β-Cyclodextrin–chitosan based carriers enhance the solubility and dissolution of baicalein through inclusion complex formation

Baicalein (BA) is a poorly water-soluble flavonoid whose limited aqueous solubility restricts its oral bioavailability and pharmaceutical performance. This study aimed to enhance BA solubility and dissolution behavior through the development of binary (BA–β-cyclodextrin) and ternary (BA–β-cyclodextrin–chitosan) inclusion systems. Solid-state characterization was performed using DSC, FTIR and XRD analysis, while thermodynamic evaluation was conducted through Higuchi–Connors phase-solubility analysis. Molecular docking and MM-GBSA calculations were employed to support host–guest interaction mechanisms. Equilibrium solubility studies revealed that pure BA exhibited an intrinsic solubility of 7.50 µg/mL, whereas the optimized 1:2 BA:β-CD binary complex achieved 65.99 µg/mL, corresponding to approximately 8.8-fold enhancement. The phase-solubility diagram displayed an AL-type profile with a calculated apparent stability constant (K_s) of 5.3 × 10² M⁻¹, confirming predominant 1:1 inclusion complex formation. Dissolution studies further demonstrated significantly improved cumulative drug release for binary systems and sustained-release behaviour for ternary complexes. These findings provide integrated thermodynamic, physicochemical, and computational evidence supporting cyclodextrin-assisted solubilization of baicalein and highlight the potential of combined inclusion–polymer systems for improving the pharmaceutical performance of poorly soluble flavonoids.