Certain carboxylic acid buffers can destabilize β-cyclodextrin complexes by competitive interaction

Thirteen buffers were investigated for their effect on the binding of adamantanol to β-cyclodextrin and hydroxypropyl-β-cyclodextrin. Stability constants for the β-cyclodextrin complex ranged from 14,800 to 46,000 M^-1, and the binding enthalpies were between -23.2 and -10.4 kJ/mole. Compared to water, the stability constant in seven carboxylic acid buffers (citric acid, maleic acid, fumaric acid, succinic acid, malonic acid, malic acid and tartaric acid) was reduced. All seven buffers exhibited a competitive mechanism. Binding constants for the interaction between β-cyclodextrin and buffers ranged from 4 to 44 M^-1, and binding enthalpies were in the range -19 to -11 kJ/mole. There was a relation between the chemical structures of the buffers and their ability to bind to cyclodextrin. All seven buffers had a carbon chain longer than three carbons. Hydroxyl groups on the carbon chain decreased the binding affinity. ¹H and ROESY NMR spectroscopy supported inclusion of the citric acid into the cyclodextrin cavity, although the results for succinic and maleic acids were ambiguous. The results demonstrated that some buffers can interact with cyclodextrin complexes, and careful considerations are necessary when choosing a buffer for cyclodextrin research.

Keywords: Binding constant; Drug formulation; Equilibrium constant; Host-guest chemistry; Hydrophobic interaction; Ionization.