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<p>Metformin, a BCS Class III drug, is limited by poor intestinal permeability despite high solubility, affecting its bioavailability. This study aimed to enhance Metformin’s permeability via cocrystallization with functional coformers. L-Cysteine was selected based on ΔpKa criteria and presence of thiol (-SH) group, known to interact with epithelial tight junctions and enhancepermeability. Cocrystals were prepared using solvent evaporation at various drug-to-coformer ratios. 1:2 Metformin–Cysteine cocrystal showed improved dissolution and strong hydrogen bonding interactions confirmed by DSC and FTIR, with PXRD indicating new crystalline phases. In vitro dissolution rates of Metformin and its cocrystals were similar; however, ex vivo experiments demonstrated a 5.9 -fold increase in permeability with the Metformin–Cysteine cocrystal. In vivo pharmacokinetic studies in Wistar rats revealed a Tmax of 1&#xa0;h, Cmax of 17.64&#xa0;µg/mL, and AUC0–∞ of 118.86&#xa0;µg&#xa0;h/mL, significantly higher than pure Metformin. These findings indicate that cocrystallization with L-Cysteine effectively enhances Metformin’s permeability and bioavailability. The thiol group in cysteine likely modulates intestinal barrier function, facilitating absorption. This study highlights the potential of functional coformers in overcoming permeability challenges in BCS Class III drugs and supports further development of Metformin–Cysteine cocrystals as improved oral formulations.</p> Graphical Abstract <p></p>

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Targeting Permeability Barriers By Strategic Selection of Thiol Containing Coformer for Novel Cocrystals of Metformin

  • 期刊论文

  • 发表日期：

    2026年6月26日

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  • Mangesh R. Bhalekar,
  • Ashwini R. Madgulkar,
  • Shweta J. Khiratkar

摘要

Metformin, a BCS Class III drug, is limited by poor intestinal permeability despite high solubility, affecting its bioavailability. This study aimed to enhance Metformin’s permeability via cocrystallization with functional coformers. L-Cysteine was selected based on ΔpKa criteria and presence of thiol (-SH) group, known to interact with epithelial tight junctions and enhancepermeability. Cocrystals were prepared using solvent evaporation at various drug-to-coformer ratios. 1:2 Metformin–Cysteine cocrystal showed improved dissolution and strong hydrogen bonding interactions confirmed by DSC and FTIR, with PXRD indicating new crystalline phases. In vitro dissolution rates of Metformin and its cocrystals were similar; however, ex vivo experiments demonstrated a 5.9 -fold increase in permeability with the Metformin–Cysteine cocrystal. In vivo pharmacokinetic studies in Wistar rats revealed a Tmax of 1 h, Cmax of 17.64 µg/mL, and AUC0–∞ of 118.86 µg h/mL, significantly higher than pure Metformin. These findings indicate that cocrystallization with L-Cysteine effectively enhances Metformin’s permeability and bioavailability. The thiol group in cysteine likely modulates intestinal barrier function, facilitating absorption. This study highlights the potential of functional coformers in overcoming permeability challenges in BCS Class III drugs and supports further development of Metformin–Cysteine cocrystals as improved oral formulations.

Graphical Abstract