Process for preparing crystalline ciclesonide with defined particle size
View Patent ↗The invention relates to a novel process for preparing crystalline ciclesonide with an advantageous particle size and to the use for producing pharmaceutical preparations, in particular for topical use. The crystalline ciclesonide obtained by the novel process has advantageous aerodynamic properties, and can be further processed to inhalable or nasally administered pharmaceutical preparations without further mechanical micronization.
1. A process for preparing a compound of the formula I
in crystalline form, with defined particle size, comprising the steps of
a) preparing a solution of the compound of the formula I in a suitable water-miscible organic solvent;
b) adding the solution obtained in a) to water and
c) isolating a precipitate with a particle diameter for 50% of the total volume of all articles (X 50 ) of less than or equal to 3 μm of the compound of the formula I which is formed.
2. The process according to claim 1 , characterized in that the suitable water-miscible organic solvent is an alcohol.
3. The process according to claim 2 , characterized in that the alcohol is selected from the group consisting of methanol, ethanol, N-propanol, isopropanol and mixtures in any mixing ratio thereof.
4. The process according to claim 3 , characterized in that the alcohol is ethanol.
5. The process according to claim 1 , characterized in that the suitable water-miscible organic solvent is selected from the group consisting of acetone, tetrahydrofuran and dimethylformamide.
6. The process according to claim 1 , characterized in that the temperature of the suitable water-miscible organic solvent is in the range from 15° C. to 10° C. below the boiling point of the solvent.
7. The process according to claim 6 , characterized in that the temperature of the suitable water-miscible organic solvent corresponds to the room temperature at which the process is carried out.
8. The process according to claim 1 , characterized in that the temperature of the water is from 10 to 50° C.
9. The process according to claim 7 , characterized in that the temperature of the water corresponds to the room temperature at which the process is carried out.
10. The process according to claim 1 , characterized in that, in step (a), the compound of the formula I is substantially in the form of the R epimer.
11. The process according to claim 10 , characterized in that the proportion of R epimer in the compound of the formula I is more than 95%.
12. The process according to claim 10 , characterized in that the compound of the formula I is ciclesonide.
13. The process according to claim 1 , characterized in that the precipitate obtained in step c) is subsequently dried.
14. The process for preparing a compound of the formula I ng to claim 1 in crystalline form with defined particle size, comprising the steps of
a) preparing a compound of the formula I by acylation of a compound of the formula II
with a suitable acylating agent;
b) crystallizing the compound of the formula I obtained in a) by adding water to a solution of the compound in a suitable water-miscible organic solvent or heating a suspension of the compound of the formula I in a mixture of a suitable water-miscible organic solvent and water,
c) removing the resulting R epimer-enriched precipitate of the compound of the formula I from the water/solvent mixture;
d) if desired repeating step b);
e) preparing a solution of the compound obtained in c) in a suitable water-miscible organic solvent;
f) adding the solution obtained in e) to water and
g) isolating a precipitate with a particle diameter for 50% of the total volume of all particles (X 50 ) of less than or equal to 3 μm which has been formed of the compound of the formula I.
15. The process according to claim 1 , where the particle size is characterized by an X 50 in the range from 1.8 to 2.0.
16. The process according to claim 14 , where the organic solvents used in steps b) and e) are the same solvents.