Crystal forms, methods for their preparation and method for preparation of olanzapine

• US 7,323,459 B2
• Filed: 12/24/2003
• Issued: 01/29/2008
• Est. Priority Date: 12/24/2002
• Status: Expired due to Fees

• Current Assignee: Teva Pharmaceuticals USA, Inc. (Teva Pharmaceutical Industries Limited)
• Original Assignee: Teva Pharmaceutical Industries Limited
• Inventors: Dolitzky, Ben Zion, Aronhime, Judith, Diller, Dov
• Primary Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US10/746,698
• Publication Number:
  US 20040198721A1
• Time in Patent Office: 1,497 Days
• Field of Search: 514/220, 540/557
• US Class Current: 514/220
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

The invention is directed to a series of novel crystalline olanzapine forms, in particular hydrated and solvated crystalline forms of olanzapine, methods of use in pharmaceutical compositions, and method of treating psychiatric disorders using the crystalline forms. One series of the crystalline forms are hydrates, i.e. water containing crystals, wherein water may be present in a ratio of about 2:1.5 to a ratio of about 1:3 olanzapine:water, while another includes solvates such as an isobutanol solvate. The olanzapine crystalline forms include Forms H, G, Y, X, K, S, Q, Z, and J.

Claims

1. Crystalline olanzapine sesquihydrate.

2. A crystalline form of olanzapine characterized by a powder X-ray diffraction pattern having peaks at about 9.1, 16.4, 18.5, 22.8, 23.8 and 24.3±

0.2 degrees two-theta.

3. The crystalline form according to claim 2, having additional peaks in the powder X-ray diffraction pattern at about 9.1, 16.4, 18.5, 22.8, 23.8 and 24.3±

0.2 degrees two-theta.

4. The crystalline form of olanzapine according to claim 3, having a powder X-ray diffraction pattern substantially as depicted in FIG. 4.

5. The crystalline form of olanzapine according to claim 2, which is a sesquihydrate.

6. A process for preparing the crystalline form according to claim 2 comprising the steps of:

a) dissolving olanzapine in an aqueous solution of HCl;

b) precipitating the crystalline form by adding base; and

c) isolating the crystals.

7. The process of claim 6, wherein olanzapine is dissolved by heating.

8. The process of claim 6, wherein the pH prior to step (c) is about 8.5.

9. The process of claim 6, further comprising cooling the solution prior to step (c).

10. Crystalline olanzapine ¾

hydrate.

11. A crystalline form of olanzapine characterized by a powder X-ray diffraction pattern having peaks at about 8.7, 14.7, 17.1, 17.8, 19.9, 21.0, 21.6, 22.3, 23.9, 25.3 and 26.5±

0.2 degrees two-theta.

12. The crystalline form according to claim 11, having additional peaks in the powder X-ray diffraction pattern at about 9.2, 9.4, 10.4, 11.5, 11.9, 12.5 and 29.7±

0.2 degrees two-theta.

13. The crystalline form of olanzapine according to claim 12, having a powder X-ray diffraction pattern substantially as depicted in FIG. 8.

14. The crystalline form of olanzapine according to claim 11, which is a ¾

hydrate.

15. A process for preparing the crystalline form according to claim 11 comprising the steps of heating Form J at a temperatures of at least about 100°

C.

16. The process of claim 15, wherein the heating temperature is about 130°

C.

17. A process for preparing the crystalline form according to claim 11 comprising exposing Form II at 100% relative humidity for a period of time ranging between 2 weeks and 2 months.

18. The process of claim 17, wherein the period of time is about 1 month.