###### Abstract  
Lipophilicity is one of many parameters involved in the biological activity of drugs, as it affects their pharmacokinetic and pharmacodynamic behavior. Generally, lipophilicity is assessed by the partition coefficient of a compound between a nonpolar phase (\(n\)-octanol) and an aqueous phase (water), expressed as P (partition coefficient) or as its decimal logarithm (Log P). The gold standard method for the experimental determination of Log P is the shake-flask method. In this context, chromatographic methods enable the direct and simple quantification of the partitioned compound between the two phases. This review discusses the use of liquid chromatography (LC) for direct and indirect determination of lipophilicity. Beyond the classical isotropic log P determination, methods for assessing anisotropic lipophilicity are also reviewed. Several examples are discussed that highlight the versatility of LC technique and current trends. The last section of this review focuses on a case study describing an experience of our group and emphasizing the dual role of LC in determining Log P.  
lipophilicity; Log P; liquid chromatography; partition coefficient; reversed-phase high-performance liquid chromatography; immobilized artificial membrane chromatography; micellar liquid chromatography 2022103390  
be determined using buffer solutions. In this case, the partitioning involving co-existing electrical species of a solute at a given pH is expressed as the distribution coefficient log D:  
\[\log\mathrm{D}^{\mathrm{pH}}=\log\sum_{i}^{n}\Bigl{(}f_{i}\times P^{i}\Bigr{)} \tag{2}\]  
where \(P^{i}\) is the partition coefficient of the electrical species \(i\) and \(f_{i}\), its molar fraction [3]. Classically, the nonaqueous phase is an isotropic organic solvent, such as \(n\)-octanol. However, artificial and natural membranes, such as liposomes and micelles (Figure 1a), have been recently used as alternative nonaqueous phases [4]. These systems are anisotropic because they establish different topographical relations between the solute and the nonaqueous phase involving different interaction forces [3]. The choice of the nonaqueous phase impacts the type of intermolecular forces encoded in the partition coefficient value. Lipophilicity is the product of all intermolecular forces involved in the partition of a solute between the two phases, assembling not only the contributions of hydrophobicity, the tendency of apolar groups or molecules to associate in an aqueous environment, but also the contributions of polarity [5]. The different intermolecular forces encoded in lipophilicity are shown in Figure 1, and they are different depending on the nonaqueous phase. While isotropic lipophilicity results from the net sum of hydrophobicity minus polarity, anisotropic lipophilicity also considers the ionic bonds [3]. Therefore, isotropic and anisotropic partition coefficients express lipophilicity on different scales. Figure 1: (**a**) Models used to determine isotropic and anisotropic lipophilicity; (**b**) forces governing intermolecular interactions between drugs and biological systems and their relationship with isotropic and anisotropic lipophilicity. Lipophilicity is a key parameter on drug discovery and design. Every single pharmacokinetic component, namely the absorption, distribution, metabolism, excretion, and toxicity (ADMET), is modulated by lipophilicity. Absorption is related to the lipophilicity because drugs typically must cross biomembrane portals to reach the sites of action. Passive permeation into or across biomembranes is modulated by the partition of the drug into the lipid membrane and from the membrane into the aqueous intracellular environment [6]. The rate-limiting step for hydrophilic compounds is the partitioning into the hydrophobic membrane layer, and for hydrophobic compounds is partitioning into the hydrophilic intracellular medium [7].