2-benzhydryloxy-N,N-dimethylethanamine

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 500 ml round bottom flask equipped with a stirrer, thermometer and heating mantle was set up. The flask was charged with 176 g of a 10% aqueous sodium hydroxide solution. Thereafter, 118 g (0.40 mole) diphenhydramine hydrochloride was slowly added, with stirring, to the flask at room temperature. The reaction mixture was then stirred for 30 minutes at 45–50° C. The reaction mixture was allowed to settle for 15 minutes and the organic layer was separated (the pH of the layer was 12.8). The organic layer consisting of the diphenhydramine free base was washed by mixing it with 100 ml of purified water and maintaining a temperature of 70–75° C. for one hour, while stirring. Stirring was then discontinued and the phases were allowed to split over a period of one hour. The lower organic layer consisting of the diphenhydramine free base was then separated. The yield of the free base was found to be 104 g (about 99% of theory) and it had a moisture content of 2.18% as determined by Karl. Fischer (K. F.) analysis. A 500 ml round bottom flask equipped with a stirrer thermometer and heating mantle The reaction mixture was then stirred for 30 minutes at 45–50° C the organic layer was separated (the pH of the layer was washed by mixing it with 100 ml of purified water maintaining a temperature of 70–75° C. for one hour while stirring Stirring to split over a period of one hour was then separated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 500 ml round bottom flask equipped with a stirrer, thermometer and heating mantle was set up. The flask was charged with 176 g of a 10% aqueous sodium hydroxide solution. Thereafter, 118 g (0.40 mole) diphenhydramine hydrochloride was slowly added, with stirring, to the flask at room temperature. The reaction mixture was then stirred for 30 minutes at 45–50° C. The reaction mixture was allowed to settle for 15 minutes and the organic layer was separated (the pH of the layer was 12.8). The organic layer consisting of the diphenhydramine free base was washed by mixing it with 100 ml of purified water and maintaining a temperature of 70–75° C. for one hour, while stirring. Stirring was then discontinued and the phases were allowed to split over a period of one hour. The lower organic layer consisting of the diphenhydramine free base was then separated. The yield of the free base was found to be 104 g (about 99% of theory) and it had a moisture content of 2.18% as determined by Karl. Fischer (K. F.) analysis. A 500 ml round bottom flask equipped with a stirrer thermometer and heating mantle The reaction mixture was then stirred for 30 minutes at 45–50° C the organic layer was separated (the pH of the layer was washed by mixing it with 100 ml of purified water maintaining a temperature of 70–75° C. for one hour while stirring Stirring to split over a period of one hour was then separated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Another typical combination composition was formulated as follows. Diphenhydramine hydrochloride 58 g (0.2 mole) was dissolved in water 100 ml, and 5N NaOH 40 ml (0.2 mole) was added slowly with stirring. Diphenhydramine free base was formed as oily white precipitates. Without isolation of the free base, N-acetyl-L-proline 48 g (0.3 mole) and N-acetyl-D-glucosamine 44 g (0.2 mole) were added with stirring into the oily mixture, and the mixture became a clear solution. Propylene glycol 100 ml and water 50 ml were added to make total volume 400 ml (444 g). This formulation contained diphenhydramine 14.5%, N-acetyl-L-proline 12% and N-acetyl-D-glucosamine 11% in a propylene glycol/water solution. The above formulation 22 g and tribenzyl citrate 10 g were mixed with hydrophilic ointment or oil-in-water cream 68 g. The composition thus prepared had pH 3.8 and contained 10% tri-benzyl citrate, 3% diphenhydramine, 2.6% N-acetyl-L-proline and 2.4% N-acetyl-D-glucosamine in a water-washable cream.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Another typical combination composition was formulated as follows. Diphenhydramine hydrochloride 58 g (0.2 mole) was dissolved in water 100 ml, and 5N NaOH 40 ml (0.2 mole) was added slowly with stirring. Diphenhydramine free base was formed as oily white precipitates. Without isolation of the free base, N-acetyl-L-proline 48 g (0.3 mole) and N-acetyl-D-glucosamine 44 g (0.2 mole) were added with stirring into the oily mixture, and the mixture became a clear solution. Propylene glycol 100 ml and water 50 ml were added to make total volume 400 ml (444 g). This formulation contained diphenhydramine 14.5%, N-acetyl-L-proline 12% and N-acetyl-D-glucosamine 11% in a propylene glycol/water solution. The above formulation 22 g and tribenzyl citrate 10 g were mixed with hydrophilic ointment or oil-in-water cream 68 g. The composition thus prepared had pH 3.8 and contained 10% tri-benzyl citrate, 3% diphenhydramine, 2.6% N-acetyl-L-proline and 2.4% N-acetyl-D-glucosamine in a water-washable cream.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 500 ml round bottom flask equipped with a stirrer, thermometer and heating mantle was set up. The flask was charged with 176 g of a 10% aqueous sodium hydroxide solution. Thereafter, 118 g (0.40 mole) diphenhydramine hydrochloride was slowly added, with stirring, to the flask at room temperature. The reaction mixture was then stirred for 30 minutes at 45–50° C. The reaction mixture was allowed to settle for 15 minutes and the organic layer was separated (the pH of the layer was 12.8). The organic layer consisting of the diphenhydramine free base was washed by mixing it with 100 ml of purified water and maintaining a temperature of 70–75° C. for one hour, while stirring. Stirring was then discontinued and the phases were allowed to split over a period of one hour. The lower organic layer consisting of the diphenhydramine free base was then separated. The yield of the free base was found to be 104 g (about 99% of theory) and it had a moisture content of 2.18% as determined by Karl. Fischer (K. F.) analysis. A 500 ml round bottom flask equipped with a stirrer thermometer and heating mantle The reaction mixture was then stirred for 30 minutes at 45–50° C the organic layer was separated (the pH of the layer was washed by mixing it with 100 ml of purified water maintaining a temperature of 70–75° C. for one hour while stirring Stirring to split over a period of one hour was then separated