Physico-chemical profiling of the 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 a 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 log K values of lisinopril (at 25.0°C and 0.15 M ionic strength) were found: log K1 = 10.75 ±0.01, log K2 = 7.13 ±0.01, log K3 = 3.13 ±0.01, log K4 = 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 were identical and assigned to the primary amino group (log K1 = log kA) and to the secondary amine basicity (log K2 = log kBA), respectively. The two carboxylates exhibited overlapping protonation characterised first by microconstants (log kDAB = 2.15 log kCAB = 3.10), revealing that the carboxylate on the proline ring has nine times greater intrinsic basicity than the carboxylate on the side chain. The distribution of protonation species (Lis2-; HLis-; H2Lis; H3Lis+; H4Lis2+) and microspecies (ABC; ABD) as a function of pH was calculated and used to interpret the pharmacokinetic and pharmacodynamic properties of lisinopril.