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

Abstract

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 L²⁻ forms two sparingly soluble species LH⁻, LH₂. Although adjusted pH less affected the spectral changes in the chromophore, ${\text{p}}K_{a1}^{\text{T}}$ = 3.70 ± 0.12, ${\text{p}}K_{a2}^{\text{T}}$ = 4.82 ± 0.08 at 25 °C and ${\text{p}}K_{a1}^{\text{T}}$ = 3.44 ± 0.08, ${\text{p}}K_{a2}^{\text{T}}$ = 4.67 ± 0.02 at 37 °C in an aqueous phosphate buffer were determined. By regression analysis of potentiometric pH-titration curves and ${\text{p}}K_{a1}^{\text{T}}$ = 3.51 ± 0.01, ${\text{p}}K_{a2}^{\text{T}}$ = 4.63 ± 0.01, at 25 °C and ${\text{p}}K_{a1}^{\text{T}}$ = 3.44 ± 0.03, ${\text{p}}K_{a2}^{\text{T}}$ = 4.51 ± 0.03 at 37 °C in an aqueous medium were estimated. Positive enthalpy values ΔH⁰(pK_a1) = 10.33 kJ·mol⁻¹, ΔH⁰(pK_a2) = 17.70 kJ·mol⁻¹ showed that the dissociation process was endothermic. The standard state Gibbs energy changes are ΔG⁰(pK_a1) = 20.03 kJ·mol⁻¹, ΔG⁰(pK_a2) = 26.43 kJ·mol⁻¹ at 25 °C and the ΔS⁰ at 25 °C and 37 °C are (ΔS⁰(pK_a1) = − 32.56 J·K⁻¹·mol⁻¹, ΔS⁰(pK_a2) = − 29.26 J·K⁻¹·mol⁻¹ at 25 °C and ΔS⁰(pK_a1) = − 30.01 J·K⁻¹·mol⁻¹, ΔS⁰(pK_a2) = − 25.92 J·K⁻¹·mol⁻¹ at 37 °C.

Graphic Abstract