 119° C. and a peak maximum at approximately 120° C.
7. The crystalline form of claim 2 , wherein the molar ratio of tenofovir alafenamide to succinic acid to fumaric acid is approximately 1:0.5:0.5 and the crystalline form is characterized by a PXRD diffractogram comprising peaks, expressed in degrees 2θ (±0.2°), at 5.6°, 10.5° and 22.2°.
8. The crystalline form of claim 7 , further comprising at least three peaks in the PXRD diffractogram, expressed in degrees 2θ (±0.2°), selected from the group consisting of: 7.2°, 9.4°, 9.7°, 11.1°, 11.5°, 13.2°, 14.1°, 16.7°, 18.9° and 27.8°.
9. The crystalline form of claim 7 , characterized by a DSC thermogram comprising an endothermic peak with a peak onset at approximately 118° C. and a peak maximum at approximately 120° C.
10. The crystalline form of claim 2 , wherein the molar ratio of tenofovir alafenamide to succinic acid to fumaric acid is approximately 1:0.75:0.25 and the crystalline form is characterized by a PXRD diffractogram comprising peaks, expressed in degrees 2θ (±0.2°), at 5.5°, 10.5° and 22.3°.
11. The crystalline form of claim 10 , further comprising at least three peaks in the PXRD diffractogram, expressed in degrees 2θ (±0.2°), selected from the group consisting of: 7.2°, 9.3°, 9.7°, 11.1°, 11.5°, 13.2°, 14.1°, 16.8°, 19°, and 28.1°.
12. The crystalline form of claim 10 , characterized by a DSC thermogram comprising an endothermic peak with a peak onset at approximately 118° C. and a peak maximum at approximately 120° C.
13. A crystalline form of tenofovir alafenamide succinate malate comprising tenofovir alafenamide, succinic acid, and L-malic acid.
14. The crystalline form of claim 13 , wherein the molar ratio of tenofovir alafenamide to succinic acid to L-malic acid is approximately 1:0.4:0.4 and the crystalline form is characterized by a PXRD diffractogram comprising peaks, expressed in degrees 2θ (±0.2°), at 5.4°, 9.9° and 15.1°.
15. The crystalline form of claim 14 , further comprising at least three peaks in the PXRD diffractogram, expressed in degrees 2θ (±0.2°), selected from the group consisting of: 11.8°, 13.2°, 13.9°, 16.5°, 19.0°, 21.10° 22.0° and 26.1°.
16. The crystalline form of claim 14 , characterized by a DSC thermogram comprising an endothermic peak with a peak onset at approximately 105° C. and a peak maximum at approximately 109° C.
17. A pharmaceutical composition comprising a crystalline form of tenofovir alafenamide succinate fumarate according to claim 2 , and one or more pharmaceutically acceptable excipients.
18. The pharmaceutical composition of claim 17 , further comprising an additional therapeutic agent selected from the group consisting of emtricitabine, darunavir, cobicistat, bictegravir, and rilpivirine.
19. A method for treating a human immunodeficiency virus (HIV) infection or a hepatitis B virus (HBV) infection comprising administering an effective amount of the crystalline form of tenofovir alafenamide succinate fumarate of claim 2 .
20. The method of claim 19 , wherein the tenofovir alafenamide succinate fumarate is used in combination with an additional therapeutic agent selected from the group consisting of emtricitabine, darunavir, cobicistat, bictegravir, and rilpivirine.