LogP and LogD, the key to understanding Lipophilicity

Definition of lipophilicity

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:

Definition of logP

logP refers to the logarithm of the Partition Coefficient, P, which is defined as the ratio of concentration of Neutral species in octanol divided the concentration of neutral species in water

Definition of logD

logD refers to the logarithm of the Distribution Coefficient, D, which is defined as the ratio of concentrations of ALL species, neutral & ionized, in octanol divided by the concentration of all species in water

Lipophilicity Profiles (logD vs pH)

A plot of logD vs pH illustrates how the overall lipophilicity of a molecule varies with pH.

The above plot shows the logD vs pH profiles for six different drugs. Diclofenac, Phenobarbital and Nifuroxime are acids, Desipramine, Diphenhydramine and Triamterene are bases. 

All six drugs have a very similar logD value at pH7.4, but the plot illustrates how their lipophilicity varies greatly with pH due to the different pKa values, logP values and acid/base character. The importance of understanding the variation in logD with pH over the physiological pH range is clear.

Our SiriusT3 instrument can measure logP values of ionizable compounds and can produce a logD vs. pH profile in just 2 hours, using less than 1mg of drug material.