Sugammadex Sodium Purification via Flash Chromatography
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Solution Overview
Problem
Current methods for synthesizing Sugammadex sodium are inefficient, particularly in achieving high purity and are not economically viable for large-scale production due to the use of hygroscopic reagents and tedious workup procedures, and existing purification techniques fail to yield high purity Sugammadex sodium.
Innovation Solution
A novel process involving the reaction of gamma cyclodextrin with a halogenating agent followed by mercaptopropionic acid in the presence of a base, combined with purification using organic solvents and flash column chromatography with reverse phase silica gel, to achieve Sugammadex sodium with greater than 98% purity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If membrane dialysis, Sephadex G-25 column chromatography, macro porous resin, zeolites, molecular sieves, slurry with neutral aluminum oxide or basic aluminum oxide are used for purification, then purification is achieved, but the purity of Sugammadex is not high and the process is costly and not feasible on large scale
Solution Approach 1:
The invention changes the purification parameters by using organic solvents (dichloromethane, ethyl acetate, n-butanol) instead of aqueous-based purification methods. This parameter change enables effective purification on large scale while achieving greater than 98% purity, resolving the contradiction between manufacturing precision and ease of manufacture.
Solution Approach 2:
The invention replaces expensive purification media (Sephadex G-25, macro porous resin, zeolites, molecular sieves) with cheaper, readily available organic solvents. This substitution maintains high purification effectiveness while significantly reducing costs and improving feasibility for large-scale production.
2Manufacturing precision
If triphenylphosphine and iodine in dimethyl formamide are used to prepare Vilsmeier Hack reagent, then the reagent is formed, but it is highly hygroscopic and difficult to handle in bulk scale requiring more washings
Solution Approach 1:
The invention extracts and eliminates the problematic Vilsmeier-Hack reagent preparation step involving triphenylphosphine, iodine, and dimethyl formamide. By using alternative reagents (phosphorous pentachloride followed by halogenating agent) and organic solvents for purification, the method removes the hygroscopic handling difficulty while maintaining effective purification.
Solution Approach 2:
The invention introduces organic solvents (dichloromethane, ethyl acetate, n-butanol) as intermediary substances that facilitate purification without the handling problems of the original system. These intermediaries enable effective impurity removal while being easy to handle on bulk scale.
3Productivity
If phosphorous pentachloride is used to synthesize Sugammadex sodium, then the synthesis proceeds, but it is highly exothermic and requires tedious workup procedure making it not suitable at large scale
Solution Approach 1:
The invention segments the synthesis process into distinct controlled steps: first forming 6-perdeoxy-6-perchloro gamma cyclodextrin, then reacting with mercaptopropionic acid in the presence of base. This segmentation allows better control of the exothermic reaction and simplifies the workup procedure by using organic solvents for purification instead of tedious aqueous workup.
Solution Approach 2:
The invention changes the reaction parameters by conducting the second step in the presence of a base (sodium hydroxide, potassium hydroxide, or cesium carbonate) and using organic solvents. This parameter change moderates the exothermic nature and dramatically simplifies the workup procedure, making the process suitable for large-scale production while maintaining high productivity.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The process effectively increases the yield and purity of Sugammadex sodium to greater than 98% while reducing impurities to less than 1%, making it more economically feasible and industrially viable.
Implementation Method 1
reacting gamma cyclodextrin with suitable halogenating agent in an organic solvent to provide 6-per-deoxy-6-perchloro gamma cyclodextrin
Implementation Method 2
reacting the 6-per-deox-6-perchloro gamma cyclodextrin intermediate with mercaptopropionic acid or its salt form or its ester in presence of base to yield Sugammadex sodium
Implementation Method 3
passing aqueous Sugammadex or its salts solution through flash column chromatography loaded with reverse phase silica gel
Data Source
AI summary
The present invention relates to an improved process for the preparation of Sugammadex sodium (1). It further relates to a novel process for the purification of Sugammadex sodium (1) having impurity A less than 2% (w/w) and impurity E less than 0.1% (w/w)