Physico-chemical Profiling of ACE-inhibitor Lisinopril: Acid-base Properties

Abstract

The acid-base chemistry of a tetraprotic, ampholyte ACE-inhibitor, lisinopril was studied by different methods. Potentiometry in aqueous medium and co-solvent technique in methanol-water mixtures as well as ¹H NMR-pH titration were applied for the highly precise measurement of protonation macroconstants. The logK values of lisinopril (at 25.0 °C and 0.15 M ionic strength) were found: logK₁ = 10.75 ± 0.01, logK₂ = 7.13 ± 0.01, logK₃ = 3.13 ± 0.01, logK₄ = 1.63 ± 0.01, calculated as an average of the best two values obtained by independent methods. NMR-pH titration was used to assign the constants to the functional groups and for the examination of site-specific, submolecular basicities of the molecule (determination of protonation microconstants). In the first two well separated protonation steps the macro- and microconstants are identical and assigned to the primary amino group (logK₁ = logk^A) and to the secondary amine basicity (logK₂ = logk^B_A), respectively. The two carboxylates exhibit overlapping protonation and characterized first here by microconstants (logk^D_AB = 2.15 logk^C_AB = 3.10) revealing that the carboxylate on proline ring has 9 times greater intrinsic basicity than the carboxylate in the side chain. The distribution of protonation species (Lis^2-; HLis^-; H₂Lis; H₃Lis⁺; H₄Lis²⁺) and microspecies (ABC; ABD) against the pH was calculated and used to interpret the pharmacokinetic and pharmacodynamic properties of lisinopril.