Potentiometric study of the encapsulation of ketoprophen by hydroxypropyl-beta-cyclodextrin. Temperature, solvent, and salt effects

The molecular encapsulation of ketoprophen (KET), a nonsteroidal antiinflammatory drug of the family of the arylpropionic acids, by the hydroxypropyl-beta-cyclodextrin (HPBCD) has been studied from pH potentiometric measurements. For that purpose, a highly accurate and fully computerized potentiometric technique is presented, together with a model developed by us to obtain simultaneously, from pH data, the dissociation constant K-a of the pure drug (which is a weak acid), and the association constants of the inclusion complexes formed by the cyclodextrin and both the nonionized (HKET) and ionized (KET-) forms of the drug, without the necessity of working with buffered solutions. The physicochemical characterization of the system HPBCD + KET has been carried out in three sections: (i) the pH of drugs solutions has been measured as a function of cyclodextrin concentration at different temperatures, ranging from 15 to 40 degrees C. From the dependency of the association constants with temperature (van't Hoff analysis), the inclusion complexes formed by HKET or KET-and the HPBCD were found to be enthalpy driven, with a favorable enthalpic term dominant over an unfavorable entropic term. This pattern could be revealing the contribution of van der Waals interactions, hydrophobic effect, and solvent reorganization as the main driven forces promoting the interaction. (ii) Solvent effects have been 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-drug interaction (CD = cyclodextrin), at 25 degrees C. A clear influence of the solvent polarity on the affinity of binding has been 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 limit conditions to have association. (iii) From the characterization of the HPBCD + KET system in the presence of constant amounts of 2:1 electrolytes, such as CaCl2, K2SO4, and ZnCl2 at 25 degrees C, neither an influence of the ionic strength of the medium nor the possible mediation of divalent cations (Ca2+, calcium effect) on the CD-drug interaction have been found.