Crystallization Yield via Solvent Composition Control
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Solution Overview
Problem
The industrial production of non-ionic X-ray contrast agents, such as iodixanol, faces challenges in optimizing the crystallization yield of 5-acetamido-N,N-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (Compound A) due to high methanol content in the mother liquor, which affects the purity and efficiency of the crystallization process.
Innovation Solution
The method involves evaporating methanol and water to reduce the methanol content in the mother liquor to more than 75% water and less than 25% methanol, allowing for increased crystallization yield without compromising the purity of Compound A, by distilling a fraction of the mother liquor under reduced pressure.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If methanol is used as a solvent in the crystallization of Compound A, then the solubility and dissolution of Compound A is improved, but the crystallization yield decreases and the mother liquor volume increases
Solution Approach 1:
The patent applies parameter changes by systematically varying the water-to-methanol ratio in the solvent mixture during crystallization. By adjusting the methanol content from high concentrations down to less than 25% (v/v), the process optimizes both solubility during dissolution and crystallization yield during the precipitation phase, resolving the contradiction between maintaining good dissolution and achieving high yield.
Solution Approach 2:
The patent implements periodic action through a two-stage crystallization process. The first stage uses higher methanol content for initial crystallization, followed by a second stage with reduced methanol content (less than 25% v/v) to maximize yield. This periodic adjustment of solvent composition allows the system to benefit from both high solubility and high crystallization efficiency at different time points.
2Quantity of substance
If high methanol content is maintained in mother liquor, then dissolution of Compound A is facilitated, but crystallization yield is reduced
Solution Approach 1:
The patent changes the solvent composition parameter dynamically during the crystallization process. By reducing methanol content to less than 25% (v/v) in the final crystallization stage, the process minimizes the amount of Compound A remaining in solution, thereby increasing crystallization yield and reducing the volume of mother liquor that would otherwise need to be processed or discarded.
3Quantity of substance
If extended crystallization time is used to improve yield, then more Compound A crystallizes, but production efficiency decreases
Solution Approach 1:
The patent uses periodic action by implementing a multi-stage crystallization process with distinct time frames for each stage. The first stage allows initial crystallization, followed by a second stage with modified solvent composition that accelerates further crystallization. This periodic approach achieves high overall yield without requiring excessively long continuous crystallization times, thereby maintaining production efficiency.
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 increases the yield of Compound A by up to 3% without reducing its purity, and reduces the total mother liquor volume by up to 40%, demonstrating improved efficiency in the crystallization process.
Implementation Method 1
methanol and water are evaporated, leading to the mother liquor containing more than about 75% (v/v) of water and less than about 25% (v/v) of methanol
Implementation Method 2
by distilling a fraction of the mother liquor under reduced pressure
Data Source
AI summary
This invention relates to an improved method for crystallizing 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (“Compound A”), an intermediate in the industrial preparation of non-ionic X-ray contrast agents. In particular, the present invention provides an industrial process for crystallization of Compound A by evaporating methanol and water from the mother liquor after an initial crystallization of Compound A following the acetylation reaction. Specifically, the mother liquor is maintained at more than about 75% (v/v) of water and less than about 25% (v/v) of alcoholic solvent.