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 parti tion coefficients (P-o/w) of 23 diuretic drugs. The measured P-o/w values r anged 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 value s were strongly depending on the aqueous-phase pH. A theoretical model link ing these values with the pH was derived for four cases: (i) molecular acid -anionic base, (ii) cationic acid-molecular base, (iii) biprotic systems wi th two acidic or basic groups showing the same charge sign, and (iv) biprot ic systems with ionizable groups showing different charges with special att ention to the amino acid case, In each case, hypothetical compounds are gra phically studied through log P-o/w vs pH curves. The apparent P-o/w coeffic ients of the diuretics were determined at pH 2.58, 5.86, and 7.39 using 0.0 1 M ammonium phosphate buffers. The results were analyzed using the theoret ical model. The P-o/w coefficients of the molecular forms agreed with the l iterature 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.