LogP
LogP, also known as the logarithm of the octanol-water partition coefficient, is a fundamental physicochemical parameter that quantifies the lipophilicity of a chemical compound, defined as \log_{10} P, where P is the equilibrium ratio of the compound's concentrations in the immiscible octanol (lipophilic) and water (hydrophilic) phases.[1][2] This metric indicates a molecule's preference for partitioning into lipid-like environments over aqueous ones, making it a key descriptor for understanding solubility, membrane permeability, and biological interactions in neutral, non-ionized forms.[3][4] In medicinal chemistry and drug discovery, LogP plays a pivotal role in predicting absorption, distribution, metabolism, and excretion (ADME) properties, helping to optimize lead compounds for oral bioavailability and efficacy.[5] For instance, Lipinski's Rule of Five specifies that a LogP value exceeding 5 is associated with poor permeability and solubility, increasing the risk of failure in clinical development for orally administered drugs.[6][7] Beyond pharmaceuticals, LogP informs environmental toxicology by estimating bioaccumulation potential and persistence in ecosystems, as higher values correlate with greater partitioning into fatty tissues or sediments.[8] However, its utility is limited for ionic or highly polar compounds, where it may underestimate interactions with biological membranes.[8] LogP values are obtained experimentally through techniques like the shake-flask method, which involves equilibrating the compound between octanol and water, followed by analytical measurement of phase concentrations, or via chromatographic methods that correlate retention times to partitioning behavior.[1][4] Computational prediction dominates early-stage screening, employing fragment-based algorithms (e.g., summing contributions from molecular substructures as in CLOGP) or atom-based approaches that account for electronic and steric effects, achieving accuracies within 0.5 log units for many datasets.[3][9] Advanced machine learning models further refine these predictions by training on large empirical datasets, enhancing reliability for novel structures.[3] The foundational ideas behind LogP trace to the late 19th century, when Charles Ernest Overton and Hans Meyer independently demonstrated that the potency of anesthetics correlated with their oil-water partitioning, establishing lipophilicity as a determinant of biological activity.[5] In the 1960s, Corwin Hansch and Toshio Fujita advanced this through quantitative structure-activity relationship (QSAR) analysis, introducing substituent constants (π values) to calculate LogP from molecular structure and standardizing the octanol-water system for broader applicability.[9] By the 1970s, Albert Leo's development of the CLOGP program at Pomona College formalized computational fragment methods, supported by extensive measured datasets, solidifying LogP as an indispensable tool in rational drug design and chemical risk assessment.[9][10]Definition and Concepts
Definition of LogP
LogP, or the logarithm of the partition coefficient, is defined as the base-10 logarithm of the ratio of the equilibrium concentrations of a neutral (un-ionized) compound in the octanol and water phases, serving as a key measure of lipophilicity. Specifically, the partition coefficient P is given by P = \frac{[\text{solute}]_{\text{octanol}}}{[\text{solute}]_{\text{water}}}, where the concentrations refer to the neutral form of the solute at equilibrium in the two immiscible phases. Thus, the equation is: \text{LogP} = \log_{10} P = \log_{10} \left( \frac{[\text{solute}]_{\text{octanol}}}{[\text{solute}]_{\text{water}}} \right) This parameter is dimensionless, as it represents the logarithm of a ratio of like units (concentrations).[11][12] The concept of LogP was introduced in the 1960s by Corwin Hansch, who coined the term in the development of quantitative structure-activity relationships (QSAR) for medicinal chemistry, building on earlier partition studies to correlate chemical structure with biological activity. In seminal work with T. Fujita, Hansch formalized LogP as a hydrophobic substituent constant (π) relative to a parent compound, enabling predictive modeling of drug potency.[13][14] In interpretation, LogP quantifies a compound's affinity for non-polar versus polar environments, with positive values indicating lipophilic preference for the octanol phase and negative values denoting hydrophilic solubility in water. Typical LogP values span from approximately -3 for highly hydrophilic substances to +10 for extremely lipophilic ones, providing a scale for assessing molecular partitioning behavior.[1][15]Octanol-Water Partition Coefficient
The octanol-water partition coefficient, denoted as LogP or log K_{ow}, utilizes n-octanol as the organic phase due to its amphiphilic nature, which includes a polar hydroxyl group capable of hydrogen bonding and a long nonpolar alkyl chain that provides hydrophobic character, thereby mimicking key features of biological membranes.[16] Water serves as the immiscible aqueous phase, representing the hydrophilic environment in biological systems. This two-phase system allows for the assessment of a solute's distribution based on its lipophilicity, with n-octanol selected over other alcohols for its low water solubility and ability to dissolve a wide range of organic compounds effectively.[16] The measurement involves the equilibrium distribution of a neutral solute between the mutually saturated n-octanol and water phases at 25°C and near infinite dilution to minimize solute-solute interactions and ensure ideality.[17] The process assumes no chemical reactions, degradation, or adsorption to the container walls, focusing purely on passive partitioning driven by solubility differences. This standardization is outlined in OECD Test Guideline 107, which specifies the shake-flask method at 25°C with low ionic strength (typically using pure water without added electrolytes unless justified for solubility). The octanol phase simulates the lipid bilayer structure of cell membranes, where the hydrophobic tail region corresponds to the alkyl chain and the polar headgroup interactions to the hydroxyl functionality, making LogP a reliable proxy for passive membrane permeability and overall lipophilicity in biological contexts. As originally proposed by Hansch and Leo, this system correlates well with transport properties across phospholipid barriers. To illustrate the range of LogP values, the following table provides examples for representative compounds, highlighting how nonpolar substances favor the octanol phase while polar ones prefer water:| Compound | LogP | Source |
|---|---|---|
| Benzene | 2.13 | Hansch and Leo (1979) |
| Ethanol | -0.31 | NIST Compilation (2009)[18] |