Application of RP-18 TLC Retention Data to the Prediction of the Transdermal Absorption of Drugs

Several chromatographic parameters (R(M)(0) and S obtained from RP-18 TLC with methanol—pH 7.4 phosphate buffer mobile phases by extrapolation to zero concentration of methanol; R(f) and R(M) obtained from RP-18 TLC with acetonitrile—pH 7.4 phosphate buffer 70:30 v/v as a mobile phase) and calculated molecular descriptors (molecular weight—M(W); molar volume—V(M); polar surface area—PSA; total count of nitrogen and oxygen atoms—(N+O); H-bond donor count—HD; H-bond acceptor count—HA; distribution coefficient—log D; total energy—E(T); binding energy—E(b); hydration energy—E(h); energy of the highest occupied molecular orbital—E(HOMO); energy of the lowest unoccupied orbital—E(LUMO); electronic energy—E(e); surface area—S(a); octanol-water partition coefficient—log P; dipole moment—DM; refractivity—R, polarizability—α) and their combinations (R(f)/PSA, R(M)/M(W), R(M)/V(M)) were tested in order to generate useful models of solutes’ skin permeability coefficient log K(p). It was established that neither R(M)(0) nor S obtained in the conditions used in this study is a good predictor of the skin permeability coefficient. The chromatographic parameters R(f) and R(f)/PSA were also unsuitable for this purpose. A simple and potentially useful, purely computational model based on (N+O), log D and HD as independent variables and accounting for ca. 83% of total variability was obtained. The evaluation of parameters derived from R(M) (R(M), R(M)/M(W), R(M)/V(M)) as independent variables in log K(p) models proved that R(M)/V(M) is the most suitable descriptor belonging to this group. In a search for a reliable log K(p) model based on this descriptor two possibilities were considered: a relatively simple model based on 5 independent variables: (N+O), log D, R(M)/V(M), E(T) and E(h) and a more complex one, involving also E(b), M(W) and PSA.