Field of invention

The present invention relates to process for the preparation of Amorphous Warfarin sodium.

Background of the invention

Warfarin sodium is chemically known as 3-(a-acetonylbenzyl)-4-hydroxycoumarin sodium salt, having molecular formula C19H15O3Na and molecular weight 330.32.

Warfarin sodium is a racemic mixture known chemically by the chemical name 4- hydroxy-3-(3-oxo-l-phenylbutyl)-2H-l-benzopyran-2-one sodium salt, is a well established, widely used oral anticoagulant and rodenticide.

Warfarin was firstly disclosed in US 2,427,578. This patent also discloses process for the prepration of Warfarin.

US 2,765,321 disclose crystalline Warfarin sodium prepared by utilizing ethanol and lithium salts.

US 3,077,481 disclose preparation of Warfarin sodium IPA clathrate. This patent is silent about the yield and purity of final product. It also discloses amorphous Warfarin sodium was obtained by evaporating organic solvent from solution of Warfarin sodium in organic solvent.

US 3,192,232 disclose Amorphous Warfarin sodium prepared by evaporation to dryness, spray drying or drum drying. These processes are disadvantages as they are less efficient for isolation of product as well as due to time consumption.

US 3,246,013 describe a process for preparing crystalline Warfarin sodium IPA clathrate through neutralization of Warfarin acid 2-propanol slurry.

Indian J. Chem., VoI 10 (1972) p 461 reported Freeze-drying of Warfarin sodium aq solution. Biosci. Biotech. Biochem. 59(6) (1995) p 995 (CA123. 105246) reported the isolation of Warfarin sodium salts by lyophilization.

WO 02/070503 disclosed a process for the pure Warfarin and Warfarin sodium from non-aqueous media. This process is silent about the purity of final product.

US 6,512,005 reported an improved method for the preparation of Warfarin and its salts to meet the pharmacopeial grade.

US 6,673,944 disclose a method for the direct preparation of pure Warfarin sodium from Warfarin using a volatile base.

US 6,610,862 disclose a method for drying of Warfarin sodium IPA clathrate.

Accordingly, there is a need to prepare amorphous Warfarin sodium by a process which not only overcomes disadvantages associated with prior art but also gives high yield and purity of final product.

Objet of the invention

It is therefore an object of the present invention is to provide a process for the preparation of amorphous Warfarin sodium.

Another object of the present invention is to provide a process for the preparation of amorphous Warfarin sodium which is operationally simple, easy to handle and applicable at an industrial scale.

Further object of the present invention is to provide a process for the preparation of amorphous Warfarin sodium comprising steps of:
i) treating Warfarin sodium clathrate with methanol to obtain a solution
ii) evaporating methanol from solution obtained in step (i) to obtain residue
iii) adding cyclohexane to the residue obtained in step (ii)
iv) isolating amorphous Warfarin sodium

Summary of the invention

According to one aspect of the present invention, it provides a process for the preparation of amorphous Warfarin sodium comprising steps of:
i) treating Warfarin sodium clathrate with methanol to obtain a solution
ii) evaporating methanol from solution obtained in step (i) to obtain residue
iii) adding cyclohexane to the residue obtained in step (ii)
iv) isolating amorphous Warfarin sodium

Detailed description of the invention

The meaning of the term “Warfarin sodium clathrate” used as starting material hereinabove that includes but mot limited to Warfarin sodium clathrate is any state of purity.

The meaning of the term “treating” as used hereinabove that includes but not limited to dissolving, suspending and mixing. In step (i), Warfarin sodium clathrate is treated with methanol at about temperature of 20-75 0 C.

The meaning of the term “evaporating” as used hereinabove that includes but not limited to evaporating organic solvent totally or in large extent. In step (ii), methanol is evaporated under atmospheric pressure optionally under high vacuum at about temperature of 60-75 0 C. The residue as mentioned in step (ii) may be mass, oily mass, semisolid, optionally solid.

In step (iii), cyclohexane is added to residue at about temperature of 20-30 0 C.

The meaning of the term “isolating” as used hereinabove that includes but not limited to filtering, centrifuging, washing and drying. In step (iv), filtering and washing takes place at about temperature of 20-30 0 C and drying takes place under vacuum optionally at atmospheric pressure.

In embodiment, Warfarin sodium clathrate was treated with Methanol and the mixture was heated to obtain solution. The solution was evaporated till large amount of Methanol was recovered. Again Methanol was added and the solution was evaporated till large amount of Methanol was recovered. High Vacuum was applied. Again Methanol was added and the mixture was filtered through hyflo and washed with Methanol. The filtrate was evaporated till large amount of. High Vacuum was applied to obtained mass. Cyclohexane was added to obtain amorphous Warfarin sodium.

Warfarin sodium clathrate used as starting material in the examples is prepared according to methods reported in the literature and prior art.

The process of the present invention is described by the following example, which is illustrative only and should not be construed so as to limit the scope of the invention in any manner.

Example 1

Warfarin sodium clathrate (100 g) was treated with Methanol (400 ml) at 20-25°C. The mixture was heated to 65-70°C. The solution was evaporated under atmospheric pressure at 65-70°C till 375-385 ml of Methanol was recovered. Again Methanol (400 ml) was added at 50-60°C and the solution was evaporated under atmospheric pressure at 65-70°C till 375-385 ml of Methanol was recovered. High Vacuum was applied for 15-20 min to remove traces of solvent at 65-70°C. Again Methanol (300 ml) was charged at 50-60°C. The mixture was filtered through hyflo and washed with Methanol (100 ml) at 20-25°C. The filtrate was evaporated under atmospheric pressure at 65-70°C to recover 375-385 ml Methanol. High Vacuum was applied for 25-30 min to remove traces of solvent at 65-70°C to obtained mass. The mass was cooled to 20-25°C. Cyclohexane (500 ml) was added to mass at 20-25°C. The mixture was stirred, filtered, washed and dried to obtain amorphous Warfarin sodium.
Purity ~ 99.5 % (by HPLC)
Yield (w/w) ~ 0.80-0.90