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Abstract
Several chromatographic parameters (RM0 and S obtained from RP-18 TLC with methanol—pH 7.4 phosphate buffer mobile phases by extrapolation to zero concentration of methanol; Rf and RM 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—MW; molar volume—VM; 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—ET; binding energy—Eb; hydration energy—Eh; energy of the highest occupied molecular orbital—EHOMO; energy of the lowest unoccupied orbital—ELUMO; electronic energy—Ee; surface area—Sa; octanol-water partition coefficient—log P; dipole moment—DM; refractivity—R, polarizability—α) and their combinations (Rf/PSA, RM/MW, RM/VM) were tested in order to generate useful models of solutes’ skin permeability coefficient log Kp. It was established that neither RM0 nor S obtained in the conditions used in this study is a good predictor of the skin permeability coefficient. The chromatographic parameters Rf and Rf/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 RM (RM, RM/MW, RM/VM) as independent variables in log Kp models proved that RM/VM is the most suitable descriptor belonging to this group. In a search for a reliable log Kp model based on this descriptor two possibilities were considered: a relatively simple model based on 5 independent variables: (N+O), log D, RM/VM, ET and Eh and a more complex one, involving also Eb, MW and PSA.
Highlights
The skin is the heaviest organ in the human body
This work has established that RM /VM is a useful descriptor of skin permeability derived from RP-18 thin layer chromatography
In a search for reliable log Kp models based on this descriptor two possibilities were considered: a relatively simple model based on 5 independent variables: (N+O), log D, RM /VM, ET and Eh (Equations (8) and (9))
Summary
The skin is the heaviest organ in the human body. Its average surface area is ca.2 m2 and it accounts for about 1/10 of the total bodyweight [1]. The skin is the heaviest organ in the human body. 2 m2 and it accounts for about 1/10 of the total bodyweight [1]. The skin provides a selective barrier, allowing transdermal delivery of drugs and providing protection against harmful chemicals. Applied drugs and other compounds enter the body via either the transepidermal pathway (diffusion across the skin layers) or the appendageal pathway (through hair follicles or sweat ducts), the latter being considered significantly less important [1]. In the transepidermal pathway the molecule permeates the skin either transcellularly or intercellularly and the preferred route depends on the solute’s molecular properties—small hydrophilic molecules prefer the transcellular route and lipophilic ones favor the opposite [1]. The rate of drug permeation through skin is expressed as the flux (J)—
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