Lipophilicity

Lipophilicity is possibly the lost important physicochemical property of a potential

drug, it plays a role in solubility, absorption, membrane penetration, plasma
protein binding, distribution, CNS penetration and partitioning into other tissues or
organs such as the liver and has an impact on the routes of clearance. It is
important in ligand recognition, not only to the target protein but also CYP450
interactions, HERG binding, and PXR mediated enzyme induction.
LogP is a component of Lipinskis Rule of 5 a rule of thumb to predict druglikeness.
The most commonly used measure of lipophilicity is LogP, this is the partition
coefficient of a molecule between an aqueous and lipophilic phases, usually
octanol and water.

Measurement of LogP can be undertaken in a variety of ways, the most common is

the shake-flask method, which consists of dissolving some of the solute in question
in a volume of octanol and water, shaking for a period of time, then measuring the
concentration of the solute in each solvent. This can be time-consuming
particularly if there is now quick spectroscopic method to measure the
concentration of the molecule in the phases. A faster method of log P
determination makes use of high-performance liquid chromatography. The log P of
a solute can be determined by correlating its retention time with similar
compounds with known log P value.

Calculation of lipophilicity
Usually it is not practical to experimentally determine the LogP of every compound
made (and it may be of interest to calculate logP prior to synthesis) and so
calculated results are used, there are a number of software toolsavailable both
desktop and online (dont use for confidential compounds).
Many of these applications work by using a large training data-set of known values
to determine fragment contributions for sub-structures and functional groups,
however logP is not a simple additive property and correction terms are needed to
allow for proximity effects, H-bonding, electronic effects etc. as shown in the
examples below.

For unknown functional groups the programs often approximate using individual
atom contributions. Because the training sets and the algorithms vary between
applications it is very important not to combine calculated results using different
tools.
Some of the tools allow the user to extend the training set using in house
measured values, this may be critical when exploring novel functional groups.

LogD
However the majority of known drugs contain ionisable groups and are likely to be
charged at physiological pH and LogP only correctly describes the partition
coefficient of neutral (uncharged) molecules. LogD the distribution constant is a
better descriptor of the lipophilicity of a molecule. This can be determined in a
similar manner to LogP but instead of using water, the aqueous phase is adjusted
to a specific pH using a buffer. Log D is thus pH dependent, hence the one must
specify the pH at which the log D was measured. Of particular interest is the log D
at pH = 7.4 (the physiological pH of blood serum).

Applications like Marvin allow the user to calculate the logD but also display the pH
distribution profile, as shown below for Warfarin.

For compounds with a pKa close to physiological pH it may be critical to consider

what might actually be the predominant ionised form.

This can also be valuable when thinking about absorption from the different
regions of the alimentary canal where the pH ranges from 1-3 in the stomach to 78 in the ileum.
LogD is also an important component many of the off-target liabilities HERG, CYP
interactions, Transporters, have strong correlations with lipophilicity.

https://en.wikipedia.org/wiki/Partition_coefficient
http://www.cambridgemedchemconsulting.com/resources/physiochem/logD.ht
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Lipophilicity (logD, logP)

Lipophilicity tells about the compounds ability to dissolve into lipohilic (nonaqueous) solutions. Lipophilicity is needed for the compounds to permeate
through the various biological membrane. Lipophilicity is typically measured as
the compounds distribution between non-aqueous (octanol) and aqueous
(water) phase and the result is expressed as a 10-base logarithm of the
concentration ratios between these phases (partition coefficient), logP. A
desired logP value (octanol-water partition coefficient) is no more than 5 (also
part of the so-called Lipinski rule-of-five; logP 5 = 1:100,000 concentration
difference between water and octanol phases).
Another common measure for lipophilicity is the distribution coefficient, logD.
lodD takes into account the compounds ionized and non-ionized forms, and
therefore the measurement is done at different pH. For un-ionizable
compounds, log P = log D at any pH and on the other hand, logP is the octanolwater partition for the neutral (un-ionized) form of the compound. Amongst the
different pH values, typically the most interesting is pH 7.4, the physiological
pH value.
For analysis of the compounds division between water and octanol phases, we
routinely use UPLC-UV or MS quantitation, depending on the presence of UV
absorbing groups in the compound.