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Preparation method of high-purity heparin quaternary ammonium salt and application thereof

A technology for heparin benzethonium chloride and quaternary ammonium salt, which is applied in the field of preparation of high-purity heparin quaternary ammonium salt, can solve the problem that the production batch of enoxaparin sodium varies greatly, the preparation process is not described in detail, and the final product is colored Serious problems such as reducing refining steps, improving the quality of finished products, and controlling the generation of impurities

Active Publication Date: 2019-04-23
上海宝维医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Heparin benzethonium chloride salt is the key intermediate in the production of enoxaparin sodium. The characteristics and preparation process of heparin benzethonium chloride salt intermediates are not described in detail in documents such as US5389618, and studies have shown that benzethonium chloride and other Impurities will affect further esterification and depolymerization reactions, resulting in large differences between production batches of enoxaparin sodium, severe coloring of the final product, difficulty in purification, and low yield

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  • Preparation method of high-purity heparin quaternary ammonium salt and application thereof
  • Preparation method of high-purity heparin quaternary ammonium salt and application thereof

Examples

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Embodiment 1

[0024] Preparation of heparin benzethonium chloride salt:

[0025] Dissolve 100g of injection-grade unfractionated heparin in 1L of purified water at room temperature to obtain a heparin solution, dissolve 250g of benzethonium chloride in 1.25L of purified water, and slowly add the heparin solution under vigorous stirring, maintain stirring at room temperature for 30min, precipitate and filter Wash several times with water until no bubbles are produced.

[0026] Add the precipitate to methanol 30 times the weight of heparin sodium (3L), continue to stir to dissolve it completely, then slowly add purified water to the solution, a total of 3L, heparin benzethonium chloride salt precipitates again in methanol / water solution, filter , the filter cake was dried at 60°C, the batch number of the intermediate was HY160901, the weight was 333g, and the content of free benzethonium chloride was determined to be 0.42% by sampling.

Embodiment 2

[0028] Preparation of heparin benzethonium chloride salt:

[0029] Dissolve 100g of injection-grade unfractionated heparin in 1L of purified water at room temperature to obtain a heparin solution, dissolve 250g of benzethonium chloride in 1.25L of purified water, and slowly add the heparin solution under vigorous stirring, maintain stirring at room temperature for 30min, precipitate and filter Wash several times with water until no bubbles are produced.

[0030] Add the precipitate to methanol 30 times the weight of heparin sodium (3L), continue to stir to dissolve it completely, then slowly add purified water to the solution, a total of 3L, heparin benzethonium chloride salt precipitates again in methanol / water solution, filter , the filter cake repeats the aforementioned steps of methanol dissolution / water precipitation once, filters, and dries the filter cake at 60°C. The batch number of the intermediate is HY160902, weighing 320g, and the content of benzethonium chloride i...

Embodiment 3

[0032] Preparation of heparin benzethonium chloride salt:

[0033] Dissolve 100g of injection-grade unfractionated heparin in 1L of purified water at room temperature to obtain a heparin solution, dissolve 250g of benzethonium chloride in 1.25L of purified water, and slowly add the heparin solution under vigorous stirring, maintain stirring at room temperature for 30min, precipitate and filter Wash several times with water until no bubbles are produced.

[0034] Add the precipitate to methanol 30 times the weight of heparin sodium (3L), continue to stir to dissolve it completely, then slowly add purified water to the solution, a total of 6L, heparin benzethonium chloride salt is precipitated in methanol / water solution again, filter , the filter cake was dried at 60°C, the batch number of the intermediate was HY160903, the weight was 325g, and the free benzethonium chloride content was determined to be 0.26% by sampling.

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Abstract

The invention discloses a preparation method and application of high-purity heparin quaternary ammonium salt. The preparation method comprises the following steps: respectively dissolving ordinary heparin and excessive quaternary ammonium salt in a water phase, mixing and reacting to obtain heparin benzyl ammonium chloride, filtering and separating, dissolving the heparin benzyl ammonium chloridein an organic phase which is mutually soluble with water, adding purified water, gradually precipitating the heparin benzyl ammonium chloride from the mixed solution, filtering and separating, and drying to obtain the high-purity heparin benzyl ammonium chloride. The high-purity heparin benzyl ammonium chloride is used to prepare enoxaparin sodium, so that the batch-to-batch difference in the production of the enoxaparin sodium can be stably controlled, the yield can be increased, and the final finished product enoxaparin sodium can completely meet the quality requirement of European Pharmacopoeia and United States Pharmacopoeia on the bulk drug of enoxaparin sodium and preparations thereof.

Description

technical field [0001] The invention relates to the field of chemical industry, in particular to a preparation method and application of high-purity heparin quaternary ammonium salt. Background technique [0002] Unfractionated heparin (UFH) has been used for the prevention and treatment of thrombosis since the 1930s. Unfractionated heparin is a mixture of sulfated mucopolysaccharides of different lengths and molecular weights. With the difference of molecular size, its anticoagulant effect and pharmacological properties are also different. Heparin comes mainly from the small intestine of pigs and lung tissue of cattle. [0003] Low-molecular-weight heparin (LMWH) is a kind of low-molecular-weight oligosaccharide mixture obtained by fractionating or degrading unfractionated heparin as the starting material. It has anti-Xa activity and can inhibit the in vivo, Formation of thrombus and arteriovenous thrombosis in vitro, but does not affect platelet aggregation and fibrinog...

Claims

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Application Information

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IPC IPC(8): C08B37/10
CPCC08B37/0075
Inventor 蒋建华张亮王栋邢岭蒋大圆
Owner 上海宝维医药技术有限公司