Molecular Encapsulation of Flurbiprophen and/or Ibuprophen by Hydroxypropyl-β-cyclodextrin in Aqueous Solution. Potentiometric and Molecular Modeling Studies

Thermodynamic and structural studies of the binding of the nonsteroidal antiinflammatory drugs, flurbiprophen and ibuprophen, to hydroxypropyl-β-cyclodextrin (HPBCD) have been carried out from pH potentiometric measurements, molecular mechanics, and dynamics calculations. The potentiometric study was performed by measuring the pH of aqueous solutions of the drugs as a function of cyclodextrin concentration, at several temperatures ranging from 15 to 40 °C. The dissociation constants of the drugs, as well as the binding constants of the inclusion complexes formed by HPBCD and the ionized and nonionized drugs, have been simultaneously determined at all the temperatures. The nonionic forms have shown a higher affinity to HPBCD than their ionic counterparts. A van't Hoff analysis of the determined binding constants reveals that the complexes formed by the flurbiprophen species and HPBCD are enthalpy driven, with a favorable enthalpic term and an unfavorable entropic term. Both contributions are found to be temperature independent (Δ C p ° = 0). However, in the case of ibuprophen, a dependence of the thermodynamic quantities Δ H ° and Δ S ° with temperature has been found. Thus, these association processes change from entropy driven at T ≤ 25 °C to enthalpy driven at T > 25 °C, which is due to a negative Δ C p ° value, typically found in biological associations where hydrogen-bonding interactions are present. Molecular mechanics and dynamics calculations were used to obtain structural and dynamics information of the free ligands, the receptor, and the four inclusion complexes. Flurbiprophen acid has been found to enter the HPBCD cavity leaving the carboxylic group upward, while the energetically favored inclusion of flurbiprophenate, ibuprophen acid, and ibuprophenate leaves the carboxylate or carboxylic group downward. In either case, the van der Waals contacts between the phenyl ring of the ligand and a lipophilic zone of the CD cavity, the entropy factor, and possible intermolecular hydrogen bondings are shown as the main responsible of the stability of the inclusion complexes. The estimation of the conformational stability of the free and associated ligands confirms that the carboxylic species of flurbiprophen and ibuprophen are encapsulated with a higher stability than that of their ionic counterparts, in agreement with the potentiometric results.