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. Its generic name is enoxaparin. Enoxaparin sodium is a white or almost white powder, tasteless, hygroscopic, soluble in water, insoluble in ethanol, acetone and other organic solvents. Aqueous solution has a strong negative charge and can combine with some cations to form molecular complexes. An aqueous solution is stable at pH 7.

  Preparation method of enoxaparin sodium

  1. Salt formation. Weigh heparin sodium crude 30g, add proper amount of pure water to dissolve, get heparin sodium solution; 75g benzalkonium chloride was weighed and dissolved in pure water to obtain benzalkonium chloride solution. Slowly add benzathonium chloride solution to heparin sodium solution, stir while adding, stir evenly and leave for 2 hours. Then centrifuge the centrifuge operation, centrifuge the solid obtained with pure water washing, and finally the obtained heparin benzalkonium chloride wet product vacuum drying, to obtain heparin benzalkonium chloride.

  2. The esterification. 5 times dichloromethane was added to the obtained heparin benzalammonium chloride, and benzyl chloride was added to the obtained heparin benzalammonium chloride after stirring and dissolving, and the temperature was kept at 35℃ for 24 hours. At the end of the reaction, a 10% sodium acetate methanol solution containing 6 times heparin benzalammonium chloride was added, stirred for 10 minutes, left for 4 hours, and then the sediment was filtered. The filtered sediment was washed twice with methanol to obtain wet crude heparin benzalammonium chloride. Add 8% sodium chloride aqueous solution 3 times the weight of heparin ethanoammonium salt to the wet crude product of heparin benzyl ester, stir until completely dissolved, then add methanol 4 times the volume of sodium chloride solution, stir again for 10 minutes, stand for 2 hours, filter, repeat this operation 3 times to obtain the wet product of heparin benzyl ester. Benzyl heparin was obtained by vacuum drying the wet product of benzyl heparin.

Preparation method of enoxaparin sodium?

  3. The depolymerization. Purified water 20 times its weight was added to benzyl heparin, stirred to dissolve and heated to 60℃. The sodium hydroxide of 10% weight of heparin benzyl ester was dissolved in pure water, and then slowly added into the heparin benzyl ester solution, kept at 60℃, stirred for 2 hours. Then, the ph of the solution was adjusted to 6.0-6.5 with appropriate hydrochloric acid, and cooled to room temperature to obtain the depolymerization solution. Add an appropriate amount of sodium chloride to the depolymerization solution, make its concentration 10%, stir until completely dissolved, and then add methanol 60 times the weight of heparin benzyl ester while stirring, stir evenly, and then leave it for 5 hours to separate the supernatant and obtain enoxaparin sodium wet crude product.

  4. Oxidation alcohol precipitation. Add 3 times the volume of pure water by weight to the wet crude enoxaparin sodium product, stir until it is completely dissolved, and add pure water to bring the solution concentration to 20%. Then add 1% of the volume of sodium chloride solution, stir and heat to 35℃, adjust the ph of the solution to 9.5-10.0 with sodium hydroxide; Then, 1% of the volume of hydrogen peroxide (30% concentration) was added to the solution, the temperature and ph were maintained, and the oxidation solution was obtained for 8 hours. The oxidation solution was filtered with 0.45μm filter element, and the pH was adjusted to 6.0~6.5 with hydrochloric acid. Methanol, 5 times the volume of filtrate, was added after agitation, and stirred evenly. After standing for 5 hours, the supernatant was separated to obtain enoxaparin sodium oxidized alcohol precipitate.

  5. Sterilization and filtration. Add proper amount of pure water to the alcohol precipitate after oxidation, make its concentration reach 25%, stir until completely dissolved, and then filter the solution through the filter element. Sterile filtrate was dried, crushed and mixed with freeze dryer to obtain enoxaparin sodium.