The mechanochemical and supercritical fluid synthesis of β-cyclodextrin-hesperidin inclusion complex: A comparison green chemistry versus lyophilization

Hesperidin is a rutinoside of flavanone type with relevant therapeutic properties but poor water solubility which limits its therapeutic applicability. However, cyclodextrins (CDs) have been successfully used as drug carriers to enhance the solubility of several drugs, to improve their bioavailability, and therapeutic efficacy. We report herein the formation of inclusion complexes of β-cyclodextrin and hesperidin through the green approaches mechanochemistry and supercritical fluid and compare these results versus the classical lyophilization method. The resulting stoichiometries and the specific interactions of the complexes were analyzed by NMR, UV, and mass spectrometry. The β-cyclodextrin and hesperidin inclusion complex (IC) successfully obtained through green methodologies demonstrated superior levels of flavonoid content. In terms of solubility, the mechanochemistry inclusion complex showed the best improvement in solubility. We demonstrate herein that the use of green methodologies such as supercritical fluids and mechanochemistry are useful alternatives to the conventional method of lyophilization, to improve the solubility of β-cyclodextrin IC. • Supercritical fluids and mechanochemistry enhance solubility of flavonoid Hesperidin. • Comparison of two green methodologies to the lyophilization method for complex formation. • Physicochemical parameters of inclusion complexes analyzed using multiple techniques. • Green methodologies enhance the content of hesperidin in inclusion complexes.