Field of Invention
The present invention relates to a process for the preparation of crystaUine form-II of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5] benzodiazepine and to a method of preparation there of. 2-Methyl-4-(4-methyl-1 -piperazinyl)-1 OH-thieno[2,3-b][l,5]benzodiazepine (Olanzapine) can be represented by Figure-I.

Olanzapine is useful for treating psychotic and mild anxiety states. Olanzapine and its acid addition salts, having pharmaceutical properties, particularly useful in treatment of disorders of the central nervous system. Background of Invention:
US 5,229,382 discloses the preparation of Olanzapine and its acid addition salts, having pharmaceutical properties, particularly in the treatment of disorders of the central nervous system and the patent does not refer to any specific polymorphic crystalline forms of Olanzapine.
EP 0 733 635 Bl claims Form-II of Olanzapine. The patent also states that the product obtained according to the process described in US 5,229,382 as Olanzapine Form-L

Furthennore, EP 0 733 635 Bl discloses the d values for Form-I and Form-II from their X-ray Diffractograms. The d values are as follows:
d value d value
Form-1 Form-2
9.94 10.26
8.55 8.57
8.24 7.47
6.88 7.12
6.37 6.14
6.24 6.07
5.58 5.48
5.30 5.21
4.98 5.12
4.83 4.98
4.72 4.76
4.62 4.71
4.53 4.47
4.46 4.33
4.29 4.22
4.23 4.14
4.08 3.98
3.82 3.72

3.74 3.56 3.69 3.53 3.58 3.38 3.50 3.25 3.33 3.12 3.28 3.08 3.21 3.06 3.11 3.01 3.05 2.87 2.94 2.81 2.81 2.72
2.74 2.64 2.65 2.60 2.63
2.59
US 6,348,458 Bl discloses the preparation of a series of crystalline polymorphic forms of Olanzapine namely Form-Ill, Form-IV and Form-V. The d values for these
forms from their X-Ray Diffractograms are also incorporated in the patent and are
mentioned in the following Table-1.


The main objective of the present invention is to prepare crystaUine Form-II of Olanzapine. The process of the present invention is simple, non-hazardous and easily scalable for commercial production.

Summary of the Invention
The present invention is directed to provide a novel process for the preparation of Form-II of Olanzapine. The present invention also embodies the novel process for the preparation of crystalline Form-II of Olanzapine, which comprises dissolving the Olanzapine monohydrate or Olanzapine dihydrate or Olanzapine Form-I in an organic solvent or solvents following by subsequent cooling and isolation to get desired polymorph Form-II of Olanzapine.
The process of the present invention is simple, eco friendly and well suited for industrial scale up.
Detailed Description of the Invention:
The main aspect of the present invention is to provide simple and novel process for the preparation crystalline Form-II of Olanzapine, which can be identified by X-ray powder diffraction. The XRD values of present invention are matched with the XRD values of form-II of EP 0 733 635 Bl.
Another embodiment of the present invention is to provide the process for the preparation of Form-II of Olanzapine, which comprises, a) dissolving the Olanzapine monohydrate or Olanzapine dihydrate or Olanzapine Form-I in an organic solvent(s) such as nitrile solvents such as acetonitrile, butyronitrile preferably acetonitrile, aromatic hydro carbons such as benzene, toluene, Xylene preferably toluene, halo solvents such as dichloromethane, chloroform, ethylene dichloride etc, ester solvents such as methyl acetate, ethyl acetate, butyl acetate preferably ethyl acetate, keto solvents such as acetone, methyl propyl ketone, methyl iso butyl ketone preferably acetone, alcohols such

as methanol, ethanol, isopropanol, n-butanol, 2-butanol etc or dissolving the Olanzapine Form-I in solvents such as ethyl acetate, acetonitrile, n-butanol, toluene, chloroform, dichloromethane etc and adding the dissolved solution to a solvent like water, hexane, cyclohexane, diethyl ether, heptane etc for separation, dissolving the Olanzapine Form-1 by acidification using Methane sulfonic acid, trifluoroacetic acid in a solvents selected from methanol, water or methanol and water mixture or a combination of above described solvents at ambient temperature or at hot condition or at reflux
b) optionally treating the dissolved solution with carbon
c) filtering the reaction solution to get particle free solution
d) cooling the reaction solution to get precipation or optionally adding the anti solvents such as n-hexane, n-heptane, isooctane, cyclohexane, water etc. or vice-versa for the separation of Olanzapine Form-II from reaction solution or adding organic bases like tri-butylamine, triethylamine, diisopropyl ethyl amine etc for making basification of the acidic solution.
e) isolating the desired Form-II of Olanzapine by conventional methods.
The present invention hence is directed to the preparation of crystalline Form-II of Olanzapine, which is simple and commercially viable process for its preparation. The present invention is illustrated by the following examples, which are not intended to limit the scope of the invention.

Examples:
Preparation of Olanzapine Form-II from Form-I.
Example-1.
Olanzapine Form-I (5.0 grams) was suspended in water (100.0 ml). Methane sulfonic
acid (3.5 gm) was added to the above reaction mass and observed the dissolution. The
reaction solution was filtered, basified with tryethylamine (5.0 ml) and stirred at 25 -
35*^C for 1 - 2 hours. The separated product was filtered, washed with water (50 0
ml) and dried to get crystalline Form-II of Olanzapine. (Yield: 3.8 grams, 76%).
Example-2.
Olanzapine Form-I (15.0 grams) was suspended in acetonitrile (225.0 ml). The
reaction mixture was heated to reflux to get a clear solution. Thus obtained solution
was filtered and the filtrate was divided in 3 equal portions, named as A, B and C for
convenient.
Portion A of the above filtrate was added to Water (40 ml) and stirred at 25-35 ° C for
1-2 hours the separation of the solid. The separated soHd was filtered, washed with
water (10.0 ml) and dried to afford crystalline Form-II of Olanzapine.
Portion B of the above filtrate was added n-Hexane (40 ml) and stirred at 25-35 ^ C
for 1-2 hours for the separation of the soUd. The separated solid was filtered, washed
with n-Hexane (5.0 ml) and dried to afford crystalline Form-II of Olanzapine.
Portion C of the above filtrate was added Cyclohexane (50 ml) and stirred at 25-35 °
C for 1-2 hours for the separation of the soUd. The separated sohd was filtered,
washed with cyclohexane (15.0 ml) and dried to afford crystalline Form-II of
Olanzapine.

Preparation of Olanzapine Form-II from Olanzapine monohydrate. £xample-3.
Olanzapine monohydrate (5.0 grams) was suspended in acetone (25.0 ml) and the reaction mixture was heated to reflux. The obtained reaction solution was treated with carbon (1.0 g) and filtered. The reaction solution thus obtained was stirred at 25 - 35^ C for the separation of the solid. The obtained solid was filtered, washed with acetone (5.0 ml) and dried to afford crystalline form-II of Olanzapine. (Yield: 2.8 grams, 56 %) Example-4.
Olanzapine monohydrate (5.0 grams) was suspended in Ethyl acetate (25.0 ml) and the reaction mixture was heated to reflux. The obtained reaction solution was treated with carbon (1.0 gram) and filtered. The reaction solution thus obtained was cooled to 25-35 ^ C followed by 0-5 ° C. The reaction mass was maintained at 0 - 5*^C for 30 -60 minutes to afford the sohd mass. The obtained solid mass was filtered, washed with ethyl acetate (5.0 ml) and dried to obtain crystalline form-II of Olanzapine. ExampIe-5.
Olanzapine monohydrate (20.0 grams) was suspended in Acetonitrile (260.0 ml) and the reaction mixture was heated to reflux. The reaction solution thus obtained was treated with carbon (2.0 grams) and filtered. The filtrate thus obtained was distilled to minimum volume and then cooled to 0-5 ° C to afford the solid mass. The obtained solid mass was filtered, washed with acetonitrile (10,0 ml) and dried to afford crystalline form-II of Olanzapine. (Yield: 13.0 grams, 65 %)

Preparation of Olanzapine Form-II from Olanzapine dihydrate. Example-6.
Olanzapine dihydrate (10.0 grams) was suspended in acetonitrile (130.0 ml) and the reaction mixture was heated to reflux. The obtained reaction solution was treated with carbon (1.0 grams) and filtered. The filtrate was distilled to a minimum volume and then cooled to 0-5 ° C. The reaction mass was stirred at 0-5*^ C for 30 - 60 minutes. The separated solid mass was filtered and dried afford crystalline form-II of Olanzapine. (Yield: 6.6 grams, 66%)
It is noteworthy to mention that Olanzapine monohydrate, Olanzapine dihydrate and Olanzapine Form-I, which are used in above processes can be prepared by the methods disclosed in WO 02/18390.
It is also important to mention that XRD values of Form-II obtained by above examples are matched with the characteristic XRD values of form-II of EP 0 733 635 Bl.

We Claim:
L A novel process for the preparation of Form-II form of 2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno[2,3-b][l,5] benzodiazepine (Olanzapine), which comprises of:
a) dissolving the Olanzapine monohydrate or Olanzapine dihydrate or Olanzapine Form-I in an organic solvent(s) such as nitrile solvents like acetonitrile, butyronitrile preferably acetonitrile, aromatic hydro carbons such as benzene, toluene, Xylene preferably toluene, halo solvents such as dichloromethane, chloroform, ethylene dichloride etc, ester solvents such as methyl acetate, ethyl acetate, butyl acetate preferably ethyl acetate, keto solvents such as acetone, methyl propyl ketone, methyl iso butyl ketone preferably acetone, alcohols such as methanol, ethanol, isopropanol, n-butanol, 2-butanol etc or dissolving the Olanzapine Form-I in solvents such as ethyl acetate, acetonitrile, n-butanol, toluene, chloroform, dichloromethane etc and adding the dissolved solution to a solvent like water, hexane, cyclohexane, diethyl ether, heptane etc for separation, dissolving the Olanzapine Form-1 by acidification using Methane sulfonic acid, trifluoroacetic acid in a solvents selected from methanol, water or methanol and water mixture or a combination of above described solvents at ambient temperature or at hot condition or at reflux
b) optionally treating the dissolved solution with carbon
c) filtering the reaction solution to get particle free solution
d) cooling the reaction solution to get precipation or optionally adding the anti solvents such as n-hexane, n-heptane, isooctane, Cyclohexane, diethyl ether, water etc. or

vice-versa for the separation of Olanzapine Form-II from reaction solution or adding organic bases like tri-butylamine, triethylamine, diisopropyl ethyl amine etc for making basification of the acidic solution, e) isolating the desired Form-II of Olanzapine by conventional methods.
2. The process as claimed in claim 1 of step (a), dissolving the Olanzapine monohydrate or Olanzapine dihydrate or Olanzapine Form-I in nitrile solvents like acetonitrile, butyronitrile preferably acetonitrile.
3. The process as claimed in claim 1 of step (a), dissolving the Olanzapine monohydrate or Olanzapine dihydrate or Olanzapine Form-I in aromatic hydro carbons such as benzene, toluene, Xylene preferably toluene.
4. The process as claimed in claim 1 of step (a), dissolving the Olanzapine monohydrate or Olanzapine dihydrate or Olanzapine Form-I in halo solvents such as dichloromethane, chloroform, ethylene dichloride etc.

5. The process as claimed in claim 1 of step (a), dissolving the Olanzapine monohydrate or Olanzapine dihydrate or Olanzapine Form-I in ester solvents such as methyl acetate, ethyl acetate, butyl acetate preferably ethyl acetate
6. The process as claimed in claim 1 of step (a), dissolving the Olanzapine monohydrate or Olanzapine dihydrate or Olanzapine Form-I in keto solvents such as acetone, methyl propyl ketone, methyl iso butyl ketone preferably acetone
7. The process as claimed in claim 1 of step (a), dissolving the Olanzapine monohydrate or Olanzapine dihydrate or Olanzapine Form-I in alcohols such as methanol, ethanol, isopropanol, n-butanol, 2-butanol etc.

8. The process as claimed in claim 1 of step (a), dissolving the Olanzapine Form-
I in solvents such as ethyl acetate, acetonitrile, n-butanol, toluene, chloroform,
dichloromethane etc.
9. The process as claimed in claim 1 of step (a), dissolving the Olanzapine by
acidification using methane sulfonic acid, trifluoroacetic acid in a solvent(s)
selected from methanol, water.
10. The process as claimed in claim 1 of step (a), dissolving the Olanzapine in a solvent or solvents at ambient condition or at hot condition ranging from 40^C to reflux temperature.
11. The process as claimed in claim 1 of step (a), where in dissolving the Olanzapine in a solvent or solvents mixture selected from any of the mentioned solvents in step(a) of claim 1.

12. The process as claimed in claim 1 of step (d ), optionally adding the anti solvents such as n-hexane, n-heptane, isooctane, Cyclohexane, di ethyl ether, water etc. for the separation of Olanzapine Form-II from reaction solution
13. The process as claimed in claim 1 of step (d ), adding the organic bases such as tri-butylamine, triethylamine, diisopropyl ethyl amine etc for the separation of Olanzapine Form-II from reaction solution.
14. The process for the prepm^ation of crystalline Form-II of Olanzapine as herein
described with particular reference to examples.