Method of UV-Metric and pH-Metric Determination of Dissociation Constants of Ionizable Drugs: Valsartan

Valsartan is used for treating high blood pressure, congestive heart failure and to increase the chances of living longer after a heart attack and to reduce the mortality rate for people with left ventricular dysfunction following a heart attack. Regression analysis of the pH-spectra with REACTLAB and of the pH-titration curve with ESAB determined two close consecutive dissociation constants. MARVIN and ACD/Percepta predicted two protonation sites. In water a soluble anion L 2− forms two sparingly soluble species LH − , LH 2 . Although adjusted pH less affected the spectral changes in the chromophore, p K a 1 T = 3.70 ± 0.12, p K a 2 T = 4.82 ± 0.08 at 25 °C and p K a 1 T = 3.44 ± 0.08, p K a 2 T = 4.67 ± 0.02 at 37 °C in an aqueous phosphate buffer were determined. By regression analysis of potentiometric pH-titration curves and p K a 1 T = 3.51 ± 0.01, p K a 2 T = 4.63 ± 0.01, at 25 °C and p K a 1 T = 3.44 ± 0.03, p K a 2 T = 4.51 ± 0.03 at 37 °C in an aqueous medium were estimated. Positive enthalpy values Δ H 0 (p K a 1 ) = 10.33 kJ·mol −1 , Δ H 0 (p K a 2 ) = 17.70 kJ·mol −1 showed that the dissociation process was endothermic. The standard state Gibbs energy changes are Δ G 0 (p K a 1 ) = 20.03 kJ·mol −1 , Δ G 0 (p K a 2 ) = 26.43 kJ·mol −1 at 25 °C and the Δ S 0 at 25 °C and 37 °C are (Δ S 0 (p K a 1 ) = − 32.56 J·K −1 ·mol −1 , Δ S 0 (p K a 2 ) = − 29.26 J·K −1 ·mol −1 at 25 °C and Δ S 0 (p K a 1 ) = − 30.01 J·K −1 ·mol −1 , Δ S 0 (p K a 2 ) = − 25.92 J·K −1 ·mol −1 at 37 °C. Graphic Abstract