(6S)-5-Methyltetrahydrofolate Salt Crystal Form C Preparation
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Solution Overview
Problem
The instability and sensitivity of (6S)-5-methyltetrahydrofolic acid and its salts to oxygen and moisture pose challenges in achieving high-purity and stable crystal forms, making conventional crystallization processes inefficient and difficult to produce pharmaceutical-grade materials.
Innovation Solution
The use of ultrasonic waves during crystallization to enhance nucleation and crystal growth, resulting in a stable crystal form C of (6S)-5-methyltetrahydrofolate calcium salt with specific X-ray diffraction peaks and high chemical purity, achieved through neutralization, heating, and ultrasonic assistance in a polar medium.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional crystallization process is used, then simple operation is achieved, but high stability and high purity crystal form cannot be obtained due to oxidation and degradation
Solution Approach 1:
The patent employs an inert atmosphere (nitrogen or argon) during the crystallization process to prevent oxidation of (6S)-5-MTHF. The reaction system is filled with inert gas and maintained under positive pressure throughout the process, creating a protective environment that eliminates oxygen contact and prevents degradation of the sensitive compound while maintaining a relatively simple crystallization procedure.
Solution Approach 2:
The patent uses intermediates such as sodium borohydride and calcium chloride in a controlled sequential manner. First, sodium borohydride reduces the pterin ring to form the tetrahydro form, then calcium chloride is added to induce crystallization. This stepwise intermediary approach ensures high purity crystal formation while maintaining process simplicity through clear阶段性 reactions.
2Reliability
If reducing agents are added to prevent oxidation, then stability is improved, but manufacturing precision and purity are compromised due to additional chemicals
Solution Approach 1:
Instead of adding reducing agents that would compromise purity, the patent creates an oxygen-excluding inert atmosphere using nitrogen or argon gas. This physical protection method prevents oxidation without introducing additional chemicals into the system, thereby maintaining high chemical purity (>99%) while achieving excellent anti-oxidation stability during crystallization and storage.
3Reliability
If long crystallization time is used, then crystal stability is improved, but productivity is reduced
Solution Approach 1:
The patent optimizes crystallization parameters including temperature (maintaining 0-5°C refrigeration), pH control (adjusting to specific ranges for different salts), and solvent selection (water, ethanol, or their mixtures). These controlled parameter changes accelerate crystal nucleation and growth rates, enabling high-stability crystals to form within 4-18 hours rather than requiring extended periods, thus improving both stability and productivity.
Solution Approach 2:
The patent performs preliminary actions by first dissolving the compound completely in the selected solvent under inert atmosphere, then adjusting pH and temperature before initiating crystallization. This pre-preparation ensures optimal conditions are established beforehand, allowing rapid and stable crystal formation once the process begins, reducing total production time while ensuring crystal quality.
4Ease of manufacture
If amorphous salt is converted to crystal form through simple cooling, then ease of manufacture is achieved, but high purity and stability are not obtained
Solution Approach 1:
The patent maintains an inert atmosphere throughout the entire crystallization process from dissolving the amorphous salt to the final crystal formation. This continuous protection against oxidation ensures that the simple cooling crystallization process yields high-purity (>99%) stable crystals without requiring complex additional purification steps, thus maintaining ease of manufacture while achieving high manufacturing 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
This method produces a crystal form with high stability, chemical purity greater than 99%, and improved bioavailability, facilitating industrial-scale production and pharmaceutical applications.
Implementation Method 1
by using ultrasonic waves to assist crystallization during the formation of a salt
Implementation Method 2
by using ultrasonic waves to assist crystallization during the formation of a salt
Implementation Method 3
the X-ray diffraction pattern has diffraction peaks at 2θ of 6.3±0.2 and 19.2±0.2, especially has one or more diffraction peaks at 2θ of 3.2±0.2, 6.3±0.2, 13.2±0.2, 14.6±0.2, 19.2±0.2, and 32.6±0.2
Data Source
Figure 1~2
Figure 3
AI summary
Disclosed are a crystal form of (6S)-5-methyltetrahydrofolate salt and a method for preparing the same. The crystal form is: Form C of the crystal form of (6S)-5-methyltetrahydrofolate calcium salt, where the X-ray diffraction pattern has diffraction peaks at the 2θ angles of 6.3±0.2 and 19.2±0.2; or the crystal form of (6S)-5-methyltetrahydrofolate strontium salt, where the X-ray diffraction pattern has diffraction peaks at the 2θ angles of 6.5±0.2 and 22.0±0.2. The crystal form of (6S)-5-methyltetrahydrofolate salt of the present invention has the advantages of excellent physicochemical properties, good stability, high purity, good reproducibility, and being more suitable for production on an industrial scale.