This application claims priority to Indian patent application No. 2697/CHE/2008 filed on November 04, 2008, the contents of which are incorporated by reference in their entirety,

FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation of stable and pure amorphous valganciclovir hydrochloride.

BACKGROUND OF THE INVENTION

Valcyte (Valganciclovir HC1 tablets) contains Valganciclovir Hydrochloride, a hydrochloride salt of the L-valyl ester of ganciclovir that exist as a mixture of two diastereomers. Valganciclovir hydrochloride is a white to off-white crystalline powder with a molecular formula of CwHizNtOs.HCL The chemical name for Valganciclovir hydrochloride is L-valine, 2-(2-amino-1, 6-dihydro-6-oxo-purin-9-yl)-methoxy-3-hydroxy-1-propanyl ester monohydrochloride. Valganciclovir hydrochloride is a polar hydrophilic compound. The chemical structure of Valganciclovir hydrochloride having the formula (1)

European patent No. 375329 discloses ester prodrugs of Ganciclovir i.e. Valganciclovir and its physiologically acceptable salts thereof, having advantageous bioavailability when administered by an oral route.

US 2007/0129385A1 discloses the process for the preparation of an amorphous valganciclovir hydrochloride by using spray drying technique or azeotropic distillation of reaction mass. This application also discloses the conversion of crystalline or mixture of crystalline and amorphous in to amorphous Valganciclovir hydrochloride. According to this application spray drying technique, azeotropic distillation is used for the preparation of an amorphous Valganciclovir hydrochloride.

Amorphous Valganciclovir hydrochloride obtained by the prior art processes does not have the stability and it is converting into crystalline form over a period of time.

Therefore, there is a need to develop a process for stable and pure amorphous Valganciclovir hydrochloride.

The present invention relates to a novel process for preparing the stable amorphous valganciclovir hydrochloride, which is stable at various conditions,

OBJECT OF THE INVENTION

The object of the present invention relates to a novel process for the preparation of stable and pure amorphous valganciclovir hydrochloride using a stabilizer.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig, 1 is an X-ray powder diffraction (XRD) pattern of stable amorphous Valganciclovir hydrochloride,

SUMMARY OF THE INVENTION

The main aspect of the present invention is to provide a novel process for the preparation of stable amorphous valganciclovir hydrochloride by using a stabilizer such as poly vinylpyrrolidone (PVP), hydroxypropyl cellulose (HPQ, hydroxypropyl methyl cellulose (HPMC) and amberlite.

DETAILED DESCRIPTION OF THE INVENTION

The term 'residue* in the present invention, refers to a gummy mass, a non-crystalline solid, pasty or sticky material

The present invention relates to novel process for the preparation of stable amorphous valganciclovir hydrochloride, wherein, protected valganciclovir is subjected to hydrogenation in presence of catalyst and solvent under hydrogen pressure followed by adding stabilizer and isolating stable amorphous valganciclovir hydrochloride.

In one embodiment, the present invention relates to the process for the preparation of stable amorphous valganciclovir hydrochloride comprising the steps of:

a) dissolving protected valganciclovir in a solvent,

b) deprotecting the protected valganciclovir by hydrogenation in the presence of catalyst and aqueous hydrochloride,

c) removing the solvent to get valganciclovir hydrochloride residue,

d) dissolving the residue in a mixture of solvents,

e) adding stabilizer, and

f) isolating stable amorphous Valganciclovir hydrochloride.

According to present invention, protected valganciclovir is dissolved in solvent selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol or mixtures thereof and hydrogenated by spurging hydrogen gas in presence of HC1 using a catalyst such as palladium on carbon. Filtering the catalyst and removing the solvent forms a residue which is dissolved in a mixture of solvents such as water and methanol and added with a stabilizer such as polyvinylpyrrolidone (PVP) followed by distilling the solvent leaves a solid. The solid thus obtained is dissolved in organic solvents such as mixture of ethyl acetate and cyclohexane and removed the solvent by distillation under vacuum to afford pure and stable amorphous valganciclovir hydrochloride.

According to the present invention, the suitable stabilizer that can be used in the present invention includes polyvinylpyrrolidone (PVP) of grade K-30, K-90, K-12, Hydroxy propyl cellulose (HPC), Hydroxpropyl methyl cellulose (HPMC) and amberlite.

In another embodiment, the present invention relates to the process for the preparation of stable amorphous valganciclovir hydrochloride comprising the steps of:

a) dissolving Valganciclovir hydrochloride with an alcoholic solvent,

b) adding a stabilizer,

c) removing the alcoholic solvent to get valganciclovir hydrochloride residue,

d) dissolving the residue in a mixture of solvents, and

e) isolating stable amorphous Valganciclovir hydrochloride.

According to present invention, Valganciclovir hydrochloride is dissolved in an alcoholic solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol or their mixtures thereof and treated with stabilizer followed by removal of solvent. The residual residue is dissolved in a mixture of solvents such as esters selected from ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and hydrocarbons selected from cyclohexane, toluene, xylene, n-hexane, n-heptane or mixtures thereof. Removing the solvent using conventional techniques like freeze drying or distillation affords stable and pure amorphous valganciclovir hydrochloride.

In yet another embodiment, the present invention relates to the process for the preparation of stable amorphous valganciclovir hydrochloride comprising the steps of:

a) dissolving valganciclovir hydrochloride in water,

b) adding polyvinylpyrrolidone,

c) removing water using freeze drier, and

d) isolating pure Valganciclovir hydrochloride.

According to the present invention, Valganciclovir hydrochloride is dissolved in water followed by treatment with stabilizer such as polyvinylpyrrolidone. Removing water by techniques such as freeze drying affords stable and pure amorphous valganciclovir hydrochloride.

The following non-limiting examples illustrate specific embodiments of the present invention. They should not construe it as limiting the scope of present invention in anyway.

Example 1:

Protected valganciclovir (10g) was dissolved in methanol (130ml) and hydrogenated by spurging hydrogen gas in presence of cone. HC1 (30ml) in presence of 5% palladium on carbon (0.5gm). The reaction mass is treated with the gas for 3 to 12 hrs at 20°C to 40°C.

After completion of the reaction, the catalyst was removed by filtration. To the filtrate was added methanol (20ml). The filtrate was concentrated under vacuum to give residue.

To the residue water (20 ml), methanol (70 ml) and polyvinylpyrrolidone (10 g) was added and stirred the reaction mass till the completion of the reaction. Methanol was distilled under vacuum below 50°C to give solid. To the solid was added ethyl acetate (10ml) & cyclohexane (10ml) and removed by distillation under vacuum. The solid product was dried under vacuum below 85°C to afford pure amorphous 2-(2-amino-1,6-dihydro-6-oxo-purin-9-y l)-methoxy-3 -hydroxy-1 -propy 1-L-valinate hydrochloride.

Example 2:
Valganciclovir hydrochloride (10g) was dissolved in methanol (200ml) and added (10 g) polyvinylpyrrolidone. The reaction mixture was stirred at room temperature for 10 min to get clear solution. Methanol was distilled under vacuum below 50°C. To the residue, ethyl acetate (10ml) & cyclohexane (10ml) was added, stir the reaction mixture and filter the reaction mixture. The solid product was dry under vacuum below 85°C to get pure amorphous Valganciclovir hydrochloride.

Example 3:
Valganciclovir hydrochloride (5g) was dissolved in water (200ml) and added (20 g) polyvinylpyrrolidone. The reaction mixture was stirred at room temperature to get clear solution. The resulting solution was filtered through hiflow bed to remove the undissolved particulate. The resulting clear solution was freeze dried. The solid obtained was identified as stable amorphous form of Valganciclovir hydrochloride.

We claim

1. A process for the preparation of stable amorphous valganciclovir hydrochloride
comprising the steps of:

a) dissolving protected valganciclovir in a solvent,

b) deprotecting the protected valganciclovir by hydrogenation in the presence of catalyst and aqueous hydrochloride,

c) removing the solvent to get valganciclovir hydrochloride residue,

d) dissolving the residue in a mixture of solvents,

e) adding stabilizer, and

f) isolating stable amorphous Valganciclovir hydrochloride.

2. The process according to claim 1, wherein the solvent is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol or mixtures thereof

3. The process according to claim 1, wherein the hydrogenation is done by spurging hydrogen gas in presence of HCl and a catalyst

4. The process according to claim 3, wherein the catalyst is palladium on carbon.

5. A process for the preparation of stable amorphous valganciclovir hydrochloride comprising the steps of:

a) dissolving Valganciclovir hydrochloride with an alcoholic solvent,

b) adding a stabilizer,

c) removing the alcoholic solvent to get valganciclovir hydrochloride residue,

d) dissolving the residue in a mixture of solvents, and

e) isolating stable amorphous Valganciclovir hydrochloride.

6. The process according to claim 5, wherein the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol or their mixtures thereof.

7. The process according to claim 1 or 5, wherein the residue is dissolved in mixture of solvents selected from esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and hydrocarbons selected from cyclohexane, toluene, xylene, n-hexane, n-heptane or mixtures thereof

8. The process according to claim 1 or 5, wherein the stabilizer is selected from polyvinylpyrrolidone (PVP) of grade K-30, K-90, K-12, Hydroxy propyl cellulose (HPC), Hydroxpropyl methyl cellulose (HPMC) and amberlite.

9. A process for the preparation of stable amorphous valganciclovir hydrochloride comprising the steps of:

a) dissolving valganciclovir hydrochloride in water,

b) adding polyvinylpyrrolidone,

c) removing water using freeze drier, and

d) isolating pure Valganciclovir hydrochloride.

10. The process according to the preceding claims, wherein the solvent is removed by distillation, spray drying or freeze drying.