Disodium Methylene-THF Lyophilizate for Stable High-Content Formulation
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Solution Overview
Problem
Existing formulations of 5,10-methylene-(6R)-tetrahydrofolic acid (5,10-CH2-(6R)-THF) are susceptible to oxidation and chemical degradation, particularly in aqueous solutions and amorphous forms, leading to high impurity levels and unsatisfactory stability, solubility, and active ingredient content.
Innovation Solution
A lyophilized composition comprising the disodium salt of 5,10-methylene-(6R)-tetrahydrofolic acid (5,10-CH2-(6R)-THF*Na2) combined with citrate and an alkali metal sulfate, prepared without additional reducing agents or antioxidants, achieves enhanced stability and solubility, allowing for high content formulations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If 5,10-CH2-(6R)-THF is formulated in aqueous solution or amorphous form, then solubility and ease of administration are improved, but chemical stability and purity deteriorate due to oxidation and degradation
Solution Approach 1:
The patent transforms the chemical form of the active ingredient from the acid form to the disodium salt form (5,10-CH2-(6R)-THF*Na2). This parameter change in chemical state fundamentally alters the properties: the disodium salt exhibits superior stability in aqueous solutions and amorphous forms while maintaining high solubility, thereby resolving the contradiction between ease of administration and chemical stability
Solution Approach 2:
The patent creates a composite formulation by combining the disodium salt of 5,10-CH2-(6R)-THF with specific excipients including citrate and sulfate. This composite material approach enhances both the solubility and stability simultaneously, as the excipients work synergistically with the disodium salt to prevent oxidation and degradation while maintaining aqueous solubility
2Stability of the object's composition
If reducing agents and antioxidants are added to stabilize 5,10-methylenetetrahydrofolic acid, then chemical stability is improved, but formulation complexity and manufacturing complexity increase
Solution Approach 1:
The patent extracts and eliminates the need for reducing agents and antioxidants from the formulation by using the disodium salt form of 5,10-CH2-(6R)-THF. This extraction of unnecessary components simplifies the formulation while maintaining chemical stability, as the disodium salt inherently resists oxidation without requiring additional stabilizing agents
Solution Approach 2:
The disodium salt form of 5,10-CH2-(6R)-THF provides self-stabilization properties, where the compound protects itself against oxidation and degradation through its inherent chemical structure. This self-service capability eliminates the need for external reducing agents and antioxidants, thereby reducing formulation and manufacturing complexity
3Quantity of substance
If high content formulations of 5,10-CH2-(6R)-THF are prepared, then therapeutic effectiveness is improved, but stability and purity deteriorate due to increased susceptibility to oxidation
Solution Approach 1:
The patent changes the chemical parameter from acid form to disodium salt form, which fundamentally alters the oxidation susceptibility. This parameter change enables high content formulations (with increased active ingredient quantity) to maintain stability and purity, as the disodium salt form is inherently more resistant to oxidation than the acid form
Solution Approach 2:
The patent develops a composite formulation system where the disodium salt of 5,10-CH2-(6R)-THF is combined with citrate and sulfate excipients. This composite material approach stabilizes high content formulations by preventing oxidation and degradation, thereby enabling both high active ingredient content and maintained stability/purity
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 composition maintains high purity and stability, with lyophilizates containing over 20% w/w 5,10-CH2-(6R)-THF*Na2, and demonstrates stability even at room temperature for extended periods, suitable for reconstitution and administration.
Implementation Method 1
5,10-CH2-(6R)-THF is highly susceptible to oxidation and chemical degradation... The disodium salt of 5,10-methylene-(6R)-tetrahydrofolic acid... maintains high purity and stability
Implementation Method 2
A lyophilized composition comprising the disodium salt of 5,10-methylene-(6R)-tetrahydrofolic acid... lyophilizates containing over 20% w/w 5,10-CH2-(6R)-THF*Na2
Data Source
AI summary
The present invention relates to stable formulations and lyophilizates comprising a high content of the disodium salt of 5,10-methylene-(6R)-tetrahydrofolic acid, sulfate and citrate.