Crystalline forms of an NRTTI compound
The present disclosure provides novel anhydrate crystalline Forms 1 and 4 of 4′-Ethynyl-2-fluoro-2′-deoxyadenosine and pharmaceutical compositions thereof, each of which may be useful for the inhibition of HIV reverse transcriptase, the treatment or prophylaxis of HIV infection and/or the treatment, prophylaxis and/or delay in the onset or progression of AIDS or ARC.
1. Crystalline anhydrous Form 1 of 2′ deoxy-4′-C-ethynyl-2-fluoroadenosine (EFdA) characterized by:
(1) a powder x-ray diffraction pattern with peaks at diffraction angles degrees 2 theta (+/−) 0.2° of 4.48, 11.79, 14.70 and 25.81 in a powder x-ray diffraction obtained using Cu K alpha radiation, and/or
(2) a solid state 19 F NMR spectrum comprising any two of the following peaks: −114.75, −117.09 and −118.92 ppm.
2. The crystalline anhydrous Form 1 of EFdA according to claim 1 , characterized by a powder x-ray diffraction pattern with peaks at diffraction angles degrees 2 theta (+/−) 0.2° of 4.48, 11.79, 14.70, 25.81, 8.99, 12.39, 16.88 and 27.42.
3. The crystalline anhydrous Form 1 of EFdA according to claim 1 , characterized by a powder x-ray diffraction pattern with peaks at diffraction angles degrees 2 theta (+/−) 0.2° of 4.48, 11.79, 14.70, 25.81, 8.99, 12.39, 16.88, 27.42, 10.39, 15.51, 18.09 and 20.16.
4. Crystalline anhydrous Form 1 of EFdA according to claim 1 characterized by a solid state 19 F NMR spectrum comprising the following peaks: −114.75, −117.09 and −118.92 ppm.
5. The crystalline anhydrous Form 1 of EFdA according to claim 1 , characterized by a solid state 19 F NMR spectrum comprising the following peaks: −117.09 and −118.92 ppm.
6. The crystalline anhydrous Form 1 of EFdA according to claim 1 , further characterized by:
(1) a TGA data showing 0.1 wt. % loss up to 133° C., followed by thermal decomposition above 240° C., or
(2) a TGA curve as shown in FIG. 3 .
7. Crystalline anhydrous Form 4 of 2′ deoxy-4′-C-ethynyl-2-fluoroadenosine (EFdA) having the powder x-ray diffraction pattern as shown in FIG. 7 .
8. The crystalline anhydrous Form 4 of EFdA of claim 7 further characterized by a solid state 19 F NMR spectrum comprising peaks at −116.96 and −118.36 ppm.
9. The crystalline anhydrous Form 4 of EFdA according to claim 8 , further characterized by:
(1) TGA data showing 0.02 wt. % loss up to 148° C., followed by thermal decomposition above 250° C.; or
(2) a TGA curve as shown in FIG. 9 .
10. A solid dosage pharmaceutical composition comprising the crystalline anhydrate Form 1 of EFdA according to claim 1 and a pharmaceutically acceptable carrier.
11. A solid dosage pharmaceutical composition comprising the crystalline anhydrate Form 4 of EFdA according to claim 7 and a pharmaceutically acceptable carrier.
12. The pharmaceutical composition of claim 10 , wherein the composition is adapted for long-acting parenteral administration.
13. The pharmaceutical composition of claim 11 , wherein the composition is adapted for long-acting parenteral administration.
14. The crystalline anhydrous Form 1 of EFdA according to claim 1 , characterized by a powder x-ray diffraction pattern comprising six or more of the 2-theta values listed in Table 1, +/−0.2° 2-theta.
15. The crystalline anhydrous Form 1 of EFdA according to claim 1 , characterized by a powder x-ray diffraction pattern comprising nine or more of the 2-theta values listed in Table 1, +/−0.2° 2-theta.
16. The crystalline anhydrous Form 4 of EFdA according to claim 7 , characterized by a powder x-ray diffraction pattern comprising six or more of the 2-theta values listed in Table 4, +/−0.2° 2-theta.
17. The crystalline anhydrous Form 4 of EFdA according to claim 1 , characterized by a powder x-ray diffraction pattern comprising nine or more of the 2-theta values listed in Table 4, +/−0.2° 2-theta.
18. The crystalline anhydrous Form 4 of EFdA according to claim 7 , characterized by a powder x-ray diffraction pattern with peaks at diffraction angles degrees 2 theta (+/−) 0.2° of 4.48, 11.79, 12.39, 14.70, 15.51, 18.09, 25.81, and 27.42.