Thermodynamic study of the interaction between calcium and zoledronic acid by calorimetry

Bisphosphonates (BPs) are widely used to treat calcium disorders because of their structural and functional similarities with the organic pyrophosphates present in plasma and urine. BPs are well known for their strong interactions with calcium, and they have been shown to bind to hydroxyapatite or bone; however, no model exists for studying in greater detail how BPs and particularly amino-bisphosphonates (N-BPs) such as zolendronate (Zol) bind to free calcium. The aim of this work was to determine the effect of pH on Ca2+/Zol complex formation using isothermal titration calorimetry (ITC) because these effects might have important implications for the future development of a solid dosage form. In this study, using a predictive model, we can observe, the existence of three Ca2+/Zol complexes. Knowledge of the binding constant for each complex is helpful for predicting the predominance of the different species at different Ca2+/Zol ratios. Binding is due to ionic interaction between Ca2+ and the negative charges formed by dissociated Zol as a function of the pKa. Ca2+ fixation induces a strong rearrangement of the surrounding water molecules and causes proton release or uptake. The pH-dependent affinity of calcium for each site based on the model used in this work is proposed in detail, which might facilitate the development of new bisphosphonates and enable further elucidation of their mode of action. (C) 2016 Elsevier Ltd. All rights reserved.