This application claims priority to Indian patent application No. 1058/CHE/2010 filed on April 15, 2010, the contents of which are incorporated by reference in their entirety.

Field of the invention:

The present invention relates to a process for the preparation of pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II.

Background of the invention:

Valacyclovir is an L-valyl ester prodrug of acyclovir. Acyclovir is an acyclic analog of a natural nucleoside which has been found to have high anti-viral activity.

Acyclovir is widely used in the treatment and prophylaxis of viral infections in humans, particularly infections caused by the herpes group of viruses. See Goodman and Gilman's, The Pharmacological Basis of Therapeutics 1193-1198 (9th ed. 1996).
The chemical name of Valacyclovir hydrochloride is L-valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester, monohydrochloride. It has the following structural formula:

Valacyclovir hydrochloride is a white to off-white powder with the molecular formula C13H20N6O4«HCI and maximum solubility in water at 174 mg/mL. The Pka's for Valacyclovir hydrochloride are 1.90, 7.47, and 9.43.

It is advantageous to administer Valacyclovir rather than acyclovir because acyclovir is poorly absorbed from the gastrointestinal tract after oral administration in both animals and humans. In contrast, Valacyclovir is rapidly absorbed from the gastrointestinal tract after oral administration. Moreover, Valacyclovir is converted rapidly and virtually completely to acyclovir after oral administration in healthy adults. The conversion of Valacyclovir is thought to result from first-pass intestinal and hepatic metabolism through enzymatic hydrolysis.

Acyclovir kills viruses by inhibiting viral DNA synthesis. Because acyclovir is a guanosine analog which lacks the 3'-hydroxyl on the side chain, it causes DNA chain termination during viral DNA replication. In virus infected cells, acyclovir is converted to the monophosphate derivative (acyclovir-MP) by a viral enzyme, thymidinine kinase.

Acyclovir-MP is then phosphorylated to the diphosphate and triphosphate analogs by cellular enzyme. Incorporation of activated acyclovir into the primer strand during viral DNA replication, leads to chain termination, since without the 3'hydroxyl the DNA chain can not be extended. Since infected cells lack the viral enzyme thymidine kinase, acyclovir is selectively activated only in cells infected with viruses that code for the appropriate kinases.

U. S. Pat. No. 4,199, 574 discloses the treatment of viral infections with acyclovir.
The basic NCE patent for Valacyclovir is EP 0 308 065B (the '065 patent") discloses amino acid esters of the purine nucleoside acyclovir, pharmaceutically acceptable salts thereof and their use in the treatment of herpes virus infections. Also disclosed are pharmaceutical formulations and processes for the preparation of such compounds. Valacyclovir and its salts, including the hydrochloride salt, are among the disclosed compounds. Example IA relates to the preparation of Valacyclovir as free base and Example IB relates to the preparation of Valacyclovir hydrochloride monohydrate. The only enabling disclosure of a salt of Valacyclovir in EP 0 308 065B is of Valacyclovir hydrochloride monohydrate.

EP 0 804 436 discloses an anhydrous crystalline form of Valacyclovir hydrochloride.
EP 1436295 discloses various polymorphic crystalline forms of Valacyclovir hydrochloride which are designated Forms I and II and IV-VII.

EP 1453834 discloses an anhydrous polymorphic crystalline form of Valacyclovir hydrochloride.

EP 1575953 discloses an anhydrous polymorphic crystalline form of Valacyclovir hydrochloride.

WO 04106338 A discloses various polymorphic crystalline forms of Valacyclovir hydrochloride which are designated Forms VIII-XIV.

WO 05000850A discloses various polymorphic crystalline forms of Valacyclovir hydrochloride which are designated Forms V and VIII-XII.

WO 05085247A discloses various polymorphic crystalline forms of Valacyclovir hydrochloride which are designated Forms I, II, IV, VI and VII.

The prior art processes result in the formation of valacyclovir hydrochloride polymorphic form II as a mixture. The present invention covers a process for the preparation of valacyclovir hydrochloride which results in pure crystalline valacyclovir hydrochloride polymorphic form II with improved quality.

Object & Summary of the Invention

The main object of the present invention relates to a process for the preparation of Valacyclovir hydrochloride polymorphic form II.

Another object of the present invention relates to a process for the preparation of pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II with improved quality.

Drawings

Figure 1 represents powder X - ray diffraction diagram of Valacyclovir hydrochloride polymorphic Form II

Detailed description of the Invention

The present invention provides a process for the preparation of Valacyclovir hydrochloride polymorphic form II.

In one embodiment, the present invention provides a process for the preparation of pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II.

In another embodiment, the present invention provides pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II characterized by PXRD as shown in Figure 1.

In yet another embodiment, the present invention provides a process for the preparation of pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II comprising the steps of

i) dissolving Valacyclovir hydrochloride in a solvent,

ii) adding antisolvent, and

iii) isolating Valacyclovir hydrochloride form II.

According to the present invention Valacyclovir hydrochloride is dissolved in a solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, cyclohexanol; polar aprotic solvents like dimethyl sulfoxide, dimethyl formamide or mixtures thereof.
According to the present invention, the anti-solvent is selected from alcohols such as n-butanol, isopropanol, n-propanol. Removing the solvent by conventional techniques such as filtration, distillation, vacuum distillation or drying thus obtaining pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II.

In yet another embodiment, the present invention provides a process for the preparation of pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II comprising the steps of

a) dissolving Valacyclovir hydrochloride in a organic solvent,

b) optionally adding seed crystals of form II,,

c) adding an anti solventyand

d) isolating pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II

According to the present invention Valacyclovir hydrochloride is dissolved in a solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, cyclohexanol; aprotic solvents like dimethyl sulfoxide, dimethyl formamide or mixtures thereof. The resultant solution is optionally seeded with seed crystals of Valacyclovir hydrochloride form II. Adding this solution to a second solvent selected from alcohols such as n-butanol and removing the solvent by conventional techniques such as filtration, distillation, vacuum distillation or drying obtains pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II.

In yet another embodiment, the present invention provides a process for the preparation of pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II comprising the steps of

a) dissolving Valacyclovir hydrochloride in a mixture of water and water miscible aprotic solvent,

b) adding seed crystals of anhydrous form II to an alcoholic solvent

c) adding the contents of step a to the pre seeded alcoholic solvent of step b, o-w

d) isolating pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II

According to the present invention, Valacyclovir hydrochloride is dissolved in water or water miscible aprotic solvents like dimethyl sulfoxide or dimethyl formamide. Separately, an alcoholic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, cyclohexanol and seed crystals of Valacyclovir hydrochloride form II are taken in a round bottom flask under nitrogen atmosphere. The solution containing valaciclovir hydrochloride is slowly added to pre seeded second solvent. Removing the solvent obtains pure Valacyclovir hydrochloride polymorphic form II.

In yet another embodiment, the present invention provides a process for the preparation of pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II comprising the steps of

a) dissolving Valacyclovir hydrochloride in a mixture of water and water miscible aprotic solvent,

b) adding seed crystals of anhydrous form II to an alcoholic solvent,

c) adding the contents of step b to step of

d) isolating pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II

According to the present invention, Valacyclovir hydrochloride is dissolved in water or water miscible aprotic solvents like dimethyl sulfoxide or dimethyl formamide. Separately, an alcoholic solvent selected from alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, cyclohexanol and seed crystals of Valacyclovir hydrochloride form II are taken in a round bottom flask under nitrogen atmosphere. Pre seeded second solvent mixture is slowly added to the solution containing Valacyclovir hydrochloride. Removing the solvent obtains pure Valacyclovir hydrochloride polymorphic form II.

The examples mentioned below explain all the aspects of the present invention. The examples are given to illustrate the details of the invention and should not be construed to limit the scope of the present invention.

Examples:

Example 1: Preparation of Valacyclovir hydrochloride Form II

20 g of hydrated valacyclovir hydrochloride was dissolved in N,N-dimethyl formamide (100 ml) at 25-30°C. The resulting solution was filtered through hiflow to remove any undissolved particulate and washed with N,N-dimethyl formamide (10 ml). n-Butanol (150 ml) was taken in RB flask and cooled to 0-5°C under nitrogen atmosphere. The above valacyclovir solution was added slowly to n-butanol for 0.5h at 0-5°C and maintained under agitation for 5-6h at 0-5°C under nitrogen atmosphere. The solid obtained was filtered, washed with n-butanol (20 ml) and dried under vacuum at 50°C for 12h. The product obtained was identified as crystalline valacyclovir hydrochloride Form II.

Example 2: Preparation of Valacyclovir hydrochloride Form II

100 g of hydrated valacyclovir hydrochloride was dissolved in N,N-dimethyl formamide (500 ml) at 25-30°C and stirred for 15 minutes. The resulting solution was filtered through hiflow to remove any undissolved particulate and washed with N,N-dimethyl formamide (50 ml). n-Butanol (1500 ml) was taken in RB flask and cooled to 20-25°C under nitrogen atmosphere. The above valacyclovir solution was slowly added to n-butanol at 20-25°C and stirred for 4-5h at 20-25°C under nitrogen atmosphere. The solid obtained was filtered and dried under vacuum at 50°C for 15h. The product obtained was identified as crystalline valacyclovir hydrochloride Form II.

Example 3: Preparation of Valacyclovir hydrochloride Form II

100 g of hydrated valacyclovir hydrochloride was dissolved in N, N-dimethyl formamide (500 ml) at 25-30°C and stirred for 15 minutes. The resulting solution was filtered through hiflow to remove any undissolved particulate and washed with N,N-dimethyl formamide (50 ml). n-Butanol (1500 ml) was taken in RB flask and cooled to 10-15°C under nitrogen atmosphere. The above valacyclovir solution was added slowly to n-butanol at 10-15°C and stirred for 3h at 10-15°C under nitrogen atmosphere. Slowly the temperature is raised to 20-25°C and stirred for 2h at 20-25°C under nitrogen atmosphere. The solid obtained was filtered and dried under vacuum at 50°C for 15h. The product obtained was identified as crystalline valacyclovir hydrochloride Form II.

Example 4: Preparation of Valacyclovir hydrochloride Form II

50 g of hydrated valacyclovir hydrochloride was dissolved in N, N-dimethyl formamide (250 ml) at 25-30°C and stirred for 15 minutes. The resulting solution was filtered through hiflow to remove any undissolved particulate and washed with N,N-dimethyl formamide (25 ml). n-Butanol (750 ml) was taken in RB flask and cooled to -10 to -15°C under nitrogen atmosphere. The above valacyclovir solution was added slowly to n-butanol at -10 to -15°C and stirred for 15h at -10 to -15°C under nitrogen atmosphere. The solid obtained was filtered and dried under vacuum at 50°C for 15h. The product obtained was identified as crystalline valacyclovir hydrochloride Form II.

Example 5: Preparation of Valacyclovir hydrochloride Form II

50 g of hydrated valacyclovir hydrochloride was dissolved in N, N-dimethyl formamide (250 ml) at 25-30°C and stirred for 15 minutes. The resulting solution was filtered through hiflow to remove any undissolved particulate and washed with N,N-dimethyl formamide (25 ml), and to this filtrate added Form II seeds (250mg) and stirred for 4-5hrs at 25-30 °C. After 1hr the material was precipitated out. Then added n-Butanol (250ml) and stirred for 1hr at 25-30 °C and the solid obtained was isolated and identified as crystalline valacyclovir hydrochloride Form II.

Example 6: Preparation of Valacyclovir hydrochloride Form II

50 g of hydrated valacyclovir hydrochloride was dissolved in N, N-dimethyl formamide with 10% water (250 ml) at 25-30°C and stirred for 15 minutes. The resulting solution was filtered through hiflow to remove any undissolved particulate and washed with N,N-dimethyl formamide (25 ml). n-Butanol (750 ml) and Form II (250mg) seeds were taken in RB flask at 25-30°C under nitrogen atmosphere. The above valacyclovir solution was added slowly to n-butanol at 25-30°C and stirred for 1h at 25-30°C under nitrogen atmosphere. Then cooled to 0-5°C and stirred for 1hr. The solid obtained was filtered and slurried in n-butanol (3x400ml) at 90-100°C followed by filtration at same temperature. The solid obtained was dried under vacuum at 70-80°C for 15h.The product obtained was identified as crystalline valacyclovir hydrochloride Form II.

Example 7: Preparation of Valacyclovir hydrochloride Form II

50 g of hydrated valacyclovir hydrochloride was dissolved in N, N-dimethyl formamide with 20% water (250 ml) at 25-30°C and stirred for 15 minutes. The resulting solution was filtered through hiflow to remove any undissolved particulate and washed with N,N-dimethyl formamide (25 ml). n-Butanol (750 ml) and Form II (250mg) seeds were taken in RB flask at 25-30X under nitrogen atmosphere. The above valacyclovir solution was added slowly to n-butanol at 25-30°C and stirred for 1h at 25-30°C under nitrogen atmosphere. Then cooled to 0-5°C and stirred for Ihr.The solid obtained was filtered and slurried in n-butanol (3x400ml) at 90-100°C followed by filtration at same temperature. The solid obtained was dried under vacuum at 70-80°C for 15h. The product obtained was identified as crystalline valacyclovir hydrochloride Form II.

WE CLAIM:

1) A process for the preparation of pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II comprising the steps of

a) dissolving Valacyclovir hydrochloride in a mixture of water and water miscible aprotic solvent,

b) adding seed crystals of anhydrous form II to a alcoholic solvent/

c) adding the contents of step a to the pre seeded alcoholic solvent of step of

d) isolating pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II

2) The process according to claim 1, wherein the water miscible aprotic solvent is selected from N, N-dimethyl formamide or dimethyl sulfoxide.

3) The process according to claim 1, wherein the alcoholic solvent is n-Butanol.

4) A process for the preparation of pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II comprising the steps of

a) dissolving Valacyclovir hydrochloride in a organic solvent,

b) adding antisolvent, and

c) isolating Valacyclovir hydrochloride form II.

5) A process for the preparation of pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II comprising the steps of

a) dissolving Valacyclovir hydrochloride in a organic solvent

b) optionally adding seed crystals of form II,

c) adding anti-solvent, and

d) isolating pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II.

6) The process according to claims 4 and 5 wherein the organic solvent is methanol, N, N-dimethyl formamide or dimethyl sulfoxide.

7) The process according to claims 4 and 5 wherein the antisolvent solvent is n-butanol

8) A process for the preparation of pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II comprising the steps of

a) dissolving Valacyclovir hydrochloride in a mixture of water and water miscible aprotic solvent,

b) adding seed crystals of anhydrous form II to an alcoholic solvent.

c) adding the contents of step b to step a/

d) isolating pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II

9) The process according to claims 8 wherein the miscible aprotic solvent is selected from N, N- dimethyl formamide, dimethyl sulfoxide and alcoholic solvent is n-butanol.

10) Pure anhydrous crystalline Valacyclovir hydrochloride polymorphic form II according to claim 1, 2 and 5 having a powder X-ray diffraction pattern as substantially depicted in figure 1.