Partition coefficient

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A partition coefficient is a measure of differential solubility of a compound in two solvents. The log ratio of the concentrations of the solute in the solvent is called LogP. The best known of these partition coefficients is the one based on the solvents octanol and water. The octanol-water partition coefficient is a measure of the hydrophobicity and hydrophilicity of a substance. In the context of drug-like substances, hydrophobicity is related to absorption, bioavailability, hydrophobic drug-receptor interactions, metabolism and toxicity.

Contents

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Application

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Shake Flask (or tube) Method

The classical and most reliable method of LogP determination is the Shake-flask method, which consists of mixing a known amount of solute in a known volume of octanol and water, then measuring the distribution of the solute in each solvent. The most common method of measuring the distribution of the solute is by UV/VIS spectroscopy. There are a number of pros and cons to this method:

Pros:

  • Most accurate method
  • Accurate for broadest range of solutes (neutral and charged compounds applicable)
  • Chemical structure does not have to be known beforehand.

Cons:

  • Time consuming (>30 minutes per sample)
  • Octanol and water must be premixed and equilibrated (takes at least 24hrs to equilibrate)
  • Complete solubility must be attained.
  • The concentration vs. UV-Vis response must be linear over the solute's concentration range. (See Beer-Lambert law)

As an alternative to UV/VIS spectroscopy other methods can be used to measure the distribution, one of the best is to use a carrier free radiotracer. In this method (which is well suited for the study of the extraction of metals) a known amount of a radioactive material is added to one of the phases. The two phases are then brought into contact and mixed until equilibrium has been reached. Then the two phases are separated before the radioactivity in each phase is measured. If an energy dispersive detector can be used (such as a high purity germanium detector) then it is possible to use several different radioactive metals at once, with the more simple gamma ray detectors it is only possible to use one radioactive element in the sample.

If the volume of both of the phases are the same then the math is very simple.

For a hypothetical solute (S)

D or P = radioactivity of the organic phase / radioactivity of the aqueous phase

D or P = [Sorganic]/[Saqueous]

In such an experiment using a carrier free radioisotope the solvent loading is very small, hence the results are different to those which are obtained when the concentration of the solute is very high. A disadvantage of the carrier free radioisotope experiment is that the solute can absorb on the surfaces of the glass (or plastic) equipment or at the interface between the two phases. To guard against this the mass balance should be calculated.

It should be the case that

radioactivity of the organic phase + radioactivity of the aqueous phase = initial radioactivity of the phase bearing the radiotracer

For nonradioactive metals, it is possible in some cases to use ICPMS or ICPOES. Sadly ICP methods often suffer from many interferences which do not apply to gamma spectrscopy so hence the use of radiotracers (counted by gamma ray spectrscopy) is often more straightforward.

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HPLC determination

A faster method of LogP determination makes use of high-performance liquid chromatography. The LogP of a solute can be determined by correlating it's retention time with similar compounds with known logP values.

Pros:

  • Fast method of determination (5-20 minutes per sample)

Cons:

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Electrochemical methods

In the recent past some experiments using polarised liquid interfaces have been used to examine the thermodynamics and kinetics of the transfer of charged species from one phase to another. Two main methods exist.

  • ITIES, Interfaces between two immiscible electrolyte solutions which for example has been used at Ecole Polytechnique Fédérale de Lausanne. [1]
  • Droplet experiments which have been used by Alan Bond, Frank Marken[2] and also by the team at the Ecole Polytechnique Fédérale de Lausanne. Here a reaction at a triple interface between a conductive solid, droplets of a redox active liquid phase and an electrolyte solution have been used to determine the energy required to transfer a charged species across the interface.
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Prediction

Computer programs calculate logP several different ways:

  • Fragment Method
It has been shown that the logP of compound can be determined by the sum of its fragments. Fragmentary logP values have been determined statistically. This method gives mixed results and is generally not trusted to have accuracy of more than +/- 0.1 units.
Neural networks are usually very successful for calculating logP values when trained with compounds that have similar chemical structures and known logP values.
  • Other methods
Many programs utilize combinations of the above two methods. Other methods include Kohonen maps.
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Limitations

LogP is not an accurate determinant of solubility for ionisable drugs as if the drug is in an acidic form it will be poor at passing through lipid membranes. In these cases the distribution coefficient (D) should be used.

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See also

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External links

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LogP calculators

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Further information

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Commercial products

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Computational information

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