Iodixanol Crystallization in Isopropanol Methanol Solvent Mixture
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for manufacturing iodixanol, a non-ionic X-ray contrast agent, face low yield, high costs, and inefficient purification processes, particularly due to the reliance on preparative liquid chromatography and excessive energy consumption in crystallization under high thermal conditions.
Innovation Solution
A purification process using a solvent mixture of water, methanol, and isopropanol is employed, where the water content is minimized and isopropanol is gradually added to the crude iodixanol solution, allowing for a single crystallization step that reduces total crystallization time to under 4 days and enhances purification efficiency, achieving high product purity and yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If preparative liquid chromatography is used for purification, then product purity is improved, but manufacturing cost and time consumption increase significantly
Solution Approach 1:
The patent changes the physical parameters of the purification process by using controlled crystallization conditions (temperature, solvent composition, addition rate) instead of chromatography. The crystallization is performed by gradually adding isopropanol to an aqueous iodixanol solution at controlled temperatures (0-25°C), which alters the solubility parameters to achieve high purity (98-99.5%) product recovery without the need for expensive chromatography equipment and operations.
2Speed
If crystallization is performed under elevated pressure and high temperature, then crystallization speed is improved, but energy consumption increases
Solution Approach 1:
The patent utilizes the phase transition of iodixanol from dissolved state to crystalline state by controlling solvent composition rather than relying on high thermal energy. The process involves adding isopropanol to aqueous solution to reduce solubility, inducing crystallization at moderate temperatures (0-25°C) and atmospheric pressure, thereby achieving fast crystallization without excessive energy input.
3Manufacturing precision
If multiple reaction steps are used to synthesize iodixanol, then product purity is improved, but process complexity and cost increase
Solution Approach 1:
The patent extracts the purification function from the complex multi-step synthesis process by implementing a dedicated crystallization step. The crude reaction mixture from the dimerization of Compound A is directly subjected to crystallization by adding isopropanol to aqueous solution, separating the pure iodixanol crystals from impurities in one operation, thereby simplifying the overall process while maintaining high purity.
4Quantity of substance
If dimerization of Compound A is performed, then iodixanol production is achieved, but yield remains low and purification becomes more difficult
Solution Approach 1:
The patent converts the harmful effect of crude mixture complexity into a benefit by using it as the direct feed for crystallization. The crude reaction mixture containing iodixanol and impurities from dimerization is without pre-purification subjected to crystallization, where the controlled solubility differences enable selective crystallization of pure iodixanol, turning the complex crude mixture into an advantage for direct crystallization 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 approach results in a cost-effective and efficient purification of iodixanol, achieving a purity of 98.0-98.5% within 1-4 days, significantly reducing energy input and solvent usage while maintaining high output per reactor volume, thus meeting pharmacopeial specifications.
Implementation Method 1
crystallization comprising the steps of a) adjusting the water content in an aqueous solution of the crude product to reach the desired water concentration; b) adding about 1 to 3 l methanol per kg iodixanol; c) gradually adding a total of about 1.5 to 4 l isopropanol per kg iodixanol in one or several portions
Data Source
AI summary
A process for the manufacture of iodixanol by performing a crystallization process of the crude product in a solvent mixture comprising water, methanol and isopropanol. The crude product may be obtained in aqueous solution from dimerisation of 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide (“Compound A”).