FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
TITLE OF THE INVENTION:
NOVEL POLYMORPHIC FORM W OF OLANZAPINE AND PROCESS FOR THE PREPARATION THEREOF
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to novel polymorphic Form W of olanzapine and a process for the preparation thereof.
The following specification particularly describes the invention and the manner in which it is to be performed.

4. DESCRIPTION
The present invention provides a novel polymorphic Form W of olanzapine and a process for the preparation thereof.
Olanzapine of the formula I is chemically known as 2-Methyl-4-(4-methyl-1-piperazinyl)-1 OH-thieno [2,3-b][1,5]benzodiazepine. Olanzapine is indicated in the treatment of psychotic conditions including schizophrenia, schizophrenia-form diseases, and acute mania.
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U.S. Patent No. 5,229,382 disclosed olanzapine synthesis by condensation of thienobenzodiazepine(4-amino-2-methyl-10H-thieno-[2,3-b]-[1,5] benzodiazepine) and N-methylpiperazine in a mixture of toluene and dimethylsulfoxide, which are high boiling organic solvents.
U.S. Patent No. 6,906,062 disclosed Form I of olanzapine and process for the preparation thereof. U.S. Patent No. 5,736,541 discloses Form II of olanzapine having a specific X-ray diffraction pattern.
U.S. Patent No. 5,703,232 and European Patent No. 733,634 disclosed solvates of anhydrous olanzapine with methanol, ethanol and isopropanol.
U.S. Patent No. 6,348,458 disclosed form III, IV and V of olanzapine. U.S. Patent No. 6,020,487 discloses dihydrate forms B, D and E of olanzapine.
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U.S. Patent No. 6,740,753 disclosed Form X of olanzapine and process for preparation thereof.
U.S. Patent Application No. 2005/153954 discloses Form VI of olanzapine and process for preparation thereof.
PCT Patent Application WO 2002/18390 discloses monohydrate-l and dihydrate-I of olanzapine.
PCT Patent Application WO 2004/113346 discloses amorphous form of olanzapine and process for the preparation thereof.
Different polymorphic forms of olanzapine and process for their preparation are also disclosed in U.S. Patent Application Nos. 2004/0198721; 2004/0048854; 2005/0239772; 2005/0272720; 2006/0040920; 2007/0066602; 2007/0021605; 2007/007284 and PCT Patent Application Nos. 2004/056833; 2006/006185; 2006/025065; 2006/027800; 2006/030300.
The present inventors have developed an olanzapine in a novel polymorphic form referred as polymorphic form W that is stable, consistently reproducible and useful to make pharmaceutical compositions.
In one of the aspect of the present invention there is provided a novel polymorphic Form W of olanzapine.
In another aspect of the of the present invention there is provided a polymorphic Form W of olanzapine having a characteristic XRD pattern as depicted in Figure I.
In yet another aspect of the present invention there is provided a novel polymorphic Form W of olanzapine having a characteristic XRD pattern as
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depicted in Figure I with the 2 theta values at 8.38, 12.02, 13.40, 15.82, 16.84, 18.22, 19.72, 20.16, 21.28, 22.00, 22.96, 24.34, 25.64 ± 0.2° 29.
In yet another aspect of the present invention there is provided Form W of olanzapine having moisture content of about 2.0%w/w or less.
In yet another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of polymorphic Form W of olanzapine and one or more pharmaceutically acceptable carriers, excipients or diluents.
In yet another aspect there is provided a process for the preparation of polymorphic Form W of olanzapine, wherein the said process comprises of,
removing moisture from a solution of olanzapine ,
isolating polymorph Form W of olanzapine from reaction mass thereof.
Olanzapine dihydrate used as starting material can be prepared by the person skilled in the art through the teaching of U.S. Patent No. 5,229,382. Olanzapine dihydrate is dissolved in solvent capable to remove moisture such as dichloromethane, ethyl acetate, and toluene. The reaction mixture is stirred at room temperature to get clear solution. Partial removal of the solvent from the reaction mixture precipitates the product, which is further cooled to 5° C.
The product is filtered, washed and dried at room temperature to get crude olanzapine. Crude olanzapine is further treated with alcohol at reflux for about 1-2 hour. Allow the reaction mixture to cool at room temperature for 2-3 hours and stirrer for 6 to 10 hours. The obtained solid is filtered, washed and dried at room temperature to give Form W of olanzapine.
The alcohol may include on or more of methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol and the like. The moisture can be removed by drying under vacuum, dissolving or suspending olanzapine in a solvent capable of removing
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moisture by azeotropic distillation or by passing the solution of olanzapine through a bed of activated molecular sieves or variant thereof wherein the activated bed removes moisture. For removing moisture by azeotropic distillation methylene chloride can be employed or by using any solid drying agent.
Figure I depicts X-ray powder diffraction pattern of Form W of Olanzapine.
Powder XRD of the samples was determined by Rigaku X-Ray diffractometer model no. 2200-v Japan.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1: Preparation of Polymorph "W" of Olanzapine
Olanzapine dihydrate (20 gm) was dissolved in dichloromethane (250 ml) and stirred the reaction mixture at room temperature to get clear solution. Concentrated the solution under vacuum at 35-40° C until 1 to 2 times dichloromethane obtained as residual volume. The obtained solution was cooled to 5° C and stirred for one hour and solid obtained was filtered, washed with chilled dichloromethane and dried at room temperature to get crude olanzapine (17 gm). Crude olanzapine (5 gm) was taken in ethanol (50 ml) and reflux the mixture under stirring for about 1-2 hour. Allow the reaction mixture to cool at room temperature for 2-3 hours and stirrer it over night. The solid obtained was filtered, washed with chilled ethanol and dried at room temperature to get polymorph W of olanzapine. Yield: 3.75 gm Moisture Content: 2% w/w
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WE CLAIM:
1. Novel polymorphic form "W" of olanzapine.
2. Polymorphic Form W of olanzapine having a characteristic XRD pattern as depicted in Figure I.
3. Olanzapine of claim 1, having characteristics 2 theta values at 8.38,12.02, 13.40, 16.84, 18.22, 19.72, 20.16, 21.28, 22.00, 22.96, 24.34, 25.64 ± 0.2° 2θ.
4. A process for the preparation of Form W of olanzapine wherein the said process comprises of,

a) removing moisture from a solution of olanzapine ,
b) isolating polymorph Form W of olanzapine from reaction mass thereof.
5. A process of claim 4, wherein solvent for removing moisture is methylene
chloride.
6. A process of claim 4, wherein polymorph W is isolated by refluxing
olanzapine in alcohol which includes one or more of methanol, ethanol, n-
propanol, isopropyl alcohol, n-butanol.
7. Olanzapine Form W having moisture content of about 2.0% w/w or less.
8. A pharmaceutical composition comprising a therapeutically effective
amount of olanzapine polymorphic Form W, and one or more
pharmaceutical^ acceptable carriers, excipient or diluents.

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Abstract
The present invention provides a novel polymorphic Form 'W of olanzapine and a process for the preparation thereof.

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