Polymorphs and salts of a kinase inhibitor
The present invention relates to novel crystalline polymorphic salt forms of 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid, processes for the preparation thereof, compositions thereof and their use in methods of treatment and prevention of conditions mediated by casein kinase (CK) and/or poly(ADP-ribose)polymerase (PARP).
1. A crystalline polymorph of a salt of compound (I):
characterized by having powder X-ray diffraction pattern peaks of 2θ at about:
(a) 26.2°, and 27.2°, the salt being sodium salt Form II; or
(b) 25.9°, 27.1° and 27.9°, the salt being sodium salt Form III; or
(c) 22.8°, and 25.3°, the salt being sodium salt Form IV; or
(d) 12.3° and 31.3°, the salt being sodium salt Form V; or
(e) 20.7° and 26.0°, the salt being sodium salt Form VI; or
(f) 12.2° and 17.7°, the salt being sodium salt Form VII; or
(g) 24.4° and 25.4°, the salt being sodium salt Form VIII; or
(h) 15.8° and 16.5°, the salt being sodium salt Form IX; or
(i) 23.6° and 28.4°, the salt being sodium salt Form X; or
(j) 24.4°, 24.9° and 26.4°, the salt being sodium salt Form XI; or
(k) 26.3° and 30.7°, the salt being sodium salt Form XII.
2. The crystalline polymorph of claim 1 , wherein the sodium salt Form II is characterized by having powder X-ray diffraction pattern peaks of 2θ at about 10.4°, 11.9°, 15.1°, 15.6°, 26.2°, and 27.2°.
3. The crystalline polymorph of claim 1 , wherein the sodium salt Form II is characterized by having the powder X-ray diffraction pattern substantially as shown in FIG. 2 .
4. The crystalline polymorph of claim 1 , wherein the sodium salt Form II is further characterized by having a water content between about 13% and about 17%.
5. The crystalline polymorph of claim 4 , wherein the sodium salt Form II has a water content of about 15%.
6. The crystalline polymorph of claim 1 , wherein the sodium salt Form II is further characterized by having an endotherm at about 90° C. as shown by DSC.
7. The crystalline polymorph of claim 1 , wherein the sodium salt Form III is characterized by having powder X-ray diffraction pattern peaks of 2θ at about 8.2°, 25.9°, 26.1°, 27.1°, and 27.9°.
8. The crystalline polymorph of claim 1 , wherein the sodium salt Form III is characterized by having the powder X-ray diffraction pattern substantially as shown in FIG. 7 .
9. The crystalline polymorph of claim 1 , wherein the sodium salt Form III is further characterized by having a water content between about 3% and about 7%.
10. The crystalline polymorph of claim 9 , wherein the sodium salt Form III has a water content of about 5%.
11. The crystalline polymorph of claim 1 , wherein the sodium salt Form III is further characterized by having an endotherm at about 120° C. as shown by DSC.
12. The crystalline polymorph of claim 1 , wherein the sodium salt Form IV is characterized by having powder X-ray diffraction pattern peaks of 2θ at about 19.5°, 21.6°, 22.8°, 24.1°, 24.6°, 26.9°, and 29.5°.
13. The cc polymorph of claim 1 , wherein the sodium salt Form IV is characterized by having the powder X-ray diffraction pattern substantially as shown in FIG. 11 .
14. The crystalline polymorph of claim 1 , wherein the sodium salt Form IV is further characterized by having a water content of less than about 5%.
15. The crystalline polymorph of claim 14 , wherein the sodium salt Form IV has a water content of about 2%.
16. The crystalline polymorph of claim 1 , wherein the sodium salt Form IV is further characterized by having endotherm at about 100° C. as shown by DSC.
17. The crystalline polymorph of claim 1 , wherein the sodium salt Form V is characterized by having powder X-ray diffraction pattern peaks of 2θ at about 12.3°, 21.8°, 224°, and 31.3°.
18. The crystalline polymorph of claim 1 , wherein the sodium salt Form V is characterized by having powder X-ray diffraction pattern substantially as shown in FIG. 16 .
19. The crystalline polymorph of claim 1 , wherein the sodium salt Form VI is characterized by having powder X-ray diffraction pattern peaks of 2θ at about 11.4°, 14.6°, 16.1°, 20.7°, and 26.0°.
20. The crystalline polymorph of claim 1 , wherein the sodium salt Form VI is characterized by having the powder X-ray diffraction pattern substantially as shown in FIG. 17 .
21. The crystalline polymorph of claim 1 , wherein the sodium salt Form VII is characterized by having powder X-ray diffraction pattern peaks of 2θ at about 11.7°, 12.2°, 13.8°, 14.4°, 15.9°, 17.7°, 18.5°, 19.7°.
22. The crystalline polymorph of claim 1 , wherein the sodium salt Form VII is characterized by having the powder X-ray diffraction pattern substantially as shown in FIG. 18 .
23. The crystalline polymorph of claim 1 , wherein the sodium salt Form VII is further characterized by having a water content between about 3% and about 7%.
24. The crystalline polymorph of claim 23 , wherein the sodium salt Form VII has a water content of about 5%.
25. The crystalline polymorph of claim 1 , wherein the sodium salt Form VIII is characterized by having powder X-ray diffraction pattern peaks of 2θ at about 10.2°, 14.0°, 14.4°, 18.4°, 24.4°, 24.9°, and 25.4°.
26. The crystalline polymorph of claim 1 , wherein the sodium salt Form VIII is characterized by having the powder X-ray diffraction pattern substantially as shown in FIG. 19 .
27. The crystalline polymorph of claim 1 , wherein the sodium salt Form IX is characterized by having powder X-ray diffraction pattern peaks of 2θ at about 14.2°, 15.8°, 16.0° and 16.5°.
28. The crystalline polymorph of claim 1 , wherein the sodium salt Form IX is characterized by having the powder X-ray diffraction pattern substantially as shown in FIG. 21 .
29. The crystalline polymorph of claim 1 , wherein the sodium salt Form X is characterized by having powder X-ray diffraction pattern peaks of 2θ at about 13.8°, 23.6°, 25.3° and 28.4°.
30. The crystalline polymorph of claim 1 , wherein the sodium salt Form X is characterized by having the powder X-ray diffraction pattern substantially as shown in FIG. 22 .
31. The crystalline polymorph of claim 1 , wherein the sodium salt Form XI is characterized by having powder X-ray diffraction pattern peaks of 2θ at about 22.6°, 24.4°, 24.9°, 26.4°, 28.5° and 30.7°.
32. The crystalline polymorph of claim 1 , wherein the sodium salt Form XI is characterized by having the powder X-ray diffraction pattern substantially as shown in FIG. 23 .
33. The crystalline polymorph of claim 1 , wherein the sodium salt Form XII is characterized by having powder X-ray diffraction pattern peaks of 2θ at about 14.8°, 21.9°, 23.8°, 26.3°, 27.6°, and 30.7°.
34. The crystalline polymorph of claim 1 , wherein the sodium salt Form XII is characterized by having the powder X-ray diffraction pattern substantially as shown in FIG. 24 .
35. The crystalline polymorph of claim 1 , wherein the crystalline polymorph is substantially pure.
36. A composition comprising a crystalline polymorph of claim 1 , and a pharmaceutically acceptable carrier.