S-Acetyl Glutathione Crystalline Form A Bioavailability
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Solution Overview
Problem
The absorption of glutathione (GSH) is hindered by its poor bioavailability due to rapid hydrolysis in the intestine, and existing polymorphic forms of S-acetyl glutathione (SAG) can affect dissolution rate, solubility, and bioavailability, which are not adequately addressed by previous methods.
Innovation Solution
The identification and characterization of crystalline form A of SAG, along with a method for its production using specific solvent mixtures and crystallization conditions, which distinguishes it from polymorphic form B, enhancing bioavailability and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GSH is administered orally to replenish intracellular levels, then the intended biological effect is achieved, but the compound undergoes rapid hydrolysis in the intestine reducing absorption efficiency
Solution Approach 1:
The invention segments the GSH molecule by acetylating the sulfhydryl group to form S-acetyl glutathione (SAG). This chemical modification protects the molecule from intestinal hydrolysis while allowing cellular uptake, after which intracellular thioesterases cleave the acetyl group to release active GSH inside the cells.
2Reliability
If SAG is used as a precursor to replenish GSH levels, then absorption and stability are improved, but polymorphic forms with different dissolution rates and solubilities affect bioavailability
Solution Approach 1:
The invention changes the physical and chemical parameters of SAG by identifying and characterizing specific polymorphic forms (Form A, Form B, and amorphous form) with distinct dissolution rates, solubilities, and stability profiles. This allows selection of the optimal polymorphic form for specific pharmaceutical or nutraceutical applications to maximize bioavailability.
3Reliability
If high oral doses of GSH are administered to guarantee significant absorption, then the intended effect may be achieved, but the dosage increases and the compound remains unstable in plasma
Solution Approach 1:
The invention uses SAG as an intermediary compound that is more stable in plasma and more efficiently absorbed than GSH itself. SAG serves as a prodrug that is converted to active GSH intracellularly, thereby reducing the required oral dose while ensuring adequate GSH replenishment.
4Reliability
If sublingual or parenteral administration is used to improve bioavailability, then absorption is enhanced, but the administration route becomes more complex and invasive
Solution Approach 1:
The invention modifies the chemical structure of GSH by acetylation to create SAG, which has improved oral bioavailability due to protection from intestinal hydrolysis and enhanced plasma stability. This allows effective GSH replenishment through simple oral administration rather than requiring complex sublingual or parenteral routes.
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
Crystalline form A of SAG exhibits improved bioavailability, stability, and dissolution rate, making it suitable for pharmaceutical and nutraceutical compositions, particularly for oral administration, with higher purity and assay values compared to the amorphous form.
Implementation Method 1
The SAG thus assimilated by the tissues is hydrolysed by cytoplasmic thioesterase and, by hydrolysis of the acetyl group, produces reduced GSH which is available for all the biological functions wherein it is required.
Implementation Method 2
crystalline form A can be prepared by a process comprising the following steps: a) dissolution of SAG in water at a temperature ranging between 75°C and 80°C; b) immediate cooling of the solution obtained in step a) to a temperature of below 55°C, preferably to a temperature ranging between 45°C and 55°C, followed by further cooling until incipient crystallisation; c) cooling to 20-25°C of the mass obtained in step b) in the presence of minimal stirring (60-120 rpm), followed by continued stirring of the mass at 20-25°C for between 2 and 12 hours
Data Source
Figure 1
Figure 2
Figure 2A
AI summary
Disclosed are two crystalline forms of S-acetyl glutathione (SAG) called Form A and Form B, obtained by crystallisation of SAG from mixtures of water-acetone, water-ethanol or water-methanol, preferably acetone, under controlled conditions. The crystalline forms are characterised by X-ray powerder diffrraction, IR spectrum and DSC. Forms A and B can be advantageously used as ingredients of pharmaceutical or nutraceutical formulations.