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
"NOVEL POLYMORPHIC FORM OF ETHACRYNIC ACID AND SODIUM ETHACRYNATE"
Enaltec Labs Pvt Ltd. an Indian Company, having its Registered Office at 17thFloor, Kesar Solitaire, PlotNo.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

NOVEL POLYMORPHIC FORM OF ETHACRYNIC ACID AND SODIUM
ETHACRYNATE
FIELD OF THE INVENTION:
The present invention relates to novel polymorphic form of ethacrynic acid herein after refer as crystalline form I and novel polymorphic form of sodium ethacrynate herein after refer as crystalline form II. The present invention further relates to processes for preparing crystalline form I of ethacrynic acid and crystalline form II of sodium ethacrynate and pharmaceutical composition thereof.
BACKGROUND OF THE INVENTION:
Ethacrynic acid is an unsaturated ketone derivative of an aryloxyacetic acid. It is designated chemically as [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 "EDECR1N". 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 crystallization of ethacrynic acid in mixture of benzene and cyclohexane solvent and resulting ethacrynic acid has a melting point at 118.5-120.5°C.
US Patent No. 3,322,821 describes the 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 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 crystallization of ethacrynic acid in carbon tetrachloride and resulting ethacrynic acid has a melting point at 124.5-125.5°C.
Drug Development And Industrial Pharmacy, 11 (2&3), 461-472 (1985) R.J. Yarwood and J.H. Collett discloses crystalline form of sodium ethacrynate herein after refer as crystalline form I of sodium ethacrynate and also discloses amorphous form of sodium ethacrynate. The crystalline form of sodium ethacrynate describe in it is unstable and converted in to amorphous form.
Therefore, there is a need in art to develop stable crystalline form of sodium ethacrynate and additional solid state forms of ethacrynic acid and sodium ethacrynate.
The present applicant of the patent has surprisingly found a new crystalline polymorphic form of ethacrynic acid, which is designated as crystalline form I and stable crystalline form II of sodium ethacrynate.

SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a novel polymorphic form of ethacrynic acid hereinafter refer as crystalline form I.
A second aspect of the present invention is to provide a novel polymorphic form of sodium ethacrynate hereinafter refer as crystalline form II.
A third aspect of the present invention is to provide processes for preparing crystalline form I of ethacrynic acid.
A fourth aspect of the present invention is to provide processes for preparing crystalline form II of sodium ethacrynate.
Another aspect of the present invention is to provide a pharmaceutical composition comprising crystalline form I of ethacrynic acid.
Another aspect of the present invention is to provide a pharmaceutical composition comprising crystalline form II of sodium ethacrynate.
Another aspect of the present invention is to provide a process for preparing crystalline form I of ethacrynic acid comprising the steps of:
a. providing a solution of ethacrynic acid in non-polar organic solvents
b. stirring the solution obtained in step a for period of 30 minutes to 8 hours at a
temperature in the range of 0°C to 30°C and
c. isolating crystalline form I of ethacrynic acid.
Another aspect of the present invention is to provide a process for preparing crystalline form II of sodium ethacrynate comprising the steps of:
a. treating a solution of ethacrynic acid in water with sodium ion source to get sodium ethacrynate solution,

b. stirring the solution obtained in step a for period of 30 minutes to 6 hours at a
temperature in the range of 0°C to 30°C and
c. isolating crystalline form II of sodium ethacrynate.
Another aspect of the present invention is to provide a process for preparing crystalline form II of sodium ethacrynate comprising the steps of:
a. treating a solution of ethacrynic acid in polar aprotic solvents with sodium ion source to
get sodium ethacrynate solution,
b. stirring the solution obtained in step a for period of 30 minutes to 15 hours at a
temperature in the range of 0°C to 50°C and
c. isolating crystalline form II of sodium ethacrynate.
Another aspect of present invention is to provide crystalline form I of substantially pure ethacrynic acid and crystalline form II of substantially pure sodium ethacrynate having less than 0.1% weight / weight of compounds of structural formula II, III, IV, V, VI, VII and VIII.


Another aspect of present invention is to provide crystalline form I of ethacrynic acid, wherein the X50 value of the crystals are from 1 to 200 microns.
Another aspect of present invention is to provide an injectable depot formulation comprising crystalline form II of sodium ethacrynate, wherein the X50 value of the crystals are from 1 to 200 microns.
DETAIL DESCRIPTION OF THE INVENTION:
A crystalline form I of ethacrynic acid may be characterized by X-ray diffraction pattern having peaks at 6.0, 12.1, 13.2, 14.8, 15.2, 15.8, 16.6, 18.7, 20.3, 21.7, 22.1, 24.8, 25.0, 26.0, 26.6, 27.3 ± 0.2 degrees two theta.
A crystalline form I of ethacrynic acid may be characterized by X-ray diffraction pattern as depicted in Figure 1.
A crystalline form I of ethacrynic acid may be characterized by X-ray diffraction pattern having following peaks:

Pos.
[°2Th.] Height
[ctsl Area
[cts*°2Th.] FWHM [°2Th.] d-spacing
[Al Re!. Int.
[%]
6.0635 2697.98 400.68 0.1004 14.56434 100.00
6.7561 44.01 6.54 0.1004 13.07275 1.63
9.5051 23.65 5.85 0.1673 9.29720 0.88
12.1479 594.43 117.71 0.1338 7.27988 22.03
12.5431 167.44 24.87 0.1004 7.05137 6.21
13.2269 692.85 102.90 0.1004 6.68834 25.68
14.5065 188.95 32.74 0.1171 6.10113 7.00

14.8043 1188.83 176.56 0.1004 5.97907 44.06
15.2476 159.65 23.71 0.1004 5.80622 5.92
15.8889 442.74 65.75 0.1004 5.57326 16.41
16.6924 226.41 33.63 0.1004 5.30677 8.39
17.3594 46.87 8.12 0.1171 5.10435 1.74
18.7023 341.64 50.74 0.1004 4.74075 12.66
19.0357 40.46 6.01 0.1004 4.65846 1.50
19.4579 91.15 13.54 0.1004 4.55833 3.38
19.9233 29.53 8.77 0.2007 4.45288 1.09
20.1348 52.18 9.04 0.1171 4.40658 1.93
20.3702 165.63 32.80 0.1338 4.35618 6.14
20.7735 71.38 10.60 0.1004 4.27252 2.65
21.7311 179.45 35.53 0.1338 4.08636 6.65
22.1620 1676.12 331.90 0.1338 4.00788 62.12
23.6997 51.98 7.72 0.1004 3.75119 1.93
24.2355 145.22 28.76 0.1338 3.66947 5.38
24.8025 1187.29 235.10 0.1338 3.58684 44.01
25.0570 594.07 88.23 0.1004 3.55099 22.02
26.0194 158.79 39.30 0.1673 3.42179 5.89
26.6409 897.25 177.67 0.1338 3.34335 33.26
27.3032 442.48 76.67 0.1171 3.26373 16.40
27.8469 55.72 11.03 0.1338 3.20124 2.07
28.2524 50.04 9.91 0.1338 3.15620 1.85
28.6290 149.87 22.26 0.1004 3.11554 5.55

29.6884
77.57 11.52 0.1004 3.00674 2.88
29.8846 127.46 18.93 0.1004 2.98743 4.72
30.5181 160.51 31.78 0.1338 2.92685 5.95
31.1027 144.62 28.64 0.1338 2.87316 5.36
31.7982 179.05 35.45 0.1338 2.81188 6.64
32.1995 44.92 11.12 0.1673 2.77775 1.66
32.5058 23.59 4.67 0.1338 2.75227 0.87
33.1647 118.07 35.07 0.2007 2.69908 4.38
33.9006 21.16 3.14 0.1004 2.64216 0.78
34.3997 97.89 33.92 0.2342 2.60495 3.63
34.9371 41.80 8.28 0.1338 2.56611 1.55
35.3801 26.96 8.01 0.2007 2.53498 1.00
36.7813 22.42 3.33 0.1004 2.44156 0.83
37.3359 50.80 12.57 0.1673 2.40656 1.88
37.7299 44.50 7.71 0.1171 •2.38233 1.65
38.3805 44,06 15.27 0.2342 2.34343 1.63
38.7777 33.58 6.65 0.1338 2.32033 1.24
39.6057 17.25 5.98 0.2342 2.27371 0.64
A crystalline form II of sodium ethacrynate may be characterized by X-ray diffraction pattern
having peaks at 3.3, 6.6 ± 0.2 degrees two theta.
A crystalline form II of sodium ethacrynate may be characterized by X-ray diffraction pattern as depicted in Figure 2.

A crystalline form II of sodium ethacrynate may be characterized by X-ray diffraction pattern having following peaks:

Pos.
[°2Th.] Height [ets] Area
|cts*°2Th.| FWHM
[°2Th.I d-spacing
[A] Rel. Int.
3.3586 9154.75 1494.06 0.1224 26.28548 100.00
6.6582 1443.92 196.37 0.1020 13.26474 15.77
7.0021 77.11 12.58 0.1224 12.61407 0.84
9.9237 150.55 32.76 0.1632 8.90599 1.64
17.1418 70.07 22.87 0.2448 5.16863 0.77
17.9301 72.11 27.46 0.2856 4.94314 0.79
20.0188 38.92 16.94 0.3264 4.43186 0.43
20.9741 25.88 16.90 0.4896 4.23211 0.28
22.1835 5.18 4.51 0.6528 4.00404 0.06
23.9590 45.78 34.86 0.5712 3.71118 0.50
24.9658 85.13 23.16 0.2040 3.56376 0.93
"28.5895 15.16 13,19 0.6528 3.11975 0.17
30.3164 103.68 16.92 0.1224 2.94586 1.13
31.5884 24.39 21.23 0.6528 2.83008 0.27
33.4013 508.74 138.38 0.2040 2.68050 5.56
33.7053 423.62 115.22 0.2040 2.65701 4.63
37.0788 7.34 7.99 0.8160 2.42265 0.08
38.3962 13.55 8.85 0.4896 2.34250 0.15

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.
A solution of ethacrynic acid in non-polar organic solvents may be formed by suspending ethacrynic acid in non-polar organic solvents at a temperature in the range of 20°C to 60°C.
The examples of non-polar organic solvents may include but not limited to pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1, 4-dioxane, chloroform, diethyl ether, methyl tertiary butyl ether or mixture(s) thereof.
A solution of ethacrynic acid in non-polar organic solvents may have ether organic solvents.
The examples of ether solvents may include diethyl ether, diisopropyl ether, dioxane or methyl tertiary butyl ether.
The crystalline form I of ethacrynic acid may be formed by stirring the solution of ethacrynic acid in non-polar organic solvents at a temperature in the range of 0°C to 30°C for a period of 30 minutes to 8 hours.
The crystalline form I of ethacrynic acid may be isolated by the steps of filtration, centrifugation, washing, drying or the combinations thereof
The isolated crystalline form I of ethacrynic acid may be dried at a temperature in the range of 40°C to 60°C for a period of 2 hours to 12 hours under reduced pressure.
The solution of ethacrynic acid in water or polar aprotic solvents may be formed by dissolving ethacrynic acid in water or polar aprotic solvents at 20° to 50°C.
A solution of sodium ethacrynate may be formed by treating solution of ethacrynic acid in water or polar aprotic solvents with sodium ion source at 0° to 50°C.

The examples of polar aprotic solvents may include but not limited to dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethylsulfoxide or mixture(s) thereof.
The source of sodium ion may include but not limited to sodium hydroxide, sodium bicarbonate or sodium methoxide.
The crystalline form II of sodium ethacrynate may be formed by stirring the solution of sodium ethacrynate in water or polar aprotic solvents at a temperature in the range of 0°C to 50°C for a period of 30 minutes to 15 hours.
The crystalline form II of sodium ethacrynate may be isolated by the steps of filtration, centrifugation, washing, drying or the combinations thereof
The isolated crystalline form II of sodium ethacrynate may be dried at a temperature in the range of 40°C to 60°C for a period of 2 hours to 8 hours under reduced pressure.
A pharmaceutical composition of ethacrynic acid comprising crystalline form I of ethacrynic acid and pharmaceutically acceptable excipients.
A pharmaceutical composition of sodium ethacrynate comprising crystalline form II of sodium ethacrynate and pharmaceutically acceptable excipients.
An injectable depot formulation comprising crystalline form 11 of sodium ethacrynate, wherein the X50 value of the sodium ethacrynate crystals are from 1 to 200 microns.
BRIEF DESCRIPTION OF THE DRAWING:
Figure 1 illustrates a powder X-ray diffraction pattern of crystalline form 1 of ethacrynic acid.

Figure 2 illustrates a powder X-ray diffraction pattern of crystalline form II of sodium ethacrynate.
XRD diffraction measurement was performed on X-Ray powder diffractometer Bruker D8
Advance powder diffractometer with the detector Lynxeye (Bruker). The analysis conditions
were as follows:
Scan range [°2-theta]: 2-39.98;
Scan mode: continuous;
Step size [°2-theta]: 0.0170°;
Scan step time[s]: 51.04 seconds;
Sample spin: 15 rpm;
Sample holder: glass;
Measurement Temperature [°C]: 25
Anode Material: Cu
K-Alpha[A]: 1.54060
Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The sample might be mixed with n-dodecane in order to avoid the environment contamination by airborne particles coming from the powder. The ground sample or its suspension with n-dodecane was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.
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 crystalline form I of ethacrynic acid
The Ethacrynic acid (lOgm) was suspended in cyclohexane (25ml) and resulting solution was
stirred for 1 hour at 25-30°C. The resulting solids were filtered, washed with cyclohexane (5ml)
and dried at 50-55°C for 5 hours under reduced pressure to get title compound.
Yield:-9.7gm
Purity: 99.94% (By HPLC)
XRD: As depicted in Figure 1
Example 2: Preparation of crystalline form I of ethacrynic acid
A solution of Ethacrynic acid (lOgm) in methyl tertiary butyl ether (10ml) was added cyclohexane (50ml), and then resulting suspension was stirred for 1 hour at 25-30°C. The resulting solids were filtered, washed with cyclohexane (10ml). The resulting solids were added water (15ml), concentrated hydrochloric acid (0.3ml) and then resulting suspension was stirred for 30 minutes at 25-30°C. The resulting solids were filtered, washed with water (10ml) and dried at 50-55°C for 8 hours under reduced pressure to get title compound. Yield: 9.6gm
Purity: 99.98% (By HPLC) XRD: As depicted in Figure 1
Example 3: Preparation of crystalline form II of sodium ethacrynate
A solution of ethacrynic acid (30gm) in water (100ml) was added a sodium bicarbonate solution
(15gm in 500ml water) and stirred for 1 hour at 25-30°C. The resulting solution was filtered
through hyflo bed and cool the filtrate up to 0-5°C and then maintain the solution for 1 hour at
same temperature. The resulting solid was added acetone (150ml) and stirred for 30 minutes at 0-
10°C and then filtered the solid obtained, wash with acetone (100ml) and dried at 50-55°C for 4
hours under reduced pressure to get title compound.
Yield:21.5gm
Purity: 99.92% (By HPLC)
XRD: As depicted in Figure 2

Example 4: Preparation of crystalline form II of sodium ethacrynate
A solution of ethacrynic acid (150gm) in tetrahydrofuran (2400ml) was added a sodium hydroxide solution (19.8gm in 84ml water) and stirred for 12 hours at 30-35°C. The resulting solids were filtered and wash with tetrahydrofuran (150ml). The resulting solids were added tetrahydrofuran (750ml), stirred for 1 hour at 30-35°C and then filtered the solids, washed with tetrahydrofuran (150ml) and dried at 55-60°C for 8 hours to get title compound. Yield: 144.8gm Purity: 99.98% (By HPLC) XRD: As depicted in Figure 2

WE CLAIM:
1. A compound which is crystalline form I of ethacrynic acid having substantially the same X-ray diffraction pattern as depicted in Figure 1 and further characterized by X-ray diffraction pattern having peaks at 6.0, 12.1, 13.2, 14.8, 15.2, 15.8, 16.6, 18.7,20.3,21.7, 22.1, 24.8, 25.0, 26.0, 26.6, 27.3 ± 0.2 degrees two theta.
2. A process for preparing crystalline form I of ethacrynic acid comprising the steps of:
a. providing a solution of ethacrynic acid in non-polar organic solvents
b. stirring the solution obtained in step a for period of 30 minutes to 8 hours at a
temperature in the range of 0°C to 30°C and
c. isolating crystalline form I of ethacrynic acid.
3. The process according to claim no. 2 wherein, a solution of ethacrynic acid in non-polar organic solvents is formed by suspending ethacrynic acid in non-polar organic solvents such as pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1, 4-dioxane, chloroform, diethyl ether, methyl tertiary butyl ether or ether organic solvents such as diethyl ether, diisopropyl ether, dioxane or methyl tertiary butyl ether at a temperature in therangeof20°C to 60°C.
4. The process according to claim no. 2 wherein, crystalline form I of ethacrynic acid is formed by stirring the solution of ethacrynic acid in non-polar organic solvents at a temperature in the range of 0°C to 30°C for a period of 30 minutes to 8 hours and isolated by the steps of filtration, centrifugation, washing, drying at a temperature in the range of 40°C to 60°C for a period of 2 hours to 12 hours under reduced pressure.
5. The compound which is crystalline form II of sodium ethacrynate having substantially the same X-ray diffraction pattern as depicted in Figure 2 and further characterized X-ray diffraction pattern having peaks at 3.3, 6.6 ± 0.2 degrees two theta.
6. A process for preparing crystalline form II of sodium ethacrynate comprisingthe steps of:

a. treating a solution of ethacrynic acid in water or polar aprotic solvents with
sodium-ion source to'get sodium ethacrynate solution,
b. stirring the solutionvobtained in stop a for period of 30 minutes to 15 hours at a
temperature in the range of 0°C to 50°C and
c. isolating crystalline form II of sodium ethacrynate.
7. The process according to claim no. 6 wherein, the solution of ethacrynic acid in water or polar aprotic solvents is formed by dissolving ethacrynic acid in water or polar aprotic solvents such as dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethylsulfoxide or mixture(s) thereof at 20° to 50°C and a solution of sodium ethacrynate is formed by treating solution of ethacrynic acid in water or polar aprotic solvents with sodium ion source such as sodium hydroxide, sodium bicarbonate or sodium methoxide at 0° to 50°C.
8. The process according to claim no. 6 wherein, the crystalline form II of sodium ethacrynate is formed by stirring the solution of sodium ethacrynate in water or polar aprotic solvents at a temperature in the range of 0°C to 50°C for a period of 30 minutes to 15 hours and isolated by the steps of filtration, centrifugation, washing, drying dried at a temperature in the range of 40°C to 60°C for a period of 2 hours to 8 hours under reduced pressure.
9. The substantially pure crystalline form I of ethacrynic acid and crystalline form II of
sodium ethacrynate having-less than 0.1% weight / weight of compounds of structural
formula II, III, IV, V, VI, VII and VIII.


10. An injectable depot formulation comprising crystalline form II of sodium ethacrynate, wherein the X50 value of the sodium ethacrynate crystals are from 1 to 200 microns.