Inclusion complexes (ICs) of metronidazole (MTZ) with β-cyclodextrin (BCD) and its derivative 2-hydroxypropyl-β-cyclodextrin (HPBCD) were prepared to improve its apparent solubility. A 1:1 stoichiometry has been proposed for both ICs according to the Job's plots. The estimation of association constants and thermodynamic parameters demonstrated that the incorporation of MTZ in both cavities of cyclodextrins (CDs) is a spontaneous exothermic process. Nuclear magnetic resonance spectroscopy (NMR), two-dimensional (2D) NMR, Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM) investigations were used to ascertain the structure of ICs and that prove their formation. Thermal analysis showed that the thermal stability of MTZ was improved in the presence of both CDs. The in vitro drug release of ICs showed a considerable increase in the dissolution rate in comparison with the pure MTZ. An improvement of antibacterial activity was observed after encapsulation, especially for MTZ-HPBCD IC. Then chitosan (CS) nanoparticles (NPs) were prepared from the preformed MTZ-HPBCD IC by ionic gelation method. FTIR confirmed that MTZ-HPBCD IC has successfully entrapped in CS NPs. Transmission electron microscopy (TEM), field emission scanning electron microscopy (FE-SEM) images and dynamic light scattering (DLS) show that the NPs have a spherical shape with a uniform diameter. The in vitro release profile of NPs showed a controlled-release of MTZ suggesting that such MTZ-HPBCD IC-loaded CS NPs can be an efficient alternative to modify the MTZ release and increase its solubility.
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