Liraglutide Solid Phase Synthesis Purity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current processes for preparing Liraglutide are costly, generate biological impurities, and are not environmentally friendly, with high solvent usage and complex purification steps, making them unsuitable for large-scale production and resulting in low purity and high production costs.
Innovation Solution
A solid phase synthesis process using protected glycine with an activating agent and solvent, followed by sequential coupling of amino acids with N-terminal Fmoc protection, and purification using reverse-phase HPLC with ammonium salts and buffers, achieving high purity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If biological route is used for Liraglutide preparation, then production can be achieved, but biological impurities are generated requiring immense purification process
Solution Approach 1:
The patent applies preliminary action by protecting the N-terminal of GLP-1(7-37)-OH with Fmoc group before the acylation reaction. This preventive measure avoids the formation of impurities at the N-terminal position during the subsequent reaction with Nα-alkanoyl-Glu(ONSu)-OtBu, thereby reducing purification requirements while maintaining production capability
2Manufacturing precision
If reverse-phase HPLC purification is performed for intermediate GLP-1(7-37)-OH, then purity is improved, but production cost increases and large amount of solvent is required
Solution Approach 1:
The patent changes the reaction parameters by performing the acylation reaction in solid phase rather than liquid phase, and by protecting the N-terminal with Fmoc group. These parameter changes eliminate the need for extensive reverse-phase HPLC purification steps, thereby reducing solvent consumption (particularly acetonitrile) while maintaining product purity
3Device complexity
If N-terminal of GLP-1(7-37)-OH is not protected, then synthesis is simpler, but impurities are generated requiring additional purification steps
Solution Approach 1:
The patent applies preliminary action by introducing Fmoc protection at the N-terminal before the acylation reaction. This preliminary step prevents impurity formation during the reaction, and the protective group is subsequently removed in a final deprotection step, overall simplifying the purification process while maintaining product purity
4Ease of operation
If liquid phase acylation is performed, then reaction is easier to conduct, but large amount of waste liquid is generated
Solution Approach 1:
The patent replaces the liquid phase mechanical reaction system with a solid phase reaction system. The acylation is performed on resin-bound GLP-1(7-37)-OH, which allows for easier filtration and washing, significantly reducing waste liquid generation while maintaining ease of operation through standard solid phase peptide synthesis techniques
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 results in Liraglutide with a purity of greater than 99.5% and improved solubility, meeting ICH guidelines and being chemically stable, thus overcoming the limitations of previous methods.
Implementation Method 1
purification is performed using reverse-phase HPLC
Data Source
AI summary
The present invention relates to an improved process for the preparation of Liraglutide. The present invention further related an improved process for the preparation of substantially pure material having a purity of greater than or equal to 99.5% by HPLC.