ADMET and DMPK, Vol. 1 No. 2, 2013.
Izvorni znanstveni članak
https://doi.org/10.5599/admet.1.1.3
Physico-chemical Profiling of the ACE-inhibitor Lisinopril: Acid-base Properties
Krisztina Takács-Novák
; Semmelweis University, Department of Pharmaceutical Chemistry
Katalin Deák
; Semmelweis University, Department of Pharmaceutical Chemistry
Szabolcs Béni
; Semmelweis University, Department of Pharmaceutical Chemistry
Gergely Völgyi
; Semmelweis University, Department of Pharmaceutical Chemistry
Sažetak
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 = 2.15 log = 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.
Ključne riječi
proton speciation; logK; potentiometry; NMR-pH titration
Hrčak ID:
112502
URI
Datum izdavanja:
13.4.2013.
Posjeta: 3.654 *