FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"A PROCESS OF PREPARING ETHACRYNATE SODIUM"
Enaltec Labs Pvt Ltd. an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navy Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

A PROCESS OF PREPARING ETHACRYNATE SODIUM
FIELD OF THE INVENTION:
The present invention relates to process of preparing ethacrynate sodium and pharmaceutical composition thereof.
BACKGROUND OF THE INVENTION:
Ethacrynate sodium is chemically defined as sodium salt of [2, 3-dichloro-4-(2-methylene-l-oxobutyl) phenoxy] acetic acid and is known from US Patent No. 3,255,241 and is represented by compound of structural formula I.

Ethacrynic acid and its sodium salt are sold in USA under the proprietary name of "EDECRIN". It is indicated for treatment of edema when an agent with greater diuretic potential than those commonly employed is required.
• Treatment of the edema associated with congestive heart failure, cirrhosis of the liver and renal disease, including the nephrotic syndrome.
• Short-term management of ascites due to malignancy, idiopathic edema, and lymphedema.
• Short-term management of hospitalized pediatric patients, other than infants, with congenital heart disease or the nephrotic syndrome.

• Intravenous SODIUM EDECRIN is indicated when a rapid onset of diuresis is desired, e.g., in acutepulmonary edema, or when gastrointestinal absorption is impaired or oral medication is not practicable.
US Patent No. 3,255,241 describes the process of preparing ethacrynic acid and crystallization of ethacrynic acid in mixture of benzene and cyclohexane solvent and resulting ethacrynic acid has ameltingpointatll8.5-120.5°C.
US Patent No. 3,322,821 describes the process of preparing ethacrynic acid and crystallization of ethacrynic acid in methylcyclohexane and resulting ethacrynic acid has a melting point at 124.5-125.5°C.
US Patent No. 3,478,085 describes the process of preparing ethacrynic acid and crystallization of ethacrynic acid in cyclohexane and resulting ethacrynic acid is amorphous in nature and has a melting point at 124.5-125.5°C.
US Patent No. 3,479,402 describes the process of preparing ethacrynic acid and crystallization of ethacrynic acid in carbon tetrachloride and resulting ethacrynic acid has a melting point at 124.5-125.5°C.
Our own Indian patent application no. 2112/MUM/2011 describes process of preparing anhydrous ethacrynate sodium (Crystalline form II) comprising of treating solution of ethacrynic acid in water or polar aprotic solvents with sodium ion source at 0° to 50°C.
Drug Development And Industrial Pharmacy, 11 (2&3), 461-472 (1985) R.J. Yarwood and J.H. Collett describes process of preparing freeze dried ethacrynate sodium comprising of treating aqueous slurry of ethacrynic acid with sodium hydroxide up to pH 7.0 and resulting solution was poured into metal trays and rapidly frozen to -50°C at a rate of approximately -10°C min-1. The obtained crystalline ethacrynate sodium is unstable and it is converted in to amorphous ethacrynate sodium. It also describes ethacrynate sodium as hydrates (like pseudo hydrate, dihydrate).

Therefore, there is a need in art to develop stable solid state form of ethacrynate sodium and process of preparing thereof.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide stable form of ethacrynate sodium hereinafter refer as monohydrate form.
A second aspect of the present invention is to provide ethacrynate sodium monohydrate form characterized by having water content 5.0% wt/wt to 6.0% wt/wt.
A third aspect of the present invention is to provide processes of preparing ethacrynate sodium monohydrate form.
Another aspect of the present invention is to provide process of preparing ethacrynate sodium monohydrate form comprising the steps of:
a. providing a solution of ethacrynic acid in mixture of water and alcohol solvent,
b. treating a solution obtained in step-a with sodium ion source and,
c. isolating ethacrynate sodium monohydrate form.
Another aspect of the present invention is to provide process of preparing ethacrynate sodium monohydrate form comprising the steps of:
a. providing a solution of ethacrynic acid in an ether solvent,
b. treating a solution obtained in step-a with sodium ion source and,
c. isolating ethacrynate sodium monohydrate form.
Another aspect of the present invention is to provide pharmaceutical composition comprising ethacrynate sodium monohydrate form.

DETAIL DESCRIPTION OF THE INVENTION:
The ethacrynic acid used in the present invention may be formed by methods known in the art such as those described in U.S. Patent nos. 3,255,241; 3,322,821; 3,478,085 and 3,479,402 which are incorporated herein by reference only.
The solution of ethacrynic acid in mixture of water and alcohol solvent can be prepared by dissolving ethacrynic acid in alcohol solvent followed by addition of water at a temperature in the range of 20° to 60°C to get solution of ethacrynic acid in mixture of water and alcohol solvent.
The solution of ethacrynic acid in an ether solvent can be prepared by dissolving ethacrynic acid in ether solvent at a temperature in the range of 20° to 60°C to get solution of ethacrynic acid in an ether solvent.
The alcohol solvent can be selected from the group comprising, but not limited to, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.
The ether solvents can be selected from the group comprising, but not limited to, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.
The ethacrynate sodium monohydrate form can be prepared by treating the solution of ethacrynic acid in mixture of water and alcohol solvent with sodium ion source at a temperature in the range of 0° to 60°C to get solution of ethacrynate sodium in mixture of water and alcohol solvent and then stirring the solution of ethacrynate sodium in mixture of water and alcohol solvent at a temperature in the range of 0°C to 50°C for a period of 30 minutes to 38 hours.
The ethacrynate sodium monohydrate form can be prepared by treating the solution of ethacrynic acid in an ether solvent with sodium ion source at a temperature in the range of 0° to 60°C to get solution of ethacrynate sodium in an ether solvent and then stirring the solution of ethacrynate

sodium in an ether solvent at a temperature in the range of 0°C to 50°C for a period of 30 minutes to 38 hours.
The sodium ion source can be selected from the group comprising, but not limited to sodium hydroxide, sodium carbonate, sodium bicarbonate or sodium methoxide.
The sodium ion source used herein can be present in the form of aqueous solution.
The ethacrynate sodium monohydrate form may be isolated by the steps of filtration, centrifugation, washing, drying or the combinations thereof
The isolated ethacrynate sodium monohydrate form may be dried at a temperature in the range of 30°C to 50°C for a period of 1 hour to 12 hours under reduced pressure.
A pharmaceutical composition of ethacrynate sodium comprising ethacrynate sodium monohydrate form and pharmaceutically acceptable excipients.
An injectable depot formulation comprising ethacrynate sodium monohydrate form, wherein the X50 value of the sodium ethacrynate crystals are from 1 to 200 microns.
EXAMPLES:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the processes of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of ethacrynate sodium monohydrate form.
The ethacrynic acid (50gm) was dissolved in ethanol (500ml) at 25°C and then water (50ml) was added to the solution to get solution of ethacrynic acid in ethanol and water. The resulting solution was added sodium hydroxide solution (6.6gm in 28ml water) and stirred for 20 hours at

25-30°C. The resulting solids were filtered and washed with ethanol (50ml) and dried at 35-40°C for 12 hours under reduced pressure to get title compound. Yield: 48.2gm
Example 2: Preparation of ethacrynate sodium monohydrate form.
A solution of ethacrynic acid (lOOgm) in tetrahydrofuran (1600ml) was added a sodium hydroxide solution (13.2gm in 56ml water) and stirred for 36 hours at 30-35°C. The resulting solids were filtered and wash with tetrahydrofuran (100ml). The resulting solids were added tetrahydrofuran (500ml), stirred for 1 hour at 30-35°C and then filtered the solids, washed with tetrahydrofuran (100ml) and dried at 30-35°C for 8 hours under reduced pressure to get title compound. Yield: 96.5gm

WE CLAIM:
1. A process of preparing ethacrynate sodium monohydrate form comprising the steps of:
a. providing a solution of ethacrynic acid in mixture of water and alcohol solvent,
b. treating a solution obtained in step-a with sodium ion source and,
c. isolating ethacrynate sodium monohydrate form.
2. The process according to claim no. 1, wherein the solution of ethacrynic acid in mixture of water and alcohol solvent is prepared by dissolving ethacrynic acid in alcohol solvent followed by addition of water at a temperature in the range of 20° to 60°C to get solution of ethacrynic acid in mixture of water and alcohol solvent.
3. The process according to claim no. 1, wherein the ethacrynate sodium monohydrate form is prepared by treating the solution of ethacrynic acid in mixture of water and alcohol solvent with sodium ion source at a temperature in the range of 0° to 60°C to get solution of ethacrynate sodium in mixture of water and alcohol solvent and then stirring the solution of ethacrynate sodium in mixture of water and alcohol solvent at a temperature in the range of 0°C to 50°C for a period of 30 minutes to 38 hours.
4. The process according to claim nos. 1, 2 and 3, wherein the alcohol solvent is selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.
5. A process of preparing ethacrynate sodium monohydrate form comprising the steps of:
a. providing a solution of ethacrynic acid in an ether solvent,
b. treating a solution obtained in step-a with sodium ion source and,
c. isolating ethacrynate sodium monohydrate form.
6. The process according to claim no. 5, wherein the solution of ethacrynic acid in an ether
solvent is prepared by dissolving ethacrynic acid in ether solvent at a temperature in the
range of 20° to 60°C to get solution of ethacrynic acid in an ether solvent.

7. The process according to claim no. 5, wherein the ethacrynate sodium monohydrate form is prepared by treating the solution of ethacrynic acid in an ether solvent with sodium ion source at a temperature in the range of 0° to 60°C to get solution of ethacrynate sodium in an ether solvent and then stirring the solution of ethacrynate sodium in an ether solvent at a temperature in the range of 0°C to 50°C for a period of 30 minutes to 38 hours.
8. The process according to claim nos. 5, 6 and 7, wherein the ether solvents is selected from the group comprising of tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.
9. The process according to claim nos. 1, 3, 5, and 7, wherein the sodium ion source is selected from the group comprising of sodium hydroxide, sodium carbonate, sodium bicarbonate or sodium methoxide.
10. The process according to claim nos. 1 or 5, wherein the ethacrynate sodium monohydrate form is isolated by the steps of filtration, centrifugation, washing and dried at a temperature in the range of 30°C to 50°C for a period of 1 hour to 12 hours under reduced pressure.