3-(diaminomethylidene)-1,1-dimethylguanidine;hydrochloride

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Metformin hydrochloride is screened through a 1 mm sieve. Screened metformin hydrochloride is granulated in a fluid bed granulator with a solution of povidone in demineralized water and dried in the same device. Dried granulate is screened through a 1 mm sieve. The obtained granulate, microcrystalline cellulose and ethylcellulose are homogenously blended in a bin blender. Pre-sieved magnesium stearate is added to the obtained blend and blended in bin blender so that the final blend is obtained. The final blend is compressed into a bilayer tablet as disclosed in Examples 16 and 17. dried in the same device Dried granulate Pre-sieved magnesium stearate is added to the obtained blend is obtained

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Metformin hydrochloride is screened through a 1 mm sieve. Screened metformin hydrochloride is granulated in fluid bed granulator with the solution of povidone in demineralized water and dried in the same device. The dried granulate is screened through a 1 mm sieve. The obtained granulate, microcrystalline cellulose and hydrogenated castor oil are homogenously blended in a bin blender. Pre-sieved magnesium stearate is added to the obtained blend and blended in a bin blender so that the final blend is obtained. The final blend is compressed into a bilayer tablet as disclosed in Examples 14 and 15. dried in the same device Pre-sieved magnesium stearate is added to the obtained blend is obtained

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Metformin hydrochloride is screened through a 1 mm sieve. Screened metformin hydrochloride is granulated in a fluid bed granulator with a solution of povidone in demineralized water and dried in the same device. The dried granulate is screened through a 1 mm sieve. The obtained granulate, microcrystalline cellulose and hydroxypropylcellulose are homogenously blended in a bin blender. Pre-sieved magnesium stearate is added to the obtained blend and blended in a bin blender so that the final blend is obtained. dried in the same device Pre-sieved magnesium stearate is added to the obtained blend is obtained

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Metformin hydrochloride is screened through 1 mm sieve. Screened metformin hydrochloride is granulated in a fluid bed granulator with a solution of povidone in demineralized water and dried in the same device. The dried granulate is screened through a 1 mm sieve. The obtained granulate, microcrystalline cellulose and hydroxypropylmethylcellulose are homogenously blended in a bin blender. Pre-sieved magnesium stearate is added to the obtained blend and blended in a bin blender so that the final blend is obtained. The final blend is compressed into a bilayer tablet as disclosed in Examples 11 in 12. dried in the same device Pre-sieved magnesium stearate is added to the obtained blend is obtained

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Metformin hydrochloride is screened through 1 mm sieve. Screened metformin hydrochloride and hydroxypropylmethylcellulose are granulated in fluid bed granulator with demineralized water and dried in the same device. Dried granulate is screened through 1 mm sieve. Obtained granulate and microcrystalline cellulose are homogenously blended in a bin blender. Pre-sieved magnesium stearate is added to the obtained blend and blended in a bin blender so that the final blend is obtained. dried in the same device Dried granulate Obtained granulate is obtained

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The Metformin Resin Complex was prepared by first dissolving 225 g of metformin HCl in 4 L of purified water, and then slowly adding 735 g of AMBERLITE™ IRP-69 resin with continuous mixing. The dispersion was mixed for 4 hours and upon completion, allowed to settle before decanting the supernatant. The slurring/decanting process was repeated twice with sufficient amounts of purified water. The wet resin complex was then dried in a VWR™ convection oven maintained at 50° C. until moisture content was about 25%. KOLLICOAT™ SR-30D (250 g) was first mixed with 150 g of purified water and the mixture was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass. The wet mass was again dried in a 50° C. VWR™ convection oven to the moisture content about 20%. The semi-dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill and drying continued at 50° C. until the moisture content was between 3-7%. The dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill. slowly adding 735 g of AMBERLITE™ The dispersion was mixed for 4 hours and upon completion before decanting the supernatant The wet resin complex was then dried in a VWR™ convection oven KOLLICOAT™ SR-30D (250 g) was first mixed with 150 g of purified water the mixture was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass The wet mass was again dried in a 50° C The semi-dried granules were then milled through a 40 mesh screen drying continued at 50° C. until the moisture content The dried granules were then milled through a 40 mesh screen

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The Metformin Resin Complex was prepared by first dissolving 225 g of metformin HCl in 4 L of purified water, and then slowly adding 735 g of AMBERLITE™ IRP-69 resin with continuous mixing. The dispersion was mixed for 4 hours and upon completion, allowed to settle before decanting the supernatant. The slurring/decanting process was repeated twice with sufficient amounts of purified water. The wet resin complex was then dried in a VWR™ convection oven maintained at 50° C. until moisture content was about 25%. KOLLICOAT™ SR-30D (250 g) was first mixed with 150 g of purified water and the mixture was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass. The wet mass was again dried in a 50° C. VWR™ convection oven to the moisture content about 20%. The semi-dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill and drying continued at 50° C. until the moisture content was between 3-7%. The dried granules were then milled through a 40 mesh screen using CO-MIL™ brand mill. slowly adding 735 g of AMBERLITE™ The dispersion was mixed for 4 hours and upon completion before decanting the supernatant The wet resin complex was then dried in a VWR™ convection oven KOLLICOAT™ SR-30D (250 g) was first mixed with 150 g of purified water the mixture was then slowly added to the wet resin complex in a Hobart type mixer (Kitchen Aid) to form a uniform mass The wet mass was again dried in a 50° C The semi-dried granules were then milled through a 40 mesh screen drying continued at 50° C. until the moisture content The dried granules were then milled through a 40 mesh screen

反応条件: temp:12.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 100.1 g of metformin hydrochloride, 36.5 g of paraldehyde and 4 g of Dowex DR-2030 in 237.8 ml of isobutanol was heated under reflux for 6 hours. The catalyst was subsequently filtered off, and some of the solvent was removed by distillation. The remainder of the solution was cooled to 10-15° C., and the white precipitate was separated off, giving 93.5 g (80.7%) of 4-amino-3,6-dihydro-2-dimethylamino-6-methyl-1,3,5-triazine hydrochloride. was heated under reflux for 6 hours The catalyst was subsequently filtered off some of the solvent was removed by distillation the white precipitate was separated off

反応条件: temp:12.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1002.6 g of metformin hydrochloride, 359.1 g of paraldehyde and 51.6 g of toluene-4-sulfonic acid monohydrate in 2405.9 g of isobutanol was heated under reflux for 6 hours. Some of the solvent was removed by distillation. The mixture was cooled to 12° C., and the white precipitate was separated off, giving 953.8 g (81.4%) of 4-amino-3,6-dihydro-2-dimethylamino-6-methyl-1,3,5-triazine hydrochloride. was heated under reflux for 6 hours Some of the solvent was removed by distillation the white precipitate was separated off

反応条件: temp:12.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1002.6 g of metformin hydrochloride, 359.1 g of paraldehyde and 51.6 g of toluene-4-sulfonic acid monohydrate in 2405.9 g of isobutanol was heated under reflux for 6 hours. Some of the solvent was removed by distillation. The mixture was cooled to 12° C., and the white precipitate was separated off, giving 953.8 g (81.4%) of 4-amino-3,6-dihydro-2-dimethylamino-6-methyl-1,3,5-triazine hydrochloride. was heated under reflux for 6 hours Some of the solvent was removed by distillation the white precipitate was separated off

反応条件: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Comparative experiment) A mixture of 250.2 g of metformin hydrochloride, 213.6 g of acetaldehyde diethyl acetal and 12.5 g of toluene-4-sulfonic acid monohydrate in 500 ml of isobutanol was heated under reflux for 40 hours. Some of the solvent was removed by distillation. The mixture was cooled to 10° C., and the white precipitate was separated off, giving 224.7 g (77.4%) of 4-amino-3,6-dihydro-2-dimethylamino-6-methyl-1,3,5-triazine hydrochloride. was heated under reflux for 40 hours Some of the solvent was removed by distillation the white precipitate was separated off

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 20 g (2 molar equivalents) of metformin hydrochloride, 4.83 g (2 molar equivalents) of sodium hydroxide and 8.09 g (1 molar equivalent) of malic acid were stirred in 90 ml of water at 100° C., and acetone was added dropwise thereto at room temperature. Then, the produced crystal was stirred at room temperature for 1 hour, filtered and dried in hot air, thus obtaining 10.69 g (yield: 45.1%) of metformin malate. at room temperature filtered dried in hot air