A simplified high-pressure liquid chromatography method for determining lipophilicity for structure-activity relationships

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Abstract
A highly deactivated octadecyl-bonded silica column and a mobile phase consisting of a water-methanol mixture in the range of blood pH and ionic strength are used to correlate log k'' with biological activity for a series of sulfonamides and barbiturates. The results were compared to literature methods by using retention volume (VR) and retention indexes (I). For the 9 sulfonamides tested, log VR and log k'' were used with and without correction for ionization. For each biological end point (protein binding and minimum inhibitor concentration against Eschericia coli from 2 sources) and each independent variable (log k'' and log VR) the residual standard derviation for the regression was determined. The standard derviations were compared in an F test for each of 12 relevant regressions. Log k'' was statistically superior in 4 cases, while log VR was superior in one case. Overall, the methods were statistically indistinguishable. Log k'' values and I values for 15 barbiturates were regressed against 3 biological end points [hypnotic activity (the minimum effective dose in rabbits), inhibition of Arbacia egg cell division and inhibition of rat brain respiration]. Standard deviations were compared by an F test, and the 2 methods were indistinguishable as far as the goodness of biological correlations are concerned. Procedures for controlling the column''s activity are presented. Choices for an appropriate mobile phase are discussed, and a method of calculating pH and ionic strength in a methanol-aqueous mobile phase is presented.