Cosolvent effects on the complexation of the antifungal propiconazole nitrate with β-cyclodextrin: a combined molecular dynamics and NMR study

Understanding the effects of cosolvents in cyclodextrin (CyD)-drug complexation is essential for optimizing drug formulations, as cosolvents influence solubility, stability, and binding affinity. In this study, the inclusion complexation of propiconazole nitrate (PCZH-NO₃) with β-cyclodextrin (β-CyD) in mixed dimethyl sulfoxide (DMSO)/water solvent systems was investigated using molecular dynamics (MD) simulations and nuclear magnetic resonance (NMR) spectroscopy. MD simulations revealed that DMSO exhibits a strong affinity for the β-CyD cavity, effectively displacing water molecules even at low concentrations highlighting the competitive nature of DMSO and PCZH-NO₃ for inclusion within the β-CyD cavity. Enhanced sampling simulation techniques and potential of mean force (PMF) calculations demonstrated that complexation is most favorable at low DMSO concentrations (∼5% v/v), with a gradual decrease in binding affinity as DMSO levels increase, ultimately leading to complex destabilization at high DMSO ratios. 1H-NMR and ROESY spectra confirmed these findings, with chemical shift variations and ROESY cross-peaks indicating a weakening of host-guest interactions with increasing DMSO concentration. The results provide molecular-level insights into the role of cosolvents in modulating drug-CyD interactions, highlighting the need to tailor solvent environments to enhance the stability and efficacy of β-CyD inclusion complexes for pharmaceutical applications.