Mechanistic insights into drying methods: how they govern the structure and bioactivity of resveratrol-HP-β-CD inclusion complexes

Resveratrol (RES), a polyphenol with notable therapeutic potential, faces clinical limitations due to poor water solubility and low bioavailability. This study aimed to enhance the solubility and stability of RES by forming inclusion complexes with hydroxypropyl-β-cyclodextrin (HP-β-CD) using three drying methods: spray drying (SD), freeze-drying (FD), and solvent evaporation (SE). Phase solubility analysis confirmed the successful formation of a stable complex (K = 5278 M^-1) at an optimal 1:2 RES: HP-β-CD ratio. Among the dried products, the spray-dried complex (RHSD) demonstrated superior performance in moisture content, yield, and resveratrol content. It achieved the highest solubility enhancement (89-fold increase). In contrast, the freeze-dried complex (RHFD) showed the most potent antioxidant activity (IC₅₀ = 14.01 μg/mL). Physicochemical characterization via FTIR confirmed the formation of the inclusion complex. At the same time, XRD and SEM analyses revealed that RHSD possessed an amorphous structure, whereas RHFD and RHSE exhibited semi-crystalline characteristics. Subsequent drug-release studies demonstrated that RHSD followed non-Fickian release kinetics, unlike the diffusion-controlled release of RHFD and RHSE. These findings demonstrate that spray drying produces complexes with optimal physicochemical properties for solubility and dissolution, while freeze drying better preserves antioxidant activity, providing crucial insights for developing resveratrol-cyclodextrin formulations in pharmaceutical applications.