In this study, hydrogels containing azelaic acid were developed using chitosan or HPMC (1-7%) for local treatment of acne vulgaris. Physicochemical properties such as viscosity, pH and mechanical properties were evaluated. In vitro release and ex vivo permeability studies were performed using Franz diffusion cell system. The pH of the hydrogels were highly compatible with the skin pH and varied between 4.38–5.84. The cumulative release percentages of the hydrogels at the end of 6 hours were 65-78%, whereas the marketed product yielded 50% drug release. According to the ex vivo permeability results, azelaic acid accumulated in the skin were found to be 9.38 ± 0.65% (marketed cream), 19.53 ± 1.06% (K3), 10.96 ± 1.91% (H6). The antiacne studies with Cutibacterium acnes revealed that K3 (29.45 ± 0.95) and H6 (32.35 ± 0.15) had higher inhibition zones compared to the marketed cream (24.50 ± 0.90). Additionally, the gels were found to be highly stable as a result of the stability studies for 6 months. Among the hydrogels that were prepared based on experimental findings, K3 (3% Chitosan) and H6 (6% HPMC) represented elevated in vitro release profile, higher permeability and increased antiacne activity. The findings of this research suggest that the developed hydrogels might be an alternative to the marketed product. Graphical Abstract

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.