Preparation method of enoxaparin sodium?

  Enoxaparin sodium is a low molecular weight heparin used as an anticoagulant for the prevention and treatment of deep vein thrombosis or pulmonary embolism. Enoxaparin sodium is white or almost white powder, tasteless, with moisture, soluble in water, insoluble in ethanol, acetone and other organic solvents. It has a strong negative charge in aqueous solution and can combine with some cations to form molecular complexes. Aqueous solution is more stable at pH 7.

  1. Into salt. 30g of crude heparin sodium was weighed and purified water was added to dissolve the heparin sodium solution. Benzethonium chloride 75g was weighed and purified water was added to dissolve to obtain benzethonium chloride solution. Slowly add benzathonium chloride solution to heparin sodium solution, stir while adding, stir evenly, let stand for 2 hours. Then centrifuge the centrifuge operation, the centrifuged solid was washed with purified water, and finally the obtained heparin benzyl chloride ammonium salt wet product was vacuum dried to get heparin benzyl chloride ammonium salt.

Preparation method of enoxaparin sodium?

  2.Esterification. To the heparin benzyl ammonium chloride to add 5 times the volume of methylene chloride, stir to dissolve to join heparin benzyl again after 1 times the volume of benzyl chloride ammonium chloride, maintain temperature 35 ℃, mixing reaction for 24 hours, end of the reaction to join heparin benzyl line 6 times the volume of 10% ammonium chloride sodium acetate methanol solution, stirring for 10 minutes, let stand for 4 hours, The precipitation was filtered and washed twice with methanol to obtain wet heparin benzyl ester. Add 8% sodium chloride solution 3 times by weight and volume of heparin benzol chlorammonium salt to wet crude heparin benzyl ester, stir until completely dissolved, then add methanol 4 times by volume of sodium chloride solution, stir again for 10 minutes, stand for 2 hours, filter and repeat this operation three times, get wet heparin benzyl ester. Heparin benzyl ester can be obtained by vacuum drying wet heparin benzyl ester.

  3. The depolymerization. Purified water 20 times its weight and volume was added to heparin benzyl ester, which was dissolved while stirring, and heated to 60℃ at the same time. Weigh 10% of the weight of heparin benzyl ester sodium hydroxide dissolved in purified water, and then slowly added into the heparin benzyl ester solution, maintain the temperature of 60℃, stirring reaction for 2 hours, then with appropriate amount of hydrochloric acid to adjust the solution pH6.0~6.5, cooling the solution to room temperature, depolymerization solution. Add an appropriate amount of sodium chloride to the depolymerization solution at a concentration of 10%, stir until it is completely dissolved, then add methanol 60 times the weight of heparin benzyl ester in the stirred state, stir evenly and stand for 5 hours, then separate the supernatant to obtain enoxaparin sodium wet crude product.

Preparation method of enoxaparin sodium?

  4. Oxidation alcohol precipitation. Add purified water 3 times its weight to enoxaparin sodium wet crude product, stir until completely dissolved, add purified water to make the solution concentration of 20%. Then add 1% of the volume of sodium chloride solution, stir, heat up to 35℃, adjust the solution pH with sodium hydroxide to 9.5~10.0; Then add 1% of the volume of hydrogen peroxide solution (30% concentration), maintain the temperature, pH, oxidation for 8 hours, to get the oxidation solution. The oxidized solution was filtered through a 0.45μm filter element, pH6.0~6.5 was adjusted with hydrochloric acid, and methanol, 5 times the volume of the filtrate, was added under agitation, and stirred evenly. After standing for 5 hours, the supernatant was separated, and the alcohol precipitated product of enoxaparin sodium was prepared.

  5. Sterilization and filtration. Add an appropriate amount of purified water to the oxidized alcohol sediment, make its concentration 25%, stir until completely dissolved, filter the solution through the filter element. The sterilized filtrate was dried by lyophilizer, crushed and mixed to produce enoxaparin sodium.