FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - "A PROCESS FOR PURIFICATION OF VALSARTAN"
2. Applicant(s)
(a) NAME : ALEMBIC LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.


FIELD OF INVENTION
The present invention relates to a process for purification of Valsartan of formula (I).
BACKGROUND OF THE INVENTION
Valsartan is chemically known as (S)-N-(1-Carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine, having formula C24H29N5O3 and molecular weight 435.52. The current pharmaceutical product containing this drug is being sold by Novartis using the tradename Diovan in the form of tablets.
Valsartan belongs to group of angiotensin II antagonists which are useful in the treatment of hypertension, anxiety, glaucoma and cardiac attacks. Valsartan is an orally active specific angiotensin II antagonist acting on the AT1 receptor subtype. It is useful in regulating high blood pressure and cardiac insufficiency.
Valsartan is first disclosed in US Patent No. 5,399,578 which also discusses its process for preparation. The final product is recrystallized from ethyl acetate. Another example in same patent recites recrystallization from diisopropyl ether. However these processes for purification do not give Valsartan with high purity.
Journal of Labelled Compounds and Radiopharmaceuticals 2000, 43, 1245-1252 reports recrystallization of Valsartan a (1:1) mixture of ethyl acetate-hexane. However, it does not provide any enabling disclosure with respect to the crystallization i.e. crystallization by precipitation or slurrying or any the process. Moreover it also remains silent about the resultant form of Valsartan.

US application no. 20050059827 describes a process for preparing Valsartan containing less than bout 5000ppm residual solvent comprising triturating the Valsartan containing less than 10% organic solvent in water or with humid air in a fiuidized bed drier. However, in this process the drying of the final product which is obtained from aqueous suspension takes longer time.
The content of residual solvent in the final product is always a cause of concern with respect to Food and Drug Authorities (FDA) requirement. Therefore, it is required to have the solvent content well below the level specified in the International Conference on Harmonization (ICH) guideline as per regulatory authority. The present inventors have observed that the purification according to the process mentioned in the prior art provides Valsartan with high content of solvent.
It is therefore, a need to develop a process for purification of Valsartan which results in high purity with less amount of residual solvent content preferably well below the level as per the ICH guideline for FDA requirement without any quantitative yield loss.
Therefore, present inventors have directed their research work towards developing a process for purification of Valsartan of high purity i.e. contains residual solvent less than the specified limit as given in ICH guideline. Unexpectedly, the present inventors have found out that if the crude Valsartan crystallized from an organic solvent is washed with aliphatic hydrocarbon solvent and then dried, it reduces the residual solvent level well below as per the FDA requirement. Further, the time taken for drying can also be reduced from several days to several hours.
OBJECT OF THE INVENTION
The primary object of the present invention is to provide a process for purification of Valsartan.
Another object of the present invention is to provide process for preparation of Valsartan in high purity.

Yet another object of the present invention is to provide a process for preparation of Valsartan having purity more than 99%.
Another object of the present invention is to provide a process for purification of Valsartan in without any quantitative yield loss.
Yet another object of the present invention is to provide Valsartan having residual solvent content below the level as per the International Conference on Harmonization (ICH) guideline.
SUMMARY OF THE INVENTION
Accordingly present invention provides process for purification of Valsartan to obtain valsartan of at least 99% purity, said process comprising steps of: (i) crystallizing from an organic solvent
(ii) washing the crystallized product obtained in step (i) with a solvent selected from a group consisting of aliphatic hydrocarbon solvent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for purification of Valsartan to obtain valsartan of at least 99% purity, said process comprising steps of: (i) crystallizing from an organic solvent
(ii) washing the crystallized product obtained in step (i) with a solvent selected from a group consisting of aliphatic hydrocarbon solvent.
The crude Valsartan is dissolved in an organic solvent at elevated temperature preferably at 40°C to 60°C. The product is crystallized from the solution either by reducing the volume of the solvent or cooling the solution or both. The cooling temperature ranges from about 0°C to about 5°C. The precipitate formed is isolated by conventional method such as filtration, decantation or centrifugation. The solid is washed with aliphatic hydrocarbon solvent. The product obtained after washing with aliphatic hydrocarbon solvent i.e. n-pentane is in amorphous form.

The example of organic solvent comprises ester, ketone, ether, nitrite, alcohol, chlorinated solvent and the like or mixture thereof.
The example of organic solvent include but not limited to ethylacetate, acetone, diisopropylether, acetonitrile, methanol, ethanol, propanol, chloroform, dichloromethane, dichloroethane and the like or mixture thereof.
The term "crystallization" refers to any method known to a person skilled in the art such as crystallization from single solvent or combination of solvents by dissolving the compound optionally at elevated temperature and precipitating the compound by cooling the solution or removing solvent from the solution or both. It further includes methods such as solvent/antisolvent or precipitation.
The examples of aliphatic hydrocarbon solvent include but are not limited to n-pentane, n-heptane, hexane, cyclohexane, octane and the like or mixture thereof.
It has been observed by the present inventors that the process for the purification of Valsartan as mentioned hereinabove yields Valsartan having purity of more than 99% and having residual ethyl acetate content within expectable limits of regulatory authorities.
The comparison data obtained for the final product before and after washing with the n-pentane with respect to residual ethyl acetate content is given in the table below.
Residual content of ethyl acetate in Valsartan before aliphatic hydrocarbon wash:


However, as per International Conference on Harmonization (ICH) guidelines the content of Organic Volatile Impurity (OVI) in the final product should be less than SOOOppm. Therefore, the present inventors did several experiments in order to meet the OVI limit. Following are the data obtained in the experiments.
Residual content of ethyl acetate in Valsartan after aliphatic hydrocarbon wash:

Ethylacetate, methylacetate, propylacetate, heptane, pentane, acetone, methylethylketone, tetrahydrofuaran comes under Class 3 category of solvents. Class 3 solvent content in a product is restricted up to 5000ppm as per the ICH guideline.
The process of the present invention is described by the following example, which are which are illustrative purpose only and should not be construed so as to limit the scope of the invention in any manner.
Example 1 Preparation of amorphous form of Valsartan
Valsartan Calcium (120 gm) was suspended in a mixture of Dl water (700 ml) and ethyl acetate (1000 ml) and treated with hydrochloric acid to adjust pH 1.5-2.5. The organic layer was separated and washed with water and concentrated to a solid residue material. Ethyl acetate (600 ml) was added to the residue and heated to get clear solution. The solution was cooled slowly under stirring to 0-5°C to get thick slurry. The solid is filtered. The wet solid was transferred to another RB Flask and n-Pentane (840ml) was added and stirred. The reaction

mass was filtered, washed with n-pentane and dried at 50-55°C to get the pure Valsartan. The residual ethyl acetate is well below of the ICH limit of 5000 ppm. Purity by HPLC * 99.4%

WE CLAIM:
1. A process for purification of Valsartan to obtain valsartan of at least 99%
purity, said process comprising steps of:
i) crystallizing from an organic solvent
ii) washing the crystallized product obtained in step (i) with a
solvent selected from a group consisting of aliphatic
hydrocarbon solvent.
2. A process of claim 1, wherein said organic solvent in step (i) is selected from a group comprising ester, ketone, ether, nitrile, alcohol, chlorinated solvent or mixture thereof.
3. A process of claim 2, wherein said organic solvent is selected from ethylacetate, acetone, diisopropylether, acetonitrile, methanol, ethanol, propanol, chloroform, dichloromethane, dichloroethane or mixture thereof.
4. A process of claim 1, wherein said aliphatic hydrocarbon solvent in step (ii) is selected from a group comprising n-pentane, n-heptane, hexane, cyclohexane, octane or mixture thereof.
5. A process for purification of Valsartan comprising a step of washing of Valsartan with a solvent selected from a group consisting of aliphatic hydrocarbon solvent.
6. A process of claim 5, wherein said aliphatic hydrocarbon solvent is selected from a group comprising n-pentane, n-heptane, hexane, cyclohexane, octane or mixture thereof.
Dated this 17th day of January 2007