FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
"A PROCESS FOR THE PREPARATION OF CRYSTALLINE OLANZAPINE FORM II"
Emcure Pharmaceuticals Limited.,
an Indian Company, registered under the Indian Company's Act 1957
and having its Registered Office at
Emcure House, T-184, M.I.D.C, Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of crystalline olanzapine form II. More specifically, the invention relates to a cost-effective process which provides crystalline olanzapine form EI and is represented by formula (I).

BACKGROUND OF THE INVENTION
Olanzapine of formula (I), chemically known as 2-methyl-4-(4-methyl-l-piperazinyl)-lOH-thieno [2,3-b][l,5]benzodiazepine, is useful for treating psychotic and mild anxiety state. Olanzapine and its acid addition salts, having pharmaceutical properties, particularly useful in treatment of disorders of the central nervous systems.
Various researchers have attempted to synthesize crystalline olanzapine form II of formula (I).
US 5,229,382 patent discloses a process for preparing olanzapine and its derivatives, and also their pharmaceutically acceptable salts but does not mention about any crystalline nature of olanzapine.
EP 0 733 635 Bl discloses crystalline form II and a process for its preparation by crystallization of olanzapine in ethyl acetate. The European patent also mentions on

page 2, paragraph [0002] that the method disclosed in US 5,229,382 patent produces crystalline olanzapine form I.
IN105/CHE/2003, describes a process for preparing crystalline olanzapine form II in an organic solvent from olanzapine dihydrate; the organic solvents includes acetone, ethyl acetate and acetonitrile. Further, Indian application also discloses a method to prepare form II utilizing form I by using precipitation method using acetonitrile as primary solvent and water, hexane or cyclohexane as anti solvents. Above method only discloses a process to convert form I, monohydrate or dihydrate of olanzapine to crystalline olanzapine form II.
Additionally, US 5,744,470; GB 2305860; WO 97/0033585 and WO 98/0046230 patents and patent applications discloses a 'method of use' of crystalline olanzapine form II for treatment of insomia, emesis, austism and cerebral focal ischemia in mammal respectively and a process for preparation of crystalline olanzapine form II from technical grade olanzapine by employing anhydrous ethyl acetate.
US 6,506,746 discloses a method of treating a human suffering from a cognitive dysfunction associated with Alzheimer's disease with crystalline form I (d space 10.25) and a process to prepare crystalline polymorph from organic solvents selected from acetone, tetrahydrofuran, ethyl acetate and t-butanol.
However, replication of the prior art method, resulted in an active pharmaceuticals ingredient which had lower chemical purity, yield and additionally with the formation of the associated solvates. Further, the solvents utilized in prior art for preparing form II, are not easily removed during drying. This results in organic volatile impurities in olanzapine, which ultimately reduces its purity. Regulatory authorities all over world are quite strict and have imposed stringent limits for the removal of such impurities. The present invention however, does not result in such impurities as a result of which the chemical purity is not affected.

Even though there are several methods to prepare crystalline olanzapine form II, there is need to develop an effective and efficient method, which is convenient, gives product of desired purity and easily implemented on an industrial scale.
OBJECTS OF THE INVENTION
An object of the present invention is to prepare crystalline olanzapine form II having the desired purity.
Another object of the present invention is to prepare crystalline olanzapine form II by using organic solvents which are cost-effective and easily evaporated during isolation of the final product.
SUMMARY OF THE INVENTION
The present invention is a novel process for the preparation of crystalline olanzapine form II, which comprising dissolving olanzapine in an organic solvent or mixture of solvents, in the presence of base, optionally adding a second organic solvent, heating and cooling to give crystalline olanzapine form II.
DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the present invention is to prepare crystalline olanzapine form II from olanzapine, which was prepared according to the method disclosed in WO 199846230Al.
Another embodiment of the present invention is to provide a process for the preparation of crystalline olanzapine form II, comprising of;
• dissolving olanzapine in a first organic solvent selected from the group comprising of nitro alkanes, alkyl carbonates, chlorinated hydrocarbons or mixture thereof, and a base at temperature between 25°C and 80°C.
• optionally adding a second organic solvent such as alkyl carbonates, chlorinated hydrocarbons, alcohols, water or mixture there off,
• optionally adding a base,
• cooling the reaction mixture to ambient temperature and filtering and drying the pure crystalline olanzapine form II.

It is pertinent to mention that the first organic solvent is selected from the group comprising, nitroalkanes such as nitromethane, nitroethane, nitropropane; alkyl carbonates such as dimethyl carbonates, diethyl carbonate and chlorinated hydrocarbons such as methylene chloride, ethylene chloride, etc...
The process for preparation of crystalline olanzapine form II is preferably carried out at temperature between 25°C and 80°C, more preferable between 45°C and 50°C.
A base selected from the group comprising of dimethylamine, triethylamine diisopropyl amine, is added and the resultant mixture is heated.
Further, the clear mixture thus obtained is either cooled gradually to separate out the desired form of olanzapine or a second organic solvent is optionally added.
The second organic solvent is selected from the group comprising of alkyl carbonates, such as dimethyl carbonates, diethyl carbonate; chlorinated hydrocarbons, such as methylene chloride, ethylene chloride; alcohols such as methanol, ethanol, propanol and also water.


It should be noted that prior art method result in the formation of olanzapine with associated impurities such as desmethyl olanzapine of formula (II) and olanzapine-N-oxide of formula (III). These impurities are not easily removed without affecting the yield and purity. Taking into account of the stringent limits of impurities in the drug substance, the present invention also has an inbuilt method to eliminate the impurities formed during the process of preparation of crystalline olanzapine form II by employing a base, which helps in removal of impurities of formula (II) and (III) during recrystallization.
In a further embodiment of the invention, a second organic solvent is optionally mixed with a base to eliminate the impurities formed in the preparation of crystalline olanzapine form II. The base is selected from organic amines preferably dimethylamine, triethylamine, diisopropyl amine, more preferably triemylamine and is mixed with a second organic solvent.
In a further embodiment of the invention, wherein the organic amine added is in the range of 4% to 15% volume per gram of olanzapine.
In a further embodiment of the invention, the olanzapine was dissolved in 3 to 15 volumes of first organic solvent per gram of olanzapine, but preferably between 4 and 5 volumes of organic solvent per gram of olanzapine.
In another embodiment of the invention, the ratio of the first organic solvent and second organic solvent is 5: 24 ratio.
The reaction mixture was cooled between 10°C and 35°C for 20 to 30 minutes and the solid obtained was filtered and washed with solvent.
The main embodiment of the invention is to provide an efficient, simple, method for the preparation of crystalline olanzapine form II, which can be characterized by XRD d-values. The XRD d-values (Table 1) of the crystalline olanzapine form II prepared

according to present invention is given in figure (1) and are comparable to the XRD d-values of form II of EP 0 733 653 Bl patent.
Table-l: XRD d values of crystalline olanzapine form II
d values
10.45
8.66
7.55
7.21
6.14
5.25
5.15
5.03
4.76
4.25
4.15
4.00
3.74
3.55
3.39
3.26
3.15
3.07
3.02
2.88
2.82
2.65
2.56
2.51
2.49
2.45

2.33
2.14
2.04 The principles, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention. The invention is further explained with the help of following illustrative examples, however, in no way these examples should be construed as limiting the scope of the invention.
EXAMPLES:
Example 1: Preparation of olanzapine form II (Dimethyl carbonate): Olanzapine (5gms; 0.016 moles) and dimethyl carbonate (25 ml) were heated to reflux temperature for 1 to 2 hours. After dissolution of the compound, the reaction mixture was cooled to 25°C-30°C. Finally, the obtained product was filtered and dried to give crystalline olanzapine form II. Yield: 4.5 gms and Purity: 99.7 %.
Example 2: Preparation of olanzapine form II (Nitro alkane):
Olanzapine (5gms; 0.016 moles) and nitro methane (25 ml) were heated to reflux temperature for 1 to 2 hours. After dissolution of compound, the reaction mixture was cooled to 25°C-30°C. Finally the product was filtered and dried to give crystalline olanzapine form II. Yield: 4.4 gms and Purity: 99.9 %.
Example 3: Preparation of olanzapine form II (Dimethyl carbonate and methylene
chloride):
Olanzapine (5gms; 0.016 moles), dichloromethane (25 ml) and triethylamine (0.22ml;
0.0016 moles) were heated to reflux temperature for 15 to 20 minutes; Dimethyl
carbonate (40 ml) and dichloromethane (80 ml) were added to the reaction mixture and
reflux for 15 to 20 minutes. After completion of reaction, dichloromethane was

partially distill and cooled to 25oC-30°C. The product was filtered and dried to give crystalline olanzapine form II. Yield: 4.5 gms and Purity: 99.7 %.
Example 4: Preparation of olanzapine form II (Dimethyl carbonate, methylene chloride and triethyl amine):
Olanzapine (5gms; 0.016 moles), dichloromethane {25 ml) and triemylamine (0.22ml; 0.0016 moles) were heated to reflux temperature for 15 to 20 minutes; Dimethyl carbonate (40 ml), dichloromethane (80 ml) and triethylamine (1ml) were added to the reaction mixture and refluxed for 15 to 20 minutes. After completion of reaction dichloromethane was partially distilled and cooled to 25°C-30°C. The product was filtered and dried to give crystalline olanzapine form II. Yield: 4.4 gms and Purity: 99.9 %.
Example 5: Preparation of olanzapine form II (Dimethyl carbonate, methylene chloride and water):
Olanzapine (5gms; 0.016 moles), dichloromethane (25 ml) and triethylamine (0.22ml; 0.0016 moles) were heated to reflux temperature for 15 to 20 minutes; Dimethyl carbonate (40 ml), dichloromethane (80 ml) and water (1ml) were added to the reaction mixture and refluxed for 15 to 20 minutes. After completion of reaction dichloromethane was partially distilled and cooled to 25°C-30°C. The product was filtered and dried to give crystalline olanzapine form II. Yield: 4.5 gms and Purity: 99.7 %.
Example 6: Preparation of olanzapine form II (Dimethyl carbonate and methanol): Olanzapine (5gms; 0.016 moles), dichloromethane (25 ml) and triethylamine (0.22ml; 0.0016 moles) were heated to reflux temperature for 15 to 20 minutes; Dimethyl carbonate (40 ml), methanol (80 ml) were added to the reaction mixture and refluxed for 15 to 20 minutes. After completion of reaction dichloromethane was partially distilled and cooled to 25°C-30°C. The product was filtered and dried to give crystalline olanzapine form II. Yield: 4.5 gms and Purity: 99.7 %.

Example 7: Preparation of olanzapine form II (Dimethyl carbonate, methanol and triethyl amine):
Olanzapine (5gms; 0.016 moles), dichloromethane (25 ml) and triethylamine (0.22ml; 0.0016 moles) were heated to reflux temperature for 15 to 20 minutes; Dimethyl carbonate (40 ml), methanol (80 ml) and triethylamine (1ml) were added to the reaction mixture and refluxed for 15 to 20 minutes. After completion of reaction dichloromethane was partially distilled and cooled to 25°C-30°C. The product was filtered and dried to give crystalline olanzapine form II. Yield: 4.6 gms and Purity: 99.7 %.
Example 8: Preparation of olanzapine form II (Dimethyl carbonate, methanol and water):
Olanzapine (5gms; 0.016 moles), dichloromethane (25 ml) and triethylamine (0.22ml; 0.0016 moles) were heated to reflux temperature for 15 to 20 minutes; Dimethyl carbonate (40 ml), methanol (80 ml) and water (1ml) were added to the reaction mixture and efflux for 15 to 20 minutes. After completion of reaction dichloromethane was partially distilled and cooled to 25°C-30°C. The product was filtered and dried to give crystalline olanzapine form II. Yield: 4.4 gms and Purity: 99.7 %.

We claim:
1. A process for crystalline olanzapine form II comprising of;
a) dissolving olanzapine in a first organic solvent selected from the group, nitro alkanes, alkyl carbonates, chlorinated hydrocarbons or mixture thereof and a base, at ambient to reflux temperature,
b) optionally adding a second organic solvent such as alkyl carbonates, chlorinated hydrocarbons, alcohols, water or mixture thereof,
c) optionally adding a base and
d) cooling the reaction mixture to ambient temperature, filtering and drying the pure crystalline olanzapine form II.

2. The process as claimed in claim I (a), wherein the nitro alkane is nitromethane, nitroethane, nitropropane; the alkyl carbonate is dimethyl carbonates, diethyl carbonate and the chlorinated hydrocarbon is methylene chloride, ethylene chloride or mixtures thereof.
3. The process as claimed in claim 1 (b), wherein the alkyl carbonate is dimethyl carbonate, diethyl carbonate; the chlorinated hydrocarbon is methylene chloride, ethylene chloride; and the alcohol is methanol, ethanol, propanol or mixtures thereof.
4. The process as claimed in claim 1, wherein the base is mixed with a second organic solvent.
5. The process as claimed in claim 1, wherein the base is triethylamine, diisopropyl amine.
6. The process as claimed in claim 1 (c), wherein the base added is in the range of 4% to 15% volume per gram of olanzapine.

7. The process as claimed in claim 1 (a), wherein the temperature is preferably in the range of 30°C to 80oC, more preferably 40°C to 50°C.
8. The process as claimed in claim 1 (a), wherein the volume of the first organic solvent is preferably in the range of 3 to 15 volumes per gram of olanzapine, preferably volume between 4 and 5 volumes per gram of olanzapine.
9. The process as claimed in claim 1, wherein the ratio of first solvent and second organic solvent is 5: 24 ratio.