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LogP and LogD

LogP and LogD, the key to understanding Lipophilicity

Sirius pH-metric methods can measure logP values of ionizable compounds between -1 and +7, which is the widest range of any logP measurement method. Unlike indirect chromatographic methods, they study partition directly between water and octanol, dodecane or other partition solvents. They do not suffer from problems of micro-emulsion formation and lack of dynamic range that afflict shake-flask methods. Note that accurate pKa values are required for pH-metric logP measurement.

Definition of lipophilicity

Lipophilicity characterises the affinity of molecules for lipid-like structures.

The definition agreed by IUPAC for the term "lipophilic" is:

lipophilic/ adj., -ity n.: Having an affinity for fat and high lipid solubility: a physicochemical property which describes a partitioning equilibrium of solute molecules between water and an immiscible organic solvent, favouring the latter, and which correlates with bioaccumulation.

Lipophilicity is generally expressed by the partition between water and a water-immiscible solvent, most commonly 1-Octanol in drug discovery and development.

If the molecule is ionisable, then the pH of the aqueous phase will influence the concentrations of the ionised and neutral forms of the molecule. The term logD is used to reflect the pH dependent lipophilicity of a drug:

Uses of lipophilicity

Applications of lipophilicity can be found across the pharmaceutical industry, in environmental applications, toxicology and any other field involving a potential biological effect on a living organism. It has been widely used in QSAR (Quantitative Structure-Activity Relationships), in drug and pesticide design, as well as in toxicology studies.

During drug discovery, in the pharmaceutical industry. When creating a new molecule with potential biological activity, knowledge of its lipophilicity helps to build an understanding of its ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) profile.

Lipophilicity knowledge is essential to understanding:

> Oral absorption

> Serum albumin binding

> Permeability

> CNS penetration

> Soil adsorption coefficients

> Bioconcentration factors in aquatic organisms

> Estimation of solubility - semi-empirical equations are often used to correlate logS and logP, along with other parameters.

> Pesticides occurrence in the environment

> According to EU regulations, lipophilicity expressed as logP(o/w) is a required value for any new commercially available chemical.

Applications in the pharmaceutical industry tend to correlate lipophilicity with drug absorption in-vivo. In many cases, a good correlation is obtained if octanol is used for the partition measurements, and the logD values measured at pH 5 - 7.4 (physiological pH values) provide more relevant information compared with logP.

Octanol-water partition coefficients are established as a significant physical property correlated with biological activity. An important reason is the ability of octanol to form clusters in an aqueous environment, thus providing a model for the partition into a real biological membrane. Octanol has an amphiprotic character, and as well as displaying lipophilic interaction it can form hydrogen bonds. It can therefore interact with neutral or ionised molecules, as well as with ion-pairs.

The extent to which the octanol model is the right choice to model human, animal or plant membranes, as well as environmental distribution of toxins, still has to be established. Nevertheless, a very large number of correlations between the logP value and the biological activity have been reported during the last 50 years.

Although octanol is commonly used in lipophilicity studies, the partition in other solvents is sometimes a better model for the in-vivo process. For example, it is known that hydrogen bonding plays little role in transport across the blood brain barrier, which is better modelled by alkane-water systems. Many alkanes have been used, including hexane, cyclohexane, heptane, isooctane, dodecane and hexadecane. Other investigated systems include chloroform-water (H-donor) and di-n-butylether (H-acceptor).

The main reasons for using octanol-water for lipophilicity estimations are:

> large database of experimental data;

> octanol has low vapour pressure at room temperature, therefore is suitable for different experimental methods;

> octanol has low UV absorption, therefore does not interfere in the measurement of solute concentration;

> octanol retains some of the hydrogen-bonding ability of water and is able to dissolve a significant amount of water;

> there are many methods available that reasonably model the partition in the octanol-water system

> there are many correlations between the logP value of a compound and its and biological activity, therefore it is reasonable to assume that compounds with certain logP values will be absorbed in-vivo.