Tolperisone Purification to Limit Genotoxic 4-MMPPO Impurities
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Solution Overview
Problem
Current methods for producing tolperisone result in final products with toxic impurities, such as 4-MMPPO, even at low levels, which can be genotoxic and pose health risks to patients.
Innovation Solution
Developed methods involve purifying tolperisone to reduce 4-MMPPO levels to less than 10 ppm through recrystallization and acid treatment, using solvent systems like 2-butanone and isopropanol, and incorporating a catalytic amount of acid to minimize impurity formation, along with detection methods using liquid chromatography/mass spectrometry for precise analysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current synthesis methods are used to produce tolperisone, then production efficiency and cost-effectiveness are maintained, but toxic impurities such as 4-MMPPO remain at levels that pose genotoxic risks to patients
Solution Approach 1:
The patent applies preliminary action by adding a catalytic amount of acid during the synthesis process to prevent the formation of 4-MMPPO impurity from the outset. This proactive measure addresses the genotoxicity issue before it arises, rather than attempting to remove the impurity after synthesis is complete.
Solution Approach 2:
The patent changes the chemical parameters of the synthesis process by introducing acid catalysis, which alters the reaction pathway to minimize the formation of 4-MMPPO. This parameter change transforms the synthesis conditions to achieve lower impurity levels while maintaining production efficiency.
2Object-generated harmful factors
If purification steps are added to reduce 4-MMPPO levels, then genotoxicity is minimized, but manufacturing complexity and production time increase
Solution Approach 1:
The patent uses preliminary action by incorporating acid catalysis during the synthesis step to prevent 4-MMPPO formation, thereby eliminating or minimizing the need for subsequent purification steps designed to remove this specific impurity.
Solution Approach 2:
The patent applies extraction by removing the problematic 4-MMPPO impurity through crystallization processes, separating it from the main tolperisone product to achieve the required purity levels.
3Object-generated harmful factors
If acid catalysis is used during synthesis, then 4-MMPPO formation is minimized, but control of reaction conditions becomes more challenging
Solution Approach 1:
The patent applies parameter changes by introducing acid catalysis to the synthesis process, which fundamentally alters the reaction conditions to prevent 4-MMPPO formation. The acid catalyst modifies the reaction pathway, reducing impurity generation despite the added complexity in controlling acidic reaction conditions.
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 methods effectively minimize genotoxic effects by achieving tolperisone formulations with significantly reduced 4-MMPPO levels, ensuring safer administration and reduced genotoxic hazards.
Implementation Method 1
purifying tolperisone to reduce 4-MMPPO levels to less than 10 ppm through recrystallization and acid treatment
Implementation Method 2
detection methods using liquid chromatography/mass spectrometry for precise analysis
Implementation Method 3
detection methods using liquid chromatography/mass spectrometry for precise analysis
Data Source
AI summary
The present disclosure relates to tolperisone, or a pharmaceutically acceptable salt or hydrate thereof, with 10 ppm 2-methyl-1-(4-methylphenyl)-propenone (4-MMPPO) or less, methods of producing the same, as well as compositions related thereto. The disclosure further relates to methods of treating a subject with tolperisone under conditions that limit exposure of the subject to tolerable levels of 4-MMPPO.