Effect of Organic Acid Selection on the Physicochemical Properties, Bioadhesion, and Stability of Chitosan Hydrogels

Chitosan is a promising biopolymer for drug delivery due to its biocompatibility, biodegradability, and low toxicity. However, its limited dispersibility in water restricts applications, which can be improved through organic acid salts. This study examined how acetic, lactic, glutamic, and citric acids influence the physicochemical, rheological, swelling, bioadhesive, stability, and cytotoxicity properties of chitosan hydrogels. Gels were prepared using varying chitosan-to-acid molar ratios (1:1; 1:1.2 for citrate) and characterized by NMR, FTIR, TGA, and XRD. Despite identical chitosan concentrations (2%, 3%, 3.5%), gels displayed distinct viscosity, swelling, and adhesion profiles depending on the acid. Lactate gels exhibited the most favorable overall performance, combining high viscosity (1555-6665 mPa·s), structural stability, and strong bioadhesion. Citrate gels showed the lowest viscosity (825-3550 mPa·s), cell viability, and stability but the highest bioadhesiveness, likely due to multivalent ionic interactions. Short-term stability tests revealed that low pH accelerated chitosan degradation, leading to viscosity loss up to ~90-95% within 30 days, particularly in citrate hydrogels. Cytotoxicity tests confirmed high biocompatibility, with all formulations maintaining cell viability above 80%. Overall, the findings highlight that organic acid selection is a critical determinant of chitosan gel behavior, offering guidance for tailoring safe, stable, and bioadhesive drug delivery systems.