Molecular Insights into β-Cyclodextrin Inclusion Complexes with Salbutamol and Tulobuterol: Experimental and Computational Investigation

Abstract β-Cyclodextrin (β-CD) inclusion complexes are widely employed to improve the physicochemical properties of poorly soluble drugs; however, the molecular factors governing their stability and binding affinity remain insufficiently understood. In this study, the complexation of β-CD with two β2-agonists, salbutamol (SAL) and tulobuterol (TUL), was investigated using a combined experimental and computational approach. Isothermal titration calorimetry demonstrated that both systems form spontaneous host−guest complexes characterized by favorable thermodynamic parameters, with stronger binding affinity observed for SAL. Differential scanning calorimetry confirmed enhanced thermal stability upon complexation. To elucidate the molecular basis of these differences, density functional theory (DFT) calculations were carried out at the M06-2X/6-311+G(d,p) level in both the gas phase and an aqueous environment for the isolated drugs as well as for their β-cyclodextrin complexes. The lowest-energy conformers of SAL and TUL were found to be stabilized primarily by intramolecular O−H···N hydrogen bonds and were subsequently used to construct the initial geometries of the inclusion complexes. Two possible inclusion modes (head-first and tail-first) were examined, revealing a clear preference for the head-first orientation, particularly for SAL. Symmetry-adapted perturbation theory (SAPT) analysis showed that dispersion interactions dominate host−guest stabilization, with calculated interaction energies of approximately −33 kcal/mol for SAL and −23 kcal/mol for TUL. These results provide detailed molecular-level insight into β-cyclodextrin inclusion processes and demonstrate how subtle structural differences between drug molecules influence complex stability. The combined experimental and theoretical approach offers valuable guidance for the rational design of cyclodextrin-based drug delivery systems.