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Method for preparing and purifying enoxaparin sodium

A technology of enoxaparin sodium and purified water, applied in the production and purification field of enoxaparin sodium, can solve the problems of large environmental pollution, difficult to meet the requirements of environmental impact assessment, product adsorption, etc., and achieves simple purification operation and good product clarity Effect

Inactive Publication Date: 2016-03-30
QINGDAO JIULONG BIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the enoxaparin sodium intermediate obtained after acid neutralization and alcohol precipitation often has poor clarity. If it is not refined and purified, it cannot meet the requirements of clarity in the Pharmacopoeia
[0005] The existing purification methods are mainly divided into the following types: (1) Decolorize enoxaparin sodium with activated carbon, filter through macroporous resin, and freeze-dry the filtrate to obtain purified enoxaparin sodium. This method has a better decolorization effect, but the disadvantages are There will be a large amount of products adsorbed in activated carbon and resin, and the yield can only reach about 60%; (2) Adjust the pH of enoxaparin sodium with sodium hydroxide, decolorize with hydrogen peroxide, wash with sodium chloride and ethanol, and freeze-dry , to obtain purified enoxaparin sodium. This method requires the use of highly oxidizing hydrogen peroxide, which will easily lead to the production of other by-products while removing the pigment, and it will pollute the environment greatly, and it is difficult to meet the requirements of the environmental impact assessment; (3) will Enoxaparin sodium passes through hydrophobic chromatography column and anion exchange resin in sequence, and after desalination by nanofiltration, precipitation and drying obtain purified enoxaparin sodium. This method requires multiple chromatography columns, and the product loss is very large; (4) Enoxaparin sodium is passed through filtration, microfiltration and ultrafiltration devices in sequence, and purified enoxaparin sodium is obtained after freeze-drying. The product loss of this method is small, but the operating pressure of this graded ultrafiltration is relatively high, which is not suitable for industrial use. Application; (5) Treat enoxaparin sodium with sodium chloride solution and methanol repeatedly to finally obtain enoxaparin sodium with up to standard clarity. This method is simple to operate and easy to realize in industry, but its purification effect is poor, and It is difficult to accurately determine the number of repeated treatments each time, which is not conducive to the establishment of production standards

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1: Preparation of Crude Enoxaparin Sodium

[0020] Step (1): Preparation of heparin benzethonium chloride salt

[0021] Put 1 kg of heparin sodium and 20 L of purified water into the reaction tank, stir for about 20 minutes, and transfer to the elimination tank after the dissolution is complete. Put 2.5kg of benzethonium chloride and 20L of purified water into the reaction tank, and stir for about 20 minutes. After the dissolution is complete, the benzethonium chloride solution is pumped into the elimination tank, and stirred for 30 minutes. Add 60 L of supplemented purified water into the elimination tank, continue stirring for 10 minutes, and let stand for 30 minutes. The reaction mixture was filtered, and the filter cake was beaten three times with purified water (50kg, 50kg, 60kg). Collect the filter cake and dry it under vacuum for 10 hours in hot water at 60°C±2°C and a vacuum degree greater than 0.08MPa to obtain 2.1kg of heparin benzethonium chloride s...

Embodiment 2

[0026] Example 2 Purification of Enoxaparin Sodium

[0027] 1.1 kg of the crude enoxaparin sodium prepared in Example 1 was put into 5 L of 10% sodium chloride solution, stirred and dissolved to obtain a crude enoxaparin sodium solution, which was filtered to obtain a filtrate. Put the filtrate in a centrifuge at 2000r / min for 30min to obtain supernatant and precipitate. 10L of ethanol was added to the supernatant, stirred for 1 h and then allowed to stand for 3 h to obtain a precipitate. The precipitate was dissolved into a 10wt~15wt% solution with purified water, filtered through a 0.1μm filter membrane, and then spray-dried to obtain 1.02kg of enoxaparin sodium finished product, with a purification yield of 92.7%.

Embodiment 3

[0028] Example 3 Purification of Enoxaparin Sodium

[0029] 1.1 kg of the crude enoxaparin sodium prepared in Example 1 was put into 10 L of 5% sodium chloride solution, stirred and dissolved to obtain a crude enoxaparin sodium solution, which was filtered to obtain a filtrate. Put the filtrate in a centrifuge at 2000r / min for 30min to obtain supernatant and precipitate. 10L of methanol was added to the supernatant, stirred for 1.5h and then allowed to stand for 5h to obtain a precipitate. The precipitate was dissolved into a 10wt~15wt% solution with purified water, filtered through a 0.1μm filter membrane, and then spray-dried to obtain 1.01kg of enoxaparin sodium finished product, with a purification yield of 91.8%.

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Abstract

The invention discloses a method for preparing and purifying enoxaparin sodium. After a crude enoxaparin sodium product is subjected to centrifugal separation and alcohol precipitation impurity removal, the finished enoxaparin sodium product meeting pharmacopeia standards can be obtained. The method is high in yield and easy and convenient to implement, and the product is good in clarity and capable of meeting requirements of the pharmaceutical industry.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals, and in particular relates to a production and purification method of enoxaparin sodium. Background technique [0002] Heparin has been the drug of choice for the prevention and treatment of thrombosis since the 1980s. Low-molecular-weight heparin is made from unfractionated heparin through specific chemical cutting and purification. Due to its definite curative effect, small and predictable side effects, it has gradually replaced the market position of traditional heparin. [0003] Enoxaparin Sodium (Enoxaparin Sodium) belongs to low molecular weight heparin, and its main feature is that there is a 4-enepyranuronic acid structure in the molecule. This product has strong antithrombotic effect and low risk of bleeding, and is currently one of the main therapeutic drugs for anticoagulation and antithrombosis. [0004] Enoxaparin sodium is obtained by alkaline depolymerization of benzyl ester deri...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08B37/10
CPCC08B37/0075C08B37/0003
Inventor 刘冠男刘忠凯迟培升
Owner QINGDAO JIULONG BIO PHARMA
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