Olanzapine dihydrate D

Details Olanzapine dihydrate D Olanzapine dihydrate D

1997-09-23

2001-06-26

Webman, Edward J. (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S557000

Reexamination Certificate

active

06251895

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the crystalline dihydrate D of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (referred to herein as “olanzapine”). The invention more specifically relates to a novel crystalline form which is particularly useful for preparing an aqueous olanzapine formulation.
BACKGROUND OF THE INVENTION
The stable crystalline Dihydrate D is particularly important for the commercial development of new formulations of the pharmaceutically active olanzapine. Olanzapine is useful for treating psychotic patients. Often an aqueous formulation or a formulation that is prepared using aqueous mixing is desired. Applicants have discovered that Form II olanzapine is the most stable anhydrous form of olanzapine, providing a stable anhydrous formulation with pharmaceutically desired characteristics. However, a stable dihydrate was desired to provide pharmaceutically elegant aqueous formulations.
A novel dihydrate crystal form of olanzapine has now been synthesized and characterized which possesses distinct advantages over the previously known forms, that is the material produced using the methods described in U.S. Pat. No. 5,299,382 (hereinafter referred to as “the '382 patent”), when aqueous formulations or a stable aqueous intermediate is desired. This novel dihydrate crystal form is clearly distinguishable therefrom by x-ray powder diffractometry. U.S. Pat. No. 5,229,382 is hereby incorporated by reference in its entirety.
Applicants have discovered that Dihydrate D olanzapine is essential to assure a pharmaceutically elegant, aqueous formulation. Applicants have found that olanzapine forms a Dihydrate B; however, this form appears to be quite unstable compared to Dihydrate D. Dihydrate D requires controlled conditions to prepare the substantially pure Dihydrate D material; however, once prepared, the Dihydrate D is surprisingly robust and stable. Therefore, Dihydrate D olanzapine is most desired and appears to be essential for use in preparing consistently stable commercial pharmaceutically elegant aqueous olanzapine formulations as well as for pharmaceutically elegant formulations prepared using extensive aqueous mixing.
SUMMARY OF THE INVENTION
The presently claimed invention provides the stable crystalline Dihydrate D olanzapine polymorph (herein referred to as “Dihydrate D”) having a typical x-ray powder diffraction pattern as represented by the following interplanar spacings (d) as set forth in Table 1:
TABLE 1
d
9.4511
7.7098
7.4482
6.9807
6.5252
5.7076
5.5539
5.223
4.9803
4.8908
4.784
4.6947
4.4271
4.3956
4.3492
4.2834
4.1156
3.7837
3.7118
3.5757
3.482
3.3758
3.3274
3.2413
3.1879
3.135
3.0979
3.016
2.9637
2.907
2.8256
2.7914
2.7317
2.6732
2.5863
The x-ray powder diffraction patterns set forth herein were obtained with a copper k of wavelength=1.541 Å. The interplanar spacings in the column marked “d” are reported in Angstroms. The detector was a Kevex silicon lithium solid state detector.
The present invention further provides an aqueous formulation comprising Dihydrate D as an active ingredient with one or more carriers or diluents therefor.


REFERENCES:
patent: 5229382 (1993-07-01), Chakrabarti et al.
patent: 5302716 (1994-04-01), Berger et al.
patent: 5631250 (1997-05-01), Bunnell et al.
patent: 5736541 (1998-04-01), Bunnell et al.
patent: 0 454 436 (1991-10-01), None
patent: 0 582 368 (1994-02-01), None
patent: 0 733 634 (1996-09-01), None
patent: 0 766 635 (1996-09-01), None
patent: 0 733 368 (1996-09-01), None

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