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Method for reducing content of sodium acetate impurities in Enoxaparin sodium

A technology of enoxaparin sodium and impurity content, applied in the field of biopharmaceuticals, can solve the problems of complex preparation process of enoxaparin, and achieve the effect of low cost and small environmental pollution

Inactive Publication Date: 2017-08-11
QINGDAO JIULONG BIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The preparation process of enoxaparin is complex and uses more reaction raw materials, some of which should not exceed a certain limit

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] 1) Salt formation: Add 180 mL of purified water to 30g crude heparin sodium at a ratio of 1:6 (w / v) to obtain a heparin sodium solution; at a ratio of 1:6 (w / v) to 80g benzethonium chloride Add 480mL of purified water to dissolve to obtain benzethonium chloride solution; add 360mL benzethonium chloride solution to 180mL heparin sodium solution in a ratio of 1:2 (v / v), stir while adding, and after stirring, let it stand still 2 hours; centrifuge and vacuum dry to obtain heparin benzethonium chloride salt.

[0021] 2) Esterification: Add 150 mL of dichloromethane to the heparin benzethonium chloride salt, stir to dissolve, and then add 150 mL of heparin benzethonium chloride benzyl chloride to it, maintain the temperature at 36°C, stir the reaction, and add heparin benzyl chloride to the end of the reaction 250 mL of 10% sodium acetate methanol solution of triethonium chloride, stirring for 10 minutes, standing for 4 hours, and filtering the precipitate to obtain wet crude h...

Embodiment 2

[0026] 1) Salt formation: Add 400ml of purified water to 60g crude heparin sodium to dissolve it to obtain heparin sodium solution; add 800ml of purified water to 120g benzethonium chloride to dissolve to obtain benzethonium chloride solution; add 700mL to 400mL heparin sodium solution The benzethonium chloride solution was stirred while adding, and after stirring, let it stand for 2 hours; centrifuge and vacuum dry to obtain heparin benzethonium chloride salt.

[0027] 2) Esterification: Add 350 mL of dichloromethane to heparin benzethonium chloride, stir to dissolve, then add 350 mL of heparin benzethonium chloride to it, maintain the temperature at 36°C, stir the reaction, and add heparin benzyl to the end of the reaction 400 mL of 10% sodium acetate methanol solution of triethonium chloride, stirred for 10 minutes, allowed to stand for 4 hours, and filtered the precipitate to obtain wet crude heparin benzyl ester.

[0028] 3) Decontamination of wet crude heparin benzyl ester: A...

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Abstract

The invention relates to a method for reducing the impurity content of sodium acetate in enoxaparin sodium. The steps are 1. Salt formation to obtain heparin benzethonium chloride salt; 2. Esterification, adding dichloromethane, benzyl chloride and sodium acetate methanol solution to the heparin benzethonium chloride salt to react to obtain heparin benzethonium chloride crude product ; 3. Removal of impurities from wet crude heparin benzyl ester; 4. Depolymerization; 5. Finished product. The method can greatly reduce the content of sodium acetate impurities, improve the purity and activity of enoxaparin sodium, and the process operation is convenient and safe, and is suitable for large-scale production.

Description

Technical field [0001] The field of the present invention is the field of biopharmaceuticals, and relates to a method for reducing sodium acetate impurity content in enoxaparin sodium. Background technique [0002] Low-molecular-weight heparin is a large class of antithrombotic drugs that are further processed from heparin raw materials as raw materials. Since the end of the last century, Sanofi’s enoxaparin sodium was approved by the US FDA for marketing. The advantages of small size and predictability have gradually replaced the market position of traditional heparin. Enoxaparin can effectively prevent venous thromboembolism and pulmonary embolism, and has a wide range of clinical medical uses. It has become the drug of choice for the treatment of acute venous thrombosis and acute coronary syndrome (angina pectoris, myocardial infarction) and other diseases. As the application of low-molecular-weight heparin becomes more and more extensive, its production process is further re...

Claims

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Application Information

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IPC IPC(8): C08B37/10
CPCC08B37/0075C08B37/0078
Inventor 江崇云刘乃山迟培升
Owner QINGDAO JIULONG BIO PHARMA