Speciation studies of a bisphosphonate drug. New thermodynamic insights of sodium alendronate with Ca2+ and Mg2+ in NaCl aqueous solution (0.10 ≤ I/mol kg−1 ≤ 1.02)

The thermodynamics of interaction of a second-generation bisphosphonate drug, 4-amino-1-hydroxy-1-phosphonobutyl phosphonic acid mono sodium (sodium alendronate) with H⁺, Ca²⁺ and Mg²⁺ has been investigated. The protonation constants were determined in NaCl and (C₂H₅)₄NI aqueous solutions at different ionic strengths (0.10 ≤ I/mol kg⁻¹(H₂O) ≤ 1.02) and temperatures (288.15 ≤ T/K ≤ 310.15) by using the ISE-[H⁺] potentiometry. The differences of the log K_i^H in the two ionic media were interpreted in terms of activity coefficient variations and formation of Na⁺ weak complexes. The interactions with Mg²⁺ and Ca²⁺ were studied in NaCl_(aq) (0.10 ≤ I/ mol kg⁻¹ (H₂O) ≤ 1.02) and T = 298.15 K. Two different speciation models were obtained; Ca²⁺: CaH₂L, CaHL, CaL. Mg²⁺: MgH₃L, MgH₂L, MgHL, MgL. The dependence of the thermodynamic parameters on the ionic strength and temperature was modelled by means of the Specific Ion Interaction Theory (SIT) and a modified Debye-Hückel equation including a term for the dependence on T/K. The first two protonation equilibria are exothermic, and the reactions are not favoured by an increase of the temperature whilst the last two are endothermic. The entropic contribution resulted to be the driving force of the reactions. The sequestering ability of alendronate towards the two metal cations was quantified by means of the pL_0.5 parameter calculated at different pHs and ionic strengths. It resulted that alendronate has a higher sequestration toward Mg²⁺ with respect to Ca²⁺. A simulation of the alendronate behaviour in human blood plasma was carried out.