Mechanistic insight into cyclodextrin solubilization in aquoline: thermodynamics, structure, and molecular interactions

The development of new green solvent systems capable of enhancing cyclodextrin (CD) solubility is of primary importance in CD research. This need is particularly relevant for overcoming the poor aqueous solubility of native CDs, notably β-CD, while preserving their host–guest encapsulation ability. In this framework, several approaches have been investigated, including the use of Deep Eutectic Solvents (DESs)—a new class of promising green media—as well as compounds exhibiting hydrotropic behaviour. This work presents a comprehensive investigation into the solubility behaviour of the three native CDs (α-, β-, and γ-CD) in different aqueous choline chloride (ChCl) mixtures at various water:ChCl molar ratios ( n = 2, 3, 4, 6 and 10). At n = 4, corresponding to a deep eutectic mixture (aquoline) Mangiacapre et al. (2023) [ 1 ], all CDs exhibit a maximum in solubility, exceeding in all cases values obtained from pure water. Thermodynamic analysis reveals that, in all the cases explored, the solubilization mechanism is endothermic; therefore, solubility increases with increasing temperature. Small-Angle X-ray Scattering (SAXS) experiments confirm the absence of CDs aggregation, even at concentrations approaching the solubility limits. Molecular Dynamics (MD) simulations provide insights into the solvation mechanism of β-CD in the mixture with n = 4, highlighting a cooperative network of hydrogen bonding, electrostatic, and dispersive interactions between the CD and the surrounding solvent species, with ions (Cl − + Ch) and water being comparably distributed around the β-CD. These findings indicate that aquoline provides a favourable solvation environment that enhances β-CD solubility while preventing flocculation, with ChCl likely exerting a hydrotropic effect. • Aquoline (ChCl:water 1:4) maximizes α-, β- and γ-CD solubilities vs water. • CD solubilization is endothermic; solubility rises with temperature in aquoline. • SAXS shows no cyclodextrin aggregation near solubility limits in aquoline. • MD shows ions and water evenly surround β-CD, prompting for hydrotropic ChCl.