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

Area of Science:

• Pharmaceutical Science
• Supramolecular Chemistry
• Physical Chemistry

Background:

• Cyclodextrins (CDs) are crucial pharmaceutical excipients for enhancing drug solubility via inclusion complex formation.
• Limited water solubility of common CDs restricts their application in drug formulations.
• Deep Eutectic Solvents (DESs) can improve CD solubility but may decrease complexation equilibrium constants.

Purpose of the Study:

• To investigate the impact and mechanism of cyclodextrin complexation within Deep Eutectic Solvents.
• To optimize drug solubility using cyclodextrins in DES media.
• To elucidate the solubilization mechanism of a model drug (methyl orange) with beta-cyclodextrin in a hydrated urea-choline chloride DES.

Main Methods:

• Solubility measurements of methyl orange (MO) in the presence of beta-cyclodextrin (CD) in a hydrated urea-choline chloride DES.
• Systematic variation of CD concentration and DES hydration levels.
• Molecular dynamics (MD) simulations to probe complex behavior and interactions.

Main Results:

• Maximal MO solubility was achieved in concentrated CD-in-DES mixtures at low hydration levels.
• Solubility enhancement is attributed to the increased solubility of CD⊃MO complexes in DES compared to water.
• MD simulations revealed self-association of CD⊃MO complexes into dimers and higher oligomers.

Conclusions:

• Cyclodextrin-mediated solubilization in DES is significantly enhanced by complex self-association, exceeding 1:1 binding stoichiometry.
• This self-association mechanism offers a new strategy for drug solubilization.
• The findings provide a foundation for designing advanced drug delivery systems utilizing CDs and DESs.