Iodixanol Synthesis Using Propyleneglycol Solvent
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Solution Overview
Problem
The existing methods for manufacturing iodixanol, a non-ionic X-ray contrast agent, are inefficient and costly due to the need for multiple crystallization steps to remove impurities, which are time-consuming and resource-intensive, especially in industrial-scale production.
Innovation Solution
The dimerization of 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide is carried out using propyleneglycol as a solvent in a controlled temperature range of 10 to 20°C and pH range of 11.5 to 12.0, with epichlorohydrin as the dimerization agent, to achieve higher yields and purity of iodixanol.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If 2-methoxyethanol is used as solvent in the dimerisation step, then the reaction can proceed, but the product contains large amounts of impurities requiring multiple crystallization steps
Solution Approach 1:
The patent changes the solvent parameter from 2-methoxyethanol to propyleneglycol, which fundamentally alters the reaction outcome. This parameter change results in high product purity (less than 2% impurities) without requiring multiple crystallization steps, while maintaining ease of manufacture through the use of a readily available solvent.
2Manufacturing precision
If multiple crystallization steps are performed to remove impurities, then product purity is improved, but the process becomes time-consuming and resource-intensive
Solution Approach 1:
The patent performs preliminary action by selecting propyleneglycol as the solvent before the dimerisation reaction, which pre-prevents the formation of large amounts of impurities. This preliminary choice eliminates the need for subsequent multiple crystallization steps, saving time and resources while maintaining high product purity.
Solution Approach 2:
The patent converts the potential harm of using a common solvent (that might produce impurities) into a benefit by specifically choosing propyleneglycol, which unexpectedly produces high purity product. The initial assumption that any solvent would work is transformed into a specific advantageous choice that simplifies the entire purification process.
3Manufacturing precision
If propyleneglycol is used as solvent in the dimerisation step, then impurity levels are reduced to less than 2%, but the process requires controlled temperature and pH conditions
Solution Approach 1:
The patent optimizes the temperature parameter to 10-20°C and pH parameter to 11.5-12.0 to achieve high product purity with propyleneglycol as solvent. These parameter changes enable the reaction to proceed efficiently while maintaining simple process control requirements, balancing purity achievement with operational simplicity.
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 reduces impurity levels, such as backpeaks, to less than 2%, making the production economically feasible and environmentally friendly by using a low-cost, accessible solvent, thereby optimizing the manufacturing process for iodixanol.
Implementation Method 1
the dimerisation of 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide with propyleneglycol as solvent
Implementation Method 2
the crude iodixanol produced by the synthetic chemical process is crystallized twice
Data Source
AI summary
This invention relates to the synthesis of iodixanol (1,3-bis(acetamido)-N,N′-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane), more specifically to the dimerisation of 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide with propyleneglycol as solvent.