Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-31
2002-02-19
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S557000
Reexamination Certificate
active
06348458
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel forms of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno-[2,3b][1,5] benzodiazepine (Formula A) also known as olanzapine. More specifically, the invention provides novel forms of solvate free olanzapine, methods for preparing the novel forms of olanzapine and pharmaceutical formulations containing the novel forms of olanzapine.
2. Background
As described in U.S. Pat. No. 5,736,541 (hereinafter “the '541 patent”), the synthesis of olanzapine according to the methods described in U.S. Pat. No. 5,229,382 produces a metastable, dull colored product referred to in the '541 patent as “Form I.” The '541 patent is herein incorporated by reference in its entirety. The '541 patent discloses and claims a more stable polymorphic form of olanzapine, designated as “Form II”, a method to produce “Form II” olanzapine, and pharmaceutical compositions containing “Form II” olanzapine. “Form I” and “Form II” olanzapine are characterized in the '541 patent by powder X-ray diffraction. The interplanar spacings (d-spacings) and typical relative intensities (I/I
1
) are reported.
U.S. Pat. No. 5,703,232 (hereinafter “the '232 patent”) claims lower alcohol solvates of olanzapine referred to in the '232 patent as “Form I” and methods for their preparation. The polymorph designated as “Form I” in the '232 patent has the same characteristic interplanar spacing by X-ray diffraction as “Form II” of the '541 patent and should thus be considered the same polymorph. Similarly, the polymorph designated as “Form II” in the '232 patent has the same characteristic interplanar spacing by X-ray diffraction as the polymorph designated as “Form I” in the '541 patent and should thus be considered the same polymorph. As used hereinafter the terms “Form I” and “Form II” refer to the olanzapine products designated as “Form I” and “Form II” in the '541 patent having the interplanar spacings and typical relative intensities shown in Table 1.
The present invention satisfies a need for additional stable, anhydrous and solvate-free polymorphic forms of olanzapine useful in the preparation of pharmaceutical formulations.
SUMMARY OF THE INVENTION
The present invention provides new polymorphic forms of 2-methyl-4-[4-methyl-1-piperazinyl]-10H-thieno[2,3b][1,5] benzodiazepine (olanzapine) designated as “Form III”, “Form IV” and “Form V”, methods of preparing the new polymorphic forms of olanzapine and pharmaceutical compositions containing them.
The invention produces new substantially pure polymorphs of olanzapine in high yield. The invention further differs from the prior art by requiring only aqueous solvents to prepare the stable polymorphs. The invention also provides an advantage over the prior art by isolating the new olanzapine polymorphs in a solvent free media, thus producing olanzapine free of solvates and having a negligible solvent content.
The invention provides three novel, solvate free forms of olanzapine designated Form III, Form IV and Form V. The novel forms of olanzapine are characterized by their unique x-ray diffraction patterns and infrared spectra.
The invention further provides a process for preparing the novel forms of olanzapine by first dissolving olanzapine in an aqueous organic or inorganic acid, which may be acetic acid, formic acid, hydrochloric acid, sulfuric acid, citric acid, fumaric acid or maleic acid; and is preferably hydrochloric acid, sulfuric acid, formic acid or acetic acid. The new form of olanzapine is then precipitated using an aqueous or alcoholic solution of alkali, which may be potassium hydroxide, sodium hydroxide or ammonia. The alcoholic solvent may be any mono, di, or polyhydric alcohol, preferably methanol. The olanzapines obtained typically contain less than 5% of other forms of olanzapine and less than 1% of other impurities. The desired form of olanzapine can be obtained by varying the acid or its concentration, and the temperature and pH of precipitation. The acid solution used in preparing the novel forms of olanzapine may contain between about 5% and about 50% acid. Olanzapine is preferably precipitated at a temperature between about 0° C. and about 100° C., more preferably between about 0° C. and about 35° C. and most preferably between about 10° C. and about 30° C. The final pH of the solution, after precipitation, is preferably between about 6 and about 12, and more preferably between about 8 and about 11.
The invention also provides pharmaceutical formulations containing as an active ingredient at least one of the novel forms of olanzapine according to the invention or a pharmaceutically acceptable salt thereof. The invention further provides a method of treating a psychotic condition, mild anxiety or gastrointestinal conditions by administering an effective amount of at least one of Form III, Form IV or Form V olanzapine or a pharmaceutically acceptable salt thereof to a patient.
The above objectives and advantages of the invention are illustrative, and not exhaustive, of those which can be achieved by the invention and the examples presented herein are non-limiting. Thus, these and other objectives and advantages of the invention will be apparent from the description herein, both as embodied herein and as modified in view of any variations which will be apparent to those skilled in the art.
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Hamied Yusuf K.
Kankan Rajendra N.
Rao Dharmaraj R.
Coleman Brenda
Haddaway Keith G.
Petruzzelli Julie
U & I Pharmaceuticals Ltd.
Venable
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