Solid body forms of mesoprogestin 11β-{4E-(hydroxyiminomethyl)-phenyl}-17α methoxymethyl-17β-methoxy-estra-4,9-dien-3-one
The invention relates to novel solid body forms of mesoprogestin 11β-[4E-(hydroxyiminomethyl)-phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one (oxime J 867), particularly a highly pure and stable amorphous or highly crystalline form (ansolvate/anhydrate) of compound J 867. The invention also relates to methods for producing said novel solid body forms and to the use thereof in pharmaceutical compositions. The novel solid body forms are characterized by exhibiting a high degree of stability. The solid body forms of oxime J 867 can, in particular, be used in the area of fertility control and in hormone replacement therapy.
1. Amorphous 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one, substantially separate from its corresponding Z-isomer.
2. Amorphous 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one according to claim 1 , which is substantially solvent-free.
3. Amorphous 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one of claim 1 in substantially pure form.
4. Amorphous 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one of claim 1 , which contains no more than about 1.7% weight of the corresponding Z-isomer.
5. Pharmaceutical composition that comprises amorphous 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one according to claim 1 , in combination with a pharmaceutically compatible vehicle and/or diluent.
6. A method for female birth control, for treating a hormone-dependent gynecological disorder or for hormone replacement therapy, which comprises administering to a patient an amorphous 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one according to claim 1 .
7. Amorphous 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one, substantially separate from its corresponding Z-isomer, obtained by drying of a crystalline solvate of 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one below the glass transition point of the amorphous substance, whereby the drying of the solvate is carried out during the desolvation phase with a heating rate in the product of at least 0.5° C./minute or from a solution of the solvate by spray-drying.
8. Amorphous 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one of claim 7 in substantially pure form.
9. Amorphous 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one of claim 7 , which contains no more than about 1.7% weight of the corresponding Z-isomer.
10. A crystalline solvate of 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one, substantially separate from its corresponding Z-isomer, selected from: the methyl-tert-butyl ether solvate, whereby the crystalline form is characterized by the x-ray-powder diffractogram that is depicted in FIG. 4 c (Table 2); and the ethanol solvate, whereby the crystalline form is characterized by the x-ray-powder diffractogram that is depicted in FIG. 4 a (Table 2).
11. A crystalline solvate of 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one according to claim 10 in substantially pure form.
12. A crystalline solvate of 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one according to claim 10 , which contains no more than about 1.7% weight of the corresponding Z-isomer.
13. Process for the production of amorphous 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one that comprises the drying of a crystalline solvate of 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one, according to claim 10 , below the glass transition point of the amorphous substance, whereby the drying of the solvate is carried out during the desolvation phase with a heating rate in the product of at least 0.5° C./minute or from a solution of the solvate by spray-drying.
14. Process for the production of a crystalline solvate of 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one according to claim 10 that comprises the following steps:
a) production of a solvate of 11β-[4E-(hydroxyiminomethyl)phenyl]-17α-methoxymethyl-17β-methoxy-estra-4,9-dien-3-one and dissolution of the solvate above the saturation solubility in a solvent that is different from the solvate solvent and in which the solvate-crystal structure is unstable,
b) the optional addition of another solvent as a recrystallization inhibitor, and
c) the addition of a solvating agent-solvent and crystallization of the solvate.