Field of the invention:
This invention relates to the preparation of Warfarin sodium solvates and Warfarin sodium. Specifically, the invention relates to the preparation of pure Warfarin sodium from Warfarin through new Warfarin sodium solvates.
Background of the invention:
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. Its structure is as follows

Warfarin preparation was first disclosed in US 2,427,578. GB 715,846 describes the preparation and purification by acid-base treatment. J.Am.chem.Soc. 66(1944) 902 gives the purification of Warfarin using acetone-water mixture. Crystalline Warfarin sodium is mentioned in US 2,765,321 using ethanol and lithium salts. In the entire above prior art Warfarin sodium has impurities and not of good quality. To over come the quality issues Warfarin sodium IPA clathrate is given in US 3,077,481. According the US 3,192,232 Warfarin sodium is prepared by evaporation to dryness, spray drying or drum drying. US 3,246,013 describes a process for preparing crystalline Warfarin sodium IPA clathrate through neutralization of Warfarin acid 2-propanol slurry. Indian J. Chem., Vol 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. 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 discloses a method for the direct preparation of pure Warfarin sodium from Warfarin using a volatile base. US 6,610,862 reported a method for drying of Warfarin sodium IPA clathrate.
According to the prior art process, either highly pure Warfarin or Warfarin sodium is prepared through Warfarin sodium IPA clatherate. Warfarin sodium IPA clatherate is subjected to drying to give crystalline Warfarin sodium. According to prior art processes are very difficult to prepare pure amorphous Warfarin sodium. So there is a need to have a more economical process to prepare amorphous Warfarin sodium.
Summary of the invention:
In one aspect, the present invention relates to the preparation of highly pure Warfarin sodium by drying various Warfarin sodium solvates.
In another aspect, the present invention relates to Warfarin sodium Acetone-ethyl acetate solvate.
In another aspect, the present invention relates to a method of making Warfarin sodium Acetone-ethyl acetate solvate.
In another aspect, the present invention relates to Warfarin sodium ethyl acetate solvate.
In another aspect, the present invention relates to a method of making Warfarin sodium ethyl acetate solvate.

In another aspect, the present invention relates to Warfarin sodium Ethanol-Heptane solvate.
In another aspect, the present invention relates to a method of making Warfarin sodium Ethanol-Heptane solvate.
In another aspect, the present invention relates to Warfarin sodium Acetone-Heptane solvate.
In another aspect, the present invention relates to a method of making Warfarin sodium Acetone-Heptane solvate.
In a further aspect, the present invention relates to a method of making Warfarin sodium from Warfarin sodium solvates.
Brief description of the drawings:
The invention will now be described in further detail with reference to the drawings, wherein:
FIG. 1 shows a representative x-ray diffraction diagram of Warfarin sodium Acetone-ethyl acetate solvate
FIG. 2 shows a representative x-ray diffraction diagram of Warfarin sodium ethyl acetate solvate
FIG. 3 shows a representative x-ray diffraction diagram of Warfarin Ethanol-Heptane solvate.
FIG. 4 shows a representative x-ray diffraction diagram of Warfarin sodium Acetone-Heptane solvate.

FIG. 5 shows a representative x-ray diffraction diagram of amorphous Warfarin sodium
Detailed description of the invention:
The present invention relates to process for the preparation of amorphous Warfarin sodium, wherein Warfarine is reacted with base and removing the water to give residue, which is dissolved in solvent and optionally adding another solvent to give Warfarin sodium solvate, which is subjected to drying to give amorphous Warfarin sodium.
Process for the preparation of Warfarin sodium solvate which comprising the steps of:
a) treating Warfarin or Warfarin solvate with base,
b) removing the water to give residue,
c) dissolving residue in first solvent,
d) optionally adding second solvent to step c) and
e) isolating Warfarine sodium solvate.
According to the present invention, Warfarin is crystallized in methanol to give Warfarin methanol solvate, which is treated with aqueous sodium hydroxide. Water is removed under reduced pressure to give residue. The residue is dissolved in a first solvent, which is selected from group comprising of alcohol, ketone or ester. Alcohol solvent is selected from methanol. Ketone solvent is selected from acetone and ester solvent is selected from ethyl acetate.
According to the present invention, the above dissolved Warfarin sodium is optionally treated with second solvent, which is selected from ethyl acetate or heptane.
The present invention relates to Novel crystalline solvated forms of Warfarin sodium, whereas Warfarin sodium solvate is selected from Warfarin sodium ethyl acetate solvate, Warfarin sodium acetone-ethylacetate solvate, Warfarin sodium ethanol-hepatane solvate

and Warfaarin sodium acetone-heptane solvate. These solvents are showing different pXRD patterns, which are disclosed in Figures 1 to 4.
According to the present invention, Warfarin Sodium ethyl acetate acetone solavate is containing ethyl acetate 5.0 to 10 % , Acetone 0.1 % to 3.0 %. Warfarin Sodium ethanol heptane solavate is containing ethanol 1.0 to 5.0 % , heptane 0.1 % to 3.0 %. Warfarin Sodium acetone heptane solavate is containing acetone 3.0 to 7.0 % , heptane 0.5 % to 1.5%.
According to present invention, above isolated Warfarin sodium solvate forms are subjected to drying using the different dryers, which are selected from turbo oven, a paddle rotary oven, a vacuum tray oven, and a fluid bed oven and the drying temperature is maintained between 90-15 0°C to give pure amorphous Warfarin sodium.
According to prior art process, Warfarin sodium IPA clathrate solvate is subjected to drying to remove the solvent to give crystalline Warfarin sodium, which is further converted to amorphous Warfarin sodium by different methods. It involves extra experimentation steps, it leads increase final product coast.
According to our present invention, Warfarin Sodium solvates are subjected to drying to give pure amorphous Warfarin sodium, without going through crystalline Warfarin sodium.

Examples:
The present invention will now be further explained in the following examples. However, the present invention should not be construed as limited thereby. One of ordinary skill in the art will understand how to vary the exemplified preparations to obtain the desired results.
Example 1: Preparation of Warfarin
50.0 g of 4-hydroxy coumarin, 43.14 g of benzalAcetone and 2.94 ml of triethyl amine are suspended in 500 ml water. Temperature of the reaction mass was raised and maintained at reflux temperature for about 2 to 8 hrs during which period a heavy precipitate forms. Reaction mass was cooled to 25 to 35°C and the solid product was separated by filtration. The wet cake was suspended in water and heated to 70° C and stirred for 1 hr. The suspension was cooled, filtered and washed with water. The wet cake was again suspended in 200 ml toluene, stirred at room temperature for about 1 hr and filtered. Wet cake was crystallized twice in methanol (200 ml each) as Warfarin methanol solvate and dried at temperature of 35-50°C till it becomes constant weight.
Example-2: Preparation of Warfarin sodium Acetone- ethyl acetate solvate
9.3 g of Sodium hydroxide was dissolved in 35 ml of water and slowly added over a period of 2hrs to a suspension of 80.0 g of Warfarin solvate in water at temperature of about 25 to 35°C. Reaction mass was heated to 55°C, and then cooled to 25-35°C and filtered to remove excess Warfarin. The resulting solution was treated with activated carbon and water was distilled under vacuum preferably at temperature of below 60 C. The resulting foamy Warfarin sodium was treated with 50 ml of Acetone twice to remove water. The residue was dissolved in 200 ml of Acetone, treated with activated carbon and then crystallized by the addition of 200 ml ethyl acetate.

Example-3: Preparation of Warfarin sodium ethyl acetate solvate
9.3 g of Sodium hydroxide was dissolved in 35 ml of water and slowly added over a period of 2hrs to a suspension of 80.0 g of Warfarin solvate in water at temperature of about 25 to 35°C. Reaction mass was heated to 55°C, and then cooled to 25-35°C and filtered to remove excess Warfarin. The resulting solution was treated with activated carbon and water was distilled under vacuum preferably at temperature of below 60°C. The resulting foamy Warfarin sodium was treated with 200 ml ethyl acetate and crystallized as ethyl acetate solvate.
Example-4: Preparation of Warfarin sodium Ethanol-Heptane solvate
9.3 g of Sodium hydroxide was dissolved in 35 ml of water and slowly added over a period of 2hrs to a suspension of 80.0 g of Warfarin solvate in water at temperature of about 25 to 35°C. Reaction mass was heated to 55°C, and then cooled to 25-35°C and filtered to remove excess Warfarin. The resulting solution wastreated with activated carbon and water was distilled under vacuum preferably at temperature of below 60°C. The resulting foamy Warfarin sodium was treated with 50 ml of Ethanol twice to remove water. The residue was dissolved in 200 ml of ethanol and treated with activated carbon crystallized by the addition of 200 ml Heptane.
Example-5: Preparation of Warfarin sodium Acetone-Heptane solvate
9.3 g of Sodium hydroxide was dissolved in 35 ml of water and slowly added over a period of 2hrs to a suspension of 80.0 g of Warfarin solvate in water at temperature of about 25 to 35°C. Reaction mass was heated to 55°C, and then cooled to 25-35°C and filtered to remove excess Warfarin. The resulting solution was treated with activated carbon and water was distilled under vacuum preferably at temperature of below 60°C. The resulting foamy Warfarin sodium was treated with 50 ml of Acetone twice to remove

water. The residue was dissolved in 200 ml of Acetone, treated with activated carbon and crystallized by the addition of 200 ml Heptane.
Example-6: Preparation of Warfarin sodium from Warfarin solvates
50.0 g of the Warfarin solvate was heated in commercially available drying equipment under reduced pressure of about 100 mm Hg. The material was heated at about 145°C for about 20 hrs to give Warfarin sodium as a white powder.
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.

We Claim:
1. Process for the preparation of Warfarin sodium solvate which comprising the steps
of:
a) treating Warfarin or Warfarin solvate with base,
b) removing water to give residue,
c) dissolving residue in first solvent,
d) optionally adding second solvent to step c) and
e) isolating Warfarine sodium solvate.

2. A process according to claim 1, wherein the base is selected from aqueous sodium hydroxide.
3. A process according to claim 1, wherein the first solvent group is selected from alcohol, ketone or ester.
4. A process according to claim 3, wherein the said alcohol is ethanol, ketone
solvent is selected from acetone and ester solvent is ethyl acetate.
5. A process according claim 1, wherein the second solvent is ethyl acetate or heptane.
6. A Process according to claim 1, wherein Warfarine sodium solvate is selected from Warfarin sodium ethyl acetate solvate, Warfarin sodium acetone-ethylacetate solvate, Warfarin sodium ethanol-heptane solvate and Warfaarin sodium acetone-heptane solvate.
7. Warfarin sodium acetone-ethyl acetate solvent is having the similar x-ray power diffraction pattern as shown in Figure-1

8. Warfarin sodium ethyl acetate solvent is having the similar x-ray power diffraction pattern as shown in Figure-2
9. Warfarin sodium ethanol-heptane solvent is having the similar x-ray power diffraction pattern as shown in Figure-3
10. Warfarin sodium acetone-heptane solvent is having the similar x-ray power diffraction pattern as shown in Figure-4
11. A process for the preparation of amorphous Warfarin sodium which comprises;

a) drying Warfarin sodium solvate and,
b) isolating amorphous Warfarin sodium.

12. A Process according to claim 11, wherein Warfarine sodium solvate is selected from Warfarin sodium ethyl acetate solvate, Warfarin sodium acetone-ethylacetate solvate, Warfarin sodium ethanol-hepatane solvate and Warfaarin sodium acetone-heptane solvate.
13. A process according to claim 11, wherein drying is carried out at temperature between 90-150° C.
14. A process according to claim 11, wherein drying is carried out under reduced pressure.

15. A process according to claim 11, wherein said drying step is carried out in an oven selected from the group consisting of a turbo oven, a paddle rotary oven, a vacuum tray oven, and a fluid bed oven.