Gadolinium Chelate Crystallization for Scalable One-Pot Synthesis

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Solution Overview

Problem

Existing processes for synthesizing gadolinium chelate compounds, such as formula (I), are not scalable, costly, and inefficient, with high dilution, use of toxic solvents, and cumbersome procedures like chromatography and lyophilization, making them unsuitable for large-scale production and regulatory compliance.

Innovation Solution

A one-pot protocol that avoids the use of toxic solvents like pyridine, allows higher concentration reactions, and isolates the compound as a crystalline material, reducing the need for distillation and chromatography, resulting in high purity and crystalline form production.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If high dilution and large excess of reagents are used for fragment union, then the reaction can proceed, but the manufacturing cost increases and productivity decreases

Engineering Contradiction:

Improvereaction successVSAvoidmanufacturing efficiency

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent changes the concentration parameter from high dilution to concentrated conditions (0.1-5 M), and modifies the reaction conditions to enable fragment union without requiring large excess of reagents, thereby improving productivity while maintaining reaction reliability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent eliminates the need for large excess of valuable intermediate (II) by optimizing the reaction conditions and stoichiometry, using only stoichiometric or near-stoichiometric amounts, thus reducing material waste and manufacturing cost

Inventive Principle:

Principle #16Partial or excessive action

2Ease of manufacture

If toxic solvents like pyridine are used, then the reaction can proceed, but the process becomes harmful and regulatory compliance becomes difficult

Engineering Contradiction:

Improvereaction feasibilityVSAvoidtoxicity

Core Design Contradiction:

Ease of manufactureVSObject-affected harmful factors

Solution Approach 1:

The patent replaces toxic pyridine solvent with water or water-miscible solvents, converting a harmful process into a safer one, while maintaining reaction feasibility through alternative reaction conditions and solvent systems that enable the same chemical transformation without toxic byproducts

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Solution Approach 2:

The patent uses water or water-miscible solvents as a safer, less harmful reaction environment, creating an inert-like atmosphere that eliminates the toxicity issues associated with pyridine while maintaining the necessary reaction conditions

Inventive Principle:

Principle #39Inert atmosphere (Inert environment)

3Manufacturing precision

If chromatography and lyophilization are used for isolation, then the compound can be purified, but the procedure becomes cumbersome and costly

Engineering Contradiction:

ImprovepurityVSAvoidprocedure complexity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The patent extracts the compound from the reaction mixture through simple filtration or concentration steps, taking out the desired product without requiring complex chromatography or lyophilization procedures, thereby simplifying the isolation process while maintaining high purity

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent employs simple, inexpensive isolation techniques such as filtration or evaporation instead of expensive and time-consuming chromatography and lyophilization, using disposable or simple equipment that reduces both cost and procedural complexity

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

4Loss of substance

If distillation of high boiling solvent is performed, then the solvent can be removed, but the process requires low pressures and high temperatures increasing energy consumption

Engineering Contradiction:

Improvesolvent removalVSAvoidenergy consumption

Core Design Contradiction:

Loss of substanceVSUse of energy by moving object

Solution Approach 1:

The patent changes the solvent from high boiling point pyridine to water or water-miscible solvents with lower boiling points, enabling solvent removal at lower temperatures and reduced energy consumption while maintaining the same reaction effectiveness

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20260015331A1Process Or The Preparation Of A Gadolinium Contrast Agent

Publication Date: 2026.01.15 BAYER AG

AI summary

The present invention relates to a process for the preparation of a gadolinium chelate compound of formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same. Further, the present invention relates to crystalline forms of the gadolinium chelate of formula (I), to a process for the preparation of said crystalline forms as well as to intermediate compounds in the synthesis of the gadolinium chelate compound of formula (I) and/or its crystalline forms as well as their stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.