FORM 2
THE PATENT ACT 1970
(39 of 1970)
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
A PROCESS FOR REDUCING RESIDUAL ALCOHOL CONTENT IN SOLID
VALACYCLOVIR HYDROCHLORIDE
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 provides a process for reducing residual alcoholcontent in solid valacyclovir hydrochloride. The invention further provides avalacyclovir hydrochloride having less than 1000 ppm of ethanol.
The following specification particularly describes the invention and theManner in which it is to be performed.

4. DESCRIPTION
The present invention provides a process for reducing residual alcohol content in solid valacyclovir hydrochloride. The invention further provides a valacyclovir hydrochloride having less than 1000 ppm of ethanol.
Valacyclovir is chemically, L-valyl ester of acyclovir designated as 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl L-valyl ester. It is commercially available in form of its hydrochloride salt (Formula I) as Valtrex® Tablets. Valacyclovir hydrochloride is indicated for the treatment of Herpes Zoster, Genital Herpes and Herpes labialis.

U.S. Patent No 4,957,924 provides process for preparation of valacyclovir or salt thereof wherein the process involves condensation of acyclovir with N-benzyloxycarbonyl-L-valine.
Several other processes are known in the art for preparation of valacyclovir such as U.S. Patent No 6,849,737; U.S. patent application No. 2005130993; U.S. patent application No 20050192296; U.S. patent application No 20050059684, U.S. patent application No 2005070711, U.S. patent application No 2007021444, PCT patent application Nos. WO 2006011874, WO 2006035452 and WO 2007013645.
There are several polymorphic forms of valacyclovir or its salt known in the art through U.S. Patent No 6,107,302 and U.S. Patent No 6,849,736; U.S. patent application No 2005043329, U.S. patent application No 20040197396, U.S.
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patent application No 20050085491 and U.S. patent application No 2005187229; and PCT Patent application WO 2004106338.
Although some residual process solvent in an API or drug product may be an unavoidable consequence of the manufacturing process, the level of residual process solvent should be reduced to a minimum. Clearly, methods for reducing excess process solvents like alcohols in valacyclovir hydrochloride to a level less than 5000 ppm are needed.
The present inventors have now developed an easy process for reducing residual alcohol content in solid valacyclovir hydrochloride. The present inventors have surprisingly found that when valacyclovir hydrochloride having the excess residual process alcohol content is evenly sprayed with water (12-15%) and subsequently dried at 65-70°C, then solid valacyclovir hydrochloride almost free from residual alcohol solvent is obtained. The process of present invention is simple and industrially advantageous.
Excess residual process solvent in valacyclovir hydrochloride is defined in relation to the concentration limits set for class 3 solvents by the ICH Guidelines. Accordingly, excess residual process alcohol in valacyclovir hydrochloride refers to process alcohol, especially ethanol and iso-propanol, in excess of 5000 ppm on a weight basis. Valacyclovir hydrochloride having excess residual process alcohol refers to valacyclovir hydrochloride having 5000 ppm or more, on a weight basis, residual process alcohol. Valacyclovir hydrochloride having excess residual process alcohol is a preferred starting material for use in the practice of the method of the present invention.
Similarly, valacyclovir hydrochloride almost free from residual alcohol solvent refers to solid valacyclovir hydrochloride having the alcohol content of 1000 ppm or less.
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In one of the aspect of the present invention there is provided a process for reducing residual alcohol content in solid valacyclovir hydrochloride, which includes the steps of,
a) evenly spraying the water (12-15%) over valacyclovir hydrochloride having the excess residual alcohol content
b) isolating the solid valacyclovir hydrochloride almost free from residual alcohol solvent from the reaction mass thereof.
In another aspect of present invention there is provided solid valacyclovir hydrochloride having the ethanol content of 1000 ppm or less.
In yet another aspect of the present invention there is provided a pharmaceutical composition comprising a solid valacyclovir hydrochloride having the ethanol content of 1000 ppm or less and one or more pharmaceutically acceptable excipients.
The starting material Z-Valacyclovir (CBZ-valacyclovir) may be obtained by any process known in the art for example as reported in U.S. patent No. 4,957,924.
Z-valacyclovir was deprotected under hydrogen pressure by using a catalyst such as palladium on carbon in an alcohol such as methanol, ethanol, iso-propanol and the like. To this reaction mixture hydrochloric acid was added. On completion of reaction, the reaction mixture was filtered. The filtrate was concentrated to yield a thick white residue. To the obtained residue were added sufficient water at a temperature of 50-60°C. To this, process alcohol such as ethanol was added and heated to get a clear solution.
The reaction mass was then cooled to 0 to -5°C and filtered. The wet cake obtained is dried under vacuum at 65-70°C to get the valacyclovir hydrochloride having the residual process alcohol content of 10,000 to 30,000 ppm.
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The valacyclovir hydrochloride obtained thereof was evenly sprayed with water (12-15%) and further dried at 65-70°C to obtain solid valacyclovir hydrochloride having a residual process alcohol content of 1000 ppm or less.
The present invention is further illustrated by the following example which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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
A mixture of Z-Valacyclovir (10.0 kg), 5% palladium on carbon (1 kg, 50% wet) 2.5 N hydrochloric acid (10 liters) in methanol (100 liters) was stirred for 4-5 hours under hydrogen atmosphere at 50 psi. On completion of reaction, the reaction mixture was filtered. The filtrate was concentrated. To the residue obtained, water (20 Liters) was added and filtered at 55-60°C. To the filtrate ethanol (80 Liters) was added and heated to get a clear solution.
The reaction mixture was then cooled to 0 to -5°C and filtered. The wet cake obtained was dried under vacuum at 65-70°C. After 10 hours of drying the product (having the ethanol content of 10,000 to 30,000 ppm) was evenly sprayed with water (12-15%) and further dried to obtain solid valacyclovir hydrochloride having a residual ethanol content of 1000 ppm or less.
Yield = 4.2 kg
Purity by HPLC = 98.69%
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WE CLAIM:
1. A process for reducing residual alcohol content in solid valacyclovir
hydrochloride, which includes the steps of,
a) evenly spraying the water (12-15%) over valacyclovir hydrochloride having the excess residual alcohol content
b) isolating the solid valacyclovir hydrochloride almost free from residual alcohol solvent from the reaction mass thereof.

2. A process of claim 1, valacyclovir hydrochloride having excess residual alcohol is valacyclovir hydrochloride having 5000 ppm or more, on a weight basis, residual alcohol.
3. A process of claim 1, wherein the isolation involves drying of valacyclovir hydrochloride at 65-70°C.
4. A process of claim 1, wherein the alcohol is selected from the group of methanol, ethanol, iso-propanol and the like.
5. A process of claim 1, wherein the solid valacyclovir hydrochloride almost free from residual alcohol is valacyclovir hydrochloride having residual alcohol content of 1000 ppm or less.
6. A process of claim 5, wherein solid valacyclovir hydrochloride having the residual ethanol content of 1000 ppm or less.
7. A process of claim 6, a pharmaceutical composition comprising solid valacyclovir hydrochloride having the ethanol content of 1000 ppm or less and one or more pharmaceutically acceptable excipients.

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ABSTRACT
The present invention provides a process for reducing residual alcohol content in solid valacyclovir hydrochloride. The invention further provides a valacyclovir hydrochloride having less than 1000 ppm of ethanol.
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