FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
A PROCESS FOR PREPARATION OF VALACYCLOVIR
HYDROCHLORIDE IN NOVEL POLYMORPHIC FORMS.
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 a process for preparation of valacyclovir hydrochloride in novel polymorphic forms.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention relates to a process for preparation of valacyclovir hydrochloride in novel polymorphic forms.
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.


O CH3

.HC1

FORMULA I
US Patent No 4,957,924 provides process for preparation of valacyclovir or salt thereof. Several other processes are known in the art for preparation of valacyclovir such as US Patent No 6,849,737; US Application No 2005130993; US Application No 20050192296; US Application No 20050059684, US Application No 2005070711.
There are several polymorphic forms of valacyclovir known in the art through US Patent No 6,107,302 and US Patent No 6,849,736; US Application No 2005043329, US Application No 20040197396, US Application No 20050085491 and US Application No 2005187229; and PCT Patent Application WO 2004106338.
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The present inventors have found new polymorphic forms of valacyclovir hydrochloride. The polymorphs W-1 and W-2 are stable, consistently reproducible and it could be used to make pharmaceutical compositions.
In one of the aspect of the present invention there is provided a new polymorphic form W-1 of valacyclovir hydrochloride, wherein the said polymorph is stable, consistently reproducible and is used to make pharmaceutical compositions. The XRD of the polymorph W-1 showed 20 values of major peak intensity at 3.64, 7.28, 9.10,9.86, 10.90, 11.40, 12.46, 14.30, 14.56, 20.06, 21.88, 23.60, 25.60, 26.58, 27.78 ± 20.
In another aspect of the present invention there is provided a process for preparation of valacyclovir hydrochloride polymorph W-1, wherein the said process comprises of,
a) dissolving valacyclovir hydrochloride in water
b) adding a mixture of two or more organic solvents wherein one organic solvent comprises of an alkanol and other is selected from group comprising of methanol, acetone, butanol, isopropanol and tetrahydrofuran to solution of step a)
c) isolating the valacyclovir hydrochloride polymorph W-1 from the reaction mixture thereof.
In yet another aspect of the present invention there is provided a new polymorphic form W-2 of valacyclovir hydrochloride, wherein the said polymorph is stable, consistently reproducible and is used to make pharmaceutical compositions. The XRD of the polymorph W-2 showed 20 values of major peak intensity at 3.58, 7.14, 8.56, 9.06, 9.38, 9.82, 10.68, 13.16, 16.32, 26.58, 27.78 ± 0.2° 20.
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In yet another aspect of the present invention there is provided a process for preparation of valacyclovir hydrochloride polymorph W-2, wherein the said process comprises of,
a) dissolving valacyclovir hydrochloride in water
b) adding a mixture of two or more organic solvents wherein one organic solvent comprises of an alkanol and other is selected from group comprising of acetone and n-propanol to solution of step a)
c) isolating the valacyclovir hydrochloride polymorph W-2 from the reaction mixture thereof.
Valacyclovir hydrochloride used as starting material can be prepared by methods known in the art. It was dissolved in water by heating at 50-60°C. To this solution a mixture of two or more organic solvents wherein one organic solvent comprises of an alkanol and other is selected from group comprising of methanol, acetone, butanol, n-propanol, isopropanol and tetrahydrofuran was added and stirred. The reaction mixture was then cooled and the valacyclovir hydrochloride polymorphs W-1 and W-2 were isolated. Present inventors used a number of organic solvent mixtures as tabulated in Table-1 and Table-2 for isolating polymorphs W-1 and W-2 respectively.
Table-1

S. No Solvents (ratio) Yield(%)
01 Water (1) n-propanol (1) Methanol (4) 41
02 Water (1) Methanol (4) Acetone (1) 59
03 Water d) Methanol (4) n-butanol (D 51
04 Water (D Methanol (2) n-butanol (2) 68
05 Water (D Methanol (2) Isoprapanol (2) 47
06 Water (D Methanol (2) tetrahydrofuran (2) 68
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Table-2

S.No. Solvent ratio Yield(%)
01 Water 1 Methanol 1 Acetone 4 85
02 Water 1 Methanol 2 n-propanol 4 59
03 Water 1 Methanol 2 Acetone 2 70
The alkanol can be selected from the group comprising of straight chain and branched chain CrC4 alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol and the like.
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 Preparation of valacyclovir hydrochloride polymorph W-1 and W-2
Valacyclovir Hydrochloride (10 gm) was placed in 3 necked flask equipped with reflux condenser. Water (20ml) was added and the slurry heated to 60°C, till all Valacyclovir hydrochloride was dissolved. 80ml of organic solvent mixture as specified in Table-1 and Table-2 was added and further stirred for 15 minutes. Reaction mixture was allowed to cool gradually to 0-5°C and at this temperature the slurry stirred for 1 hour and filtered. The wet cake was dried at 60°C under vacuum for 5 hours.
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WE CLAIM
1. A new polymorphic form W-1 of valacyclovir hydrochloride.
2. A stable polymorphic form W-1 of valacyclovir hydrochloride as claimed in claim 1 having XRD as depicted in Figure 1.
3. A stable polymorphic form W-1 of valacyclovir hydrochloride having XRD of the 29 values of major peak intensity at 3.64, 7.28, 9.10,9.86, 10.90, 11.40, 12.46, 14.30, 14.56, 20.06, 21.88, 23.60, 25.60, 26.58, 27.78±29.
4. A process for preparation of valacyclovir hydrochloride polymorph W-1 wherein the said process comprises of,

a) dissolving valacyclovir hydrochloride in water
b) adding a mixture of two or more organic solvents wherein one organic solvent comprises of an alkanol and other is selected from group comprising of methanol, acetone, butanol, isopropanol and tetrahydrofuran to solution of step a)
c) isolating the valacyclovir hydrochloride polymorph W-1 from the reaction mixture thereof.

5. A new polymorphic form W-2 of valacyclovir hydrochloride.
6. A stable polymorphic form W-2 of valacyclovir hydrochloride as claimed in claim 5 having XRD as depicted in Figure 2.
7. A stable polymorphic form W-2 of valacyclovir hydrochloride having XRD of the 29 values of major peak intensity at 3.58, 7.14, 8.56, 9.06, 9.38, 9.82, 10.68, 13.16, 16.32, 26.58, 27.78 ± 0.2° 29
8. A process for preparation of valacyclovir hydrochloride polymorph W-2 wherein the said process comprises of,
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a) dissolving valacyclovir hydrochloride in water
b) adding a mixture of two or more organic solvents wherein one organic solvent comprises of an alkanol and other is selected from group comprising of acetone and n-propanol to solution of step a)
c) isolating the valacyclovir hydrochloride polymorph W-2 from the reaction mixture thereof.
9. A process as claimed in claim 4 and 8, wherein alkanol can be selected from the group comprising of straight chain and branched chain CrC4 alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutyl alcohol and the like.
10.A pharmaceutical compositions comprising therapeutically effective amount of polymorphic form W-1 and W-2 of valacyclovir hydrochloride along with pharmaceutically acceptable excipient.
Dated this 30th day of October, 2006 For Wockhardt Limited
(Mandar Kodgule) Authorized Signatory
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