Approaches for Inclusion Complexes of Ezetimibe with Cyclodextrins: Strategies for Solubility Enhancement and Interaction Analysis via Molecular Docking

This study aimed to improve the solubility of ezetimibe (EZT), which has low aqueous solubility, by preparing complexes using β-cyclodextrin (β-CD) derivatives. Phase solubility studies and Job's plot confirmed a high apparent stability constant for EZT with β-CD and even higher constants with its derivatives, establishing a 1:1 stoichiometric ratio. The composites were prepared using spray drying over a range of molar ratios, and their physicochemical properties were evaluated using techniques such as scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FT-IR). Saturation solubility and in vitro dissolution tests revealed that solubility increased with higher CD molar ratios. EZT/RM-β-CD inclusion complexes (ICs) and EZT/DM-β-CD ICs exhibited a similar solubility, which was greater than that of EZT/HP-β-CD ICs and EZT/SBE-β-CD ICs (where RM, DM, HP, and SEB represent H, CH₃, -CH₂-CHOH-CH₃ and -(CH₂)₄-SO₃Na synthetic derivatives, respectively). Most complexes, except for EZT/SBE-β-CD at 1:2 or higher ratios, showed superior solubility compared with EZT powder and commercial products. Molecular docking simulations confirmed EZT inclusion within the CD, revealing hydrogen bonds and binding energies that aligned with solubility trends. These findings suggest that EZT complexes with β-CD derivatives significantly improve solubility, highlighting their potential for developing more effective oral solid formulations for hyperlipidemia treatment.