Thermodynamics and molecular insight in guest–host complexes of fluoroquinolones with β-cyclodextrin derivatives, as revealed by ATR-FTIR spectroscopy and molecular modeling experiments

β-Сyclodextrin (CD) is a perspective class of excipients used in pharmaceutical formulations to enhance solubility, bioavailability, and pharmacokinetics of various poorly soluble drugs, forming a non-covalent guest–host complex. However, the development of such formulations is usually a very laborious and time-consuming process due to lack of appropriate analytical tools to directly track and study the detailed molecular mechanism of such complex formation. Here, using guest–host complexes of fluoroquinolones (FQ) with CDs, as an example, we demonstrate the utility of ATR-FTIR to determine the thermodynamic stability, as well as structural features associated with complex formation, including involvement of certain functional groups. Furthermore, varying the CD’s side groups, we were able to tailor the CD’s geometry and binding surface to make FQ–CD interactions strong enough to potentially affect its pharmacokinetics and justify development of a new sustained-release drug formulation (dissociation constant decreased from 5 * 10−3 M to 10−5 M). 3D molecular modeling with energy optimization supports the findings and conclusions made on the basis of ATR-FTIR data analysis and explains the observed difference in dissociation constants.