Crystalline Levofolinic Acid Preparation via pH and Temperature Control
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Solution Overview
Problem
Current methods do not provide a reliable way to produce (6S)-N(5)-formyl-5,6,7,8-tetrahydrofolic acid in diastereoisomerically pure and stable crystalline form, which is necessary for convenient pharmaceutical salt production and new formulations without the need for previous salt preparation.
Innovation Solution
A process involving the preparation of a soluble levofolinate salt solution with controlled pH and temperature, followed by slow addition to a pre-heated hydroalcoholic mixture, maintaining pH between 3.0 and 4.5 and temperature between 30 and 60 °C, to achieve crystallization of levofolinic acid, ensuring diastereoisomeric purity of at least 98%.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional crystallization methods are used to produce levofolinic acid, then the production process can be simplified, but the product cannot achieve essential purity in diastereoisomerically pure crystalline form
Solution Approach 1:
The patent applies parameter changes by precisely controlling pH (maintaining between 3.0-4.5 during crystallization), temperature (30-60°C), and concentration (levofolinate salt concentration never exceeding 4% w/v) to achieve diastereoisomerically pure crystalline levofolinic acid. This resolves the contradiction by showing that careful parameter control enables high purity without requiring complex multi-step processes.
Solution Approach 2:
The patent employs preliminary action by pre-heating the hydroalcoholic mixture before adding the levofolinate salt solution, and by preparing the solution with controlled pH and concentration before crystallization begins. This preliminary preparation ensures that crystallization proceeds directly to the pure crystalline form without requiring additional purification steps.
2Ease of operation
If levofolinic acid is produced in amorphous form or as salts, then the production method is available, but it cannot be directly used for new pharmaceutical formulation without previous salt preparation
Solution Approach 1:
The patent extracts the carboxylic acid functionality from the salt form by performing acidification during crystallization, directly yielding free acid levofolinic acid in crystalline form. This eliminates the need for subsequent salt preparation steps in pharmaceutical formulation, resolving the contradiction by providing a product ready for direct formulation use.
3Productivity
If the levofolinate salt concentration in the solution is increased to improve productivity, then the crystallization efficiency may increase, but the pH control becomes more difficult and purity may be compromised
Solution Approach 1:
The patent applies partial action by limiting the levofolinate salt concentration to never exceed 4% w/v during crystallization. This controlled concentration, combined with continuous pH monitoring and adjustment, ensures both efficient crystallization and stable pH control, resolving the contradiction between productivity and precision.
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 yields essentially pure (6S)-N(5)-formyl-5,6,7,8-tetrahydrofolic acid in stable crystalline form, characterized by specific XRD peaks, with improved stability and purity compared to existing methods, allowing for effective pharmaceutical applications.
Implementation Method 1
forming a second solution, by adding said first solution and a second acid to said batch of water or hydroalcoholic mixture... upon completion of the addition of said first solution to said batch of water or hydroalcoholic mixture, stirring the thus formed second solution while the precipitation of levofolinic acid occurs
Implementation Method 2
providing a batch of water, or of a hydroalcoholic mixture containing up to 60% v/v of alcohol, pre-heated at a temperature between 30 and 60 °C... maintaining the solution at a temperature between 30 and 60 °C
Data Source
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AI summary
The present invention relates to stable crystalline (6S)-N(5)-formyl-5,6,7,8-tetrahydrofolic acid, commonly referred to as levofolinic acid, in essentially pure 6S diastereomeric form, to its use for the preparation of a dietary supplement or of a medicament, and to a pharmaceutical preparation comprising said stable crystalline (6S)-N(5)-formyl-5,6,7,8-tetrahydrofolic acid.