Polymorphs of dasatinib isopropyl alcohol and process for preparation thereof
The invention provides crystalline forms of isopropyl alcohol solvate of dasatinib, methods for their preparation, and pharmaceutical compositions thereof.
1. An isopropyl alcohol solvate of dasatinib characterized by data selected from a group consisting of: a powder x-ray diffraction pattern having any three peaks selected from the group consisting of: 6.0, 11.9, 12.0, 14.9, 17.9, 18.3, 18.8, 21.4, 22.9, 24.2 and 24.7±0.2 degrees 2-theta, a powder x-ray diffraction pattern as depicted in FIG. 18 , a solid-state 13 C NMR spectrum having signals at 139.2 and 127.6±0.2 ppm; a solid-state 13 C NMR spectrum having chemical shift differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of 14.2 and 2.6±0.1 ppm; and a unit cell with the following parameters as determined by crystal structure determination using synchrotron powder diffraction data:
Cell dimensions
Cell length a
14.9942(5)
Å
Cell length b
8.45434(22)
Å
Cell length c
22.6228(16)
Å
Cell angle alpha
90.0°
Cell angle beta
95.890(4)°
Cell angle gamma
90.0°
Cell volume
2852.67(21)
Å 3
Symmetry cell setting
monoclinic
Symmetry space group name
P 2 1 /c
a powder x-ray diffraction pattern and calculated powder x-ray diffraction pattern as depicted in FIG. 96 , and combinations thereof.
2. The isopropyl alcohol solvate of dasatinib of claim 1 , characterized by the powder x-ray diffraction pattern having any three peaks selected from the group consisting of: 6.0, 11.9, 12.0, 14.9, 17.9, 18.3, 18.8, 21.4, 22.9, 24.2 and 24.7±0.2 degrees 2-theta.
3. The isopropyl alcohol solvate of dasatinib of claim 1 , characterized by a powder x-ray diffraction pattern as depicted in FIG. 18 .
4. The isopropyl alcohol solvate of dasatinib of claim 1 , characterized by a solid-state 13 C NMR spectrum having signals at 139.2 and 127.6±0.2 ppm.
5. The isopropyl alcohol solvate of dasatinib of claim 1 , characterized by a solid-state 13 C NMR spectrum having chemical shift differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of 14.2 and 2.6±0.1 ppm.
6. The isopropyl alcohol solvate of dasatinib of claim 2 , characterized by a powder x-ray diffraction pattern having any five peaks selected from the group consisting of 6.0, 11.9, 12.0, 14.9, 17.9, 18.3, 18.8, 21.4, 22.9, 24.2 and 24.7±0.2 degrees 2-theta.
7. The isopropyl alcohol solvate of dasatinib of claim 2 , characterized by a powder x-ray diffraction pattern having peaks at 6.0 and 17.9±0.2 degrees 2-theta and any three peaks at positions selected from the group consisting of: 11.9, 14.9, 21.4, 24.2 and 24.7±0.2 degrees 2-theta.
8. The isopropyl alcohol solvate of dasatinib of claim 2 , further characterized by data selected from the group consisting of: a powder x-ray diffraction pattern with peaks at 6.0, 11.9, 12.0, 14.9, 17.9 and 18.3±0.2 degrees 2-theta and a powder x-ray diffraction pattern with peaks at 11.9, 12.0, 21.4, 22.9 and 24.7±0.2 degrees 2-theta.
9. The isopropyl alcohol solvate of dasatinib of claim 1 , further characterized by a content of isopropyl alcohol of about 9% to about 13% by weight.
10. The isopropyl alcohol solvate of dasatinib of claim 1 , having less than about 15% by weight of crystalline dasatinib forms: N-6 characterized by a powder x-ray diffraction pattern having peaks at 6.9, 12.4, 13.2, 13.8, 16.8, 17.2, 21.1, 24.4, 24.9 and 27.8±0.2 degrees 2-theta, and H1-7 characterized by a powder x-ray diffraction pattern having peaks at 4.6, 9.2, 11.2, 13.8, 15.2, 17.9, 19.5, 23.1, 23.6, 25.9 and 28.0±0.2 degrees 2-theta.
11. A formulation comprising the isopropyl alcohol solvate of dasatinib of claim 1 and at least one pharmaceutically acceptable excipient.
12. A pharmaceutical composition comprising the isopropyl alcohol solvate of dasatinib according to claim 1 , and at least one pharmaceutically acceptable excipient.
13. A method for preparing an isopropyl alcohol solvate of dasatinib characterized by data selected from a group consisting of: a powder x-ray diffraction pattern having any three peaks selected from the group consisting of: 6.0, 11.9, 12.0, 14.9, 17.9, 18.3, 18.8, 21.4, 22.9, 24.2 and 24.7±0.2 degrees 2-theta, a powder x-ray diffraction pattern as depicted in FIG. 18 , a solid-state 13 C NMR spectrum having signals at 139.2 and 127.6±0.2 ppm; a solid-state 13 C NMR spectrum having chemical shift differences between the signal exhibiting the lowest chemical shift and another in the chemical shift range of 100 to 180 ppm of 14.2 and 2.6±0.1 ppm; and a unit cell with the following parameters as determined by crystal structure determination using synchrotron powder diffraction data:
Cell dimensions:
Cell length a
14.9942(5)
Å
Cell length b
8.45434(22)
Å
Cell length c
22.6228(16)
Å
Cell angle alpha
90.0°
Cell angle beta
95.890(4)°
Cell angle gamma
90.0°
Cell volume
2852.67(21)
Å 3
Symmetry cell setting
monoclinic
Symmetry space group name
P 2 1 /c
a powder x-ray diffraction pattern and calculated powder x-ray diffraction pattern as depicted in FIG. 96 , and combinations thereof,
said method comprising crystallizing dasatinib from a mixture of isopropyl alcohol and water.
14. The method of claim 13 , wherein the crystallization comprises providing a solution of dasatinib in a mixture of isopropyl alcohol and water, and precipitating the isopropyl alcohol solvate of dasatinib to obtain a suspension.
15. The method of claim 14 , wherein the solution is provided by combining dasatinib, isopropyl alcohol and water, and heating the combination.
16. The method of claim 15 , wherein the heating is to about reflux temperature.
17. The method of claim 14 , wherein the precipitation is performed by cooling the solution
18. The method of claim 17 , wherein the cooling is to a temperature of about 20° C. to about 0° C.
19. The method of claim 13 , further comprising recovering the isopropyl alcohol solvate of dasatinib
20. A process for preparing a pharmaceutical composition comprising combining the dasatinib of claim 1 , and at least one pharmaceutically acceptable excipient.