DESC:RELATED PATENT APPLICATION(S)
This application claims the priority to and benefit of Indian Provisional Patent Application No. 201741018233 filed on May 24, 2017; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION
The present invention relates to an improved method for the preparation of substantially pure crystalline Dantrolene sodium, having purity of greater than 99.5% as determined by HPLC.

BACKGROUND OF THE INVENTION
Dantrolene sodium is a hydantoin derivative, chemically known as 3-[(E)-[5-(4-nitrophenyl) furan-2-yl] methylidene amino]-5-oxo-4H-imidazol-2-olate sodium. It is marketed in US as RYANODEX® (Dantrolene sodium) for injectable. The hydrated salt contains approximately 15% water (3-1/2 mol) and has a molecular weight of 399. The anhydrous salt (Dantrolene) has a molecular weight of 336.

Dantrolene sodium is a postsynaptic muscle relaxant. It is drug of choice used for the treatment and prevention of malignant hyperthermia, in the management of neuroleptic malignant syndrome, muscle spasticity, 2,4-dinitrophenol poisoning, in spasticity and other neuromuscular abnormalities.

The synthesis of Dantrolene sodium was reported in many patents and non-patent literature, the contents of which are hereby incorporated as reference in their entirety.

The US Patent No. 3425821 outlines the diazotization of 4-nitro-phenylamine and further reacting it with furan-2-carbaldehyde in presence of cupric chloride to form 5-(4-nitro-phenyl)-furan-2-carbaldehyde. The obtained 5-(4-nitro-phenyl)-furan-2-carbaldehyde is dissolved in dimethylformamide (DMF) and 1-aminohydantoin hydrochloride in water is added slowly, and washed with acetone to produce 32% Dantrolene free base.The prior art does not disclose the purity of Dantrolene free base.

The US Patent No. 6413785 describes the processes for making 1-aminohydantoin compounds generically using a solid support resin which facilitate the purification of intermediates. It proceeds with formation of resin-bound protected a-hydrazinyl ester, followed by synthesis of a resin-bound imine, then preparing a resin-bound secondary urea. Finally, 1-aminohydantoin compounds are formed by removing resin-bound secondary urea from the resin and cyclizing it.

J Med Chem. 1967, 10(5), 807 enumerates the synthesis of Dantrolene and sodium salt tetrahydrate by treating a solution of 5-(p-nitropheny1)-2-furaldehyde in dimethylformamide and aqueous 1-aminohydantoin hydrochloride to form Dantrolene which is further treated with anhydrous methanol and sodium methoxide to form Dantrolene sodium tetrahydrate. There is no discussion about the purity or preparation of Dantrolene sodium.

Pharmaceutical Chemistry Journal May 1984, Volume 18, Issue 5, pp 310-312 describes the synthesis of Dantrolene using 5-(p-nitrophenyl) furfural and amino-hydantoin; and the tetrahydrate sodium salt of Dantrolene by treating Dantrolene free base with sodium methoxide in anhydrous methanol.

The above prior art methods do not disclose the process for purification or the percentage purity of the Dantrolene sodium. Hence, the present inventors have reported an improved method for the preparation and purification of Dantrolene sodium using less expensive and commonly used chemicals under mild reaction conditions making it feasible for industrial use.

SUMMARY OF THE INVENTION
Accordingly, one object of the invention is to provide substantially pure Dantrolene sodium (I) having purity of greater than 99.5% as determined by High-performance liquid chromatography (HPLC).

Another object of the invention is to develop an improved process for the synthesis of substantially pure Dantrolene sodium (I).

In one aspect of the invention, there is provided a process for the preparation of Dantrolene sodium (I) having purity of greater than 99.5% as determined by HPLC,

said process comprising the steps of:
a) diazotization of 4-nitroaniline (VII)

in the presence of suitable protic solvent, sodium nitrite and hydrochloric acid to obtain 4-nitrobenzenediazonium (VI) in-situ and

further treating compound (VI) with furfuraldehyde (V)

in the presence of aqueous cupric chloride and suitable aprotic solvent to obtain 5-(4-nitrosophenyl) furan-2-carbaldehyde (IV);

b) reacting 5-(4-nitrosophenyl) furan-2-carbaldehyde (IV) with 1-aminohydantoin hydrochloride (III) in presence of suitable aprotic solvent

to form Dantrolene free base (II);

c) converting Dantrolene free base (II) into Dantrolene sodium (I) in presence of base and suitable aprotic solvent; and

d) optionally, purifying Dantrolene sodium (I).

In some embodiment of the invention, the base employed in step c) in the above described process for the preparation of Dantrolene sodium (I) is selected from a group comprising of sodium methoxide, sodium isopropoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate or the like.

In another aspect of the invention, there is provided a process for the purification of Dantrolene sodium (I), said process comprising the steps of:
a) dissolving Dantrolene sodium in a mixture of protic and aprotic solvent;
b) heating the reaction mass at 60-65°C for 1-2 hours;
c) cooling the reaction mass to 25-30°C;
d) optionally, treating the solid with aprotic solvent at 25-30°C; and
e) filtering and isolating the solid with protic solvent or aprotic solvent or mixture thereof to obtain pure Dantrolene sodium.

In some embodiment of the invention, in the above described process for the preparation and purification of Dantrolene sodium (I) the suitable protic solvent employed is selected from a group comprising of methanol, ethanol, isopropanol, n-propanol, n-butanol, water or the like; and the suitable aprotic solvent is selected from a group comprising of acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide (DMF), acetonitrile (MeCN), dimethylsulfoxide (DMSO), methyl tertiary butyl ether, hexane, cyclohexane, toulene, tetrahydrofuran or the like.

In yet another aspect of the invention, there is provided a process for preparing highly pure crystalline Dantrolene sodium (I), said process comprising the steps of:
a) dissolving Dantrolene sodium in a mixture of protic and aprotic solvent;
b) heating the reaction mass at 60-65°C for 1-2 hours;
c) cooling the reaction mass to 25-30°C;
d) optionally, treating the solid with aprotic solvent at 25-30°C; and
e) filtering and isolating the solid with protic solvent or aprotic solvent or mixture thereof to obtain pure crystalline Dantrolene sodium.

In some embodiment of the invention, crystalline form of Dantrolene sodium obtained in the above described process is characterized by X-Ray powder diffraction pattern having peaks expressed as 2? values at about 4.27, 8.51, 10.11, 11.22, 12.62, 14.61, 15.36, 13.83, 19.43, 21.00, 22.41, 23.68, 25.58, 26.13, 26.48, 27.45, 28.41, 30.45, 33.79 and 34.67 ± 0.2 degrees.
In some embodiment of the invention, crystalline form of Dantrolene sodium obtained in the above described process is having purity of greater than 99.5% as determined by the HPLC.

In some embodiment of the invention, the crystalline form of Dantrolene sodium obtained in the above described process comprises less than 0.5% (w/w) of total impurities, preferably less than 0.25% (w/w) of total impurities.

In some embodiment of the invention, the crystalline form of Dantrolene sodium obtained in the above described process comprises the following:
a. less than 0.15% (w/w) of Impurity-A;

Impurity-A

b. less than 0.15% (w/w) of Impurity-B;

Impurity-B

c. less than 0.15% w/w of Impurity-C;

Impurity-C
d. less than 0.15% (w/w) of Impurity-D or

Impurity-D

e. less than 0.15% (w/w) of Impurity-E

Impurity-E

BRIEF DESCRIPTION OF THE DRAWING
Figure 1: Infrared spectroscopy (IR) spectrum of Dantrolene sodium (I)
Figure 2: X-Ray powder diffraction (XRD) pattern of Dantrolene sodium (I)

DETAILED DESCRIPTION OF THE INVENTION
The inventors of the present invention have surprisingly found an improved method for the preparation of substantially pure crystalline Dantrolene sodium having purity of greater than 99.5% as determined by HPLC.

In one aspect of the invention, there is provided a process for the preparation of Dantrolene sodium (I) having purity of greater than 99.5% as determined by HPLC,

said process comprising the steps of:
a) diazotization of 4-nitroaniline (VII)

in the presence of suitable protic solvent, sodium nitrite and hydrochloric acid to obtain 4-nitrobenzenediazonium (VI) in-situ and

further treating compound (VI) with furfuraldehyde (V)

in the presence of aqueous cupric chloride and suitable aprotic solvent to obtain 5-(4-nitrosophenyl) furan-2-carbaldehyde (IV);

b) reacting 5-(4-nitrosophenyl) furan-2-carbaldehyde (IV) with 1-aminohydantoin hydrochloride (III) in presence of suitable aprotic solvent

to form Dantrolene free base (II);

c) converting Dantrolene free base (II) into Dantrolene sodium (I) in presence of base and suitable aprotic solvent; and

d) optionally, purifying Dantrolene sodium (I).

The Scheme 1 outlines the steps involved in the synthesis and purification of Dantrolene sodium (I).

Scheme 1

Step a) involves the diazotization of 4-nitroaniline (VII) to form 4-nitrobenzenediazonium (VI). 4-nitroaniline (VII) is reacted with a mineral acid in a suitable protic solvent, preferably, concentrated hydrochloric acid and cooled to -5 to +5°C with addition of nitrating agent, preferably sodium nitrite to form 4-nitro benzenediazonium (VI). On completion of reaction, the reaction mass was treated with furfuraldehyde (V) and dissolved in a suitable aprotic solvent and treated with an aqueous cupric chloride solution. The solid so precipitated was added to an aprotic solvent and heated at 80-90°C. The reaction mass was then cooled to 0-5°C to obtain pure 5-(4-nitrosophenyl) furan-2-carbaldehyde (IV) with purity greater than 95%.

Step b) describes the formation of (E)-1-((5-(4-nitrophenyl) furan-2-yl) methyleneamino) imidazolidine-2,4-dione (II) (Dantrolene free base), by condensing 5-(4-nitrosophenyl) furan-2-carbaldehyde (IV) with 1-aminohydantoin hydrochloride (III) in a suitable aprotic or protic solvent or mixture thereof at 25-30°C. On completion of reaction, the reaction mass was purified by treating with a suitable protic solvent to obtain (E)-1-((5-(4-nitrophenyl) furan-2-yl) methyleneamino) imidazolidine-2,4-dione (II) (Dantrolene free base) having purity greater than 95%.

Step c) describes conversion of Dantrolene free base (II) to Dantrolene sodium (I) by dissolving Dantrolene free base (II) in a suitable aprotic solvent and heating at 70-90°C; preferably 80-85 °C. The reaction mass is then filtered through Hyflo and treated with a suitable base to provide Dantrolene sodium (I).

Step d) describes the purification of the crude Dantrolene sodium obtained in step c) by treating with a protic solvent or aprotic solvent or mixture thereof to obtain substantially pure Dantroline sodium (I). In some embodiment, the term ‘substantially pure Dantroline sodium’ means Dantrolene sodium having purity greater than 99.5% purity as determined by HPLC. In some embodiment, the invention describes the purification method of Dantrolene sodium by simple treatment with a mixture of protic and aprotic solvent followed by preparing slurry in an aprotic solvent to obtain purity greater than 99.5% purity as determined by HPLC.

In some embodiment of the invention, the suitable base used in step c) in the above described process for the preparation of Dantrolene sodium (I) is selected from the group comprising of sodium methoxide, sodium isopropoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate or the like. In some embodiment, the base employed in step c) of the above described process for the preparation of Dantrolene sodium (I) is sodium methoxide .

In another aspect of the invention, there is provided a process for the purification of Dantrolene sodium (I), said process comprising the steps of:
a) dissolving Dantrolene sodium in a mixture of protic and aprotic solvent;
b) heating the reaction mass at 60-65°C for 1-2 hours;
c) cooling the reaction mass to 25-30°C;
d) optionally, treating the solid with aprotic solvent at 25-30°C; and
e) filtering and isolating the solid with protic solvent or aprotic solvent or mixture thereof to obtain pure Dantrolene sodium.

In some embodiment of the invention, in the above described process for the preparation and purification of Dantrolene sodium (I) the suitable protic solvent used in is selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, water or the like; preferably, water, and methanol is used in the present invention. In some embodiment of the invention, in the above described process for the preparation and purification of Dantrolene sodium (I) the aprotic solvent used is selected from a group comprising of acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide (DMF), acetonitrile (MeCN), dimethylsulfoxide (DMSO), methyl tertiary butyl ether, hexane, cyclohexane, toulene, tetrahydrofuran or the like; preferably, acetone, N,N-dimethylformamide (DMF) and dimethylsulfoxide (DMSO) is used in the present invention.

Most of the prior art methods do not describe a detailed purification process of Dantrolene sodium, hence, an effort has been made to provide a detailed purification procedure using common solvents with simple steps making the process less tedious and commercially applicable.

In yet another aspect of the invention, there is provided a process for preparing highly pure crystalline Dantrolene sodium (I), said process comprising the steps of:
a) dissolving Dantrolene sodium in a mixture of protic and aprotic solvent;
b) heating the reaction mass at 60-65°C for 1-2 hours;
c) cooling the reaction mass to 25-30°C;
d) optionally, treating the solid with aprotic solvent at 25-30°C; and
e) filtering and isolating the solid with protic solvent or aprotic solvent or mixture thereof to obtain pure crystalline Dantrolene sodium.

In some embodiment of the invention, crystalline form of Dantrolene sodium obtained in the above described process is characterized by X-Ray powder diffraction pattern having peaks expressed as 2? values at about 4.27, 8.51, 10.11, 11.22, 12.62, 14.61, 15.36, 13.83, 19.43, 21.00, 22.41, 23.68, 25.58, 26.13, 26.48, 27.45, 28.41, 30.45, 33.79 and 34.67 ± 0.2 degrees.

In some embodiment of the invention, crystalline form of Dantrolene sodium obtained in the above described process is having purity of greater than 99.5% as determined by the HPLC.

In some embodiment of the invention, the crystalline form of Dantrolene sodium obtained in the above described process comprises less than 0.5% (w/w) of total impurities, preferably less than 0.25% (w/w) of total impurities.

In some embodiment, the Dantrolene sodium produced in the above method is having impurities A, B, C, D and E less than 0.15% (w/w) and any unknown impurity less than 0.10% (w/w).

Impurity-A
5-(4-Nitrophenyl)-2-furaldehyde azine

Impurity-B
5-(4-Nitrophenyl)-2-furaldehyde-2-carboxymethyl semicarbazone

Impurity-C
5-(4-Nitrophenyl)-2-furancarboxyaldehyde

Impurity-D
3-[[5-(P-Nitrophenyl) furfurylidene] amino] hydantoin (Positional isomer)

Impurity-E
(E)-3-(hydroxy(5-(4-nitrophenyl) furan-2-yl) methyl)-1-(((5-(4-nitrophenyl) furan-2-yl) methylene) amino) imidazolidine-2,4-dione

In some embodiment of the invention, the crystalline form of Dantrolene sodium obtained in the above described process comprises the following:

a) less than 0.15% (w/w) of Impurity-A;
b) less than 0.15% (w/w) of Impurity-B;
c) less than 0.15% w/w of Impurity-C;
d) less than 0.15% w/w of Impurity-D or
e) less than 0.15% w/w of Impurity-E

In some embodiment, Dantrolene sodium (I) obtained in the above purification method is having purity greater than 99.5% and total impurities less than 0.5% (w/w), more preferably less than 0.25% (w/w).

Dantrolene free base produced in the above method is having purity greater than 95%.

In some embodiment, the moisture content of Dantrolene sodium (I) measured by Karl-Fischer method is found to be in the range of 14.5% and 17.0% (w/w).
In some embodiment, pure Dantrolene sodium (I) produced in the above method is crystalline, which is characterized by IR as illustrated in Figure-1 and the X-Ray powder diffractogram as shown in Figure-2 and Table-1.

Table-1: X-Ray powder diffractogram of pure crystalline Dantrolene sodium (I)
S.No. 2(?) deg Relative Intensity %
1. 4.27 18.3
2. 8.51 36.7
3. 10.11 8.60
4. 11.22 100
5. 12.62 32.70
6. 14.61 12.90
7. 15.36 24.90
8. 16.83 74.90
9. 19.43 21.60
10. 21.00 14.00
11. 22.41 12.50
12. 23.68 17.50
13. 25.58 35.40
14. 26.13 75.10
15. 26.48 36.4
16. 27.45 58.40
17. 28.41 14.40
18. 30.45 20.70
19. 33.79 11.40
20. 34.67 11.10

In some embodiment of the invention, there is provided a process for the preparation of crystalline from of Dantrolene sodium characterized by X-Ray powder diffraction pattern having peaks expressed as 2? values at about 4.27, 8.51, 10.11, 11.22, 12.62, 14.61, 15.36, 13.83, 19.43, 21.00, 22.41, 23.68, 25.58, 26.13, 26.48, 27.45, 28.41, 30.45, 33.79 and 34.67 ± 0.2 degrees, said process comprising the steps of:
a) diazotization of 4-nitroaniline (VII)

in the presence of suitable protic solvent, sodium nitrite and hydrochloric acid to obtain 4-nitrobenzenediazonium (VI) in-situ and

further treating compound (VI) with furfuraldehyde (V)

in the presence of aqueous cupric chloride and suitable aprotic solvent to obtain 5-(4-nitrosophenyl) furan-2-carbaldehyde (IV);

b) reacting 5-(4-nitrosophenyl) furan-2-carbaldehyde (IV) with 1-aminohydantoin hydrochloride (III) in presence of suitable aprotic solvent

to form Dantrolene free base (II);

c) converting Dantrolene free base (II) into Dantrolene sodium (I) in presence of base and suitable aprotic solvent; and

d) dissolving Dantroline sodium in a mixture of protic and aprotic solvent;
e) heating the reaction mass at 60-65°C for 1-2 hours;
f) cooling the reaction mass to 25-30°C;
g) optionally, treating the solid with aprotic solvent at 25-30°C; and
h) filtering and isolating the crystalline from of Dantrolene sodium with protic solvent or aprotic solvent or mixture thereof.
The following examples further illustrate present invention, but should not be construed in anyway, as to limit its scope.

EXAMPLES

EXAMPLE-1
Preparation of 5-(4-nitrosophenyl) furan-2-carbaldehyde (IV):
150 g (1.08 mol) of 4-nitroaniline (VII) was dissolved in demineralized water (DM water) and cooled to 15-20°C then concentrated hydrochloric acid was added and maintained for 1 hour with further cooling to -5 to +5°C. 78.7 g of sodium nitrite dissolved in 300 mL of DM water was added to the cooled reaction mass at -5 to +5°C to obtain diazonium salt of 4-nitro benzene diazonium (VI). On completion of the reaction, 104 g (1.08 mol) of furfuraldehyde (V) in acetone and 21.9 g (0.162 mol) copper chloride dissolved in 105 mL of DM water were further added at -5 to +5°C to intermediate (VI). The temperature of the reaction mass was raised to 15-20°C and maintained overnight. On completion of reaction, the solid was filtered and washed with water and dried. To the dried solid, 750 mL of dimethylformamide was added and heated to 85-90°C for 60-90 mins. The reaction mass was cooled to 0-5°C for 2-3 hours. The solid formed was filtered and washed with methanol to obtain the titled compound 5-(4-nitrosophenyl) furan-2-carbaldehyde (IV).
Yield%: 38.0
Purity %: 99.0

EXAMPLE-2
Preparation of 1-((5-(4-nitrophenyl) furan-2yl) methyleneamino) imidazolidine-2,4-dione (II):
80.0 g (0.368 mol) of 5-(4-nitrosophenyl) furan-2-carbaldehyde (IV) was added to 3200 mL of dimethylformamide at 25-30°C and stirred to form a clear solution. To this, 60 g (0.396 mol) of 1-aminohydantoin hydrochloride (III) in 800 mL water was added and stirred for 2-3 hours. On completion of reaction, the solid was filtered, washed with methanol and transferred to a clean and dry round bottom flask. The solid was stirred in 240 mL methanol for 1-2 hours, filtered and washed with methanol. The solid was then dried at below 55°C to obtain (E)-1-((5-(4-nitrophenyl) furan-2-yl) methylene amino) imidazolidine-2,4-dione (II).
Yield %: 88.08
Purity %: 99.6

EXAMPLE-3
Preparation of crude Dantrolene sodium (I):
100 g (0.318 mol) of Dantrolene free base (II) was dissolved in 600 mL of dimethyl sulfoxide at 25-30°C and heated to 80-85°C to obtain a clear solution. The clear solution was then filtered through Hyflo and washed with dimethyl sulfoxide in hot condition. The filtrate was transferred in a clean and dry round bottom flask, cooled to 25-30°C and mixed with 1500 mL of methanol and stirred for 15-30 mins. After 1-2 hours, methanolic sodium methoxide was added slowly at 25-30°C for 3 hours. The solid so obtained was filtered and washed with 100 mL of methanol and dried at 50-55°C to obtain crude Dantrolene sodium (I).
Yield %: 88.86
Purity %: 99.7

EXAMPLE-4
Purification of Dantrolene sodium (I):
95 g of crude Dantrolene sodium (I) was dissolved in 665 mL of dimethyl formamide and 76 mL of water with stirring at 25-30°C. The reaction mixture was heated for 1-2 hours at 60-65°C followed by cooling to 25-30°C. The solid so obtained was filtered and washed with different volumes of acetone. The solid formed was filtered, washed with 95 mL of acetone and dried below 55°C to obtain pure Dantrolene sodium (I).
Yield %: 73.6
Purity %: 99.9
,CLAIMS:
1. A process for the preparation of Dantrolene sodium (I) having purity of greater than 99.5% as determined by HPLC,

said process comprising the steps of:
a) diazotization of 4-nitroaniline (VII)

in the presence of suitable protic solvent, sodium nitrite and hydrochloric acid to obtain 4-nitrobenzenediazonium (VI) in-situ, and

further treating compound (VI) with furfuraldehyde (V)

in the presence of aqueous cupric chloride and suitable aprotic solvent to obtain 5-(4-nitrosophenyl) furan-2-carbaldehyde (IV);

b) reacting 5-(4-nitrosophenyl) furan-2-carbaldehyde (IV) with 1-aminohydantoin hydrochloride (III) in presence of suitable aprotic solvent or protic solvent or mixture thereof

to form Dantrolene free base (II);

c) converting Dantrolene free base (II) into Dantrolene sodium (I) in presence of base and suitable aprotic solvent; and

d) optionally, purifying Dantrolene sodium (I).

2. The process as claimed in claim 1, wherein the base employed in step c) is selected from a group comprising of sodium methoxide, sodium isopropoxide, sodium hydroxide, sodium carbonate, sodium bicarbonate or the like.

3. The process as claimed in claim 1, wherein the suitable protic solvent employed is selected from a group comprising of methanol, ethanol, isopropanol, n-propanol, n-butanol, water or the like; and the suitable aprotic solvent is selected from a group comprising of acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide (DMF), acetonitrile (MeCN), dimethylsulfoxide (DMSO), methyl tertiary butyl ether, hexane, cyclohexane, toulene, tetrahydrofuran or the like.

4. A process for the purification of Dantrolene sodium (I),

said process comprising the steps of:
a) dissolving Dantrolene sodium in a mixture of protic and aprotic solvent;
b) heating the reaction mass at 60-65°C for 1-2 hours;
c) cooling the reaction mass to 25-30°C;
d) optionally, treating the solid with aprotic solvent at 25-30°C; and
e) filtering and isolating the solid with protic solvent or aprotic solvent or mixture thereof to obtain pure Dantroline sodium.

5. The process as claimed in claim 4, wherein the protic solvent employed is selected from a group comprising of methanol, ethanol, isopropanol, n-propanol, n-butanol, water or the like; and the aprotic solvent used is selected from a group comprising of acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-dimethylformamide (DMF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), methyl tertiary butyl ether, hexane, cyclohexane, toulene, tetrahydrofuran or the like.

6. A process for preparing highly pure crystalline Dantrolene sodium (I),

said process comprising the steps of:
a) dissolving Dantrolene sodium in a mixture of protic and aprotic solvent;
b) heating the reaction mass at 60-65°C for 1-2 hours;
c) cooling the reaction mass to 25-30°C;
d) optionally, treating the solid with aprotic solvent at 25-30°C; and
e) filtering and isolating the solid with protic solvent or aprotic solvent or mixture thereof to obtain pure crystalline Dantrolene sodium.

7. The process as claimed in claim 6, wherein the crystalline form of Dantrolene sodium is characterized by X-Ray powder diffraction pattern having peaks expressed as 2? values at about 4.27, 8.51, 10.11, 11.22, 12.62, 14.61, 15.36, 13.83, 19.43, 21.00, 22.41, 23.68, 25.58, 26.13, 26.48, 27.45, 28.41, 30.45, 33.79 and 34.67 ± 0.2 degrees.

8. The process as claimed in claim 6, wherein the crystalline Dantrolene sodium (I) obtained is having purity of greater than 99.5% as determined by the HPLC.

9. The process as claimed in claim 6, wherein the crystalline Dantrolene sodium (I) obtained comprises less than 0.5% (w/w) of total impurities, preferably less than 0.25% (w/w) of total impurities.

10. The process as claimed in claim 6, wherein the crystalline Dantrolene sodium (I) obtained comprises the following:
a. less than 0.15% (w/w) of Impurity-A;

Impurity-A

b. less than 0.15% (w/w) of Impurity-B;

Impurity-B

c. less than 0.15% w/w of Impurity-C;

Impurity-C

d. less than 0.15% (w/w) of Impurity-D or

Impurity-D

e. less than 0.15% (w/w) of Impurity-E

Impurity-E