DESC:Field of the invention
The present invention relates to new solid form of Warfarin Potassium and processes for preparation thereof.
Background of the invention
Warfarin acid and its alkali metal salts are coumarin type derivatives known for their powerful anticoagulant properties that act by inhibiting vitamin K-dependent coagulation factors. These highly potent anticoagulants are used extensively as active pharmaceutical ingredients (APIs) and are also widely used as rodenticides in different dosages and formulations.
Oral anticoagulant Warfarin Potassium tablets is manufactured and marketed in Japan by Eisai Co., Ltd.
The chemical name of Warfarin Potassium is Monopotassium (1RS)-2-oxo-3-(3-oxo-1-phenylbutyl) chromen-4-olate, which is a racemic mixture of the R- and S-enantiomers, structurally represented by formula (I) as given below

(I)
Warfarin was first disclosed in U.S Pat. No. 2,427,578. This patent also discloses process for the preparation of Warfarin.
U.S. Pat. No. 3,192,232 relates to improvements in processes for preparation and purifying Warfarin and alkali metal derivatives of Warfarin, e.g. Warfarin Sodium and Warfarin Potassium. The patent describes a process for preparing Warfarin sodium and Warfarin Potassium salts by reacting slurry of Warfarin acid in acetone-water with less than an equivalent of sodium hydroxide or potassium hydroxide in water at room temperature.
Furthermore, the U.S. Pat. No. 3,192,232 mentions about recovering amorphous form of Warfarin Potassium from aqueous acetone solution of the same.
U.S. Pat. No. 6,512,005 discloses preparation of hygroscopic, crystalline Warfarin Potassium.
U.S. Pat. No. 8,765,976 discloses crystalline solvates of Warfarin Potassium.
Warfarin alkali metal salts such as sodium, potassium or lithium salts, are usually prepared by reacting Warfarin acid with a molar equivalent or less of the respective alkali metal bases in aqueous medium, or with the metal alkoxides in lower alkyl alcohols.
Ohnishi et al (Biosci. Biotech. Biochem. (1995), 59(6), 995-1006) have described a method for preparing Warfarin alkali metal salts by dissolving Warfarin acid in an aqueous solution containing an equivalent amount of the respective alkali metal hydroxide (lithium, sodium, potassium, rubidium and cesium) wherein the respective salts are isolated by lyophilization.
However the commercial production of APIs preferably uses systems and processes capable of providing high quality, pure intermediates and products complying with pharmacopoeial requirements.
Accordingly, there is a need to prepare new solid form of Warfarin Potassium by a process which is industrially feasible, economically viable and is conforming to pharmacopoeial requirements of purity of final product.
Furthermore the new solid form can have different solubility, stability, and mechanical behavior that can be exploited by pharmaceutical scientists.
Object of the invention
It is an object of the present invention to provide new solid form of Warfarin Potassium and processes for preparation thereof.
It is another object of the present invention wherein the process for preparation of new solid form of Warfarin Potassium comprises the step of spray drying a solution of Warfarin Potassium in a suitable solvent.
It is yet another object of the present invention is to provide a process for the preparation of new solid form of Warfarin Potassium which is operationally practicable and applicable at an industrial scale.
It is yet another object of the present invention to provide pharmaceutical composition comprising an effective amount of new solid form of Warfarin Potassium.
Brief description of the drawing
Figure-1: PXRD pattern of Form A of Warfarin Potassium.
Description of the invention
Accordingly, the present invention relates to new solid form of Warfarin Potassium and processes for preparation thereof.
As used herein and unless otherwise specified, the term “solid form” and related terms refer to physical from of a compound which may be crystalline, partially crystalline, amorphous, or mixtures thereof.
The new solid form of Warfarin Potassium of the present invention is characterized by powder X-ray diffraction (PXRD) and the like.
In an embodiment, the present invention relates to process for preparation of new solid form of Warfarin Potassium. In particular, the invention relates to a commercially feasible, large scale process for the preparation of new solid form of Warfarin Potassium.
In a preferred embodiment, the present invention relates to new solid form, Form A of Warfarin Potassium. The Form A of Warfarin Potassium wherein isopropyl alcohol content is not more than 13%, more preferably not more than 8%.
The Form A of Warfarin Potassium of the present invention is characterized by powder X-ray diffraction (PXRD) and the like.
In another embodiment, the Form A of Warfarin Potassium is characterized by a PXRD pattern, substantially as illustrated by Figure-1.
In yet another embodiment, the present invention relates to a process for the preparation of the Form A of Warfarin Potassium comprising the steps of:
a) dissolving Warfarin sodium in a suitable solvent and adjusting pH to about 1 to 3;
b) isolating the solid mass of step a) and dissolve in a suitable solvent in presence of suitable base;
c) heating the step b) reaction mixture to about 50oC to about 80oC; and
d) isolating Form A of Warfarin Potassium from reaction mixture thereof.
The acid used for adjusting the pH of the reaction mixture of step a) of the present invention is selected from the group of inorganic acids such as sulphuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, perchloric acid and the like.
The isolated solid mass of step a) is preferably dried under vacuum.
The suitable base of step b) is selected from the group of inorganic base and/or an organic base.
The inorganic base is selected from the group of alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, more preferably potassium carbonate and potassium hydroxide.
The organic base is selected from the group of alkali metal alkoxide more preferably potassium methoxide and the like. Suitable techniques for isolating Form A of Warfarin Potassium include using a rotational distillation device such as a Buchi® Rotavapor®, spray drying, thin- film drying, agitated thin film drying, freeze drying (lyophilization), and the like.
The preferred technique for isolating Form A of Warfarin Potassium is spray drying. Spray drying can be performed using any suitable and commercially available equipment.
In a preferred embodiment, the present invention relates to a process for the preparation of the Form A of Warfarin Potassium comprising the steps of:
a) providing the solution of Warfarin sodium in a solvent selected from water, acetone, isopropyl alcohol and a combination thereof and adjusting pH to about 1 to 3;
b) isolating the solid mass of step a) and dissolve in isopropyl alcohol in presence of potassium carbonate or potassium hydroxide;
c) heating the step b) solution to 50oC to about 80oC; and
d) isolating form A of Warfarin potassium.
In a further embodiment, the present invention relates to the Form A of Warfarin Potassium obtained by the process comprising the steps of;
a) providing the solution of Warfarin sodium in a solvent selected from water, acetone, isopropyl alcohol and a combination thereof and adjusting pH to about 1 to 3;
b) isolating the solid mass of step a) and dissolve in isopropyl alcohol in presence of potassium carbonate or potassium hydroxide;
c) heating the step b) solution to 50oC to about 80oC; and
d) isolating form A of Warfarin potassium.
The suitable solvent of the process of the present invention is selected from the group of ester more preferably ethyl acetate, isopropyl acetate, butyl acetate etc., ketone more preferably acetone, methyl isobutyl ketone (MIBK), butanone etc., ether more preferably methyl tert-butyl ether (MTBE), dioxane, tetrahydrofuran, diisopropyl ether, etc. alkanol more preferably, methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, pentanol etc., amide more preferably dimethyl formamide, N-methylpyrrolidone etc. nitrile more preferably acetonitrile etc., chlorohydrocarbon more preferably dichloromethane etc., alkane/cycloalkane more preferably heptane, hexane, cyclohexane etc. and water and/or combinations thereof.
The preferred suitable solvent of the invention is selected from isopropyl alcohol, water, diisopropyl ether, acetone, methyl tert butyl ketone cyclohexane and/or combinations thereof.
The Warfarin acid or salts thereof used as raw material in the present invention can be purchased from commercial sources or prepared from processes known in the art or by a novel process.
Furthermore, isolation of Form A of Warfarin Potassium may involve methods including removal of solvent, cooling, crash cooling, slow cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, freeze-drying, spray drying, adding anti-solvent or the like.
The isolated Form A of Warfarin Potassium may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure.
The recovered Form A may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
The Form A of Warfarin Potassium as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. Therefore, optionally, the solid form may be washed with a solvent or a mixture of solvents to wash out the impurities.
In one more embodiment, the present invention also provides a pharmaceutical composition comprising Form A of Warfarin Potassium of the present invention along with one or more pharmaceutically acceptable carriers, excipients, or diluents.
The Form A of Warfarin Potassium of the present invention can be used as Vitamin K antagonists. They are used for long-term anticoagulation therapy, and exhibit their anticoagulant effect by inhibition of vitamin K epoxide reductase.
The Form A of Warfarin Potassium of the present invention can be used to prepare pharmaceutical composition for the treatment and prevention of thromboembolism such as venous thrombosis, myocardial infarction, pulmonary embolism, cerebral embolism, slowly progressing cerebral thrombosis, etc. Such pharmaceutical composition can be prepared by the methods known in the literature.

The present invention is further illustrated with the following non-limiting examples.
Example-1: Preparation of Form A of Warfarin Potassium
To a mixture of 100.0 gm of warfarin sodium in 800 mL water and 100 ml acetone was added 20% aqueous sulphuric acid to adjust pH to 1.5 to 2.5. The reaction mixture was stirred at room temperature, filtered, slurry washed with 1000 mL water, suck dried and dried under vacuum at 45oC to 50oC to get dry solid. To 90 gm of the dried solid was added isopropyl alcohol 810 mL and powdered potassium carbonate 38 gm and the reaction mixture was heated to 70oC -75oC, stirred for 5 hrs, cooled and filtered. The filtrated was charcoalised with 4.5 gm of activated carbon, filtered and the filtrate was taken up for spray drying at feeding rate 10 and inlet temperature of 130 oC -140 oC. The spray drier was cooled to room temperature and unloaded to afford Form A of Warfarin Potassium.
Example-2: Preparation of Form A of Warfarin Potassium
To a mixture of 100.0 gm of Warfarin sodium in 200 mL water and 200 mL acetone was added 20% aqueous sulphuric acid to adjust pH to 2 to 3. The reaction mixture was stirred at room temperature, filtered, washed with water (500 mL X 2), suck dried and dried under vacuum at 50oC to 60oC to get dry solid. To 90 gm of the dried solid was added isopropyl alcohol 810 mL and powdered potassium carbonate 38.6 gm. The reaction mixture was heated to 65oC to 75oC, stirred for 5 hrs, cooled and filtered. The filtrate was charcoalised with 1.8 gm of activated carbon, filtered and then the filtrate was evaporated to dryness on a rotatory evaporator at temperature of 50 oC to 80 oC to afford Form A of Warfarin Potassium.
Example-3: Preparation of Form A of Warfarin Potassium
To a mixture of 50.0 gm of Warfarin acid in 500 mL isopropyl alcohol, was added powdered potassium carbonate 21.28 gm. The reaction mixture was heated to 65oC to 75oC, stirred for 4 hrs, cooled and filtered. The filtrate was evaporated on a rotatory evaporator to afford oily mass. To the oily mass was added 400 mL diisopropylether and the reaction mixture was stirred for 8 hrs at room temperature. Thereafter the reaction mixture was filtered to afford Form A of Warfarin Potassium.
Example-4: Preparation of Form A of Warfarin Potassium
To a mixture of 25.0 gm of Warfarin acid in 100 mL isopropyl alcohol, was added potassium hydroxide 4.54 gm. The reaction mixture was heated to 60oC to 65oC, stirred for 7 hrs and cooled to room temperature. The reaction mixture was spray dried at feeding rate 10 and inlet temperature of 130 oC -140 oC to afford Form A of Warfarin Potassium.
,CLAIMS:1. Form A of Warfarin Potassium.
2. Form A of Warfarin Potassium according to claim 1, having X-ray powder diffraction pattern substantially as shown in FIG. 1.
3. Form A of Warfarin Potassium obtained by the process comprising the steps of;
a) providing the solution of Warfarin sodium in a suitable solvent and adjusting pH to about 1 to 3;
b) isolating the solid mass of step a) and dissolve in isopropyl alcohol in presence of potassium carbonate or potassium hydroxide;
c) heating the step b) solution to 50oC to about 80oC; and
d) isolating form A of Warfarin potassium.
4. A process for preparation of Form A of Warfarin potassium comprising the steps of;
a) providing the solution of Warfarin sodium in a suitable solvent and adjusting pH to about 1 to 3;
b) isolating the solid mass of step a) and dissolve in isopropyl alcohol in presence of potassium carbonate or potassium hydroxide;
c) heating the step b) solution to 50oC to about 80oC; and
d) isolating form A of Warfarin potassium.
5. The process according to claim 3 or 4, wherein the acid used to adjust the pH to about 1 to 3 is sulphuric acid.
6. The process according to claim 3 or 4, wherein the suitable solvent is selected from water, acetone, isopropyl alcohol and a combination thereof.
7. The process according to claim 3 or 4, wherein the Form A of Warfarin potassium is isolated by spray drying or by rotary evaporator.