The molecular complexation of salicylic acid (o-hydroxybenzoic acid) by beta-cyclodextrin (beta-CD) and/or two of its most used derivatives, 2,6-di-O-methyl-beta-cyclodextrin (DIMEB) and hydroxypropyl-beta-cyclodextrin (HPBCD), was studied from pH potentiometric measurements. The role of the hydrophobic effect was evaluated by studying the influence of the presence of different constant amounts of a series of alcohols (methanol, ethanol, propanol, and butanol) on the CD:guest interaction at 25 degrees C. The study was carried out by measuring the pH of the hydroalcoholic solutions of the guest, whose concentration is kept constant, as a function of cyclodextrin concentration. The dissociation constant of salicylic acid and the binding constants of the inclusion complexes formed by the CD and both the nonionized (HSA) and ionized (SA-) forms of the guest were simultaneously determined at all alcohol concentrations by using a model previously derived by us. The carboxylic forms were found to bind the CD with higher affinities than the carboxylate partners, irrespective of the polarity of the medium and the cyclodextrin used. The ratio KCD:HSA/KCD:SA- is a constant value characteristic of the cyclodextrin, which points to the hydrophobic effect as one of the main forces involved in the association. A clear influence of the solvent polarity on the affinity of binding was found, in the sense that, as long as the medium becomes more apolar, the interaction between the drug and the cyclodextrin is weakened. A phenomenological limit association curve is proposed to define the limiting conditions for association in the presence of an alcohol as a cosolvent. Copyright 1999 Academic Press.