USRE39251EExpiredUtility

Polymorphs of an epothilone analog

Assignee: BRISTOL MYERS SQUIBB COPriority: Aug 16, 2000Filed: Mar 9, 2005Granted: Aug 29, 2006

Est. expiryAug 16, 2020(expired)· nominal 20-yr term from priority

Inventors:Zhenrong Guo

A61P 35/00C07D 491/04C07D 417/06C07D 417/14

PatentIndex Score

Cited by

116

References

Claims

Abstract

There are provided in accordance with the present invention two crystalline polymorphs, designated Form A and Form B, respectively, as well as mixtures thereof, of an epothilone analog represented by the formula Also provided are methods of forming the novel polymorphs, therapeutic methods utilizing them and pharmaceutical dosage forms containing them.

Claims

exact text as granted — not AI-modified

1. A crystalline polymorph of an epothilone analog represented by the formula

comprising Form A characterized by:
unit cell parameters approximately equal to the following:
Cell dimensions a = 14.152(6) Å b = 30.72(2) Å c = 6.212(3) Å Volume = 2701(4) A 3 Space group P2 1 2 1 2 1 Orthorhombic Molecules/unit cell 4 Density (calculated) (g/cm 3 ) 1.247 Melting point 182-185° C. decomposition; and

characteristic peaks in the powder x-ray diffraction pattern at values of two theta (CuKα λ=1.5406 Å at 22° C.): 5.69, 6.76, 8.38, 11.43, 12.74, 13.62, 14.35, 15.09, 15.66, 16.43, 17.16, 17.66, 18.31, 19.03, 19.54, 20.57, 21.06, 21.29, 22.31, 23.02, 23.66, 24.18, 14.98, 25.50, 26.23, 26.23, 26.46, 27.59, 28.89, 29.58, 30.32, 31.08 and 31.52.

2. A crystalline polymorph of an epothilone analog represented by the formula

comprising Form A characterized by powder x-ray diffraction substantially as shown in FIG. 1 and a Raman spectrum substantially as shown in FIG. 5.

3. A crystalline polymorph of an epothilone analog represented by the formula

comprising Form A characterized by a solubility in water of 0.1254, a solubility in a 3% aqueous solution of polysorbate 80 of 0.2511, a melting point with decomposition between 182-185° C. and a heat of solution of 20.6 k/mol.

4. A crystalline material of an epothilone analog represented by formula I:

comprising a mixture of Form A and Form B wherein Form A is characterized by:
unit cell parameters approximately equal to the following:
Cell dimensions a = 14.152(6) Å b = 30.72(2) Å c = 6.212(3) Å Volume = 2701(4) A 3 Space group P2 1 2 1 2 1 Orthorhombic Molecules/unit cell 4 Density (calculated) (g/cm 3 ) 1.247 Melting point 182-185° C. (decomposition); and

and Form B is characterized by:
unit cell parameters approximately equal to the following:
Cell dimensions a = 16.675(2) Å b = 28.083(4) Å c = 6.054(1) Å Volume = 2835(1) A 3 Space group P2 1 2 1 2 1 Orthorhombic Molecules/unit cell 4 Density (calculated) (g/cm 3 ) 1.187 Melting point 191-199° C. decomposition; and

characteristic peaks in the powder x-ray diffraction pattern at values of two theta (CuKα λ=1.5406 Å at 22° C.): 6.17, 10.72, 12.33, 14.17, 14.93, 14.88, 16.17, 17.11, 17.98, 19.01, 19.61, 20.38, 21.55, 21.73, 22.48, 23.24, 23.93, 24.78, 25.15, 25.90, 26.63, 27.59, 28.66, 29.55, 30.49 and 31.22.

5. A crystalline material of an epothilone analog represented by formula I;

comprising a mixture of Form A and Form B wherein Form A is characterized by powder x-ray diffraction substantially as shown in FIG. 1 and a Raman spectrum substantially as shown in FIG. 5 ;
and Form B is characterized by powder x-ray diffraction substantially as shown in FIG. 2 and a Raman spectrum substantially as shown in FIG. 6.

6. A crystalline material of an epothilone analog represented by formula I:

comprising a mixture of Form A and Form B wherein Form A is characterized by a solubility in water of 0.1254, a solubility in a 3% aqueous solution of polysorbate 80 of 0.2511, a melting point with decomposition between 182-185° C. and a heat of solution of 20.6 kl/mol;
and Form B is characterized by a solubility in water of 0.1907, a solubility in a 3% aqueous solution of polysorbate 80 to 0.5799, a melting point with decomposition between 191-199° C. and a heat of solution of 9.86 kl/mol.

7. A process for producing a crystalline polymorph that is Form A of the epothilone analog represented by formula I in claim 1 comprising heating a slurry of said analog represented by formula I in from about 8 to about 16 mL of ethyl acetate per gram of said analog to about 75° C. maintaining the temperature for about one hour, adding an amount of cyclohexane in a ratio to the amount of ethyl acetate of from about 1:2 to about 2:2, allowing the mixture to cool to ambient temperature, maintain the mixture with stirring from about 12 to 96 hours, further cooling it to about 5° C. over about two hours and recovering the crystalline Form A therefrom.

8. A process in accordance with claim 7 wherein the amount of cyclohexane added is in a 1:2 ratio to the amount of ethyl acetate utilized to form said slurry.

9. A process in accordance with claim 7 wherein said slurry of said analog represented by formula I in ethyl acetate is heated to about 75° C. seed crystals are added thereto and the mixture is maintained for about 30 minutes after which said amount of cyclohexane is added thereto while maintaining the mixture at about 70° C., cooling the mixture to ambient temperature, maintain the mixture with stirring for about 18 hours, further cooling it to about 5° C. over about two hours and recovering the crystalline Form A therefrom.

10. A process in accordance with claim 7 wherein said slurry of said analog represented by formula I in ethyl acetate is heated to about 75° C. for at least an hour until a solution is formed, cooling said solution to about 50° C. over about two hours, adding said seed crystals thereto when the temperature reaches about 60° C., cooling the solution to about 30° C. over about three hours, further reducing the temperature of the solution to −10° C. over about three hours during one hour of which said amount of cyclohexane is added thereto dropwise, maintaining the resultant mixture at −10° C. for about one hour and recovering the crystalline Form A therefrom.

11. A process for producing a crystalline polymorph that is Form B of the epothilone analog represented by formula I in claim 8 comprising heating a slurry of said analog represented by formula I in from about 40 to about 50 mL of ethyl acetate per gram of said analog to about 75° C. to 80° C., maintaining the temperature for about one hour thereby forming a solution, maintaining the solution at temperature for about 30 minutes, cooling the solution to about 30° C. over about two hours, further reducing the temperature of the solution to −10° C. over about one hour during which an amount of cyclohexane in a ratio to the amount of ethyl acetate of from about 1:2 to about 2:2 is added thereto dropwise over a period of about thirty minutes, maintaining the resultant mixture at −10° C. for about two hours and recovering the crystalline Form B therefrom.

12. A process in accordance with claim 11 wherein said slurry of said analog represented by formula I in ethyl acetate is heated to about 78° C. thereby forming a solution, cooling the solution to about 10° C. over about two hours, adding seed crystals when the temperature reaches 10° C., further reducing the temperature of the solution to −10° C. over about two hours during which said amount of cyclohexane is added thereto dropwise over a period of about thirty minutes, maintaining the resultant mixture at −10° C. for about two hours and recovering the crystalline Form B therefrom.

13. A crystalline polymorph of an epothilone analog represented by the formula

comprising Form B characterized by:
unit cell parameters approximately equal to the following:
Cell dimensions a = 16.675(2) Å b = 28.083(4) Å c = 6.054(1) Å Volume = 2835(1) A 3 Space group P2 1 2 1 2 1 Orthorhombic Molecules/unit cell 4 Density (calculated) (g/cm 3 ) 1.187 Melting point 191-199° C. decomposition and/or

characteristic peaks in the powder x-ray diffraction pattern at values of two theta (CuKα λ1.5406 Å at 22° C.): 6.17, 10.72, 12.33, 14.17, 14.93, 15.88, 16.17, 17.11, 17.98, 19.01, 19.61, 20.38, 21.55, 21.73, 22.48, 23.34, 23.93, 24.78, 25.15, 25.90, 26.63, 27.59, 28.66, 29.55, 30.49 and 31.22.

14. A process for producing a crystalline polymorph that is Form B of the epothilone analog represented by formula I in claim 13 comprising heating a slurry of said analog represented by formula I in from about 10 to about 20 mL of toluene per gram of said analog to about 75° C. to 80° C., maintaining the temperature for about 30 minutes, cooling the mixture to about 20° C., maintaining the temperature for about 18 hours with stirring and recovering the crystalline Form B therefrom.

15. A pharmaceutical composition which comprises as an active ingredient an effective amount a crystalline polymorph as claimed in claim 1 and one or more pharmaceutically acceptable carriers, excipients or diluents thereof.

16. A pharmaceutical composition which comprises as an active ingredient an effective amount a crystalline polymorph as claimed in claim 2 and one or more pharmaceutically acceptable carriers, excipients or diluents thereof.

17. A pharmaceutical composition which comprises as an active ingredient an effective amount a crystalline polymorph as claimed in claim 3 and one or more pharmaceutically acceptable carriers, excipients or diluents thereof.

18. A pharmaceutical composition which comprises as an active ingredient an effective amount of a crystalline polymorph of an epothilone analog represented by formula I:

and one or more pharmaceutically acceptable carriers, wherein said crystalline polymorph is a mixture of Form A and Form B, wherein Form A is characterized by:
unit cell parameters approximately equal to the following:
Cell dimensions a = 14.152(6) Å b = 30.72(2) Å c = 6.212(3) Å Volume = 2701(4) A 3 Space group P2 1 2 1 2 1 Orthorhombic Molecules/unit cell 4 Density (calculated) (g/cm 3 ) 1.247 Melting point 182-185° C. (decomposition); and

characteristic peaks in the powder x-ray diffraction pattern at values of two theta (CuKα λ=1.5406 Å at 22° C.): 6.17, 10.72, 12.33, 14.17, 14.93, 15.88, 16.17, 17.11, 17.98, 19.01, 19.61, 20.38, 21.55, 21.73, 22.48, 23.24, 23.93, 24.78, 25.15, 25.90, 26.63, 27.59, 28.65, 29.55, 30.49 and 31.22.

19. A method for treating cancer or other proliferative diseases which comprises administering to a mammal in need thereof an effective amount of a crystalline polymorph as claimed in claim 1 .

20. A method for treating cancer or other proliferative diseases which comprises administering to a mammal in need thereof an effective amount of a crystalline polymorph as claimed in claim 2 .

21. A method for treating cancer or other proliferative diseases which comprises administering to a mammal in need thereof an effective amount of a crystalline polymorph as claimed in claim 3 .

22. A method in accordance with claim 19 wherein said crystalline polymorph is administered parenterally.

23. A crystalline polymorph of an epothilone analog represented by the formula

comprising Form B characterized by powder x-ray diffraction substantially as shown in FIG. 2 and a Raman spectrum substantially as shown in FIG. 6 .

24. A crystalline polymorph of an epothilone analog represented by the formula:

comprising Form B characterized by a solubility in water of about 0.1907, a solubility in a 3% aqueous solution of polysorbate 80 of about 0.5799, a melting point with decomposition between about 191-199° C. and a heat of solution of about 9.86 kJ/mol.

25. A pharmaceutical composition which comprises as an active ingredient an effective amount of a crystalline polymorph as claimed in claim 13 and one or more non- solubilizing pharmaceutically-acceptable carriers, excipients or diluents thereof.

26. A pharmaceutical composition which comprises as an active ingredient an effective amount of a crystalline polymorph as claimed in claim 23 and one or more non- solubilizing pharmaceutically-acceptable carriers, excipients or diluents thereof.

27. A pharmaceutical composition which comprises as an active ingredient an effective amount of a crystalline polymorph as claimed in claim 24 and one or more non- solubilizing pharmaceutically-acceptable carriers, excipients or diluents thereof.

28. A method for treating cancer or other proliferative diseases which comprises administering to a mammal in need thereof an effective amount of a crystalline polymorph as claimed in claim 13 .

29. A method for treating cancer or other proliferative diseases which comprises administering to a mammal in need thereof an effective amount of a crystalline polymorph as claimed in claim 23 .

30. A method for treating cancer or other proliferative diseases which comprises administering to a mammal in need thereof an effective amount of a crystalline polymorph as claimed in claim 24 .

31. A method in accordance with claim 28 wherein said crystalline polymorph is administered parenterally.

Cited by (0)

No later patents cite this yet.

References (0)

No backward citations on record.