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The objective of this study was to investigate drug–membrane interaction by immobilized liposome chromatography (ILC; expressed as lipophilicity index log Ks) and the comparison with lipophilicity indices obtained by liposome/H2O, octan-1-ol/H2O, and immobilized artificial membrane (IAM) systems. A set of structurally diverse monofunctional compounds and drugs (nonsteroidal anti-inflammatory drugs and β-blockers) were selected in this study. This set of solutes consists of basic or acidic functionalities which are positively or negatively charged at physiological pH 7.4. No correlation was found between log Ks from ILC and lipophilicity indices from any of the other membrane model systems for the whole set of compounds. For structurally related compounds, significant correlations could be established between log Ks from ILC and lipophilicity indices from IAM chromatography and octan-1-ol/H2O. However, ILC and liposome/H2O systems only yield parallel partitioning information for structurally related large molecules. For hydrophilic compounds, the balance between electrostatic and hydrophobic interactions dominating drug partitioning is different in these two systems.

The retention behavior of neutral, positively charged, and negatively charged solutes on the IAM.PC.DD2 stationary phase was investigated and compared. A set of monofunctional compounds and complex drugs (steroids, nonsteroidal anti-inflammatory drugs, and β-blockers) were selected for this study, i.e., neutral solutes and solutes with acidic or basic functionalities which are positively charged or negatively charged at pH 7.0. The correlation between the retention factor log kw at pH 7.0 on the IAM.PC.DD2 stationary phase and the partition coefficient log Poct or the distribution coefficient log D7.0 showed that the retention mechanism depends on the charge state and structural characteristics of the compounds. The neutrals were least retained on the IAM.PC.DD2 stationary phase, and positively charged solutes were more retained than negatively charged ones. This implies that the retention of the charged solutes is controlled not only by lipophilicity but also by the electrostatic interaction with the phospholipid, with which positively charged solutes interact more strongly than negatively charged ones.

The mechanisms of retention of two recent stationary phases of interest in lipophilicity measurements, namely of the silica-based Discovery-RP-Amide-C16 phase and the polymer-based ODP-50-4B phase, were assessed and compared. A set of 41 model solutes and drugs with well-defined solvatochromic parameters were selected to allow a broad distribution of property spaces. The chromatographic results showed that, under the conditions of study, the lipophilicity index log kw obtained with the former stationary phase was more closely related to experimental log Poct values than was log kw obtained with the ODP-50-4B phase. Linear solvation/free-energy relationship (LSER) analyses showed that the retention mechanisms of the two stationary phases are different, retention on the Discovery-RP-Amide-C16 phase and partitioning in octan-1-ol/H2O being controlled by the same balance of intermolecular forces (Van der Waals volume Vw, H-bond acceptor basicity β, and dipolarity/polarizability π*).