Hydrolysis of ABA Intermediate for X-ray Contrast Agent Purity
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Solution Overview
Problem
Current methods for producing non-ionic X-ray contrast agents, such as iohexol and iodixanol, face challenges in achieving stringent purity standards due to the presence of impurities like ABA monomethylester and ABA dimer, which are difficult to remove and lead to increased costs and reduced yields in subsequent purification steps.
Innovation Solution
A process involving hydrolysis of ABA in an aqueous medium at a pH between 12 to 13 using sodium hydroxide effectively converts ABA monomethylester to ABA monoacid and removes ABA dimer, simplifying subsequent purification processes and improving yields.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional purification methods are used for ABA, then the purification process becomes complex and costly, but the impurities (ABA monomethylester and ABA dimer) remain difficult to remove
Solution Approach 1:
The patent applies preliminary action by performing hydrolysis of ABA monomethylester to ABA monoacid before the iodination step. This converts the difficult-to-remove monomethylester impurity into a form that can be easily removed during subsequent purification, preventing the impurity from carrying through to the final product and simplifying overall purification requirements
Solution Approach 2:
The patent changes the chemical parameter of the impurity by hydrolyzing ABA monomethylester into ABA monoacid through controlled base treatment. This parameter change transforms the impurity from a stable, difficult-to-remove ester form into a more reactive acid form that can be selectively removed, thereby improving purification efficiency without adding complex equipment
2Productivity
If conventional methods are used without pre-hydrolysis, then the production cost increases due to extensive purification steps, but the impurity removal efficiency remains low
Solution Approach 1:
By performing hydrolysis before iodination, the patent eliminates the need for extensive purification steps afterward. The monomethylester is converted to monoacid form that can be easily removed during standard workup procedures, significantly improving purification efficiency and reducing production costs associated with multiple purification cycles
Solution Approach 2:
The patent extracts the problematic monomethylester impurity from the reaction mixture by converting it to ABA monoacid through hydrolysis. The monoacid form can then be selectively removed during aqueous workup and purification steps, effectively taking out the impurity before it interferes with subsequent iodination and final product quality
3Reliability
If ABA monomethylester and ABA dimer are not removed before iodination, then the subsequent purification processes become more difficult and yields decrease
Solution Approach 1:
The patent performs preliminary hydrolysis of ABA monomethylester before iodination to prevent impurity formation that would compromise final product purity. By converting monomethylester to monoacid early in the process, the subsequent iodination reaction proceeds with higher reliability and the final product requires less extensive purification
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 process significantly reduces the levels of ABA monomethylester and ABA dimer, enhancing the purity of subsequent products and increasing the efficiency of the iodination reaction, thereby reducing production costs and meeting regulatory purity standards.
Implementation Method 1
the process is directed to hydrolyzing ABA under a pH between 12 to 13 in aqueous medium to convert ABA monomethylester to ABA monoacid
Data Source
AI summary
This invention relates to the preparation of non-ionic X-ray contrast agents, iohexol, ioversol, and iodixanol. It further relates to a method for improving the purity of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide (or ABA), an intermediate in the industrial preparation of these non-ionic X-ray contrast agents. In particular, it relates to a method for significantly removing ABA monomethylester and ABA dimer from ABA by hydrolyzing ABA under a pH between 12 to 13 in an aqueous medium to convert ABA monomethylester to ABA monoacid, before the iodination reaction of ABA.