Morphic forms of G1T38 and methods of manufacture thereof
This invention provides an unexpectedly stable, highly crystalline form of the di-HCl salt of for advantageous therapeutic pharmaceutical efficacy and dosage form stability.
1. An isolated crystalline Form B of the di-HCl salt of structure:
characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values selected from 6.5±0.2°, 9.5±0.4°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.3±0.2°, 19.9±0.2°, and 22.4±0.2°.
2. The isolated crystalline Form B of claim 1 , wherein the XRPD pattern comprises at least four 2θ values selected from 6.5±0.2°, 9.5±0.4°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.3±0.2°, 19.9±0.2°, and 22.4±0.2°.
3. The isolated crystalline Form B of claim 1 , wherein the XRPD pattern comprises at least the 2θ value of 9.5±0.4°.
4. The isolated crystalline Form B of claim 1 , wherein the XRPD pattern comprises at least a 2θ value of 9.5±0.2°.
5. The isolated crystalline Form B of claim 1 , wherein the XRPD pattern comprises at least the 2θ value of 19.3±0.2°.
6. The isolated crystalline Form B of claim 1 , wherein the XRPD pattern comprises at least the 2θ value of 22.4±0.2°.
7. The isolated crystalline Form B of claim 1 , characterized by an XRPD pattern having the characteristic 2θ values of FIG. 7 .
8. The isolated crystalline Form B of claim 1 characterized by differential scanning calorimetry (DSC) onset endotherms of about 105±20° C., about 220±20° C., and about 350±20° C.
9. The isolated crystalline Form B of claim 1 characterized by differential scanning calorimetry (DSC) onset endotherms of about 105±10° C., about 220±10° C., and about 350±10° C.
10. A pharmaceutical composition comprising the isolated crystalline Form B of claim 1 and a pharmaceutically acceptable excipient for solid dosage delivery.
11. A process for producing crystalline Form B of 2′-((5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)amino)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one di-HCl salt comprising the steps of
(i) heating the free base of 2′-((5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)amino)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′: 1,5]pyrrolo[2,3-d]pyrimidin]-6′-one in aqueous HCl to at least about 45° C.;
(ii) stirring the solution for at least about 15 minutes and filtering the resulting solution;
(iii) adding solvent at a temperature of at least about 45° C. and stirring the solution for at least about 15 minutes;
(iv) decreasing the temperature of the solution to about 25° C. or lower and stirring the solution for at least about 30 minutes; and
(v) filtering the solution and washing the solution with additional solvent to afford the crystalline Form B of 2′-((5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)amino)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′: 1,5]pyrrolo[2,3-d]pyrimidin]-6′-one di-HCl salt;
wherein crystalline Form B of 2′-((5-(4-isopropylpiperazin-1-yl)pyridin-2-yl)amino)-7′,8′-dihydro-6′H-spiro[cyclohexane-1,9′-pyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyrimidin]-6′-one di-HCl is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2θ values selected from 6.5±0.2°, 9.5±0.4°, 14.0±0.2°, 14.4±0.2°, 18.1±0.2°, 19.3±0.2°, 19.9±0.2°, and 22.4±0.2°.
12. The process of claim 11 , wherein the solvent used is acetone.
13. The process of claim 11 , wherein the solution is stirred for about 45 minutes in step (ii).
14. The process of claim 11 , wherein the solution is heated to at least about 50° C. in step (i).
15. The process of claim 11 , wherein the solution is heated to about 55° C. in step (i).
16. The process of claim 11 , wherein the solvent is heated to at least about 50° C. in step (iii).
17. The process of claim 11 , wherein the solution is stirred for at least about 1 hour in step (iii).
18. The process of claim 11 , wherein the solution is stirred for at least about 1 hour in step (iv).
19. The process of claim 11 , wherein the solution is stirred for at least about 2 hours in step (iv).
20. The isolated crystalline Form B of claim 1 , wherein the isolated crystalline Form B is a hydrate.