Termodynamics (solubility and protonation constants) of Risedronic acid in different media and temperatures (283.15 K to 318.15 K)

Risedronic acid (1-hydroxy-1-phosphono-2-pyridin-3-yl-ethyl phosphonic acid) belongs to the class of ligands called Bisphosphonates (BPs), which are the most important drugs used to treat bone-resorption diseases. The mechanism of action consists in the inhibition of the enzyme farnesyl diphosphate synthase, preventing osteoclastic bone resorption. Risedronic acid is generally indicated for the prevention or treatment of postmenopausal and glucocorticoid-induced osteoporosis and Paget's disease. In the last decades there is a great interest for the development of methods to understand the nature of the bisphosphonate–bone mineral recognition and binding mechanisms, therefore thermodynamic data are necessary to enable the prediction of important technological and pharmacological equilibria. In this contribution, potentiometric measurements were carried out to study the protonation constants of risedronic acid in NaCl(aq), (CH3)4NCl(aq) and (C2H5)4NI(aq) at different ionic strengths and temperatures (283.15 ≤ T / K ≤ 318.15). In the same conditions, solubility measurements were also performed. Calorimetric measurements were done to determine the protonation enthalpy values at different ionic strengths and 298.15 K. It was found that the protonation constants in NaCl(aq) are lower than in the two tetraalkylammonium salts, and the medium effect was interpreted using different thermodynamic models [Debye-Hückel type and SIT (Specific ion Interaction Theory)], in terms of variation of the activity coefficients with ionic strength or formation of weak complexes between risedronate and the ions of the supporting electrolytes. The total solubility of risedronate is higher in NaCl(aq) than the other two ionic media and, in all cases, increases with increasing temperature. Setschenow coefficients of neutral species were also computed in all the ionic media. Generally, the proton binding process resulted endothermic and the diving force is entropic in nature. Finally, data in this work were critically compared with literature findings.