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

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.

RP-18 TLC Chromatographic and Computational Study of Skin Permeability of Steroids

“…However, the solutes from the so-called “Anderson dataset” [ 40 ] form a separate subgroup, parallel to the correlation line obtained for compounds studied by other authors [ 1 , 2 ] ( Figure 1 and Figure 2 ). Skin permeability models developed earlier (Equation (1) [ 36 ]) or in this study (Equations (4), (7), (9) and (10)) were found to predict log K p of steroids fairly well (especially Equations (1) and (7)) and have the benefit of being based only on calculated descriptors (Equations (1), (9) and (10)). It was established that the applicability of equations proposed in this study ((7), (9) and (10)) extend beyond steroid compounds.…”

“…Equation (1), developed and validated in our earlier research [ 36 ]: log K p (1) = −1.39 (±0.18) − 0.35 (±0.03) ( N + O ) + 0.15 (±0.04) log D − 0.23 (±0.06) HD ( n = 60, R 2 = 0.83, R 2 adj . = 0.82, F = 92.3, p < 0.01, s e = 0.44) …”

“…Experimental skin permeability data exist only for a part of the studied group and they form three mutually incompatible steroid datasets [ 1 , 4 ], with experimental values given by Anderson et al [ 40 ] distinctively higher than expected, as already reported by Abraham et al [ 4 ]. Due to the limited availability of consistent experimental data for the studied solutes, the reference skin permeability coefficients log K p were calculated using three methods: log K p EPI based on log P ow and M w as proposed by Potts and Guy [ 10 ]; Equation (1) developed earlier [ 36 ] and based on ( N + O ), HD and log D ; and by preADMET software [ 38 ]. It was established that Equation (1), proposed for structurally unrelated, nonsteroid drugs was also applicable to the group of studied steroids, as shown using a subset of compounds whose experimental log K p data were available.…”

“…The objective of this study was to examine the relationships between the skin permeability coefficient K p and calculated and RP-18 TLC-chromatographic descriptors for a group of steroid drugs acting upon different therapeutic targets. Descriptors derived from the RP-18 thin layer chromatographic system used in this study have appeared in previous works on blood-brain barrier (BBB) permeability [ 33 , 34 , 35 ] and skin permeation [ 36 ] and, according to [ 37 ], in some instances the RP-18 TLC retention parameters are better predictors of biological activity than the RP-18 HPLC data.…”

IAM Chromatographic Models of Skin Permeation

“…However, the predictions made using Pott’s model are sufficiently good for the majority of drug-like compounds [ 9 , 10 ], thus this model is a popular tool in drugs’ ADMET studies and calculations based on it are offered by some popular ADMET prediction software packages [ 11 , 12 ]. Other proposed theoretical K p models are based on the descriptors, such as the melting point, McGowan’s characteristic volume, Abraham’s solvation parameters or H-bonding properties (total H-bond count, H-bond acceptor count, and H-bond donor count), and total nitrogen and oxygen atom count [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. QSAR studies of skin permeation published to date prove that transdermal absorption is a complex property and there are several factors contributing to it [ 4 , 7 , 24 , 25 , 26 , 27 , 28 , 29 ].…”