DOTA Synthesis via Membrane Filtration and pH Control
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Solution Overview
Problem
Current methods for synthesizing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) are limited by the need for specialized equipment due to low pH requirements in crystallization steps, resulting in contamination with sodium and chloride impurities, which complicates industrial-scale pharmaceutical production.
Innovation Solution
A method involving reacting cyclen with a halo-acetic acid and an excess base at a pH of around 11, followed by crystallization and membrane filtration at pH 3-3.5, with the addition of methanol as an organic solvent, to achieve effective purification and reduce impurities, suitable for industrial manufacturing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If crystallization is carried out at very low pH (below pH 3) to reduce sodium and chloride impurities, then purity of DOTA is improved, but specialized manufacturing equipment is required and device complexity increases
Solution Approach 1:
The patent changes the pH parameter from very low pH (below 3) to a higher pH range (3-3.5), which eliminates the need for specialized equipment while still achieving effective purification of DOTA from sodium and chloride impurities
Solution Approach 2:
The patent introduces membrane filtration as an intermediary purification step that operates at higher pH values, serving as a mediator between the crystallization process and final product purification, thereby avoiding the need for extreme pH conditions and specialized equipment
2Ease of manufacture
If crystallization is carried out at slightly higher pH values (above pH 3) to simplify equipment requirements, then ease of manufacture is improved, but DOTA is contaminated with substantial amounts of sodium and chloride requiring additional ion exchange resin purification
Solution Approach 1:
Membrane filtration is introduced as an intermediary purification step that removes sodium and chloride impurities at higher pH values, eliminating the need for additional ion exchange resin purification while maintaining ease of manufacture
Solution Approach 2:
The patent extracts and removes sodium and chloride impurities through membrane filtration at higher pH values, separating these contaminants from the DOTA product without requiring extreme pH conditions or additional complex purification steps
3Manufacturing precision
If large amounts of ion exchange resins are used to remove sodium and chloride impurities from DOTA, then purity of DOTA is improved, but device complexity and cost increase
Solution Approach 1:
Membrane filtration serves as an intermediary purification method that replaces the need for large amounts of ion exchange resins, achieving the same purification goal with simpler equipment and reduced complexity
Solution Approach 2:
The patent replaces expensive and complex ion exchange resin systems with a more economical membrane filtration approach that achieves equivalent purification results without requiring large amounts of consumable resin materials
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
This method yields DOTA with very low levels of organic and inorganic impurities, making it suitable for pharmaceutical production of MRI contrast agents, and allows for the preparation of metal-DOTA chelates, such as gadoterate meglumine, with improved purity and reduced equipment requirements.
Implementation Method 1
crystallising the reaction mixture obtained in step (a), wherein said crystallising is carried out at a pH >3 and wherein said crystallising comprises addition of an organic solvent
Implementation Method 2
wherein said crystallising comprises addition of an organic solvent
Data Source
AI summary
The present invention provides methods for the preparation of compounds useful in vivo therapeutic and diagnostic applications. In particular, the present invention provides a method for the synthesis of 1,4,7,10-tetraazacyclododecane-1,4, 7,10- tetraacetic acid (DOTA) and also methods for the preparation of metal chelates of DOTA.