Hydrophobicity of ionizable compounds. A theoretical study and measurements of diuretic octanol-water partition coefficients by countercurrent chromatography

Countercurrent chromatography was used to determine the octanol-water partition coefficients (P-o/w) of 23 diuretic drugs. The measured P-o/w values ranged over 4 orders of magnitude from 0.05 to 550 (-1.3 < log P-o/w < +2.7). All the compounds, except spironolactone, were ionizable. The P-o/w values were strongly depending on the aqueous-phase pH. A theoretical model linking these values with the pH was derived for four cases: (i) molecular acid-anionic base, (ii) cationic acid-molecular base, (iii) biprotic systems with two acidic or basic groups showing the same charge sign, and (iv) biprotic systems with ionizable groups showing different charges with special attention to the amino acid case, In each case, hypothetical compounds are graphically studied through log P-o/w vs pH curves. The apparent P-o/w coefficients of the diuretics were determined at pH 2.58, 5.86, and 7.39 using 0.01 M ammonium phosphate buffers. The results were analyzed using the theoretical model. The P-o/w coefficients of the molecular forms agreed with the literature values. The P-o/w coefficients of the ionic forms were obtained. The model also allows establishment of the acidity constants of the studied molecules.