FILED OF THE INVENTION
The present invention relates to an improved process for the preparation of Sodium nitroprusside (1) with purity level greater than 99.0%. The invention also relates to a novel process for the purification of Sodium nitroprusside (1).
BACKGROUND OF THE INVENTION
Sodium nitroprusside (1) is a vasodilator which is used for the immediate reduction of blood pressure of adult and pediatric patients with hypertension. It is also used as an analytical reagent for the detection of methyl ketones. Chemically it is known as disodium pentacyanonitrosylferrate-2-dihydrate. It was approved by the US FDA in 1974 for the treatment of severe hypertension.
The synthesis of Sodium nitroprusside (1) was reported in very few literatures. The contents of which are hereby incorporated as reference in their entirety.
Journal of American Chemical Society ,1897,19 (1), pp 23-24 discloses the preparation of Sodium nitroprusside (1) by reacting pulverized potassium ferrocyanide with concentrated nitric acid and neutralizing with sodium carbonate. The process suffers from very low yield, hence not feasible at industrial scale. Also, the prior art remains silent about the purity of the final compound obtained.
The drawbacks associated with the prior art preparation of Sodium nitroprusside (1) involves very low yield and absence of specific purity data. Thus, there is need for improved process for the preparation of Sodium nitroprusside (1) with significant purity. Hence, the present inventors hereby, provide an improved process for preparation and purification of Sodium nitroprusside (1) using simple recrystallization method resulting in with more yield and high purity, which is suitable and feasible at commercial scale.

OBJECTIVE OF THE INVENTION
Accordingly, one objective of the present invention is to provide an improved process
for the preparation of substantially pure Sodium nitroprusside (1) with more than 99.0%
purity.
Another objective of the present invention is to provide a process for the purification of
Sodium nitroprusside (1) using process, resulting in high purity of Sodium nitroprusside
(1).
SUMMARY OF THE INVENTION
Accordingly, in one aspect of the present invention provides an improved process for the preparation of Sodium nitroprusside (1) with purity more than 99.0%.
In another aspect, the present invention provides a purification process of Sodium nitroprusside (1) to obtain Sodium nitroprusside (1) with purity more than 99.0%o by simple recrystallization technique.
In another aspect, the present invention provides a process for the preparation of Sodium nitroprusside (1) comprising of the following steps:
a) providing a solution of potassium ferrocyanide trihydrate (3) in a suitable protic solvent;
b) heating the reaction mixture to a suitable temperature;
c) adjusting pH of the reaction mass using suitable acid;
d) adding a solution of sodium nitrite (2) to the reaction mixture;
e) adjusting pH of the reaction mass using suitable base;
f) adding suitable protic solvent to the reaction mass; and
g) isolating Sodium nitroprusside (1).
In another embodiment, the present invention provides a process for the purification of Sodium nitroprusside (1) comprising:
a) providing a solution of Sodium nitroprusside (1) in a suitable solvent;

b) adding another suitable solvent or mixture of solvents;
c) cooling the reaction mass to a suitable temperature;
d) isolating pure Sodium nitroprusside (1).
Yet, in another embodiment, the present invention provides an alternative process for the purification of Sodium nitroprusside (1) comprising:
1. providing a solution of crude Sodium nitroprusside (1) in a suitable solvent;
2. heating the reaction mass to a suitable temperature;
3. filtering the reaction mass;
4. cooling the reaction mass to a suitable temperature; and
5. isolating pure Sodium nitroprusside (1).
Sodium nitroprusside (1) obtained after purification is having purity greater than 99.0% and more preferably greater than 99.5%.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates X-Ray powder diffraction (XPRD) pattern of pure Sodium nitroprusside (1).
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of Sodium nitroprusside (1) as illustrated in scheme-1 comprising:
a) providing a solution of potassium ferrocyanide trihydrate (3) in a suitable protic solvent;
b) heating the reaction mixture to a suitable temperature;
c) adjusting pH of the reaction mass using suitable acid;
d) adding a solution of sodium nitrite (2) to the reaction mixture;
e) adjusting pH of the reaction mass using suitable base;
f) adding suitable protic solvent to the reaction mass; and
g) isolating Sodium nitroprusside (1).

In some embodiment, scheme-1 proceeds with reacting potassium ferrocyanide trihydrate (3) with sodium nitrite (2) in a suitable protic solvent and heated with the addition of a suitable acid at 60-100 °C, preferably 80-85 °C, more preferably 90-95 °C.
The suitable acid used in the present invention may be selected from a group comprising of hydrochloric acid (HC1), hydrobromic acid, trifluoroacetic acid (TFA), nitric acid, sulphuric acid, boric acid, periodic acid, phosphoric acid, p-toluene sulfonic acid, methane sulfonic acid, formic acid and acetic acid. Preferably, sulphuric acid was used in the present invention.

The reaction mass obtained in step a) was cooled and neutralized with a suitable base. The reaction mass was cooled to 10-40 °C, preferably 15-30 °C, more preferably 20-25 °C. The reaction mass was then filtered under vacuum through Hyflo and the filtrate distilled off to obtain Sodium nitroprusside (1).
The suitable bases used in the present invention may be selected from a group comprising of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium bicarbonate, sodium bicarbonate or the like, preferably sodium carbonate was used in the present invention.
In another embodiment, the present invention provides a process for the preparation of potassium ferrocyanide trihydrate (3) as illustrated in scheme 2.
In another embodiment, the present invention provides process for the preparation of potassium ferrocyanide trihydrate (3) by reacting potassium ferrocyanide decahydrate (4) with potassium chloride in a suitable solvent and heating the reaction mass to a temperature of 80-120° C, preferably to 90-95° C. The reaction mass may be cooled to 0-40° C, preferably 10-15° C and potassium ferrocyanide trihydrate (3) isolated from suitable solvent.
In another embodiment, the suitable solvents used in the present invention may be selected from a group comprising of protic or aprotic solvents, preferably protic solvents may be used selected from a group comprising of water, methanol, ethanol,

and isopropyl alcohol or mixtures thereof, preferably water , methanol and isopropyl alcohol were used in the present invention.
In another embodiment, the present invention provides a process for the purification of Sodium nitroprusside (1) comprising:
a) providing a solution of Sodium nitroprusside (1) in a suitable solvent;
b) adding another suitable solvent or mixture of solvents;
c) cooling the reaction mass to a suitable temperature;
d) isolating pure Sodium nitroprusside (1).
Sodium nitroprusside (1) obtained may be purified by dissolving Sodium nitroprusside (1) in a protic solvent or mixture of solvents and filtering through micron filter. The filtrate may be cooled to 0-30° C, preferably at 0-10° C and solvent partially distilled off. The remaining concentrate may be cooled to 15-30° C, preferably 20-25 ° C, filtered under vacuum and dried to isolate Sodium nitroprusside (1).
Yet, in another embodiment, the present invention provides an alternative process for the purification of Sodium nitroprusside (1) comprising:
1. providing a solution of crude Sodium nitroprusside (1) in a suitable solvent;
2. heating the reaction mass to a suitable temperature;
3. filtering the reaction mass and removing excess solvent;
4. cooling the concentrate to a suitable temperature; and
5. isolating pure Sodium nitroprusside (1).
Sodium nitroprusside (1) may be dissolved in a suitable solvent and heated to 60-65 °C and filtered. The filtrate may be distilled off and the concentrate cooled, filtered and dried under vacuum to yield Sodium nitroprusside (1).

The suitable solvents used for the purification may be selected from a group comprising of protic or aprotic, preferably protic solvents may be used comprising of methanol, ethanol, propanol, butanol, isopropyl alcohol or the like, preferably water, methanol and isopropyl alcohol or mixtures thereof were used in the present invention.
The heating may be carried out at a range between 60-120 °C, preferably between 60-100 °C and more preferably between 60-75 °C. The cooling temperature applied for isolation may be less than about 40°C, less than about 30°C, less than about 20 °C, less than about 10 °C, less than about 0 °C or any other suitable temperatures.
In another embodiment the Sodium nitroprusside (1) obtained after purification is having purity more than 99.0%, preferably more than 99.5%.
In another embodiment, the present invention provides Sodium nitroprusside (1) having ferrocyanide and ferricyanide impurities less than 0.5% (w/w), more preferably ferrocyanide impurity was less than 0.25 (% w/w), still more preferably less than 0.1% (w/w).
All the above-mentioned impurities were identified, characterized and well controlled within the limit. Further, some of the impurities were controlled below the permissible limits in the final drug substance. Hence, the above process surprisingly provides high yield and purity of Sodium nitroprusside (1) by simple purification process to meet the regulatory requirement and is thus highly advantageous on industrial scale.
In another embodiment the Sodium nitroprusside (1) obtained in the present invention is having water content less than 15 (% w/w), preferably less than 10 (% w/w) by Karl Fischer method.
In another embodiment, the pure Sodium nitroprusside (1) was characterized by an X-ray diffraction (XRD) pattern comprising of 2(9) theta values ± 0.2 degrees as tabulated in table 1 and illustrated in figure 1.

The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.
EXAMPLES
EXAMPLE 1: Preparation of Sodium nitroprusside (1)
lOOg of Potassium ferrocyanide trihydrate (3) was dissolved in 150mL of water at 25-30 °C. The reaction mass was heated to 80-90 °C and the pH of reaction mass was adjusted to 3.0-4.0 using aqueous sulphuric acid solution. 200mL of sodium nitrite (2) solution was added to the reaction mass at 80-90 °C and further heated to 90-95 °C. On completion of reaction, the reaction mass was cooled to 25-30 °C and pH of the reaction mass was adjusted to 7.0-8.0 with sodium carbonate and filtered through Hyflo. The filtrate was distilled off to half its volume and filtered through Hyflo under vacuum. The filtrate was distilled off and cooled to 25-30 °C. 330mL of isopropyl alcohol was added to the concentrate, stirred and filtered under vacuum to yield Sodium nitroprusside (1). Yield: 35%; Purity: 99.0%.

EXAMPLE 2: Purification of Sodium nitroprusside (1)
lOOg of Sodium nitroprusside (1) was dissolved in 80 mL water and 600 mL of methanol. The reaction mass cooled to 5-10 °C and filtered through Hyflo. The filtrate was further cooled to 0-10 °C and again filtered. The filtrate was distilled under vacuum below 65 °C to half its volume and cooled to 20-25 °C. The obtained solid was filtered and dried under vacuum to obtain Sodium nitroprusside (1). Yield:85%; Purity: 99.5%.
EXAMPLE 3: Alternative process for the purification of Sodium nitroprusside
(1)
lOOg of Sodium nitroprusside (1) was dissolved in 250 mL of water at 25-30 °C and heated to 60-65 °C. The reaction mass was filtered under vacuum through 0.2 \i micron filter and the filtrate was distilled off. The concentrate was cooled at 20-25 °C, filtered and dried under vacuum to obtain Sodium nitroprusside (1) Yield: 88%; Purity: 99.89%.
EXAMPLE 4: Alternative process for the purification of Sodium nitroprusside
(1)
lOOg of Sodium nitroprusside (1) dissolved in 70 mL water and 500 mL of methanol. The reaction mass cooled to 5-10 °C and filtered through Hyflo. The filtrate was further cooled to 0-10 °C and filtered. The filtrate was distilled off to half its volume under vacuum and cooled to 20-25 °C. The obtained solid was dissolved in 200 mL of water at 25-30 °C and heated to 60-65 °C. The reaction mass was filtered under vacuum through 0.2 u. micron filter and the filtrate was distilled off. The reaction mass was cooled at 20-25 °C, filtered and dried under vacuum to obtain Sodium nitroprusside (1) Yield: 80%; Purity: 99.8%.

We claim:
1. A process for the preparation of Sodium nitroprusside (1)
comprising:
a. providing a solution of potassium ferrocyanide trihydrate (3)
(3)
b. heating the reaction mixture to a suitable temperature;
c. adjusting pH of the reaction mass using suitable acid;
d. adding a solution of sodium nitrite (2) to the reaction mixture;
e. adjusting pH of the reaction mass using suitable base;
f. adding suitable protic solvent to the reaction mass; and
g. isolating Sodium nitroprusside (1).
2. The process as claimed in claim 1, wherein suitable acid used is selected from a group comprising of hydrochloric acid, hydrobromic acid, trifluoroacetic acid, nitric acid, sulphuric acid, boric acid, periodic acid, phosphoric acid, p-

toluene sulfonic acid, methane sulfonic acid, formic acid and acetic acid or mixtures thereof.
3. The process as claimed in claim 1, wherein the suitable bases used is selected from a group comprising of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium bicarbonate, sodium bicarbonate or the like or mixtures thereof.
4. The process as claimed in claim 1, wherein the suitable solvent is selected from water, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, acetone, dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, dimethyl formamide and dimethyl sulfoxide.
5. A process for the purification of Sodium nitroprusside (1) comprising:

a) providing a solution of Sodium nitroprusside (1) in a suitable solvent;
b) adding another suitable solvent or mixture of solvents;
c) cooling the reaction mass to a suitable temperature; and
d) isolating pure Sodium nitroprusside (1).
6. An alternate process for the purification of Sodium nitroprusside (1)
comprising:
a) providing a solution of crude Sodium nitroprusside (1) in a suitable solvent;
b) heating the reaction mass to a suitable temperature;
c) filtering the reaction mass;
d) cooling the reaction mass to a suitable temperature; and
e) isolating pure Sodium nitroprusside (1).
7. The process as claimed in claim 5 and claim 6, wherein the suitable solvents is
selected from a group comprising of methanol, ethanol, propanol, butanol,
isopropyl alcohol or mixtures thereof.

8. The process, as claimed in claim 5 and claim 6, wherein the Sodium nitroprusside (1) obtained after purification is having purity greater than. 99.0 (%, w/w) purity by HPLC.
9. The process, as claimed in claim 5, wherein the pure Sodium nitroprusside (1) is characterized by an X-ray diffraction (XRD) pattern as illustrated in figure 1.