###### Abstract
Solubility is another parameter that is modulated by lipophilicity in such a way that solubility can be calculated by an empirical formula that correlates melting point and log P with solubility [2]. In general, compounds with lower log P tend to be water-soluble. In addition to solubility, other physical parameters are related to lipophilicity, such as the flexibility of a molecule based on the presence of rotatable bonds and on the ratio of sp\({}^{3}\) carbons, the presence of polar groups, and the presence of intramolecular hydrogen bonding [8]. Drug distribution is also affected by lipophilicity. Lipophilic compounds have a large volume of distribution due to affinity to lipophilic tissues such as adipose tissue [2]. Nevertheless, lipophilicity also indirectly influences the distribution of drugs through plasma protein binding, as lipophilic compounds tend to have high plasma protein binding [9; 10]. The facility to cross the compact and protected blood-brain barrier (BBB) is also dependent on lipophilicity [6]. In general, small and highly lipophilic compounds can penetrate easier across the BBB, and increasing lipophilicity is likely to enhance BBB permeation [11]. However, increasing lipophilicity can also be associated with higher binding affinity to efflux pumps, such as P-glycoprotein [2]. Lipophilicity is also related to metabolic rate as in vivo metabolism often converts lipophilic drugs into more polar metabolites to facilitate their clearance. In addition, lipophilic compounds are more likely to be toxic [12]. One example is the interaction with the human ether-a-go-go related gene (hERG), especially for positively charged lipophilic compounds, which can cause increases in the cardiac QT interval [13]. Despite being mostly recognized for its role in pharmacokinetics, lipophilicity also plays a crucial role in the pharmacodynamic behaviour of a drug. Lipophilicity contributes to understanding ligand-target interactions, considering the different forces that govern the intermolecular interactions involved in biochemical and pharmacological processes. In fact, lipophilicity is a parameter considered in numerous quantitative structure-activity relationship studies [5; 14]. The presence of lipophilic moiety offers lead compounds with a higher probability of having anchors on protein targets with large and hydrophobic binding sites [15]. However, increasing lipophilicity to the pursuit of potency through increasing lipophilicity across the drug development comes with costs. One is the trend, known as'molecular obesity', for seeking huge and lipophilic molecules that, despite being highly potent, do not have a suitable pharmacokinetic profile [7]. Another risk is target promiscuity. Compounds that achieve their potency through the increase of lipophilicity are more likely to be less selective, increasing the risk of off-target interactions and undesirable toxicity [16]. In a nutshell, lipophilicity is probably the single most informative physicochemical parameter in modern drug discovery. Therefore, drug design seeks to control this property within a defined optimal range [15]. To fulfil this aim, suitable methods for the determination of lipophilicity are required mainly in the early steps of the drug discovery pipeline.