Development of a preformulation lipophilicity screen utilizing a C-18-derivatized polystyrene-divinylbenzene high-performance liquid chromatographic (HPLC) column.
Alkane/water partition coefficients have been predicted from the retention times of solutes using a C-18-derivatized polystyrene-divinylbenzene HPLC column (Act-I). Several classes of compounds, with molecular weights from 78 to 379 and partition coefficients ranging over several orders of magnitude, were included in the present study. A high correlation coefficient (0.953) was obtained from log-log plots of alkane/water partition coefficients versus capacity factor. A poor correlation was observed for octanol/water partition coefficient, presumably due to the hydrogen-bonding capability of octanol. The alkane/water correlation suggests that the system is devoid of significant specific solute-stationary phase interactions which are known to impart anomalous retention behavior to traditional reverse phase columns. Deviations of calculated alkane/water partition coefficients (and Hansch II alkane coefficients) from observed values could not be explained in terms of solute (or substituent) polarizability, dipole moment, sigma para, or pKHB values, further suggesting that specific interactions between the stationary phase and the solute are not significant. A molecular weight dependence that was independent of lipophilicity was observed. Thermodynamic and extra-thermodynamic parameters of retention were obtained in order to investigate retention mechanisms for the Act-I column. The molecular weight dependence does not appear to be due to size exclusion or entropic expulsion of the solute from the stationary phase. Hansch II substituent coefficients calculated from retention times were found to be similar for benzene and steroid derivatives. Thus, the Act-I column may be utilized as a rapid lipophilicity screen for drug candidates of similar molecular weight.
Lambert
W J
WJ
Upjohn Company, Kalamazoo, Michigan 49001.
Wright
L A
LA
Stevens
J K
JK
D000473:Alkanes; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D008055:Lipids; D008970:Molecular Weight; D000442:Octanols; D004364:Pharmaceutical Preparations / Q000032:analysis; D011137:Polystyrenes; D012015:Reference Standards; D012995:Solubility; D012997:Solvents; D013816:Thermodynamics; D014753:Vinyl Compounds
D000473:Alkanes; D008055:Lipids; D000442:Octanols; D004364:Pharmaceutical Preparations; D011137:Polystyrenes; D012997:Solvents; D014753:Vinyl Compounds; C004985:divinyl benzene