Crystalline form of selexipag
The present invention provides a novel crystalline form of Selexipag, Selexipag Form APO-I, which is a methanol solvate of Selexipag, compositions thereof, and the use of this crystalline form in the treatment of pulmonary arterial hypertension.
1. A methanol solvate of Selexipag, Form APO-I, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 2θ (±0.2°), at 7.5°, 12.4° and 21.7°.
2. The methanol solvate of claim 1 , wherein the molar ratio of Selexipag to methanol is between approximately 1:0.25 and approximately 1:0.75.
3. The methanol solvate of claim 2 , wherein the molar ratio of Selexipag to methanol is approximately 1:0.5.
4. The methanol solvate of claim 1 , further comprising at least three peaks, expressed in degrees 2θ (±0.2°), selected from the group consisting of: 9.4°, 11.6°, 14.1°, 15.1°, 16.7°, 17.2°, 18.3°, 19.9°, 22.3° and 23.6°.
5. The methanol solvate of claim 1 , further comprising peaks, expressed in degrees 2θ (±0.2°), at 9.4°, 11.6°, 14.1°, 15.1°, 16.7°, 17.2°, 18.3°, 19.9°, 22.3° and 23.6°.
6. The methanol solvate of claim 1 , characterized by a DSC thermogram comprising an endothermic peak with a peak onset of 55° C. and a peak maximum of 73° C.
7. The methanol solvate of claim 4 , characterized by a DSC thermogram comprising an endothermic peak with a peak onset of 55° C. and a peak maximum of 73° C.
8. The methanol solvate of claim 4 , wherein the molar ratio of Selexipag to methanol is approximately 1:0.5.
9. The methanol solvate of claim 1 , providing a PXRD diffractogram comprising peaks in substantially the same positions (±0.2° 2θ) as those shown in FIG. 1 .
10. A process for the preparation of a methanol solvate of Selexipag, Form APO-I, characterized by a PXRD diffractogram comprising peaks, expressed in degrees 2θ (±) 0.2°, at 7.5°, 12.4° and 21.7°, the process comprising:
(1) dissolving Selexipag in methanol at a suitable temperature to provide a solution;
(2) seeding the solution with:
(a) first seeds comprising a methanol solvate of Selexipag characterized by a PXRD diffractogram comprising peaks, expressed in degrees 2θ (±0.2°), at 7.5°, 12.4° and 21.7°;
(b) second seeds comprising a crystalline form of Selexipag providing a PXRD diffractogram comprising peaks, expressed in degrees 2θ (±0.2°), at 9.8°, 12.9° and 13.5°, obtained following crystallization of Selexipag from diethylene glycol; or
(c) a combination of the first and second seeds;
to provide a mixture;
(3) cooling the mixture, if necessary, to form a suspension; and
(4) filtering the suspension to isolate the methanol solvate of Selexipag.
11. The process of claim 10 , wherein the solution is seeded with the first seeds.
12. The process of claim 10 , wherein the solution is seeded with the second seeds.
13. The process of claim 10 , wherein the suitable temperature is between approximately 50° C. and approximately 70° C.
14. The process of claim 10 , wherein the mixture is cooled to a temperature of between approximately 0° C. and approximately 5° C.
15. The process of claim 10 , wherein the molar ratio of Selexipag to methanol in the methanol solvate is between approximately 1:0.25 and approximately 1:0.75.
16. The process of claim 15 , wherein the molar ratio of Selexipag to methanol in the methanol solvate is approximately 1:0.5.
17. A pharmaceutical composition comprising the methanol solvate of claim 1 , and one or more pharmaceutically acceptable excipients.
18. The pharmaceutical composition of claim 17 , wherein the pharmaceutical composition is a tablet.
19. The pharmaceutical composition of claim 18 , wherein the pharmaceutical composition comprises an amount of the methanol solvate equivalent to 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1 mg, 1.2 mg, 1.4 mg or 1.6 mg Selexipag.