FIELD OF THE INVENTION

The invention relates to an improved process for the preparation of Ethacrynate sodium of Formula-I. More particularly, the invention relates to an improved process for the preparation of Ethacrynate sodium of Formula I in a substantially pure form with a purity level greater than 99% wherein known impurities illustrated below as Formula II, Formula III, Formula IV and Formula V are either absent in the final product or are very well controlled and under the limit of as low as below 0.1% w/w. The invention also relates to highly pure crystalline form of Ethacrynate sodium and a process for the preparation thereof.

BACKGROUND OF THE INVENTION

Ethacrynic acid (EDECRIN), structurally as represented in Formula la below and chemically known as [2,3-dichloro-4-(2-methylene-l-oxobutyl) phenoxy] acetic acid is a white or practically white, crystalline powder. It is soluble in most of the organic solvents such as alcohols but very slightly soluble in water. Ethacrynic acid is supplied as a tablet for oral use. But Ethacrynic acid sodium (Ethacrynate sodium) of Formula I is soluble in water at 25 °C to the extent of about 7 %. Ethacrynic acid sodium salts (SODIUM EDECRIN) are relatively stable at pH 7 at room temperature. Ethacrynic sodium salt is supplied as a sterile freeze dried powder and administered intravenously. Ethacrynate sodium is used in the treatment of high blood pressure and the swelling caused by diseases like congestive heart failure, liver failure and kidney failure.

Ethacrynate sodium Ethacrynic acid (Formula la)

In 1985, R. J. Yarwood, and J. H. Collett (i.e., Drug Development and Industrial Pharmacy,! ! -1985, 461-472) discloses preparation of crystalline form of Ethacrynate sodium by uisng freeze-dried technique. Also, they inivestiagted water content as well as storage conditions related to its stability. All the known methods for the synthesis of Ethacrynic acid sodium involve the reaction of Ethacrynic acid with NaOH or Sodium bicarbonate solution and isolating the product using freeze drying or lyophilization. Since the Active Pharmaceutical Ingredient (API) is isolating directly from the aqueous solution, it is difficult to control the sodium content as well as the inorganic materials present in the API. Another drawback in the known art is the requirement of freeze drying or lyophlization for the isolation of the API, which is not suitable for the commercial production. Therefore, there is a need to develop an efficient and cost effective method for the commercial scale production of substantially pure stable form of Ethacrynate sodium, which is free from the above mentioned problems and known impurities.

OBJECTS OF THE INVENTION

Primary object of the invention to provide a novel process for the preparation of highly pure Ethacrynate sodium of formula I.

Another object of the invention is to provide a novel process for preparing highly pure Ethacrynate sodium of formula I, with purity level greater than 99%.

Another object of the invention is to provide a highly pure crystalline form of Ethacrynic acid sodium of formula I (Ehacrynate sodium). A further object of the invention is to provide novel processes for preparing highly pure crystalline Ethacrynic acid sodium of formula I (Ehacrynate sodium).

Yet another object of the invention is to provide substantially pure crystalline form of Ethacrynic acid sodium of formula I (Ehacrynate sodium) with known impurities represented by formula II, III, IV and formula V less than 0.1% w/w.

SUMMARY OF THE INVENTION

In one aspect the present invention provides an improved process for the preparation of highly pure Ethacrynate sodium of formula I as shown in below reaction scheme-

CI O

CI

Etiiacryiiic acid Ethacrynate sodium {Formula la) (Formula I)

The above process comprises the steps of:

(a) treating a solution of Ethacrynic acid (formula la) solution in polar protic solvent with sodium salt of alkyl carboxylic acid solution in polar protic solvent;

(b) heating the solution for 1-2 hrs;

(c) filtering and washing the solid with polar protic solvent or mixture thereof; wherein the step (a) involves treatment of Ethacrynic acid (Formula la) with equimolar amount of sodium salt of alkyl carboxylic acid (RCOONa); and wherein the reaction steps (a) and (b) are carried out at temperature range about 25-80 °C. In another aspect, the invention provides an improved process for the preparation of highly pure Ethacrynate sodium of formula I comprising the steps of:

(a) treating a solution of Ethacrynic acid (formula la) in polar protic solvent or mixture thereof with sodium salt of alkyl carboxylic acid solution in polar protic solvent or mixture thereof at 50-55°C; (b) heating the solution for 1-2 hrs at 75-80 °C;

(c) filtering and washing the solid with polar protic solvent or mixture thereof.

In another aspect the present invention provides a process for preparing highly pure crystalline form of Ethacrynate sodium (Formula I) as shown in below reaction scheme-

comprising the steps of:

(a) treating a solution of Ethacrynic acid (formula la) in polar solvent with a solution of sodium ion source in polar protic solvent to get Ethacrynate sodium solution at 50-55°C;

(b) heating the solution for 1-2 hrs at 70-80°C;

(c) cooling the suspension and filtering the solid at 25-30°C;

(d) washing and slurring the solid in polar protic solvents or mixtures thereof;

(e) isolating Ethacrynate sodium (formula I) and drying at below 55°C.

The crystalline form obtained above is characterized by X-ray diffraction pattern having peaks at 3.3, 6.5 and 33.2 +0.2 degrees two theta.

In any of the above process the quantity of sodium salt of alkyl carboxylic acid in step (a) is in an amount ranging from 0.5 to 1.4 equivalents; preferably in an amount ranging from 0.8 to 1.3 equivalents.

In any of the above process the sodium ion source sodium salt of alkyl carboxylic acid in step (a) is selected from group comprising sodium salt of methyl carboxylic acid, sodium salt of ethyl carboxylic acid, sodium salt of propyl carboxylic acid or 2-ethyl hexanoic acid sodium salt (sodium 2-ethyl hexanoate) or the like; preferably the sodium salt of alkyl carboxylic acid in step (a) is sodium 2-ethyl hexanoate. In any of the above process the solvent(s) is/are a single solvent or mixture of any two solvents selected from the group comprising lower alkyl alcohols such as ethanol, methanol, isopropyl alcohol, n-propanol and n-butanol; preferably when mixture is used the solvent is mixture of isopropyl alcohol and methanol.

The final product Ethacrynate sodium of formula I as obtained by any of above said processes is greater than 99% pure and comprises less than 0.1% w/w of known impurities of formula II, formula III, formula IV and formula V.

The above said isolation step (e) comprises the steps of filtration, washing and drying or the combinations thereof. The above said step (d) is performed at a temperature range of -5 to 30°C or preferably at 10 to 35°C for a period of 1-2 hrs.

In another aspect the present invention further provides a crystalline form of Ethacrynic acid sodium of formula I, wherein said crystalline form is characterized by X-ray diffraction pattern having peaks at 3.3, 6.5 and 33.2 +0.2 degrees two theta and further characterized X-ray diffraction having the peaks as depicted in below table- 1, X-ray diffraction as depicted in figure- 1 and differential scanning chromatogram (DSC) as depicted in Figure-2. Table- 1

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

Figure- 1: Illustrates a powder X-ray diffraction pattern of crystalline form of Ethacrynic acid sodium (Ethacrynate sodium, formula I).

Figure-2: Illustrates a differential scanning chromatogram of crystalline form of Ethacrynic acid sodium (Ethacrynate sodium, formula I).

DETAILED DESCRIPTION THE INVENTION

The present invention discloses an improved process for the preparation of Ethacrynate sodium (Formula I) in a substantially pure form with purity level greater than 99%, wherein known impurities such as Formula II, Formula III, Formula IV and Formula V as shown below are absent in the final product or very well controlled under the limit. The final product comprises less than 0.1% w/w of impurity compounds of structural formula II, III, IV and formula V. Compound of formula I is used as an API in the pharmaceutical preparations/composition used in the treatment of high blood pressure and the swelling caused by diseases like congestive heart failure, liver failure and kidney failure.

Thus in one aspect, the present invention provides novel processes for the preparation of Ethacrynic acid sodium (Ethacrynate sodium, Formula I) in significantly high yield and substantially pure crystalline form as shown in below Scheme- 1:

Etiiacryaic acid Ethacrynate sodium

(Foi!iiala la) (Formula I)

Scheme- 1

The present process involves treatment of Ethacrynic acid (Formula la) with equimolar amount of sodium salt of alkyl carboxylic acid (RCOONa) in an organic solvent or mixture of organic solvents. The salt formation of Ethacrynic acid with sodium salt of alkyl ((R represent alkyl and Na represent sodium), i.e., methyl, ethyl, propyl, etc) carboxylic acid can be carried out at 25 to 80 °C and the quantity of sodium salt of alkyl carboxylic acid can be used in amount ranging from 0.5 to 1.4 equivalents.

Suitable sodium salt of alkyl carboxylic acid used for this reaction step may be selected from the group comprising sodium salt of methyl carboxylic acid, sodium salt of ethyl carboxylic acid, sodium salt of propyl carboxylic acid or 2-ethyl hexanoic acid sodium salt or the like.

Suitable organic solvent or mixture thereof may be selected from polar solvents selected from the group comprising lower alkyl alcohols such as ethanol, methanol, isopropyl alcohol, ft-propanol, n-butanol etc and mixtures thereof. In one embodiment, the sodium salt of alkyl carboxylic acid (RCOONa) used is sodium 2- ethyl hexanoate. Number of equivalents of sodium salt of alkyl carboxylic acid used ranges from 0.5 to 1.4 equivalents and in one particular reaction the quantity used is from about 0.8 to 1.3 equivalents. Temperature of the reaction ranges from about 40 to 80 °C and best results is obtained at temperature range of 60-80 °C.

Finally, the product is isolated from the reaction mixture by cooling it to a temperature range from about -5 to 30°C.

In another aspect the obtained Ethacrynic acid sodium is slurred in polar protic solvents or mixtures thereof. Ethacrynic Acid sodium obtained by the present process is 95-98% pure and is further purified from polar protic solvents selected from the group comprising alcohols like Methanol, Ethanol, Isopropyl alcohol; water; or mixtures thereof.

The major process impurities which are eliminated during the purification of Ethacrynic acid sodium according to the present invention are impurities of formula II, III, IV and V (as shown above), thus obtaining Ethacrynic acid sodium in substantially pure form with a purity greater than 99%.

In one aspect the present invention provides a novel process for preparing Ethacrynic acid sodium of formula I comprising the steps of:

(a) treating a solution of Ethacrynic acid (formula la) in polar protic solvent or mixture thereof with sodium salt of alkyl carboxylic acid solution in polar protic solvent or mixture thereof at 50-55°C;

(b) heating the solution for 1-2 hrs at 75-80 °C;

(c) filtering and washing the solid with polar protic solvent or mixture thereof;

wherein the step (a) involves treatment of Ethacrynic acid (Formula la) with equimolar amount of sodium salt of alkyl carboxylic acid (RCOONa).

The said polar protic solvents are solvents selected from the group comprising alcohols like Methanol, Ethanol, Isopropyl alcohol; water; or mixtures thereof. In one embodiment the organic solvent used is mixture of Isopropyl alcohol and Methanol (MeOH).

The said sodium salt of alkyl carboxylic acid is selected from group comprising sodium salt of methyl carboxylic acid, sodium salt of ethyl carboxylic acid, sodium salt of propyl carboxylic acid or 2-ethyl hexanoic acid sodium salt or the like. Preferably in one embodiment, the said sodium salt of alkyl carboxylic acid is 2-ethyl hexanoic acid sodium salt (sodium 2-ethyl hexanoate).

In another aspect of the invention provides a crystalline form of Ethacrynic acid sodium of formula I, wherein the said crystalline form of Ethacrynic acid sodium (Ethacrynate sodium, formula I) is characterized by powder X-ray diffraction pattern as presented in Figure- 1 and differential scanning chromatogram (DSC) as presented in Figure-2.

The crystalline form of sodium ethacrynate may be formed by slurring the solution of sodium ethacrynate polar protic solvents at a temperature in the range of 10 to 35°C for a period of 1-2 hrs. The crystalline form of ethacrynic acid sodium may be isolated by the steps of filtration, washing and drying or the combinations thereof.

Optionally the crystalline form of ethacrynic acid sodium is obtained by slurring ethacrynic acid sodium in a mixture of 1% water in polar aprotic solvent at 25-30°C for 1- 2 hrs.

The isolated crystalline form of sodium ethacrynate may be dried at a temperature of less than 50°C under reduced pressure until MC (Moisture Content) reaches between 5 to 6.5.

In one embodiment the present invention provides a crystalline form of Ethacrynate sodium which may be characterized by X-ray diffraction pattern having peaks at 3.3, 6.5 and 33.2 +0.2 degrees two theta.

The crystalline form of said Ethcrynate sodium may be characterized by X-ray diffraction as depicted in figure- 1.

The said crystalline form of Ethacrynate sodium may be characterized by X-ray diffraction having the peaks as depicted in table- 1.

Table-1:

33.18 2.69 100

33.58 2.66 6

36.63 2.45 8

40.11 2.24 7

43.64 2.07 8

Thus in one embodiment the invention provides a process for preparing crystalline form of Ethacrynate sodium (Formula I) comprising the steps of : (a) treating a solution of Ethacrynic acid (formula la) in polar solvent with a solution of sodium ion source in polar protic solvent to get Ethacrynate sodium solution at 50-55°C;

(b) heating the solution for 1-2 hrs at 70-80°C;

(c) cooling the suspension and filtering the solid at 25-30°C;

(d) washing and slurring the solid in polar protic solvents or mixtures thereof;

(e) isolating Ethacrynate sodium (formula I) and drying at below 55°C.

Another aspect the invention provides substantially pure crystalline form of ethacrynic acid sodium (Ethacrynate sodium) having impurities less than 0.1% w/w of compounds of structural formula II, III, IV and formula V.

In one embodiment in any of the above said processes, the Ethacrynic acid sodium (formula I) obtained is more than 99% pure and comprises impurities less than 0.1% w/w of com ounds of structural formula II, III, IV and formula V (2-ethylhexanoic acid).

Ethacrynic acid Fromula I

Scheme-2 Moreover, the sodium ethacrynate as obtained by the novel process by any of the processes as described above and above Scheme- 1 and Scheme-2, is substantially pure, more specifically greater than 99% pure; and the known impuritis such as impurity Formula II, III, IV and V are absent or very well controlled under the limit, more specifically said impurities are less than 0.1% w/w in the fiinal product.

In order to test the advantages of the developed process over the prior art procedure, ethacrynic acid sodium is synthesized using NaOH (1.1 equiv.) and NaHC0 ₃ (l.lequiv.) as the source of sodium. It is observed that the acid impurity II is increased from 0.33 % to 3.33 % under the reaction conditions. Comparison of purities of sodium Ethacrynate synthesized using inorganic bases and 2-ethyl hexanoate is presented in Table 2.

Table-2: Comparison study of preparation of Ethacrynate sodium with different reagents

ND: Not Detected

In conclusion, the authors have disclosed a novel process for the synthesis of Ethacrynate sodium.

DEFINITIONS

The following terms shall have for the purpose of this application, including the claims appended here to, the respective meanings set forth below.

The term "sodium salt of alkyl carboxylic acids" when used herein includes linear or branched alkyl groups of carboxylic acid sodium such as sodium methylcarboxylic acid, sodium ethylcarboxylic acid, sodium propylcarboxylic acid, sodium isopropyl carboxylic acids , sodium 2-ethyl hexanoate or the like.

The term 'alcoholic solvent' when used herein includes lower alkyl alcohols such as ethanol, methanol, isopropyl alcohol, n-propanol, n-butanol or the like.

The term solvent when used herein includes protic solvent, or mixtures thereof.

MC: Moisture Content

API: Active Pharmaceutical Ingredient The following examples further illustrate the present invention, but should not be construed in any way as to limit its scope.

Example- 1

Preparation of Ethacrynate Sodium of formula I

A solution of Ethacrynic acid (formula la) (30 g, 0.098 mol) in isopropyl alcohol (240 mL) was added a solution of sodium 2-ethyl hexanoate (19.7 g, 0.118 mol) in 240 ml of isopropyl alcohol at 50-55°C. The resultant solid suspension was stirred at same temperature for 2.0 hr. Then, raised the reaction mass temperature to 75-80°C and stirred for 2.0 hr. The resulting solid suspension was cooled to room temperature, filtered and washed with isopropyl alcohol (150 mL). The obtained solid was dried for 10-12 hr at below 55 °C under reduced pressure to get title compound as white solid.

Yield: (30 g, 93%)

Purity: 99.82 (by HPLC)

Example-2

Preparation of Ethacrynate Sodium of formula I

A solution of sodium 2-ethyl hexanoate (6.57 g, 0.039mol) in 80mL of isopropyl alcohol was heated to 50-55 °C. Then, added a solution of ethacrynic acid (formula la) (10 g, 0.032 mol) in isopropyl alcohol (80 mL) at same temperature. The resultant solid suspension was stirred at same temperature for 2.0 hr. Then, raised the reaction mass temperature to 75-80 °C and stirred for 2.0 hr. The resulting solids were filtered and washed with isopropyl alcohol (50 mL). The obtained solid was dried under reduced pressure for 10-12 hr at below 55 °C to get title compound as white solid.

Yield: (9.5 g, 88%) Purity: 99.79 (by HPLC)

Example-3

Preparation of Ethacrynate Sodium of formula I

A solution of ethacrynic acid (formula la) (10 g, 0.032 mol) in isopropyl alcohol :MeOH (60:20 mL) was added a solution of sodium 2-ethyl hexanoate (4.38 g, 0.026 mol) in 80 mL of isopropyl alcohol: MeOH (6:2) at 50-55 °C. The resultant solid suspension was stirred at same temperature for 2.0 hr. Then, raised the reaction mass temperature to 75-80 °C and stirred for 2.0 hr. The resulting solids were filtered, washed with isopropyl alcohol (50 mL) and dried under reduced pressure for 10-12 hr at below 55 °C to get title compound as white solid.

Yield: (9.0 g, 84%)

Purity: 99.62 (by HPLC) Example-4

Preparation of Ethacrynate Sodium of formula I

A solution of ethacrynic acid (formula la) (25 g, 0.082 mol) in isopropyl alcohol (200 mL) was added a solution of sodium 2-ethyl hexanoate (13.7 g, 0.082 mol) in 200 mL of isopropyl alcohol at 50-55 °C. The resultant solid suspension was stirred at same temperature for 2.0 hr. Then, raised the reaction mass temperature to 75-80 °C and stirred for 2.0 hr. The resulting solids were cooled to room temperature, filtered and washed with isopropyl alcohol (150 mL). The obtained solid was dried for 10-12 hr at below 55 °C under reduced pressure to get title compound as white solid.

Yield: (9.0 g, 90%)

Purity: 99.86 (by HPLC)

Example-5

Preparation of Ethacrynate Sodium of formula I

A solution of sodium 2-ethyl hexanoate (6.57 g, 0.039 mol) in 80 mL of isopropyl alcohol was heated to 50-55 °C. Then, added a solution of ethacrynic acid (formula la) (10 g, 0.032 mol) in isopropyl alcohol (80 mL) at same temperature. The resultant solid suspension was stirred at same temperature for 2.0 hr. Then, raised the reaction mass temperature to 75-80 °C and stirred for 2.0 hr. The resulting solids were cooled to 0-5°C and filtered, washed with isopropyl alcohol (50 mL). The obtained solid was dried under reduced pressure for 10-12 hr at below 55 °C to get title compound as white solid.

Yield: (9.8 g, 85%)

Purity: 99.8 (by HPLC)

Example-6

Preparation of Ethacrynate Sodium of formula I

A solution of sodium 2-ethyl hexanoate (6.02 g, 0.039 mol) in 80 mL of isopropyl alcohol was heated to 50-55 °C. Then, added a solution of ethacrynic acid (formula la) (10 g, 0.032 mol) in isopropyl alcohol (80 mL) at same temperature. The resultant solid suspension was stirred at same temperature for 15 minutes. Then, raised the reaction mass temperature to 70-75 °C and stirred for 1.0 hr. The resulting solids were cooled to 20-25°C and filtered, washed with isopropyl alcohol (50 mL). The obtained solid was dried under reduced pressure for 10-12 hr at below 55 °C to get title compound as white solid.

Yield: 80-85%

Purity: 99.9 (by HPLC)

Example-7

Process to remove unreacted Ethacrynic acid and 2-ethylhexanoic acid (formula V) impurity:

10 g of ethacrynic acid (formula la) sodium was dissolved in 100 ml of Isopropyl alcohol and stirred for 30 minutes at 25-30°C. Filtered and washed the solid with 100 ml of Isopropyl alcohol. The above obtained solid was taken in 80 ml of Isopropyl alcohol and dried under vacuum for 4-5hrs at 40-45°C until MC complies (MC limit: 5.0-6.5). If MC does not comply then the obtained solid was taken into 80 ml of 1% solution of water in Isopropyl alcohol mixture and stirred for 30 min at 25-30 °C. Filtered and washed the solid with 2X100 mL of Isopropyl alcohol. Dried the final compound under vacuum for 4- 5 hrs at 40-45 °C until MC complies.

Storage conditions: The obtained compound was stored under nitrogen atmosphere at - 20°C.

Yield: 80-85 %

Purity: 99.9(by HPLC)

MC: 5.6 % w/w