Process for preparing crystalline ciclesonide with defined particle size

• US 20060128954A1
• Filed: 03/26/2004
• Published: 06/15/2006
• Est. Priority Date: 03/27/2003
• Status: Active Grant

• Current Assignee: Covis Pharma GmbH (Apollo Global Management, Inc.)
• Original Assignee: Altana Pharma AG (Takeda Pharmaceutical Company Limited)
• Inventors: Schmidt, Beate
• Granted Patent: US 9,422,327 B2
• Time in Patent Office: Days
• US Class Current: 540/63
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 5/44 Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
• CPC Class Codes: C07J 71/00 Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring spiro-condensed heterocyclic rings C07J21/00, C07J33/00, C07J43/00

Abstract

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.

Claims

1. A process for preparing a compound of the formula I

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 the compound of the formula I has the chemical name 16,17-[(cyclohexylmethylene)bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)pregna-1,4-diene-3,20-dione [11beta, 16alpha (R,S)].

11. The process according to claim 1, characterized in that the compound of the formula I is substantially in the form of the R epimer.

12. The process according to claim 11, characterized in that the proportion of R epimer in the compound of the formula I is more than 95%.

13. The process according to claim 11, characterized in that the compound of the formula I is ciclesonide.

14. The process according to claim 1, characterized in that the precipitate obtained in step c) is subsequently dried.

15. The process for preparing a compound of the formula I according 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 which has been formed of the compound of the formula I.

16. The process according to claim 1, where the particle size is characterized by an X₅₀ of less than or equal to 10.

17. The process according to claim 16, where the particle size is characterized by an X₅₀ in the range from 1.8 to 2.0.

18. The process according to claim 15, where the organic solvents used in steps b) and e) are the same solvents.

19. A compound of the formula obtainable according to the process of claim 1 without a further micronization step, where the compound is in inhalable form.

20. The compound according to claim 19, wherein the compound of the formula I has a particle size characterized by an X₅₀ in the range from 1.8 to 2.0.

21. The compound according to claim 19, which is not in micronized form.

25. A pharmaceutical composition comprising a compound according to claim 19, which compound is present as solid particles together with one or more pharmaceutically acceptable excipients.

26. A pharmaceutical composition according to claim 25, which is an aqueous suspension of the compound.

27. A pharmaceutical composition according to claim 25, which is a dry powder.

22. A crystalline ciclesonide with a particle size characterized by an X₅₀ of less than or equal to 10.

24. A crystalline ciclesonide according to claim 22, which is not in micronized form.

23. A crystalline ciclesonide with a particle size characterized by an X₅₀ in the range from 1.8 to 2.0.