WO2006035452A1

WO2006035452A1 - Novel pseudomorph of valaciclovir hydrochloride

Info

Publication number: WO2006035452A1
Application number: PCT/IN2005/000270
Authority: WO
Inventors: Satyanarayana Chava; Seeta Ramanjaneyulu Gorantla; Jyothi Basu Abbineni
Original assignee: Matrix Laboratories Ltd
Priority date: 2004-09-27
Filing date: 2005-08-11
Publication date: 2006-04-06

Abstract

The present invention relates to a stable novel pseudomorph of Valaciclovir hydrochloride and the process for its preparation by the debenzylation of 2-[(2-Amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl N- [(benzyloxy)carbonyl]L-valinate by bubbling hydrogen gas in presence of HCl, isolating the product in a mixture of ethanol and water followed by crystallization in aq.ethanol, drying under vacuum and allowing to adsorb moisture at ambient conditions.

Description

"Novel pseudomorph of Valaciclovir hydrochloride"

The present invention relates to novel pseudomorph of Valaciclovir hydrochloride and the process for its preparation.

Background of the Invention:

Valaciclovir hydrochloride, [2-(2-araino-l,6-dihydro-6-oxo-purin-9-yl)methoxy]ethyl L- valinate hydrochloride has the formula as given below.

-^HCI

Valaciclovir hydrochloride

Valaciclovir is an L- valine ester of Acyclovir. Acyclovir possesses antiviral activity and is widely used in the treatment of prophylaxis of viral infections in human beings, particularly infections caused by the herpes group of viruses. However, acyclovir is poorly absorbed from the gastrointestinal tract upon oral administration and this low bioavailability means multiple high doses of oral drug may need to be administered, especially for the treatment of less sensitive viruses or infections.

Preparation of Valaciclovir and its salts including hydrochloride salt are disclosed in U.S. Patent No. 4,957,924. The disclosed process for the preparation of valaciclovir hydrochloride monohydrate involves the condensation of CBZ-L- Valine with acyclovir in presence of 4-dimethylaminopyridine and dicyclo hexylcarbodiimide in dimethyl formamide and purification by flash chromatography yielded the intermediate 2-[(2- Amino- 1 ,6- dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl-N-[(benzyloxy)carbonyl] L- valinate. Debenzylation of the above intermediate with 5% Pd/C catalyst in presence of 0.5 M aq. HCl, at a hydrogen pressure of 50 psi for about one day followed by removal of catalyst, concentration of the solvent afforded the white solid which was recrystallized from water/ethanol yielded the valaciclovir hydrochloride monohydrate. The above disclosed process has the drawback of debenzylation under pressure in presence of aqueous HCl for longer time i.e. for a day. There by the process requires a special equipment to carryout the reaction under acidic and pressure conditions.

U.S. Patent No.6, 107,302 disclosed anhydrous valaciclovir hydrochloride and the process for its preparation. It further disclosed that the anhydrous valaciclovir hydrochloride has the water of hydration not more than 3.0% and characterized by its X-ray diffractions.

The PCT publication WO 03/22209 disclosed various polymorphs/ pseudomorphs of valaciclovir hydrochloride, pharmaceutical compositions containing them and the processes for preparation. The disclosed crystalline forms are form-I, form-II, form-IV, form-V, form- VI and form- VII which include valaciclovir hydrochloride monohydrate, valaciclovir hydrochloride dihydrate and valaciclovir hydrochloride sesquihydrate. The disclosed polymorphs, pseudomorphs are characterized by chemical analysis, XRD, DSC and theromogravimetric analysis. Valaciclovir hydrochloride form-I is characterized as sesquihydrate and form-FV is characterized as dihydrate. The disclosed methods used for particular embodiments are slurry method, vapour incubation method and the precipitation method.

There is a long felt need of the industry to have a process for the preparation of valaciclovir hydrochloride with out involving the special equipment during debenzylation reaction.

Summary of the invention:

The main object of the present invention is to provide a stable novel crystalline valaciclovir hydrochloride pseudomorph. Another object of the present invention is to provide the process for the preparation of stable novel crystalline valaciclovir hydrochloride pseudomorph. Yet another object of the present invention is to provide a process for the preparation of valaciclovir hydrochloride without using special pressure equipment.

Accordingly in the present invention 2-[(2-Amino-l,6-dihydro-6-oxo-9H-purin-9- yl)methoxy]ethyl N-[(beri2yloxy)carbonyl]L-valinate is debenzylated with palladium on carbon catalyst by bubbling hydrogen gas in presence of HCl,followed by filtration of catalyst, concentration and crystallization of the product in a mixture of ethanol and water. The compound is further recrystallized aq.ethanol (Scheme-1), isolation, drying under vacuum and allowing to adsorb moisture at ambient conditions affords the valaciclovir hydrochloride pseudomorph.

Scheme-1

Valaciclovir hydrochloride

The prepared valaciclovir hydrochloride pseudomorph is a novel, stable crystalline hydrate, having the water of hydration about 4.5% to about 9.5%. The valaciclovir hydrochloride pseudomorph is designated as pseudohydrate as the water present in the product is both the physically adsorbed and chemically bounded water, which is confirmed by the thermal analysis (DSC, TGA). In fact the product can be called as a cluster of vaiaciclovir hydrochloride pseudohydrates, characterized by its unique TGA and DSC thermograms. Brief description of the drawings:

1. Fig.1 - XRD of valaciclovir HCl pseudomorph

2. Fig.2 - TGA of valaciclovir HCl pseudomorph 3. Fig.3 - DSC of valaciclovir HCl pseudomorph

Detailed description of the invention: Thus in accordance with the present invention preparation of valaciclovir hydrochloride pseudomorph essentially comprises the following steps.

- Debenzylating 2-[(2-Amino-l,6-dihydro-6-oxo-9H-purin-9-yl) methoxy]ethyl N- [(benzyloxy)carbonyl]L-valinate with palladium on carbon by bubbling hydrogen gas without maintaining the pressure in presence of HCl

- Removing the catalyst followed by removal of solvent

- Crystallizing the product from ethanol - water

- Dissolving the isolated solid in water

- Removing insolubles if any - Adding ethanol to the clear solution

- Isolating the precipitated product

- Drying the wet cake under vacuum followed by allowing the product to absorb the moisture in ambient conditions

2-[(2-Amino-l,6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl N-

[(benzyloxy)carbonyl]L-valinate is suspended in a mixture of methanol' and THF, 5% palladium on carbon or 10% palladium on carbon catalyst is added and hydrogen gas is bubbled through the reaction mass at a temperature of about 1O⁰C to about 45⁰C preferably at 2O⁰C to 35⁰C for about 45 min to 8 hrs. Catalyst is removed, THF and methanol mixture is distilled off under vacuum at temperature below 6O⁰C. Ethanol is added and adjusted the water content of the reaction mass to about 15% to about 35% preferably about 20% to about 30%. The temperature of the reaction mass is raised to about 40 to 45⁰C to get a solution, cooled the reaction mass to a temperature of 5⁰C to 30°C.The precipitated valaciclovir hydrochloride is isolated which can be further recrystallized as follows.

Wet valaciclovir hydrochloride is dissolved in water at temperature of about 25⁰C to about 65⁰C, insolubles are removed (if any), ethanol is added and the reaction mass is cooled to a temperature of 2O⁰C to 3O⁰C, precipitated product is isolated and the wet cake is dried at temperature of about 45⁰C to about 55⁰C under vacuum for about 6 to 18 hrs (till the ethanol content comes to about 2 to 4 %) and then dried at room temperature (Allowed to adsorb / absorb moisture upto a level of about 8 % to 9.5%) for about 4 to 6hrs afforded the valaciclovir hydrochloride pseudomorph.

2- [(2- Amino- 1 ,6-dihydro-6-oxo-9H-purin-9-yl)methoxy] ethyl- N- [(benzyloxy)carbonyl]L-valinate is prepared by the prior art methods.

The invention is further illustrated with the following example

Example: Preparation of valaciclovir hydrochloride pseudomorph.

Step-1:-

10Og of 2-[(2-Amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy] ethyl] N-[(benzyloxy) carbonyl]L-valinate is suspended in mixture of THF (1320 ml), methanol (1320 ml) and 240 ml of 0.5M aqueous hydrochloric acid is added. Reaction mixture maintained for about 15 min to get a clear solution. 10 g of 10% Palladium on carbon catalyst is added to the reaction mixture and hydrogen gas is bubbled into the reaction mass for about 3 hrs at temperature of 25⁰C - 3O⁰C. The catalyst is filtered, washed the catalyst with 100 ml of 1:1 mixture of THF, methanol, combined the filtrate, washings and distilled off the solvents under vacuum at temperature of below 6O⁰C. 300 ml of ethanol is added to the reaction mass and adjusted the moisture content to 23% by addition of ethanol. The reaction mass is cooled to 25°C-30°C, mixed for about 30 min and the temperature is raised to 40°C-45°C. Reaction mass is mixed for about 30 min at 40°C-45°C, slowly cooled to 2O⁰C and mixed for about 1 hr at 20°C-25°C. The precipitated product is filtered, washed the wet cake with 50 ml of chilled ethanol.

Weight of the wet cake is 9Og.

Step-2:-

The wet cake (90 g) obtained in the above step is suspended in 100 ml DM water and the temperature is raised to 50°C-55°C, mixed for about 15 min at 50⁰C - 55⁰C and filtered the solution through hyflow bed to remove insoiubles. Filtrate is cooled to 40°C-45°C, 340 ml ethanol is added at temperature of 40°C-45°C and cooled the reaction mass to 20°C-30°C. Reaction mass is mixed for about 15 min and the temperature is raised to 35⁰C-45^oC₅maintained for about 15 min at 35°C-45°C, cooled to 20⁰C- 25⁰C and maintained for about 30 min at 20°C-25°C.The precipitated product is filtered, washed the wet cake with 50 ml of chilled ethanol and dried at 50°C-55°C under vacuum for about 12 hrs (ethanol content is 2.3%. The material is further dried at 25°C-35°C (allowed to absorb the moisture content) for 4 hrs (till the moisture content becomes 8.6%).

The dry weight of valaciclovir hydrochloride pseudomorph is 45 g. Moisture content: 8.6%

The typical XRD, TGA and DSC are as shown in Fig.1 to Fig.5

Claims

We claim:

1. A process for the preparation of valaciclovir hydrochloride pseudomorph comprising steps

- Debenzylating 2-[(2-Amirio-l,6-dihydro-6-oxo-9H-purin-9~yI) methoxyjethyl N- [(ben2yloxy)carbonyl]L-valinate with palladium on carbon by bubbling hydrogen gas without maintaining the pressure in presence of HCl

- removing the catalyst followed by removal of solvent - crystallizing the product from ethanol - water

- dissolving the isolated solid in water

- removing the insolubles (if any)

- adding ethanol to the clear solution

- isolating the precipitated product ^' - drying the wet cake under vacuum followed by allowing the product to absorb the moisture in ambient conditions

2. A process as claimed in claim 1, wherein hydrogen gas bubbling is at temperature of

1O⁰C to 45⁰C.

3. A process as claimed in claim 1, wherein the palladium on carbon catalyst is either 5% or 10% w/w.

4. A process as claimed in claim 1, wherein the hydrogen gas bubbling is for about 45 min to 8 hrs.

5. A process as claimed in claim 1, wherein the solvent is removed under vacuum at temperature of below 60⁰C.

6. A process as claimed in claim 1, wherein product is crystallized from ethanol having the moisture content about 12% to 30% and more preferably about 20% to 30%.

7. A process as claimed in claims 1, wherein drying is performed at temperature of 50°C~55°C under vacuum.

8. A process as claimed in claim 1, wherein the product is allowed to absorb moisture up to 9.5%.

9. Crystalline valaciclovir hydrochloride psuedomorph.

10. Crystalline valaciclovir hydrochloride pseudomorph as claimed in claim 9, wherein characterized by having x-ray diffractogram as shown in Fig.1

11. Crystalline valaciclovir hydrochloride pseudomorph as claimed in claims 9, wherein characterized by showing the DSC endotherms as shown in Fig 3-5.

12. Crystalline valaciclovir hydrochloride pseudomorph as claimed in claims 9 to 11, having the moisture content about 4.5% to about 9.5%.