Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Method for refining sugammadex sodium

A technology of sugammadex sodium and a purification method, applied in the field of drug synthesis, can solve the problems of easy generation of acid degradation impurities, high purification cost, influence on the stability of cyclodextrin substrates and the like

Active Publication Date: 2019-12-31
SICHUAN KELUN PHARMA RES INST CO LTD
View PDF12 Cites 15 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015]1) Column chromatography or adsorbent purification such as silica gel column, Sephadex G25, macroporous resin, ion exchange resin, etc., the purification cost is high, and the process Relatively limited, not universal, not conducive to industrial scale-up production;
[0016]2) Repeated use of strong inorganic acid for dissociation will have an impact on the stability of the cyclodextrin substrate of sugammadex sodium, and it is easy to produce acid-degraded impurities , affecting the drug safety of sugammadex sodium products;
[0017]3) Under conventional recrystallization purification conditions, adding protective agents such as triphenylphosphine, glutathione, and cysteine, although it can inhibit the oxidation of impurities It is easy to remove some impurities in sugammadex sodium, but for dimer impurities, its physical and chemical properties are very similar to sugammadex sodium. In the conventional recrystallization process, it is usually enriched in sugammadex sodium. Sodium sugar, difficult to remove
[0018] In order to ensure the safety of follow-up preparations and clinical medication, it is necessary to control the content of individual impurities in sugammadex sodium below 0.1%, preferably to remove it, and now Some conventional purification processes cannot be realized

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Method for refining sugammadex sodium
  • Method for refining sugammadex sodium
  • Method for refining sugammadex sodium

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0105] Preparation of crude sugammadex sodium:

[0106] Iodo γ-cyclodextrin can be prepared by iodination of γ-cyclodextrin. For the preparation method, refer to the literature Methods for Selective Modifications of Cyclodextrins, Chem. Rev. 1998, 98, 1977-1996.

[0107] Step (1): Add sodium hydride (7.16 kg, 60%) to dry DMF (317 L) under nitrogen atmosphere and ice bath. Slowly add the mixed solution of tri-p-tolylphosphine (1.74kg)-3-mercaptopropionic acid (9.52kg)-DMF (12.2L) dropwise at 0-10°C, heat up to 65-75°C and react under stirring after the addition, and then Slowly add the mixed solution of all-iodo γ-cyclodextrin (12.16kg)-tri-p-tolylphosphine (0.46kg)-DMF (63.4L) dropwise, and continue stirring for about 4 hours. The reaction solution was lowered to 0-10°C, water (60.9 L) was added, and the temperature was raised to 55-70°C with stirring for about 2 hours. The reaction solution was cooled to room temperature, suction filtered, the filter cake was dissolved in w...

Embodiment 1

[0111] Embodiment 1: Refining of sugammadex sodium

[0112] Step (1): Under the protection of nitrogen, dissolve 0.2 kg of sugammadex sodium crude product in 0.4 L of water, add 0.6 LDMF dropwise at room temperature, the system becomes turbid, stand to separate layers, separate liquid, and temporarily store the upper mother liquid;

[0113] Step (2): Under the protection of nitrogen, continue to add 0.2L water to dissolve the viscous organic phase in the lower layer, add 0.3L DMF dropwise, precipitate solid, filter, and combine the filtrate with the upper mother liquor;

[0114] Step (3): Under the protection of nitrogen, raise the temperature of the combined mother liquor in step (2) to 50-70°C, add 1.6L DMF dropwise, cool down to 0-10°C to crystallize, filter and dry to obtain purified sugammadex Sodium sugar (0.188Kg, total yield 94%).

[0115] The sugammadex sodium refined product that the present embodiment obtains carries out HPLC detection, as figure 1 The experimenta...

Embodiment 2

[0118] Embodiment 2: Refining of sugammadex sodium

[0119] Step (1): under the protection of nitrogen, dissolve 0.2 kg of sugammadex sodium crude product in 0.4 L of water, add 0.8 LDMAc dropwise at room temperature, the system is turbid, stand to separate layers, separate liquid, and temporarily store the upper mother liquid;

[0120] Step (2): Under the protection of nitrogen, continue to add 0.2L water to dissolve the viscous organic phase in the lower layer, add 0.4L DMAc dropwise, precipitate solid, filter, and combine the filtrate with the upper mother liquor;

[0121] Step (3): Under the protection of nitrogen, raise the temperature of the combined mother liquor in step (2) to 50-70°C, add 1.2L DMAc dropwise, cool down to 0-10°C to crystallize, filter and dry to obtain purified sugammadex Sodium sugar (0.182Kg, total yield 91%, total purity 99.54%, impurity A was not detected, impurity B content was 0.065%).

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a method for refining sugammadex sodium. The method comprises the following steps: liquid separating and refining a crude sugammadex sodium product in a poor solvent / water system, preferentially separating out and enriching dimer impurities which are difficult to remove into solids to remove, separating (liquid separating and filtering) to obtain a mother liquor, further adding a poor solvent for crystallizing to obtain high-purity sugammadex sodium. According to the refining method provided by the invention, the contents of dimer impurities A and B can be effectively reduced; the total purity of the refined sugammadex sodium is greater than 99.5%, the impurity A is not detected in the finished product, the content of impurity B is less than 0.1%, the content of other single impurity is less than 0.1%, the adopted reagents are all conventional and easy to obtain, the operation is simple and safe, and the method is very suitable for industrial amplification underconventional production conditions.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a method for refining sugammadex sodium, in particular to a method for reducing the content of impurity A or impurity B in sugammadex sodium. Background technique [0002] Sugammadex Sodium was first developed by Organon Biosciences (Organon Corporation), which was acquired by Schering-Plough in 2007, and Schering-Plough merged with Merck in 2009. Sugammadex sodium is currently owned and sold by Merck. In 2008, Sugammadex Sodium was launched in Europe for the first time, and then in Japan, the United States and other countries, and is now on the market in 75 countries. It was approved for listing in China on April 26, 2017. [0003] Sugammadex sodium, chemical name: 6-full deoxy-6-full (2-carboxyethyl) thio-γ-cyclodextrin sodium salt, English name: sugammadex, trade name: Bridion, is a modified γ-cyclodextrin, the first and only selective muscle relaxant...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C08B37/16A61K31/724A61P21/00
CPCC08B37/0012C08B37/0003A61K31/724A61P21/00
Inventor 李发光高宏祁浩飞侯云泽刘群肖宇胡佰艳霍翔宏王琦王利春王晶翼
Owner SICHUAN KELUN PHARMA RES INST CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com