Evaluation of the interaction between anti-inflammatory drugs and β-cyclodextrin by calorimetric measurements

Abstract

In drug formulation, cyclodextrins (CD) are used as excipients to form non-covalent inclusion complexes by introducing all or part of the neutral drug molecule (D) into the CD’s cavity. The formation of D:CD complexes causes positive changes in the physicochemical properties of drugs such as their solubility, chemical stability, and bioavailability. This study evaluates the stability constant (𝐾B) of the complex formed between ketoprofen and a β-CD, named Caraway, under conditions close to those of the gastrointestinal tract. Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID), propionic acid derivative, ionizable and poorly soluble in water. For ionizable drugs, 𝐾B depends on the pH. For this reason, the study of the pH influence on 𝐾B is of great interest to pharmacists to know how pH influences the strength of complexation and the further release of the drug to the therapeutic target. To obtain the 𝐾B vs. pH profile, experimental 𝐾B constants have been determined by Isothermal Titration Calorimetry (ITC) using 0.15 mM ketoprofen and 2.0 mM Caraway solutions at 25 ºC, in a range of pH values from 3 to 6. ITC is one of the most interesting methods since it allows the characterization of the stability constants, stoichiometry, enthalpy, and entropy of the interaction mechanisms of cyclodextrins with drugs. The titration curves have been fitted considering a 1:1 stoichiometry model to obtain the thermodynamic parameters 𝐾𝐵,Δ𝐻 and Δ𝑆. The 𝐾B vs. pH profile has been obtained for the ketoprofen and Caraway complex. There is a good agreement between the experimental data and the values predicted by the expression of the stability constant, proving the great utility of ITC measurements in the study of D:CD interactions. The interaction between ketoprofen and Caraway under the experimental conditions varies from 8.1·102 M-1 (pH 3) to 2.6·102 M-1 (pH 6), being one order of magnitude lower as the one observed for ibuprofen, NSAID chemically and biologically similar to ketoprofen.