Multiwavelength UV-metric and pH-metric determination of the multiple dissociation constants of the lesinurad.

Potentiometric and spectrophotometric pH-titrations of the lesinurad for three consecutive dissociation constants determination were compared. Lesinurad is a selective inhibitor of uric acid reabsorption as part of a combination of medicines to treat high levels of uric acid in blood, also called hyperuricemia. Nonlinear regression of the pH-spectra with REACTLAB and SQUAD84 and of the pH-titration curve with ESAB determined three multiple close dissociation constants. The protonation scheme of lesinurad was suggested. A sparingly soluble anion L of lesinurad was protonated to the still soluble species LH, LH and LH in pure water. Three consecutive thermodynamic dissociation constants were estimated pK = 2.09, pK = 4.25, pK = 6.58 at 25 °C and pK = 1.96, pK = 4.16, pK = 6.32 at 37 °C by UV-metric spectra analysis. The graph of molar absorption coefficients shows that the spectrum of species LH and LH vary in colour, while protonation of chromophore LH to LH has less influence on chromophores in the lesinurad molecule. Three multiple thermodynamic dissociation constants of 1 × 10 M lesinurad were determined by the pH-metric analysis pK = 2.39, pK = 3.47, pK = 6.17 at 25 °C and pK = 2.08, pK = 3.29, pK = 6.03 at 37 °C. The values of enthalpy ΔH(pK) = 19.19 kJ mol, ΔH(pK) = 13.29 kJ mol, ΔH(pK) = 38.39 kJ mol, show the dissociation process is endothermic. The positive values of ΔG(pK) = 11.93 kJ mol, ΔG(pK) = 24.26 kJ mol, ΔG(pK) = 37.56 kJ mol at 25 °C indicate that the dissociation process of pK is not spontaneous, which was confirmed by its value of entropy ΔS(pK) = 24.37 J mol, ΔS(pK) = -36.79 J mol, ΔS(pK) = 2.79 J mol. Three macro-dissociation constants of lesinurad and protonation locations were predicted by MARVIN and ACD/Percepta.