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 FOR THE PREPARATION OF PURE HYDRALAZINE HYDROCHLORIDE"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, Plot No.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.

A PROCESS FOR THE PREPARATION OF PURE HYDRALAZINE
HYDROCHLORIDE
FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of pure hydralazine hydrochloride.
BACKGROUND OF THE INVENTION:
Hydralazine hydrochloride (hydrazinophthalazine compound with the chemical name 1-hydrazinophthalazine monohydrochloride) is antihypertensive drug and is known from U.S. Patent No. 2,484,029.
The chemical structure of hydralazine hydrochloride can be represented by compound of structural formula I.

U.S. Patent No. 2,484,029 describes process for the preparation of hydralazine hydrochloride comprises preparing 1-chlorophthalazine [from phthalazinone by the process reported in Ber. D. deutsch. chem. Ges., Vol., 26 page 521 (1893)], and the obtained 1-chlorophthalazine was further reacted with a mixture of 100 parts by volume of ethanol and 90 parts by volume of hydrazine hydrate. The hydrazine thus obtained was recrystallized from methanol and converted to the hydrochloride salt on warming in alcoholic or aqueous hydrochloric acid. The hydralazine hydrochloride obtained by this process is found to contain several impurities at about 0.5%, has a

greater than 0.01% level of hydrazine content and does not comply with the present pharmaeopoeial requirements for the drug. The U.S. Pharmacopoeia requires the hydrazine at a level less than 0.001%, and the European Pharmacopoeia requires any individual impurities to be present at levels not more than 0.2%.
U.S. Patent No. 7,220,858 describes process for the preparation of hydralazine hydrochloride comprises preparing chlorophthalazine from phthalazinone and phosphorous oxychloride, separating using a first solvent such as and alkane having 5 to 7 carbons and a second solvent (such as tetrahydrofuran), reacting the isolated chlorophthalazine with hydrazine in presence of alcohol to produce hydralazine, and treating the hydralazine with hydrochloric acid to yield hydralazine hydrochloride. It is disclosed that the product hydralazine hydrochloride obtained by this process contains phthalazine impurities less than 0.5% and hydrazine content less than 0.0005%.
The process of the US'858 has a number of drawbacks. The chlorophthalazine prepared as disclosed in this patent was found to contain more insoluble matter. In addition, the process of isolating chlorophthalazine involves decanting the supernatant liquid mixture containing several volumes of hexane and phosphorous oxychloride, a cumbersome operation and that is a serious limitation towards scaling-up the disclosed process. The description in the US'858 patent of the hydralazine hydrochloride produced is pale yellow in color, and off-white after recrystallization from ethanol.
U.S. Patent No. 7,807,830 describes process for the preparation of hydralazine hydrochloride comprises reacting phthalazinone with approximately equimolar equivalent phosphorous oxychloride in toluene at a temperature of about 45°C to about 65°C for about 3 hours and then ethyl acetate and sulfuric acid were added to complete precipitation of the 1-chlorophthalazine salt (1-chlorophthalazine hydrochloride/sulfate) which is free of chlorophosphorylphthalazine. The obtained 1-chlorophthalazine salt was reacted with an excess of hydrazine hydrate in absence /presence of organic solvent (short chain aliphatic alcohol) at predetermined temperature (preferably between 0°C and about 30°C) and precipitated with methanol to get hydralazine base. The obtained hydralazine base was purified by using activated carbon treatment in methanol and

then purified hydralazine base in methanol was purged with hydrochloric acid gas to precipitate hydralazine hydrochloride.
The US'830 patent also described purification of hydralazine hydrochloride comprises dissolving crude hydralazine hydrochloride in hot water in the presence of activated carbon and chelating agent such as EDTA, filtering hot solution, adding methanol to filtrate, adjusting the pH of the solution up to 3 to 4.5 by base (Sodium hydroxide/ sodium bicarbonate), and cooling the solution to get pure hydralazine hydrochloride. It is disclosed that the product hydralazine hydrochloride obtained by this process contains any individual impurity not more than 0.05%, total impurities less than 0.5% and hydrazine content not more than 0.001%.
The inventors of this application have found alternative process for the preparation of pure hydralazine hydrochloride.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a process for the preparation of pure hydralazine hydrochloride.
According to another aspect, the present inventionrelates to a process for the preparation of pure hydralazine hydrochloride comprising the steps of:
a. preparing hydralazine acid addition salt except hydralazine hydrochloride, and
b. converting acid addition salt prepared in step-a into pure hydralazine hydrochloride.
According to another aspect, the present invention relates to a process for the preparation of pure hydralazine hydrochloride comprising the steps of:
a. preparing hydralazine hydrobromide, and
b. Converting hydralazine hydrobromide into pure hydralazine hydrochloride.

According to another aspect, the present invention relates to a pharmaceutical composition comprising pure hydralazine hydrochloride obtained by process comprising the steps of:
a. preparing hydralazine acid addition salt except hydralazine hydrochloride, and
b. converting acid addition salt prepared in step-a into pure hydralazine hydrochloride.
According to another aspect, the present invention relates to a pharmaceutical composition comprising pure hydralazine hydrochloride obtained by process comprising the steps of:
a. preparing hydralazine hydrobromide, and
b. converting hydralazine hydrobromide into pure hydralazine hydrochloride.
DETAIL DESCRIPTION OF THE INVENTION:
In one embodiment of the invention provides a process for the preparation of pure hydralazine hydrochloride.
The hydralazine used herein may be prepared by the processes known in the art such as those described herein US Patent No. 2,484,029 which is incorporated herein by reference only.
In another embodiment of the invention provides a process for the preparation of pure hydralazine hydrochloride comprising the steps of:
a. preparing hydralazine acid addition salt except hydralazine hydrochloride,
b. converting acid addition salt prepared in step-a into pure hydralazine hydrochloride.
The hydralazine acid addition salt may be prepared by reacting hydralazine with acid in an organic solvent to get hydralazine acid addition salt.
The examples of acid may be selected from the group comprising of inorganic acid or organic acid.
The examples of inorganic acid may include but not limited to hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid etc.

The examples of an organic acid may include but not limited to formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid etc.
The examples of an organic solvent may include alcohol solvents, ketone solvents, ester solvents, nitrile solvents, halogenated aliphatic hydrocarbon solvents, ether solvents or mixtures thereof.
The alcohol solvents may be selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.
The ketone solvents may be selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof.
The ester solvents may be selected from the group comprising of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof.
The nitrile solvents may be selected from the group comprising of acetonitrile, propionitrile or mixture(s) thereof.
The halogenated aliphatic hydrocarbon solvents may be selected from the group comprising of dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof.
The ether solvents may be 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.

The reaction of hydralazine with acid may be carried out at a temperature in the range of 20°C to 80°C and then cooling the resulting reaction mixture at a temperature in the range of -5°C to 10°C to get hydralazine acid addition salt.
The hydralazine acid addition salt may be isolated by the steps of filtration, centrifugation, washing, drying or the combinations thereof.
The isolated hydralazine acid addition salt may be dried at a temperature in the range of 40°C to 60°C for a period of 30 minutes to 8 hours under reduced pressure.
The hydralazine acid addition salt may be converted in to pure hydralazine hydrochloride by treating aqueous solution of hydralazine acid addition salt with inorganic base and then with hydrochloric acid at a temperature in the range of 20°C to 80°C. The resulting reaction mixture was added above mentioned organic solvent and then cooling the resulting reaction mixture at a temperature in the range of-5°C to 10°C to get pure hydralazine hydrochloride.
The examples of inorganic base may include but not limited to hydroxides alkali metal or alkaline earth metal such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide etc., carbonates of alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate etc.
The hydrochloric acid used in herein in may be in the form of aqueous solution or in gaseous form.
The pure hydralazine hydrochloride may be isolated by the steps of filtration, centrifugation, washing, drying or the combinations thereof.
The isolated hydralazine hydrochloride may be dried at a temperature in the range of 40°C to 80°C for a period of 1 hour to 12 hours under reduced pressure.

EXAMPLES
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way
Example 1: Preparation of hydralazine hydrobromide
A solution of hydralazine (25 gm) in isopropanol (625 ml) was added aqueous solution of
hydrobromic acid (48%, 125 ml) and then resulting reaction mixture was heated to 70-80°C and
stirred for 30 minutes. The resulting reaction mixture was slowly cooled to 10-15°C and then
cooled to 0-5 °C to get solid. The resulting solids were filtered and washed with cold isopropanol
and dried at 50-55°C for 2 hours under reduced pressure to title compound.
Yield: 37.2 gm.
Purity: 99.8% (By HPLC)
Example 2: Preparation of pure hydralazine hydrochloride.
A solution of hydralazine hydrobromide (30.0 gm) in water (300ml) was added aqueous sodium hydroxide solution (10%), 50 ml) and stirred for 30 minutes at 25-30°C. The resulting reaction mixture was added aqueous hydrochloric acid solution (15% 180 ml) and stirred at 70-80°C for 40 minutes. The resulting reaction mixture was added ethanol (200 ml) and cooled to 25-30°C and then further cooled to 5-10°C to get solid. The resulting solids were filtered, washed with cold ethanol (30 ml) and dried at 40-45°C for 4 hours under reduced pressure to get title compound. Yield: 24.5 gm Purity: 99.9% (By HPLC)

WE CLAIM:
1. A process for the preparation of pure hydralazine hydrochloride comprising the steps of:
a. preparing hydralazine acid addition salt except hydralazine hydrochloride, and
b. converting acid addition salt prepared in step-a into pure hydralazine hydrochloride.
2. The process according to claim no. 1, wherein hydralazine acid addition salt is prepared by reacting hydralazine with acid in an organic solvent at a temperature in the range of 20°C to 80°C.
3. The process according to claim no. 2, wherein an acid is selected from the group comprising of inorganic acid such as hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid etc. or organic acid such as formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid.
4. The process according to claim no. 2, wherein an organic solvent is selected from the group comprising of alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof, ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof, ester solvent such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof, nitrile solvents such as acetonitrile, propionitrile or mixture(s) thereof, halogenated aliphatic hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof, ether solvents such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.

5. The process according to claim no. 1, wherein hydralazine acid addition salt is converted in to pure hydralazine hydrochloride by treating aqueous solution of hydralazine acid addition salt with inorganic base and then with hydrochloric acid at a temperature in the range of 20°C to 80°C. The resulting reaction mixture was added organic solvent and then cooling the resulting reaction mixture at a temperature in the range of-5°C to 10°C.
6. The process according to claim no. 5, wherein inorganic base is selected from the group comprising of hydroxides alkali metal or alkaline earth metal such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide etc., carbonates of alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate etc.
7. A process for the preparation of pure hydralazine hydrochloride comprising the steps of:
a. preparing hydralazine hydrobromide, and
b. converting hydralazine hydrobromide into pure hydralazine hydrochloride.
8. A pharmaceutical composition comprising pure hydralazine hydrochloride obtained by
process comprising the steps of:
a. preparing hydralazine acid addition salt except hydralazine hydrochloride, and
b. converting acid addition salt prepared in step-a into pure hydralazine hydrochloride.
9. A pharmaceutical composition comprising pure hydralazine hydrochloride obtained by
process comprising the steps of:
a. preparing hydralazine hydrobromide, and
b. converting hydralazine hydrobromide into pure hydralazine hydrochloride.