Continuous Crystallization of Iodinated Aryls

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Solution Overview

Problem

Current industrial-scale purification of iodinated aryl compounds, such as X-ray contrast agents, through crystallization is time-consuming and equipment-intensive, often resulting in limited purity and high supersaturation, which fails to meet the purity criteria set by health authorities for in vivo administration.

Innovation Solution

A continuous crystallization process is employed, where iodinated aryl compounds are purified by adding anti-solvents to the crude product in a solvent, allowing for increased yield and purity while reducing the demand on time and equipment size, using a mixture or single anti-solvents with moderate boiling points, typically below 150°C, to facilitate efficient crystal growth.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Manufacturing precision

If batch crystallisation is performed to purify iodinated aryl compounds, then purity can be achieved, but the process requires considerable equipment size and time consumption

Engineering Contradiction:
ImprovepurityVSAvoidyield per volume and time unit
Core Design Contradiction:
Manufacturing precisionVSProductivity

Solution Approach 1:

The patent transforms the static batch crystallisation process into a dynamic continuous crystallisation process. The system maintains steady-state operation with continuous feed of crude product and anti-solvent, continuous removal of purified crystals, and dynamic control of crystallisation parameters. This enables the process to achieve both high purity (≥98%) and high productivity by operating continuously rather than in discrete batches, directly resolving the contradiction between manufacturing precision and productivity

Inventive Principle:
Principle #15Dynamics

Solution Approach 2:

The patent implements continuous crystallisation where the purification action never stops. Crude product solution and anti-solvent are continuously fed into the crystalliser, crystals continuously form and are removed, maintaining uninterrupted purification. This continuous operation eliminates the idle time between batches and maximizes equipment utilization, simultaneously achieving high purity and high yield per volume-time unit

Inventive Principle:
Principle #20Continuity of useful action

2Productivity

If high supersaturation is used to promote crystal growth kinetics, then crystallisation speed increases, but purity of crystallised compounds decreases

Engineering Contradiction:
Improvecrystal growth speedVSAvoidpurity
Core Design Contradiction:
ProductivityVSManufacturing precision

Solution Approach 1:

The patent carefully controls the supersaturation parameter throughout the continuous crystallisation process. By regulating the feed rates of crude product and anti-solvent, and controlling temperature, the system maintains optimal supersaturation levels that promote adequate crystal growth kinetics while preventing excessive supersaturation that would cause impurity incorporation. This parameter optimization resolves the contradiction between crystal growth speed and purity

Inventive Principle:
Principle #35Parameter changes

Solution Approach 2:

The continuous crystallisation system incorporates feedback control mechanisms to monitor and adjust crystallisation parameters in real-time. By continuously measuring conditions such as temperature, concentration, and crystal formation rate, the system can adjust anti-solvent feed rate and other parameters to maintain optimal supersaturation levels, ensuring both adequate growth speed and high purity in the crystallised product

Inventive Principle:
Principle #23Feedback

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 continuous crystallization process enhances the throughput per volume and time unit, maintaining and potentially increasing the purity of iodinated compounds, thereby meeting the stringent purity requirements for X-ray contrast agents and optimizing industrial-scale production.

Implementation Method 1

purification by continuous crystallisation of the corresponding crude product containing the compounds in a solvent, by addition of one or more anti-solvents during the process

Methodology Applied
Scientific EffectCrystallisation: Crystallisation

Implementation Method 2

The crystallisation is also promoted by high supersaturation

Methodology Applied
Scientific EffectSupersaturation: Supersaturation

Implementation Method 3

addition of one or more anti-solvents during the process

Methodology Applied
Scientific EffectAnti-solvent effect: Liquid-Liquid Extraction

Data Source

PatentUS8829241B2Continuous crystallisation process of iodinated phenyl derivatives
Publication Date: 2014.09.09 GE HEALTHCARE AS

AI summary

The invention describes a process for the purification of iodinated aryl compounds where the purification is performed by continuous crystallization of a crude product in a solvent with addition of anti-solvent. The continuous crystallization process is performed in one or more crystallizers at a temperature up to the boiling point of the content of the crystallizer.