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)(4)NI 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-Huckel 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