FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"Cost effective, one pot process for synthesis of highly pure Metformin
Hydrochloride substantially free from Melamine and Cyanoguanidine"


2. APPLICANT (S)
(a) NAME: WANBURY LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies Act, 1956
(c) ADDRESS: B- Wing, 10th Floor, BSEL Tech Park, Sector 30 A,
Plot No. 39/5 & 39/5A, Opp. Vashi Railway Station, Navi- Mumbai- 400 703, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.


Technical field:
This invention relates to cost effective, one pot process for synthesis of highly pure Metformin Hydrochloride substantially free from Melamine and Cyanoguanidine.
Background of the invention
Metformin is a typical biguanide, chemically known as (N, N- dimethyl imidocarbonimidic diamide). Metformin is an oral antihyperglycemic drug used in the management of non-insulin-dependent diabetes mellitus (NIDDM). It is typically used as pharmaceutically acceptable salt preferably Hydrochloride salt. Metformin Hydrochloride is currently marketed as GLUCOPHAGE(R) tablets by Bristol-Myers Squibb Co. Each GLUCOPHAGE(R) tablet contains 500, 850 or 1000 mg of Metformin Hydrochloride. There is no fixed dosage regimen for the management of hyperglycemia in diabetes mellitus with GLUCOPHAGE(R). Dosage of GLUCOPHAGE(R) is individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended dose of 2550 mg per day.
Metformin Hydrochloride is a white to off white crystalline compound with a molecular formula C4H11N5 HCL with molecular wt of 65.63. Metformin HCL is freely soluble in water and practically insoluble in acetone, ether and chloroform.
US 3174901 disclose composition containing dimethyl biguanide used in the form of Hydrochloride salt wherein it is used for treating diabetes by oral administration.
2
Metformin Hydrochloride (N, N-dimethylimidodicarbonimidic diamide Hydrochloride) of formula I is a member of the biguanide class of oral antihyperglycemics which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose.


Metformin is commercially manufactured by condensation of dimethyl amine (Formula II) in the form of Hydrochloride and Dicyanodiamide, also called as Cyanoguanidine (Formula III) as shown in scheme 1.
(Scheme-1)

During this condensation, number of impurities are formed which are present in Metformin Hydrochloride along with starting materials. Major impurities so far detected in commercial Metformin Hydrochloride are dimethyl amine Hydrochloride (formula II), Cyanoguanidine (formula III), N,N-dimethyI-I,3,5-triazine-2,4,6-triamine or N,N-dimethyl melamine (Formula IV), I,3,5-triazine-2,4,6-triamine or melamine (Formula V) and N,N-dimethylguanidine (Formula VI).

All the impurities listed above, are potentially hazardous to human health. Literature references related to toxicological studies of those impurities are as follows
Dimethyl amine Hydrochloride(II):
Dimethyl amine is the immediate precursor of dimethylnitrosamine, a.known potent carcinogen in a wide variety of animal species (Food and Chemical Toxicology 36,
3

923-927, (1998)) Olfactory sensory cells are highly sensitive to the toxic effects of dimethyl amine {Buckley et al. Toxicol. Sci. 5, 341-352 (1985)).
Cyanoguanidine (III):
The body weight gains are significantly lowered due to intake of Cyanoguanidine (K. Yasuhara et al. Food and Chemical Toxicology 35, 475-480(1997)). The substance decomposes on heating or reaction with acid to produce toxic gases including ammonia and hydrogen cyanide.
Melamines:
Repeated dose toxicity studies of melamine shows that melamine produces urinary bladder stones (urolithiasis), hyperplastic epithelial changes in the urinary bladder and calcerous deposits in the proximal kidney tubules. Long term effects noted are inflammation and occurrence of transitional cell papillomas and carcinomas of the urinary bladder. {MelnickR. L. etal. Toxicol. Appl. Pharmacol. 72, 292-303 (1985)).
Limits of those impurities in BP and Ph Eur are 0.02% (200 ppm) for Cyanoguanidine, 0.05% (500 ppm) for individual and 0.3% (3000 ppm) for total impurities.
It means a person consuming 1000 mg tablet of Metformin a day, possibly consumes -110 grams of impurities listed above, which are potentially hazardous to human health.
Thus it was necessary to develop a process for production of Metformin which will contain impurity level well below above permissible limits which is disclosed in present invention.
Objects of the invention:
The main object of the invention is to produce remarkably pure Metformin Hydrochloride with high throughput with exceptionally low amount of Cyanoguanidine and Melamine.
4

Summary of the invention:
According to the present invention, highly pure Metformin Hydrochloride is prepared in one pot.
In a preferred aspect, the invention discloses a process for preparation of highly pure Metformin Hydrochloride, wherein said process comprises reacting dimethylamine Hydrochloride prepared insitu with Dicyanodiamide (DCDA) at a temperature ranging 135-140°C for 5-10 hrs to obtain Metformin Hydrochloride substantially free from the impurities, Melamine and Cyanoguanidine.
Detailed description of the invention
The invention will now be described in detail in connection with certain preferred embodiment so that various aspects thereof may be more fully understood and appreciated.
In accordance with the above, highly pure Metformin Hydrochloride is prepared in one pot. In the present process, dimethylamine Hydrochloride is prepared insitu by purging dimethyl amine gas into water followed by treatment with Cone, HCl to get dimethyl amine hydrochloride. The maximum water is advantageously removed by distillation under vacuum followed by azeotropic distillation by using xylene. Dicyanodiamide (DCDA) is added into the flask and the reaction mass is heated to 135-140°C for 5-10 hrs to obtain complete conversion.
After completion of reaction, Metformin thus formed is extracted into water and concentrated. The contents are cooled to 25-35°C, centrifuged the material, and washed with methanol to get highly pure Metformin hydrochloride which is substantially free from the impurities, Melamine and Cyanoguanidine.
Advantage of the above process is as it produces extremely pure Metformin Hydrochloride with high yields. All impurities are well below the limits specified by pharmacopeias. For instance Cyanoguanidine obtained by the process are 30-50 ppm verses pharmacopeial limit of 200ppm. Melamine content obtained is 0-20 ppm verses
5

pharmacopeial limit of 500 ppm. Single unidentified impurity, obtained is 50-80 ppm verses pharmacopeial limit of 1000 ppm. Total impurities obtained are 300-500 ppm verses pharmacopeial limit of 3000 ppm.
The following example is presented to illustrate the working of the present invention, but is not limiting the scope of the individual embodiment presented.
Exam pie-1
Synthesis of Metformin Hydrochloride:-
Dimethylamine gas (428 g ) was purged into water (640 ml) to get about 40 % solution. This solution was charged into reactor containing 30 % cone. HC1 (1160 g). Thus, insitu prepared dimethyl amine hydrochloride was subjected to distillation under vacuum and traces of water were removed by azeotropic distillation using 2 to 5 volumes of xylene and added 700 g of DCDA to the reactor. The reaction mass was heated to 135-140°C for 5-10 hrs. About 2-5 volume of purified water was charged thereafter; separated xylene and aqueous layers. About 50% water from aqueous solution was distilled and cooled the reaction mass to ambient temperature. The product thus obtained was filtered washed with methanol and dried at 75-80°C for 5-6 hrs. Yield:-1000 g
6

We claim:-
1. A one pot process for production of highly pure Metformin Hydrochloride substantially free from the impurities, Melamine and Cyanoguanidine comprising following steps:
a) purging dimethylamine gas into water to prepare dimethylamine solution;
b) preparing insitu dimethylamine Hydrochloride solution by treating dimethyl amine with Cone. Hydrochloric acid solution;
c) distilling water by vacuum, followed by azeotropic distillation of water using xylene to get dimethylamine hydrochloride insitu.
d) heating mixture of Cyanoguanidine and insitu prepared dimethylamine Hydrochloride in xylene at 135-138°C;
e) extracting Metformin Hydrochloride formed in reaction into water; and
f) isolating Metformin Hydrochloride by distillation of water followed by filtration, washing with methanol and drying.
Dated this 26th day of June 2008
* *
Dr. Gopakumar G. Nair Agent for the Applicant
7