Human Insulin Methyl Ester Production via Dioxane Solvent and Buffering
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Solution Overview
Problem
Current methods for producing Human Insulin methyl ester by enzymatic reaction face challenges in reducing impurities like des B (23-29) and Cyclized form of desB-30, and achieving high purity, particularly when using Dimethyl formamide as a solvent.
Innovation Solution
The process employs dioxane as a solvent in combination with sodium carbonate and sodium bicarbonate, which reduces impurities by 40% and 60% respectively, and enhances the purity of Human Insulin Methyl ester by 10% compared to processes using Dimethyl formamide, through specific enzymatic reactions and crystallization conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If Dimethyl formamide is used as solvent in enzymatic reaction, then reaction proceeds efficiently, but impurity levels (des B (23-29) and Cyclized form of desB-30) remain high
Solution Approach 1:
The patent changes the solvent parameter from Dimethyl formamide to Dioxane, and adjusts pH parameters using sodium carbonate and sodium bicarbonate buffers. This parameter change resolves the contradiction by achieving both efficient reaction progression and reduced impurity levels (des B (23-29) reduced by 40%, Cyclized form of desB-30 reduced by 60%), thereby improving manufacturing precision while controlling harmful factors.
2Manufacturing precision
If traditional enzymatic reaction conditions are used, then production process is simple, but purity enhancement is limited
Solution Approach 1:
The patent introduces specific parameter changes including pH adjustment using sodium carbonate and sodium bicarbonate buffers, and temperature control during crystallization. These controlled parameter changes achieve 10% purity enhancement without significantly increasing process complexity, as the same enzymatic reaction framework is maintained with optimized conditions rather than fundamentally changing the process architecture.
3Object-generated harmful factors
If dioxane and sodium salts are used in enzymatic reaction, then impurity reduction is achieved, but process conditions become more specific and controlled
Solution Approach 1:
The patent specifies particular parameter ranges: pH 7.4-8.5 maintained through sodium carbonate and sodium bicarbonate buffers, temperature control during crystallization, and specific solvent composition (dioxane with controlled water content). These controlled parameter changes reduce impurity levels (des B (23-29) by 40%, Cyclized form of desB-30 by 60%) while maintaining reasonable adaptability within defined ranges, allowing the process to be adjusted within established boundaries without requiring complete redesign.
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 use of dioxane and sodium salts in the enzymatic reaction significantly reduces impurities and increases the purity of Human Insulin Methyl ester, achieving higher yields and improved purity profiles compared to traditional methods.
Implementation Method 1
dioxane induces cleavage of insulin precursor by trypsin
Implementation Method 2
enzymatic reaction
Implementation Method 3
amidation with an L-threonine ester
Implementation Method 4
sodium carbonate and sodium bicarbonate
Implementation Method 5
crystallization procedure
Data Source
Figure 1
Figure 2
Figure 3~4
AI summary
The present invention relates to production of Human Insulin methyl ester by enzymatic reaction. The present invention further relates to production and enhancement of purity of Human Insulin Methyl ester.