PROCESS FOR THE PREPARATION OF METFORMIN

Abstract

The present invention relates to an improved process for the preparation of metformin hydrochloride, an important drug in the first line treatment of Type II Diabetes.

Claims

1. Process for the preparation of metformin HCl comprising the steps (a) heating a mixture of dimethylammonium chloride, dicyanodiamide, water in an amount from 0 to 20% by weight and metformin HCl in an amount from 0 to 50% by weight, each based on the total weight of dimethylammonium chloride and dicyanodiamide present in the mixture, to a temperature in the range from 70 C. to 250 C. and maintaining the temperature in such range for a time from 0.1 minutes to 20 hours; (b) cooling the reacted mixture and collecting crystalline metformin HCl obtained.

2. Process for the preparation of metformin HCl comprising the steps (a) continuously feeding dimethylammonium chloride, dicyanodiamide, water in an amount from 0 to 20% by weight and metformin HCl in an amount from 0 to 50% by weight, each based on the total weight of dimethylammonium chloride and dicyanodiamide present in the mixture to a reactor, under continuous stirring and under continuous heating the mixture to a temperature in the range from 70 C. to 250 C.; (b) cooling the reacted mixture and collecting crystalline metformin HCl obtained.

3. Process according to claim 1, characterized in that metformin HCl is present in an amount from 0 to 20% by weight, preferably in an amount from 0 to 10% by weight more preferably in an amount of about 5% by weight and most preferably in an amount of 0% by weight, each based on the total weight of dimethylammonium chloride and dicyanodiamide present in the mixture.

4. Process according to claim 1, characterized in that in step (a) the mixture is heated to a first temperature in the range from 70 C. to 120 C., which temperature is maintained for a certain time, and then heated in to a second temperature in the range from 120 C. to 250 C., which temperature is maintained for a certain time.

5. Process according to claim 2, characterized in that the process is run in one continuous reactor or in a combination of continuous reactors in series.

6. Process according to claim 5, characterized in that the process is run in a combination of continuous reactors in series whereat in step (a) the mixture is heated in a first reactor to a first heating temperature in the range from 70 C. to 120 C., which temperature is maintained for a certain time, then heated in a second reactor to a second heating temperature in the range from 110 C. to 160 C., which temperature is maintained for a certain time and then heated in a third reactor to a third temperature in the range from 140 C. to 250 C., which temperature is maintained for a certain time.

7. Process according to claim 1, characterized in that the sum of all times at which the heating temperature(s) is/are maintained for a certain time ranges from 0.1 minutes to 10 hours.

8. Process according to claim 6, characterized in that the first heating temperature is maintained for 0.1 min to 2 hours and the second heating temperature is maintained for 0.1 min to 3 hours and the third heating temperature is maintained for 0.1 min to 5 hours.

9. Process according to claim 2, characterized in that the continuous reactor is a continuous stirred tank reactor, a single or twin-screw extruder, a single or twin-screw kneader or a combination of continuous stirred tank reactors, single or twin-screw extruders and single or twin-screw kneaders.

10. Process according to claim 1, characterized in that dimethylammonium chloride and dicyanodiamide are present in the mixture to each other in a molar ratio of from 1.0 to 2.0:1, preferably in a molar ratio of about 1.15:1.

11. Process according to claim 1, characterized in that the mixture processed in step (a) contains water in an amount from 0 to 10% by weight, preferably from 0 to 5% by weight, and more preferably about 3% by weight, each based on the total weight of dimethylammonium chloride and dicyanodiamide present in the mixture.

12. Process according to claim 1, characterized in that the mixture processed in step (a) further contains an additive that increases the reaction selectivity and/or the viscosity of the melted mixture.

13. Process according to claim 12, characterized in that the additive is sodium chloride, celite or silica, preferably celite, or a blend of two or more materials thereof.

14. Process according to claim 12, characterized in that an additive is present in the mixture in an amount from 0.001 to 50% by weight, preferably from 0.01 to 10% by weight, more preferably from 0.1 to 5% by weight, based on the total weight of dimethylammonium chloride and dicyanodiamide present in the mixture.

15. Process according to claim 11, characterized in that the mixture comprises as additive about 1% celite by weight, based on the total weight of dimethylammonium chloride and dicyanodiamide present in the mixture.

16. Process according to claim 1, characterized in that dimethylammonium chloride is added as a mixture with water, which mixture is prepared by preparing a solution of dimethylammonium chloride containing 20 to 50% water by weight and concentrating such solution to 0.1 to 20% water by weight, preferably to 0.1 to 10% water by weight, more preferably to about 0.1 to 6% water by weight, each based on the total weight of dimethylammonium chloride and water.

Description

EXAMPLE 1 (BATCH PROCESS, ONE HEATING STEP)

[0038] 250 g of dicyanodiamide, 315.22 g of dimethylammonium chloride and 16.96 mL of water was added to a 1 L reactor. The reactor is heated to 145 C. for 3 hours. As the reaction proceeds, metformin hydrochloride precipitates from the mixture. The reactor is cooled to room temperature, demineralized water is added to the reactor and the resulting slurry is removed. Metformin HCl is obtained in 89% purity.

EXAMPLE 2 (BATCH PROCESS, TWO HEATING STEPS)

[0039] 3432 g of dicyanodiamide, 4320 g of dimethylammonium chloride and 232.5 mL of water was added to a reactor. The reactor is heated to 105 C. until a homogeneous melt if formed. The melt mixture is transferred to a 12 L twin screw, co-rotating batch kneader and heated to 130 C. for 1 hour, followed 145 C. for 2.5 hours. As the reaction proceeds, metformin hydrochloride precipitates from the mixture. The reactor is cooled to room temperature, demineralized water is added to the reactor and the resulting slurry is removed. Metformin HCl is obtained in 94% purity.

EXAMPLE 2 (CONTINUOUS PROCESS)

[0040] Dicyanodiamide, dimethylammonium chloride in a molar ratio of 1:1.15 and water (3% by weight relating to the total weight of dimethylammonium chloride and dicyanodiamide present in the mixture) was continuously fed to a 6 L stirred vessel heated to 100 C. The melt mixture was transferred at a rate of 4 kg/hr into a stirred reactor, where it is heated to 135 C. for a residence time of 15 mins. The partially reacted material is continuously discharged into a twin-screw kneader, where it is stirred at 175 C. for 45 mins to obtain complete conversion. The product is continuously discharged from the second kneader at a rate of 4 kg/hr via a vertical twin-screw conveyor into a collection flask. The solid mixture collected contains metformin in 89% purity.

EXAMPLE 3 (BATCH PROCESS USING MIXTURE OF DIMETHYLAMMONIUM CHLORIDE AND WATER)

[0041] 450 g of a 70% aqueous solution of dimethylammonium chloride was added to a reactor equipped with a distilling column. The mixture was concentrated at 130 C. for 2.5 hours until the water content was approximately 5%. To this mixture, 250 g of dicyanodiamide was added. The reactor is heated to 145 C. for 3 hours. As the reaction proceeds, metformin hydrochloride precipitates from the mixture. The reactor is cooled to room temperature, demineralized water is added to the reactor and the resulting slurry is removed.