Physicochemical profiling of Sartans: detailed study of ionisation constants and distribution coefficients

A detailed investigation of the ionisation and lipophilicity profiles of selected sartans (Valsartan, Losartan, Irbesartan, Candesartan, Candesartan cilexetil), a class of antihypertensives commonly used in therapy, is presented. The pKa macroconstants were determined by integrated potentiometry, capillary electrophoresis and UV spectrophotometry techniques. The measured pKa macroconstants were connected with the ionisable centres present in each molecule with the aid of model compounds. Potentiometric titrations with the GLpKa apparatus were performed to determine the distribution profile (log D versus pH) of Valsartan, while the shake-flask procedure was used to characterise the distribution profile of the other compounds. Valsartan showed a lipophilicity profile consistent with the presence of two acidic centres. Losartan and Irbesartan, containing one acidic centre and one basic centre, displayed the classical bell-shaped profile of ordinary ampholytes. By contrast, a more complex situation emerged in the case of Candesartan, due to the large number of ionisation equilibria involved. The low solubility of Candesartan cilexetil, together with the ease of hydrolysis of the ester moiety, prevented a successful investigation of its ionisation and lipophilicity profiles.