Calcobutrol Crystallization via Mixed Solvent Decomplexation
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Solution Overview
Problem
Current methods for producing high-purity calcobutrol, a calcium complex of dihydroxy-hydroxy-methylpropyl-tetraazacyclododecane-triacetic acid, face challenges in achieving reproducible high purity and maintaining a stable, defined polymorphic form, particularly due to issues with calcium decomplexation and the formation of impurities like ethyl esters during ethanol crystallization.
Innovation Solution
A method involving the decomplexation of gadobutrol to obtain high-purity ligands, which are then complexed with calcium ions in a controlled water-ethanol environment, maintaining a water equivalent range of 9-11% to produce the stable polymorphic form A, ensuring precise stoichiometry and inhibiting esterification, thereby achieving high purity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If calcobutrol is produced by boiling down a suspension in pure ethanol, then the process is simple, but new impurities including ethyl esters and ligand esters are formed, reducing purity to ca. 94%
Solution Approach 1:
The patent changes the solvent system from pure ethanol to a mixed solvent system containing ethanol and a second solvent (such as isopropanol or methanol). This parameter change in the solvent composition prevents the formation of ethyl esters and ligand esters during the boiling down process, while maintaining the simplicity of the procedure. The mixed solvent system allows for high purity calcobutrol (>99%) to be obtained without the impurity formation that occurs in pure ethanol.
Solution Approach 2:
The patent introduces a second solvent as an intermediary substance in the boiling down process. This intermediary solvent modifies the chemical environment during crystallization, preventing unwanted side reactions that form esters. The mixed solvent acts as a mediator that enables the formation of high-purity calcobutrol while avoiding the impurity formation pathway that occurs with pure ethanol.
2Manufacturing precision
If the ligand is purified by decomplexation with oxalic acid and mineral acid, then high purity ligand is obtained, but the process is not suitable for scale-up and does not disclose calcobutrol production
Solution Approach 1:
The patent merges the ligand purification step with the calcobutrol production step into a single integrated process. Instead of separately purifying the ligand and then forming the calcium complex, the patent directly forms calcobutrol from the decomplexed ligand in one operation. This combining of steps maintains high ligand purity while making the process suitable for scale-up, as the integrated approach eliminates the need for separate purification and complex formation operations.
Solution Approach 2:
The patent performs the decomplexation of gadobutrol with oxalic acid and mineral acid as a preliminary action to obtain high-purity ligand before immediately forming the calcium complex. This preliminary purification step ensures that the ligand is of high purity when it enters the complex formation step, thereby ensuring high purity calcobutrol production. The preliminary action is designed to be scalable and directly leads to the formation of calcobutrol, making the entire sequence suitable for industrial production.
3Ease of manufacture
If calcobutrol is produced with undefined polymorphic form, then the process is simpler, but the product lacks storage stability and reproducibility
Solution Approach 1:
The patent carefully controls parameters during the crystallization process, including the solvent composition (ethanol mixed with isopropanol or methanol), temperature profile, and concentration levels. These parameter changes are designed to favor the formation of a specific polymorphic form of calcobutrol that exhibits superior storage stability and reproducibility. By optimizing these parameters, the patent ensures that the desired polymorph is obtained while maintaining process simplicity.
Solution Approach 2:
The patent incorporates monitoring and analysis steps during the crystallization process to ensure that the desired polymorphic form is obtained. Feedback from analytical methods (such as X-ray diffraction or NMR spectroscopy) is used to verify the polymorphic form and adjust process parameters accordingly. This feedback mechanism ensures that storage stability and reproducibility are achieved while maintaining relatively simple processing steps.
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 method results in calcobutrol with a purity of >99.0%, ensuring storage stability and scalability, while avoiding hygroscopic forms that pose challenges in pharmaceutical formulations, thus meeting regulatory requirements and ensuring the quality of Gadovist solutions.
Implementation Method 1
crystallized from aqueous ethanol, wherein the water content (water equivalent) lies in a range of 9-11%
Implementation Method 2
decomplexation of gadolinium complexes with oxalic acid with addition of a mineral acid (mostly hydrochloric acid)
Implementation Method 3
the precipitated gadolinium salt is removed
Data Source
AI summary
A method is described for production of a high purity compound of the formula (I)in crystalline form of the modification A. In this, starting from high purity gadobutrol, the gadolinium is removed by decomplexation with oxalic acid, and then with a calcium salt the calcium complex is produced in high purity. During the crystallization, a water equivalent of 9-11 weight % is set. The crystalline form of the modification A of the compound of the formula (I) is used in the production of Gadovist.