Self-association of cyclodextrin inclusion complexes in a deep eutectic solvent enhances guest solubility

Cyclodextrins are widely used pharmaceutical excipients known to increase the solubility of drug compounds through formation of inclusion complexes. A prominent limitation of common cyclodextrins is their own scarce solubility in water, which renders them unsuitable for many drug formulations. Cyclodextrin solubility can be enhanced in appropriate media such as Deep Eutectic Solvents (DESs). However, DESs can also reduce the equilibrium constant for host-guest complexation, making it challenging to optimize drug solubility using cyclodextrin. To determine the impact and mechanism of cyclodextrin complexation in DES, we tracked changes in the solubility of methyl orange (MO), serving as a hardly soluble model compound, in the presence of β-cyclodextrin (CD) in hydrated urea-choline chloride DES. The highest achievable MO solubility is obtained in concentrated CD-in-DES mixtures at low hydration, resulting from the higher solubility of CD⊃MO complexes in DES compared to water as a solvent. Combining our results with molecular dynamics simulations, we provide evidence that CD⊃MO complexes self-associate into dimers and larger oligomers. This self-association of complexes greatly enhances MO solubilization by CD beyond that expected from the canonical 1:1 binding stoichiometry. This newly unraveled solubilization mechanism via cyclodextrins and its facilitation by DES should aid the design of future drug formulations.