Cyclodextrin binding constants as a function of pH for compounds with multiple pKa values

Complex formation between cyclodextrins and ionizable guest molecules depends on pH. In general, the neutral species of an ionizable guest molecule has the highest affinity for the cyclodextrin cavity, but ionized species will also be able to form complexes with cyclodextrins. This work presents a theoretical expression for the relationship between the stability constant and pH for interaction between neutral cyclodextrins and ionizable guest molecules with multiple pKa values. Input parameters for the theoretical expression are pKa values of the guest molecule and stability constants for the complex at specific pH values. The pH profile of the stability constant for a complex depends on the acid-base properties of the guest and the closeness of the pKa values, and examples of pH profiles for polyprotic acids, bases and amphoteric guests are shown. Empirical data sets from the literature were used to confirm the accuracy of the theoretical expression, and Monte Carlo simulations were used to validate that the theoretical expression yield a good fit to empirical data. Lastly, an experimental protocol was suggested, and a freely available graphical user interface was presented to facilitate easy use of the theoretical expression.