Ionization constants and distribution coefficients of phenothiazines and calcium channel antagonists determined by a pH-metric method and correlationwith calculated partition coefficients

The pH-metric technique was used to determine the ionization constants and distribution coefficients of 10 phenothiazines and five ionizable calcium c hannel antagonists. Because the studied compounds were poorly water soluble and quite lipophilic with partition coefficients in the range of 3.5 to 5. 5, organic cosolvents had to be added for the determination of the ionizati on constants to avoid precipitation of the free bases. The effect of the co solvents dioxane and methanol on the extrapolation to pure water was compar ed. For both cosolvents a very good agreement with accessible published ion ization constants was obtained, however the slope of the regression line wa s much smaller for dioxane, yielding more reliable estimates according to t he standard deviation of the extrapolated values. Thus, dioxane might be pr eferable to methanol as a cosolvent for the determination of ionization con stants of sparingly water soluble bases. Also the n-octanol/water partition coefficients were determined and compared with published data and values c alculated with the ClogP, ACD, and HINT programs. Although the obtained val ues were approximate in conformity with the published data, the calculated partition coefficients differed from the experimental ones considerably for the majority of the investigated compounds. Furthermore, the ion pair part itioning and the distribution coefficients at physiological pH 7.4 were det ermined. The pH-dependent distribution profiles showed the strong influence of the ionization constants and of the distribution of the ion pairs on th e overall distribution. This result strongly suggests that greater use shou ld be made of measured distribution coefficients in quantitative structure- activity relationship studies. The potentiometric method is a convenient wa y to determine the distribution properties of drug molecules at pH values r elevant for the biological system under investigation.