Cyclodextrin-based inclusion complexes to enhance the solubility and oral bioavailability of indapamide: experimental and computational approaches

Objective: Indapamide, a thiazide-like diuretic, exhibits very low aqueous solubility, which restricts its oral bioavailability and therapeutic efficacy. This study aimed to enhance its solubility and stability by forming inclusion complexes with various cyclodextrins. Significance: Poor aqueous solubility remains a major challenge for oral delivery of many diuretics and other BCS class II drugs. Cyclodextrin inclusion offers a safe and pharmaceutically accepted strategy to overcome these limitations. By quantitatively bridging phase-solubility/van?t Hoff thermodynamics (?G?, ?H?, ?S?) with molecular modeling metrics (?E, orientation Approach A vs B), this work provides a mechanistic explanation of host?guest recognition and stability that goes beyond prior indapamide?CD reports. The study identifies SBE-?-CD as superior on mechanistic grounds (synergistic electrostatic and H-bonding interactions consistent with enthalpy-driven binding; ?E?= ?28.8 kcal?mol?1; ~8.7-fold solubility gain) and benchmarks preparation methods (freeze-drying > co-evaporation > kneading) while linking amorphization and HPLC retention shifts to complexation efficiency. Collectively, these advances yield a practical, generalizable decision framework for rational excipient and process selection in formulations of poorly water-soluble drugs. Methods: Five cyclodextrins (?-CD, ?-CD, ?-CD, hydroxypropyl-?-CD, and sulfobutylether-?-CD) were systematically evaluated using an integrated experimental?computational approach. Phase-solubility studies were performed to determine stoichiometry and stability constants, and thermodynamic parameters (?G?, ?H?, ?S?) were derived from van?t Hoff analysis conducted over the temperature range of 293?313 K. Solid-state characterization was carried out using SEM, XRD, and HPLC . Molecular modeling with HyperChem was performed at the MM+ and PM3 levels to assess host?guest orientations, binding energies, and electronic properties. Results: Phase solubility analysis confirmed the formation of 1:1 A L-type complexes, with sulfobutylether-?-CD achieving the highest solubilization (~8.7-fold), followed by hydroxypropyl-?-CD and ?-CD, while ?-CD showed minimal effect. Thermodynamic evaluation revealed that the inclusion process was spontaneous, exothermic, and enthalpy-driven. SEM and XRD demonstrated transformation of indapamide from crystalline to amorphous state, and HPLC confirmed efficient encapsulation. Molecular modeling showed favorable host?guest interactions, with sulfobutylether-?-CD providing the most stable binding (?E = ?28.8 kcal?mol?1). Conclusions: The integrated findings highlight the superior potential of modified cyclodextrins, particularly sulfobutylether-?-CD, as excipients for improving solubility, dissolution, and oral bioavailability of indapamide. These results establish a mechanistic foundation for future formulation strategies targeting poor