The present invention relates to an improved process for the preparation of Metformin compound of formula-I or its pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Metformin hydrochloride is described chemically as N,N- Dimethylimidodicarbonimidic diamide hydrochloride (CAS# 1115-70-4). The empirical formula of Metformin hydrochloride is C ₄ H ₁₁ N ₅ .HCI and its molecular weight is 165.62 g/mol. The molecular structure of Metformin hydrochloride is represented by Formula I.

Formula I

Metformin, also known by other name like 1,1-dimethylbiguanide, it is first described in the scientific literature in J. Chem, Soc, 1922, 121, 1790. It is the only one available biguanide, most widely prescribed orally administered antidiabetic drug for the treatment of type 2-diabetes. It is also used for the treatment of polycystic ovary syndrome

The advantages of Metformin hydrochloride are a very low risk of hypoglycaemia, weight neutrality and reduced risk of cardiovascular morbidity and mortality. In US patent no. 2,448,448 discloses use of 1, 1-dimethylbiguanide in dyeing of textile fibers, wherein 1,1-dimetylbiguanide is prepared by reacting dicyandiamide with dimethylamine. In US patent no 3, 174,901 discloses composition containing 1,1- dimethylbiguanide in the form of hydrochloride salt used for treating diabetes by oral administration.

In DE patent no. 1023757 discloses preparation of Metformin hydrochloride by reacting dicyandiamide with dimethylamine hydrochloride in xylene at reflux temperature and crystallization with water to obtain Metformin hydrochloride with 47% yield.

In FR patent no 2322860 discloses preparation of Metformin hydrochloride by reacting equimolar amounts of dimethylamine and dicyandiamide in xylene followed by treating with HC1 gas to obtain crude Metformin hydrochloride is further purified by methanol.

In US patent application no 2011/021634 discloses preparation of Metformin hydrochloride substantially free from dimethylamine wherein an aqueous solution of Metformin hydrochloride is concentrated to remove water and the obtained residue is treated with C1-C4 alcohols to obtain pure Metformin hydrochloride.

In an Indian patent 189077 discloses a preparation of Metformin hydrochloride in absence of solvents followed by purification to obtain pure Metformin hydrochloride crystals.

In CN patent no 100391939 discloses a preparation of Metformin hydrochloride by treating 40% aqueous dimethylamine solution with 31% hydrochloric acid followed by dicyandiamide in ethanol to get crude compound, followed by recrystallization with ethanol to obtain Metformin hydrochloride with 75-80 % yield.

In IN patent application No. 1350/MUM/2007 discloses preparation of highly pure Metformin hydrochloride substantially free from melamine and cyanoguanidine impurities by condensation of dimethylamine hydrochloride with dicyandiamide in xylene; extracting the product into water followed by distillation of water under vacuum at 65-72°C and crystallizing Metformin hydrochloride from methanol or a mixture of water and methanol.

In IN patent application No. 1346/MUM/2008 discloses a one-pot process for preparation of highly pure Metformin hydrochloride substantially free from melamine and cyanoguanidine impurities by reacting dimethylamine hydrochloride solution prepared insitu with cyanoguanidine in xylene, extracting metformin hydrochloride in to water, and distillation of around 50% of water followed by isolation.

In PCT publication no. 2010146604 discloses a preparation of Metformin hydrochloride using hydrocarbon solvents, followed by treating with water and alcoholic solvents to get Metformin hydrochloride as a product.

In PCT publication no. 2014041566 discloses a preparation of Metformin hydrochloride by removing solvents from the Metformin hydrochloride solution using agitated thin film dryer technique.

In Pharmaceutical Chemistry Journal, 1987, 21 (12), 892-894 discloses a preparation of Metformin hydrochloride by using n-butanol, followed by purification with isopropanol to obtain Metformin Hydrochloride as a final product with 65% yield. Above mentioned prior art processes for the preparation of Metformin hydrochloride suffers from several disadvantages like decrease in yield of final compound, difficult in removal of the solvents during process, formation of several impurities during process, which are not economic at commercial scale. Further prior art processes involves non food grade solvent which will impact the final compound.

Substantially these factors affect the commercial viability of manufacturing process of Metformin hydrochloride. Therefore, there is a need to develop an improved process for the preparation of Metformin hydrochloride which can be practiced on large scale to produce Metformin hydrochloride in a cost efficient manner.

OBJECTIVE OF THE INVENTION

The main object of the present invention is to provide an improved process for the preparation of highly pure Metformin hydrochloride compound of Formula I.

Another object of the present invention is use of single organic solvent for the preparation of highly pure Metformin hydrochloride compound of Formula I.

Yet another object of the present invention is use of single alcoholic solvent for the preparation of pure Metformin hydrochloride compound of Formula I. Yet another object of the present invention is use of n-butanol (is also a food grade material use in the industries) alcoholic solvent for the preparation of pure Metformin hydrochloride compound of Formula I. SUMMARY OF THE INVENTION

In an embodiment, the present invention provides an improved process for the preparation of Metformin hydrochloride compound of formula I, which comprises the steps of

i) treating dimethyl amine in the form of hydrochloride (DMA HCI) with 2- cyanoguanidine (DCDA) in presence of alcoholic solvent at ambient to reflux temperature.

ii) isolation of Metformin by filtration.

iii) With or without washing step (ii) with alcoholic solvent and drying to get compound of formula- 1 as a pure product.

According to present invention the term alcohol includes primary, secondary and tertiary alcohols, preferably primary alcohols; more preferably n-butanol.

In the first aspect of invention is use of minimum amount of n-butanol for the preparation of Metformin Hydrochloride.

In the second aspect of invention is use of 0.4 to 4.0 kg of n-butanol for 1 kg of 2- cyanoguanidine. In the third aspect of invention is preparation of Metformin hydrochloride having purity > 99.9 % In the fourth aspect of the invention is preparation of high yield of Metformin hydrochloride is about >92 to 98 %.

In the fifth aspect of invention is preparation of highly pure Metformin hydrochloride, with residual quantity of Dimethyl amine is less than 5 ppm.

Unlike prior art the present invention involves the use of n-butanol , which is also a food grade material use in the industries, will minimize the multiple residual solvents and improves the quality and purity of the API which leads to consumption of finished formulations at patient end for safe use.

BRIEF DESCRIPTION OF DRAWINGS

Figure: 1 depicts X-ray diffraction pattern of crystalline Metformin hydrochloride as per example- 1.

Figure: 2 depicts X-ray diffraction pattern of crystalline Metformin hydrochloride as per example-2. Figure: 3 depicts X-ray diffraction pattern of crystalline Metformin hydrochloride as per example-3.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an improved process for the preparation of highly pure metformin hydrochloride crystal by using single alcoholic solvent. The simple process offers high yield and low level of impurities makes the process more convenient and economical, particularly on commercial scale. In an embodiment, the invention provides a process for preparation of Metformin hydrochloride, which comprises the steps of:

i) treating dimethyl amine in the form of hydrochloride (DMA HC1) with 2- cyanoguanidine (DCDA) in presence of alcoholic solvent at ambient to reflux temperature.

ii) isolation of Metformin by filtration.

iii) With or without washing step (ii) with alcoholic solvent and drying to get compound of formula- 1 as a pure product. 2-cyanoguanidine and dimethyl amine hydrochloride were added to alcoholic solvent to form the reaction mixture. The reaction mixture is condensed using the cooling water condenser for 16-28 hr. The resulting reaction mass is cooled to ambient temperature, preferably 10-110°C. The reaction mass is filtered to receive the wet mass. The wet mass can be washed with n-butanol and dried to get pure Metformin hydrochloride. The reaction mass is filtered and dried using standard techniques that have been widely used in industry.

The alcohols that are selected include primary, secondary and tertiary alcohols, preferably primary alcohols; more preferably n-butanol.

According to another aspect of invention, the Metformin hydrochloride prepared by this method have purity >99.9%.

In another aspect of the invention is preparation of high yield of Metformin hydrochloride is about >92 to 98%.

In yet another aspect of invention is preparation of highly pure Metformin hydrochloride, with residual quantity of Dimethyl amine is less than 5 ppm. The final product has low level of other impurities wherein melamine and 2- cyanoguanidine (DCDA) is less than 0.02%, more preferably 0.01%. EXAMPLES

In the following examples, the preferred embodiment of the present invention is described only by way of illustrating the processes of the invention. However, these are not intended to limit the scope of the invention in any way.

Example: 1 Preparation of Metformin hydrochloride (Formula 1)

84.07 g of 2-cyanoguanidine and 81.54 g of Dimethyl amine hydrochloride were added to 100 g of n-butanol in a 500 mL glass flask. The flask was equipped with cooling water condenser and the flask was allowed to reflux for 16 h The resulting reaction mass was cooled to ambient temperature, preferably 10-110°C and filtered. The obtained wet solid was washed with 50g of n-butanol and dried to get Pure Metformin hydrochloride (160g).

EXAMPLE 2: Preparation of Metformin hydrochloride (Formula 1)

100 g of 2-cyanoguanidine and 108 g of Dimethyl amine hydrochloride were added to 400 g of n-butanol in a 1000 mL glass flask. The flask was equipped with cooling water condenser and the flask was allowed to reflux for 28 h. The resulting reaction mass was cooled to ambient temperature, preferably 10-110°C and filtered. Dried the obtained solid at 50° ^" 75°C, to get Pure Metformin hydrochloride (188 g)

EXAMPLE 3: Preparation of metformin hydrochloride (Formula 1)

1 Kg of 2-cyanoguanidine and 1.15 Kg of Dimethyl amine hydrochloride were added to 2 Kg of n-butanol in a 5 L glass flask. The flask was equipped with cooling water condenser and the flask was allowed to reflux for 22 h. The resulting reaction mass was cooled to ambient temperature, preferably 10-110°C and filtered. Dried the obtained solid at 50° ^" 75°C, to get Pure Metformin hydrochloride (1.9 Kg) Above obtained Metformin Hydrochloride samples were analyzed for related substances by HPLC as per the European Pharmacopoeia monograph (Ph. Eur) 8.0

Single Maximum Metformin

Total

Examples Unknown Hydrochloride

impurities

Impurity purity

1 0.02% 0,03% 99.97%

2 0,02% 0,05% 99.95%

3 0,01 % 0,04% 99.96%

Content of related impurity- A, Impurity -F and Melamine is as follows:

Examples Related compound A Impurity-F content Melamine content

1 0.01 % 2 ppm Not detected

2 0.01 % 3 ppm Not detected

3 0.01 % 2 ppm Not detected

Related compound- A is 2-cyanoguamdine

Impurity -F is Dimethylaniine