Iodixanol Purification via Ethanol Crystallization

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Solution Overview

Problem

Current methods for manufacturing iodixanol, a non-ionic X-ray contrast agent, face low yield, high costs, and time-consuming purification processes, particularly due to the reliance on preparative liquid chromatography and excessive solvent use in crystallization.

Innovation Solution

A purification process utilizing ethanol as a solvent for crystallization, allowing for a single-step crystallization of crude iodixanol, reducing energy input, solvent amounts, and crystallization time, while achieving high purity and efficiency.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Manufacturing precision

If preparative liquid chromatography is used for purification, then high purity iodixanol is achieved, but the process becomes expensive and time-consuming

Engineering Contradiction:

ImprovepurityVSAvoidpurification time

Core Design Contradiction:

Manufacturing precisionVSLoss of time

Solution Approach 1:

The patent changes the purification parameter from liquid chromatography to crystallization, achieving high purity through controlled crystallization conditions including temperature, solvent composition, and pH adjustments, thereby eliminating the need for expensive and time-consuming chromatography

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent utilizes phase transition from dissolved state to crystalline state for purification. By controlling the phase transition through temperature changes and solvent removal, iodixanol crystallizes in pure form, separating it from impurities without requiring chromatography

Inventive Principle:

Principle #36Phase transitions

2Manufacturing precision

If preparative liquid chromatography is used for purification, then high purity iodixanol is achieved, but the cost increases significantly

Engineering Contradiction:

ImprovepurityVSAvoidmanufacturing cost

Core Design Contradiction:

Manufacturing precisionVSEase of manufacture

Solution Approach 1:

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent replaces expensive chromatography materials with simple, inexpensive crystallization solvents and equipment, making the purification process economically viable for large-scale production

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

3Manufacturing precision

If multiple crystallization steps are performed to achieve desired purity, then purification effectiveness is improved, but the process becomes time-consuming

Engineering Contradiction:

ImprovepurityVSAvoidpurification speed

Core Design Contradiction:

Manufacturing precisionVSProductivity

Solution Approach 1:

The patent performs preliminary actions during synthesis to minimize impurities, including optimizing reaction conditions and using protective groups strategically, so that fewer crystallization steps are needed to achieve the desired purity level

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent optimizes crystallization parameters such as solvent composition, temperature profile, and pH to maximize purification efficiency in a single step, reducing the need for multiple sequential crystallizations

Inventive Principle:

Principle #35Parameter changes

4Manufacturing precision

If high amounts of solvent are used in crystallization, then purification effectiveness is improved, but solvent consumption and cost increase

Engineering Contradiction:

ImprovepurityVSAvoidsolvent consumption

Core Design Contradiction:

Manufacturing precisionVSLoss of substance

Solution Approach 1:

The patent optimizes solvent parameters including composition, volume, and temperature to achieve maximum purification efficiency with minimum solvent consumption, balancing purity achievement with resource conservation

Inventive Principle:

Principle #35Parameter changes

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

The process achieves iodixanol purity meeting US Pharmacopeia specifications within 1-4 days, with improved economic and environmental outcomes by minimizing solvent use and energy consumption, and producing crystals that are easier to filter and wash.

Implementation Method 1

A purification process utilizing ethanol as a solvent for crystallization, allowing for a single-step crystallization of crude iodixanol

Methodology Applied

Scientific EffectCrystallization: Crystallisation

Implementation Method 2

crystallization of crude iodixanol

Methodology Applied

Scientific EffectPhase change: Phase Change

Data Source

PatentEP1960349B1Purification of iodixanol

Publication Date: 2015.11.18 GE HEALTHCARE AS

AI summary

A process for the manufacture of iodixanol by performing a purification process of the crude product in a solvent comprising ethanol. 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").