Thermodynamics of interaction between risedronic acid and metal cations: investigations in solution and in solid state

Risedronic acid (see Figure 1) belongs to the class of biphosphonates (BP), widely used in the medical field to treat bone disorders. Bisphosphonates (BPs, e.g., alendronate, risedronate, and ibandronate) help to maintain bone mass, to inhibit osteoclast-mediated bone resorption, and to reduce the risk of both vertebral and non-vertebral fractures. The clinical efficacy of BPs is mainly based on two key properties: their capacity to strongly bind hydroxyapatite crystals of bone, and their inhibitory effects on osteoclast precursors and mature osteoclasts. Interaction of risedronate with metal cations is poorly investigated. Qualitatively, it is indicated that adsorption of risedronate is inhibited when the drug is taken with mineral water containing high levels of calcium or magnesium, but chemico-physical results are missing. In this work, the interaction of risedronate with Ca2+, Cu2+, Pb2+ and Zn2+ is investigated by means of potentiometric and calorimetric measurements to determine thermodynamic parameters (ΔG, ΔH and TΔS). The most important species resulted to be the M2L and variously protonated MHiL (with i from 0 to 2) depending on the specific metal cation considered. During all the measurements, the formation of a sparingly soluble species has been noted starting from very acidic pH values (~3.5). Thus, four solid samples have been properly prepared and characterized by means of a combination of spectroscopic techniques (μ-XRF, XRD and Raman) and thermal analysis (TG-DTA). In addition, the solubility of these compounds has also been determined by the shake-flask method followed by differential pulse-anodic stripping voltammetry at different NaCl concentrations, to determine Setschenow and activity coefficients. Preliminary results show that the solubility of lead and copper risedronate increases with chloride concentration, probably due to the formation of chloro complexes with Pb2+ and Cu2+. The combination of several analysis suggests the following conclusions:  the insoluble species seems to be M2BP;  the role of water is still under question;  the coordination seems to involve only the phosphonic groups, rather than amino one.