Crystalline forms of 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one
View Patent ↗The present invention relates to crystalline forms of 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one. The invention relates in particular to two crystalline ansolvate/anhydrate forms of this compound, polymorphs I and II. However, the present invention also relates to crystalline solvates, for example methanol and ethanol solvates of 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one as precursors for preparing these two polymorphs I and II. Processes for preparing polymorph I by displacement crystallization or by trituration are described. Selection of the last solvent before formation of the ansolvate can be based on the differences in the purification behaviour of the individual solvates of 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one. Polymorph I according to the invention is particularly suitable for the manufacture of medicinal products.
1. Polymorph I of 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one, having an X-ray powder diffractogram showing lines at d=21.4 Å, d=7.7 Å d=5.8 Å and d=5.3 Å, and an IR spectrum showing bands at 3416 cm −1 , 1680 cm −1 , 1628 cm −1 and 1215 cm −1 .
2. Polymorph II of 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one, having an X-ray powder diffractogram showing lines at d=5.1 Å, d=7.1 Å, and d=5.6 Å, and an IR spectrum showing bands at 3653 cm −1 , 1682 cm −1 , 1601 cm −1 and 1209 cm −1 .
3. Pharmaceutical composition comprising polymorph I of crystalline 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one according to claim 1 .
4. Pharmaceutical composition comprising polymorph II of 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17 α-pregna-4,9-dien-3-one, according to claim 2 .
5. Pharmaceutical composition according to claim 3 comprising less than 0.2% 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-9,10-epoxy-19-nor-10α,17α-pregna-1,4-dien-3-one.
6. Process for preparing polymorph I according to claim 1 comprising displacement crystallizing said polymorph from an organic solvent that is ethanol with an antisolvent that is water with which 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one forms no solvate.
7. Process according to claim 6 , where the proportion of water is above 50 wt % and the temperature is below 50° C.
8. Process for preparing polymorph I according to claim 1 comprising trituration of an organic solvate that is ethanol solvate in a solvent that is water, in which 11β-(4-acetylphenyl)-20,20,21,21,21-pentafluoro-17-hydroxy-19-nor-17α-pregna-4,9-dien-3-one forms no solvate.
9. Process according to claim 8 , where the trituration is carried out at a temperature of 50-100° C.
10. Process according to claim 9 , where the trituration is carried out at a temperature of about 80-90° C.
11. Process according to claim 8 , wherein in the solvate impurities are depleted on preparation thereof.