Thermodynamics of inclusion within cyclodextrins and structural evidence of Cu(indomethacin)2 and Zn(indomethacin)2 complexes in aqueous solutions

Abstract

Metallocomplexes of indomethacin M(IMC)₂(H₂O)₂ (M = Cu(II), Zn(II); IMC = indomethacin) are recognized as potential anti-inflammatory drugs; however, their low solubility in water decreases their bioavailability as well as their participation in drug formulation and identification of therapeutically active species. On the other hand, cyclodextrins (CDs) are recognized for their capability to increase the amounts of different guests in solutions by forming inclusion complexes. This contribution presents a study of the thermodynamics of the interaction between water-soluble M(IMC)₂ species and various CDs. The synthesis of the M(IMC)₂(H₂O)₂ compounds is also presented, as well as their structural characterization by IR spectroscopy, XRPD and EPR, which allows us to discuss the existence of mononuclear species in the solid form of the M(IMC)₂(H₂O)₂ complexes. Moreover, a UV-vis study was performed in order to confirm that the CDs increase the solubility of the metallocomplex in water. Once the increasing solubility was established, EPR studies on the Cu(II) systems demonstrated that mononuclear soluble species of the type Cu(IMC)₂ are included in the CDs in water solution. Then, isothermal titration calorimetry was performed to monitor the inclusion of M(IMC)₂ within various CDs. The obtained heat response during titration was fit to a sequential independent binding site model; in addition to the ΔH, ΔS and ΔG thermodynamic parameters, the inclusion constants of M(IMC)₂ with CDs are reported for the first time. The main results show that inclusion is exothermic, spontaneous and, depending on the metal center of the metallocomplex, will be driven either by enthalpic or entropic contributions.