Potentiometric determination of pKa values of ACE inhibitors

Abstract

ACE (angiotensin-converting enzyme) inhibitors are drugs applied in the treatment of different cardiovascular disorders, primarily in the therapy of hypertension and congestive cardial insufficiency. The presence of peptide bond and free carboxyl group is a common structural feature of the ACE inhibitors. The latter group in ionized form is responsible for the interaction with a protonated amino group of the arginine residue in the cationic active enzyme site. In addition to carboxyl group, ACE inhibitors can contain some other ionizable groups such as primary and secondary amino groups and sulfhydryl group, giving them the properties of acids or ampholytes. pKa value represents an important parameter in physico-chemical characterization of pharmacologically active substances and it is of the utmost importance for the estimation of their behavior in vitro and in vivo. Knowledge of drug pKa values is significant not only for analytical procedures, but also in pharmaceutical industry in development of novel pharmaceutical dosage forms. Drug absorption, distribution, metabolism and elimination (ADME) depend on the degree of their ionization. pKa Values of ACE inhibitors published so far were mostly calculated applying computer programs and only in a few cases these values were experimentally determined (captopril, enalapril, lisinopril). This prompted us to determine pKa values of nine most frequently prescribed ACE inhibitors such as captopril, cilazapril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril and zofenopril. Determinations of pKa values were performed at 25 oC and constant ionic strength of 0.1 M (NaCl). Due to a slight fosinopril solubility its pKa value was determined in 50 % (w/w) methanol-water mixture. A computer program Hyperquad was used to derive pKa values from the data obtained by potentiometric titrations. The pKa values of carboxyl group (pKa1 and pKa2 of lisinopril and pKa1 for the other examined ACE inhibitors) ranged from 1.43 – 4.72. Since lisinopril molecule contains two carboxyl groups (terminal and proximal), pKa1 of 1.43 can be ascribed to more acidic proximal carboxyl group. The obtained pKa values of the secondary amino group (pKa2 of cilazapril, enalapril, quinapril, perindopril and ramipril, and pKa3 of lisinopril) ranged from 5.40 – 7.20. It has been observed that among the examined ACE inhibitors, only lisinopril and captopril participate in protolytic equilibria even at high pH of the media. The pKa4 of the primary amino group of lisinopril was 10.90 and pKa2 of the thiol function of captopril made 9.99. Keeping in mind that drug bioavailability is directly correlated with distribution of equilibium forms, percentage of equilibrium forms of the examined ACE inhibitors can be calculated on the basis of pKa values.