PARTITION COEFFICIENT: DISTRIBUTION, DISTRIBUTION, APPLICATIONS - CHEMISTRY - 2025

The partition or partition coefficient is defined as the ratio of the concentration of a chemical species or solute between two media in equilibrium. This medium can be a gas like air; a liquid such as water or oil; or a complex mixture like blood or other tissues.

The blood / air partition coefficient is important to explain the gas exchange that occurs in the lungs, between the blood and the atmosphere.

Diagram explaining the partition coefficient for three solutes between two phases. Source: Perdula

The image above demonstrates in a simplified and brilliant way the concept explained. Each figure represents an analyte, which are distributed and / or distributed between two immiscible phases: one upper and the other lower.

The green squares are predominantly in the upper phase; while the red triangles dissolve more in the lower phase, and the purple circles choose to be at the interface.

It is appreciated how K _D varies for each analyte. If K _D is greater than 1, the analyte will distribute more towards the upper phase; if its value is close to 1, it will tend to be at the interface; or if on the contrary K _D is less than 1, it will be mainly in the lower phase.

One of the forms of partition coefficient is the one existing between two immiscible liquids in equilibrium; as are the n-octane system and water. This system has been used to establish an important property of a compound: its hydrophobic or hydrophilic character.

The value of the partition coefficient (P), or partition coefficient (K), serves to indicate the hydrophobicity of a drug. Thus it can be used to predict its intestinal absorption, distribution, metabolism and excretion process.

Partition coefficient

Definition

The partition coefficient (K) of a substance, also called the partition coefficient (P), is the quotient of dividing the concentrations of a substance into two phases; made up of the mixture of two solvents that are immiscible because they have different densities and natures.

The value of the partition coefficient (K) or partition (P) is related to the difference in solubility of the substance in the immiscible liquids that are part of the mixture.

K or P = ₁ / ₂

₁ is the concentration of the substance in liquid 1. And ₂ is the concentration of the same substance in liquid 2.

Interpretation

If K or P has a value equal to 3, it indicates that the substance is 3 times more concentrated in liquid 1 than in liquid 2. But at the same time, it also indicates that the substance is more soluble in liquid 1.

Now, if the value of K or P is 0.3, the substance has a higher concentration in liquid 2; and therefore its solubility is higher in liquid 2 than in liquid 1.

Octanol / water partition coefficient

In some areas of research such as organic chemistry and pharmaceuticals, the mixture of liquids is made up of water and an apolar liquid such as n-octanol or 1-octanol, which is why the octanol partition coefficient is often referred to / water represented by Pow.

The n-octanol has a density of 0.824 g / cm ³; while water, as is known, has a density of approximately constant 1 g / cm ³. Once the two liquids have been balanced, n-octanol occupies the upper part of the mixture of immiscible liquids, which has been called Liquid 1.

A hydrophobic substance will have a higher concentration in n-octanol, once the immiscible liquids have balanced. On the other hand, a hydrophilic substance will have a higher concentration in water.

Restrictions

The partition or distribution coefficient applies for non-ionized substances. In the case where the partition coefficient is being measured in an ionizable substance, the pH should be adjusted or a buffer used in the aqueous phase to ensure that the substance is presented as undissociated.

In determining the partition coefficient, surfactant or surfactant substances should not be used, since these substances, due to their amphiphilic nature, are located at the interface of immiscible liquids.

The n-octanol / water partition coefficient is usually expressed in logarithmic form; that is, as log P or log K, due to the amplitude of the values ​​of P and K.

If the log of P for a substance is greater than 0, this is indicative that the substance is hydrophobic. Conversely, if the log of P is less than 0 (that is, negative), this indicates that the substance is hydrophilic.

Distribution coefficient (D)

The distribution coefficient (D) is the quotient between the concentration of all substances, ionized and non-ionized, in liquid 1 (n-octanol) and the concentration of the same substances in liquid 2 (water).

Once the value of the distribution coefficient (D) has been obtained, it can be expressed as a logarithm of D due to the amplitude of the values ​​of D.

To obtain the distribution coefficient (D), the aqueous phase must be buffered; in other words, at a certain pH, which must be indicated when referring to the value of the distribution coefficient obtained.

It is convenient to carry out the determination of D at pH 7.4. This pH corresponds to that of the blood and represents the conditions that drugs or compounds will encounter in the intracellular environment and in the extracellular environment.

For a non-ionizable compound, log D = log P, regardless of the pH used.

Experimental determination of a partition coefficient

There are several methods for measuring partition coefficient (P). These include the shake bottle method and high-performance liquid chromatography. Both require prior knowledge of the solubility of the test substance, both in n-octanol and in water.

Shake flask method

The sample is dissolved in n-octanol saturated with water, which will be partitioned in a separate funnel or decanted with water saturated with n-octanol. Solvent saturation is necessary to avoid solvent transfer during the partitioning process.

The separating funnel is subjected to mechanical agitation for a certain time. It is then allowed to stand for a long time to ensure complete separation. To conclude, the phases are separated by decantation.

Then, the concentration of the sample in each of the solvents is determined using a spectrophotometric method; eg UV-Visible or other method. Finally, with the data obtained, the partition coefficient and log P.

This method has the advantage of being inexpensive, reproducible and highly accurate. In summary, it is the most reliable method for determining log P.

The main disadvantage of the method is that it is very time consuming: more than 24 hours to perform liquid equilibration, stirring and phase separation during the partitioning process. Furthermore, it is applicable only to substances soluble in n-octanol and water.

High performance liquid chromatography method

The log P can be obtained by correlating the retention time of the sample with the retention time of a reference compound of similar chemical structure with a known P value.

It is a method in which the log P value is obtained in a time of less than 20 minutes. It gives log p values ​​between 0 and 6, which corresponds only to hydrophobic substances.

The disadvantage is that the P value is determined by linear regression, so several compounds of chemical structure similar to the sample and known log P values ​​should be used as reference.

Applications

Optimization of drug action

If a drug is ingested, it must reach the lumen of the small intestine, where most of the substances are absorbed. Then, it passes through the interior of the cells, dissolving in the lipid bilayer that is part of the membrane. This process is favored by the hydrophobic nature of the drug.

The drug must pass through the intestinal cells, crossing the basement membrane to reach the blood and reach the target receptors of the drug's action. Some stages of the overall process are favored by the hydrophobic nature of the drug, but others are not.

A value of the partition coefficient must be found that allows all the processes necessary for the action of the drug and the body's well-being to be satisfactory.

The use of excessively hydrophobic drugs can be toxic, as their metabolism can produce potentially harmful metabolites. On the other hand, totally hydrophilic drugs have difficulty for intestinal absorption.

Agrochemicals

The activity of insecticides and herbicides is influenced by their hydrophobic nature. However, hydrophobicity is associated with a longer half-life. Therefore, the polluting effect on the environment is prolonged, and can cause ecological damage.

Effective hydrophobic products should be produced with a shorter half-life.

Environmental care

Hydrophobic compounds tend to be pollutants for the environment, since they are drained through the soil, being able to reach groundwater and later river water.

Knowing the partition coefficient of a compound, changes can be made in its chemical structure that modify its hydrophobicity in order to reduce its polluting action on the environment.

Hydrogeology uses the octanol / water partition coefficient (Kow) to control the flow of hydrophobic compounds, both in soil and in groundwater.

References

1. Bannan, CC, Calabró, G., Kyu, DY, & Mobley, DL (2016). Calculating Partition Coefficients of Small Molecules in Octanol / Water and Cyclohexane / Water. Journal of chemical theory and computation, 12 (8), 4015–4024. doi: 10.1021 / acs.jctc.6b00449
2. Wikipedia. (2019). Partition coefficient. Recovered from: es.wikipedia.org
3. National university of Colombia. (sf). Unit 8: Experimental determination of the barbiturate partition coefficient.. Recovered from: red.unal.edu.co
4. The Sevier. (2019). Partition coefficient. Science Direct. Recovered from: sciencedirect.com
5. Seeboo Hemnath. (2019). Partition Coefficient: Definition and Calculation. Study. Recovered from: study.com