Liquid–liquid extraction

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Liquid%E2%80%93liquid_extraction 

A separatory funnel used for liquid–liquid extraction, as evident by the two immiscible liquids.

Liquid–liquid extraction, also known as solvent extraction and partitioning, is a method to separate compounds or metal complexes, based on their relative solubilities in two different immiscible liquids, usually water (polar) and an organic solvent (non-polar). There is a net transfer of one or more species from one liquid into another liquid phase, generally from aqueous to organic. The transfer is driven by chemical potential, i.e. once the transfer is complete, the overall system of chemical components that make up the solutes and the solvents are in a more stable configuration (lower free energy). The solvent that is enriched in solute(s) is called extract. The feed solution that is depleted in solute(s) is called the raffinate. Liquid–liquid extraction is a basic technique in chemical laboratories, where it is performed using a variety of apparatus, from separatory funnels to countercurrent distribution equipment called as mixer settlers. This type of process is commonly performed after a chemical reaction as part of the work-up, often including an acidic work-up.

The term partitioning is commonly used to refer to the underlying chemical and physical processes involved in liquid–liquid extraction, but on another reading may be fully synonymous with it. The term solvent extraction can also refer to the separation of a substance from a mixture by preferentially dissolving that substance in a suitable solvent. In that case, a soluble compound is separated from an insoluble compound or a complex matrix.

From a hydrometallurgical perspective, solvent extraction is exclusively used in separation and purification of uranium and plutonium, zirconium and hafnium, separation of cobalt and nickel, separation and purification of rare earth elements etc., its greatest advantage being its ability to selectively separate out even very similar metals. One obtains high-purity single metal streams on 'stripping' out the metal value from the 'loaded' organic wherein one can precipitate or deposit the metal value. Stripping is the opposite of extraction: Transfer of mass from organic to aqueous phase.

Liquid–liquid extraction is also widely used in the production of fine organic compounds, the processing of perfumes, the production of vegetable oils and biodiesel, and other industries. It is among the most common initial separation techniques, though some difficulties result in extracting out closely related functional groups.

Liquid-Liquid extraction can be substantially accelerated in microfluidic devices, reducing extraction and separation times from minutes/hours to mere seconds compared to conventional extractors.

Liquid–liquid extraction is possible in non-aqueous systems: In a system consisting of a molten metal in contact with molten salts, metals can be extracted from one phase to the other. This is related to a mercury electrode where a metal can be reduced, the metal will often then dissolve in the mercury to form an amalgam that modifies its electrochemistry greatly. For example, it is possible for sodium cations to be reduced at a mercury cathode to form sodium amalgam, while at an inert electrode (such as platinum) the sodium cations are not reduced. Instead, water is reduced to hydrogen. A detergent or fine solid can be used to stabilize an emulsion, or third phase.

Measures of effectiveness

Distribution ratio

In solvent extraction, a distribution ratio is often quoted as a measure of how well-extracted a species is. The distribution ratio (K_d) is equal to the concentration of a solute in the organic phase divided by its concentration in the aqueous phase. Depending on the system, the distribution ratio can be a function of temperature, the concentration of chemical species in the system, and a large number of other parameters. Note that D is related to the ΔG of the extraction process.

Sometimes, the distribution ratio is referred to as the partition coefficient, which is often expressed as the logarithm. Note that a distribution ratio for uranium and neptunium between two inorganic solids (zirconolite and perovskite) has been reported. In solvent extraction, two immiscible liquids are shaken together. The more polar solutes dissolve preferentially in the more polar solvent, and the less polar solutes in the less polar solvent. In this experiment, the nonpolar halogens preferentially dissolve in the non-polar mineral oil.

Although the distribution ratio and partition coefficient are often used synonymously, they are not necessarily so. Solutes may exist in more than one form in any particular phase, which would mean that the partition coefficient (K_d) and distribution ratio (D) will have different values. This is an important distinction to make as whilst the partition coefficient has a fixed value for the partitioning of a solute between two phases, the distribution ratio changes with differing conditions in the solvent.

After performing liquid–liquid extraction, a quantitative measure must be taken to determine the ratio of the solution's total concentration in each phase of the extraction. This quantitative measure is known as the distribution ratio or distribution coefficient.

Separation factors

The separation factor is one distribution ratio divided by another; it is a measure of the ability of the system to separate two solutes. For instance, if the distribution ratio for nickel (D_Ni) is 10 and the distribution ratio for silver (D_Ag) is 100, then the silver/nickel separation factor (SF_Ag/Ni) is equal to D_Ag/D_Ni = SF_Ag/Ni = 10.^[6]

Decontamination factor

This is used to express the ability of a process to remove a contaminant from a product. For instance, if a process is fed with a mixture of 1:9 cadmium to indium, and the product is a 1:99 mixture of cadmium and indium, then the decontamination factor (for the removal of cadmium) of the process is 0.11 / 0.01 = 11.

Slopes of graphs

The easy way to work out the extraction mechanism is to draw graphs and measure the slopes. If for an extraction system the D value is proportional to the square of the concentration of a reagent (Z) then the slope of the graph of log₁₀(D) against log₁₀([[Z]]) will be two.

Measures of success

Success of liquid–liquid extraction is measured through separation factors and decontamination factors. The best way to understand the success of an extraction column is through the liquid–liquid equilibrium (LLE) data set. The data set can then be converted into a curve to determine the steady state partitioning behavior of the solute between the two phases. The y-axis is the concentration of solute in the extract (solvent) phase, and the x-axis is the concentration of the solute in the raffinate phase. From here, one can determine steps for optimization of the process.

Techniques

Batchwise single stage extractions

This is commonly used on the small scale in chemical labs. It is normal to use a separating funnel. Processes include DLLME and direct organic extraction. After equilibration, the extract phase containing the desired solute is separated out for further processing.

Dispersive liquid–liquid microextraction (DLLME)

A process used to extract small amounts of organic compounds from water samples. This process is done by injecting small amounts of an appropriate extraction solvent (C₂Cl₄) and a disperser solvent (acetone) into the aqueous solution. The resulting solution is then centrifuged to separate the organic and aqueous layers. This process is useful in extraction organic compounds such as organochloride and organophsophorus pesticides, as well as substituted benzene compounds from water samples.

Direct organic extraction

By mixing partially organic soluble samples in organic solvent (toluene, benzene, xylene), the organic soluble compounds will dissolve into the solvent and can be separated using a separatory funnel. This process is valuable in the extraction of proteins and specifically phosphoprotein and phosphopeptide phosphatases.

Another example of this application is extracting anisole from a mixture of water and 5% acetic acid using ether, then the anisole will enter the organic phase. The two phases would then be separated. The acetic acid can then be scrubbed (removed) from the organic phase by shaking the organic extract with sodium bicarbonate. The acetic acid reacts with the sodium bicarbonate to form sodium acetate, carbon dioxide, and water.

Caffeine can also be extracted from coffee beans and tea leaves using a direct organic extraction. The beans or leaves can be soaked in ethyl acetate which favorably dissolves the caffeine, leaving a majority of the coffee or tea flavor remaining in the initial sample.

Multistage countercurrent continuous processes

Coflore continuous countercurrent extractor.

These are commonly used in industry for the processing of metals such as the lanthanides; because the separation factors between the lanthanides are so small many extraction stages are needed. In the multistage processes, the aqueous raffinate from one extraction unit is fed to the next unit as the aqueous feed, while the organic phase is moved in the opposite direction. Hence, in this way, even if the separation between two metals in each stage is small, the overall system can have a higher decontamination factor.

Multistage countercurrent arrays have been used for the separation of lanthanides. For the design of a good process, the distribution ratio should be not too high (>100) or too low (<0.1) in the extraction portion of the process. It is often the case that the process will have a section for scrubbing unwanted metals from the organic phase, and finally a stripping section to obtain the metal back from the organic phase.

Mixer–settlers

Battery of mixer-settlers counter currently interconnected. Each mixer-settler unit provides a single stage of extraction. A mixer settler consists of a first stage that mixes the phases together followed by a quiescent settling stage that allows the phases to separate by gravity.

Continuous separation of oil& water mixture

A novel settling device, Sudhin BioSettler, can separate an oil-water emulsion continuously at a much faster rate than simple gravity settlers. In this photo, an oil-water emulsion, stirred by an impeller in an external reservoir and pumped continuously into the two bottom side ports of BioSettler, is separated very quickly into a clear organic (mineral oil) layer exiting via the top of BioSettler and an aqueous (coloured with a red food dye) layer being pumped out continuously from the bottom of BioSettler.

In the multistage countercurrent process, multiple mixer settlers are installed with mixing and settling chambers located at alternating ends for each stage (since the outlet of the settling sections feed the inlets of the adjacent stage's mixing sections). Mixer-settlers are used when a process requires longer residence times and when the solutions are easily separated by gravity. They require a large facility footprint, but do not require much headspace, and need limited remote maintenance capability for occasional replacement of mixing motors. (Colven, 1956; Davidson, 1957)

4 stage battery of mixer-settlers for counter-current extraction.

Centrifugal extractors

Centrifugal extractors mix and separate in one unit. Two liquids will be intensively mixed between the spinning rotor and the stationary housing at speeds up to 6000 RPM. This develops great surfaces for an ideal mass transfer from the aqueous phase into the organic phase. At 200–2000 g, both phases will be separated again. Centrifugal extractors minimize the solvent in the process, optimize the product load in the solvent and extract the aqueous phase completely. Counter current and cross current extractions are easily established.

Extraction without chemical change

Some solutes such as noble gases can be extracted from one phase to another without the need for a chemical reaction (see absorption). This is the simplest type of solvent extraction. When a solvent is extracted, two immiscible liquids are shaken together. The more polar solutes dissolve preferentially in the more polar solvent, and the less polar solutes in the less polar solvent. Some solutes that do not at first sight appear to undergo a reaction during the extraction process do not have distribution ratio that is independent of concentration. A classic example is the extraction of carboxylic acids (HA) into nonpolar media such as benzene. Here, it is often the case that the carboxylic acid will form a dimer in the organic layer so the distribution ratio will change as a function of the acid concentration (measured in either phase).

For this case, the extraction constant k is described by k = [HA_organic]²/[HA_aqueous]

Solvation mechanism

Using solvent extraction it is possible to extract uranium, plutonium, thorium and many rare earth elements from acid solutions in a selective way by using the right choice of organic extracting solvent and diluent. One solvent used for this purpose is the organophosphate tributyl phosphate (TBP). The PUREX process that is commonly used in nuclear reprocessing uses a mixture of tri-n-butyl phosphate and an inert hydrocarbon (kerosene), the uranium(VI) are extracted from strong nitric acid and are back-extracted (stripped) using weak nitric acid. An organic soluble uranium complex [UO₂(TBP)₂(NO₃)₂] is formed, then the organic layer bearing the uranium is brought into contact with a dilute nitric acid solution; the equilibrium is shifted away from the organic soluble uranium complex and towards the free TBP and uranyl nitrate in dilute nitric acid. The plutonium(IV) forms a similar complex to the uranium(VI), but it is possible to strip the plutonium in more than one way; a reducing agent that converts the plutonium to the trivalent oxidation state can be added. This oxidation state does not form a stable complex with TBP and nitrate unless the nitrate concentration is very high (circa 10 mol/L nitrate is required in the aqueous phase). Another method is to simply use dilute nitric acid as a stripping agent for the plutonium. This PUREX chemistry is a classic example of a solvation extraction. In this case, D_U = k [TBP]²[NO₃^-]².

Ion exchange mechanism

Another extraction mechanism is known as the ion exchange mechanism. Here, when an ion is transferred from the aqueous phase to the organic phase, another ion is transferred in the other direction to maintain the charge balance. This additional ion is often a hydrogen ion; for ion exchange mechanisms, the distribution ratio is often a function of pH. An example of an ion exchange extraction would be the extraction of americium by a combination of terpyridine and a carboxylic acid in tert-butyl benzene. In this case

D_Am = k [terpyridine]¹[carboxylic acid]³[H⁺]⁻³

Another example is the extraction of zinc, cadmium, or lead by a dialkyl phosphinic acid (R₂PO₂H) into a nonpolar diluent such as an alkane. A non-polar diluent favours the formation of uncharged non-polar metal complexes.

Some extraction systems are able to extract metals by both the solvation and ion exchange mechanisms; an example of such a system is the americium (and lanthanide) extraction from nitric acid by a combination of 6,6'-bis-(5,6-dipentyl-1,2,4-triazin-3-yl)-2,2'-bipyridine and 2-bromohexanoic acid in tert-butyl benzene. At both high- and low-nitric acid concentrations, the metal distribution ratio is higher than it is for an intermediate nitric acid concentration.

Ion pair extraction

It is possible by careful choice of counterion to extract a metal. For instance, if the nitrate concentration is high, it is possible to extract americium as an anionic nitrate complex if the mixture contains a lipophilic quaternary ammonium salt.

An example that is more likely to be encountered by the 'average' chemist is the use of a phase transfer catalyst. This is a charged species that transfers another ion to the organic phase. The ion reacts and then forms another ion, which is then transferred back to the aqueous phase.

For instance, the 31.1 kJ mol⁻¹ is required to transfer an acetate anion into nitrobenzene, while the energy required to transfer a chloride anion from an aqueous phase to nitrobenzene is 43.8 kJ mol⁻¹. Hence, if the aqueous phase in a reaction is a solution of sodium acetate while the organic phase is a nitrobenzene solution of benzyl chloride, then, when a phase transfer catalyst, the acetate anions can be transferred from the aqueous layer where they react with the benzyl chloride to form benzyl acetate and a chloride anion. The chloride anion is then transferred to the aqueous phase. The transfer energies of the anions contribute to that given out by the reaction.

A 43.8 to 31.1 kJ mol⁻¹ = 12.7 kJ mol⁻¹ of additional energy is given out by the reaction when compared with energy if the reaction had been done in nitrobenzene using one equivalent weight of a tetraalkylammonium acetate.

Types of aqueous two-phase extractions

Polymer–polymer systems. In a Polymer–polymer system, both phases are generated by a dissolved polymer. The heavy phase will generally be a polysaccharide, and the light phase is generally Polyethylene glycol (PEG). Traditionally, the polysaccharide used is dextran. However, dextran is relatively expensive, and research has been exploring using less expensive polysaccharides to generate the heavy phase. If the target compound being separated is a protein or enzyme, it is possible to incorporate a ligand to the target into one of the polymer phases. This improves the target's affinity to that phase, and improves its ability to partition from one phase into the other. This, as well as the absence of solvents or other denaturing agents, makes polymer–polymer extractions an attractive option for purifying proteins. The two phases of a polymer–polymer system often have very similar densities, and very low surface tension between them. Because of this, demixing a polymer–polymer system is often much more difficult than demixing a solvent extraction. Methods to improve the demixing include centrifugation, and application of an electric field.

Polymer–salt systems. Aqueous two-phase systems can also be generated by generating the heavy phase with a concentrated salt solution. The polymer phase used is generally still PEG. Generally, a kosmotropic salt, such as Na₃PO₄ is used, however PEG–NaCl systems have been documented when the salt concentration is high enough. Since polymer–salt systems demix readily they are easier to use. However, at high salt concentrations, proteins generally either denature, or precipitate from solution. Thus, polymer–salt systems are not as useful for purifying proteins.

Ionic liquids systems. Ionic liquids are ionic compounds with low melting points. While they are not technically aqueous, recent research has experimented with using them in an extraction that does not use organic solvents.

DNA purification

Main article: DNA extraction

The ability to purify DNA from a sample is important for many modern biotechnology processes. However, samples often contain nucleases that degrade the target DNA before it can be purified. It has been shown that DNA fragments will partition into the light phase of a polymer–salt separation system. If ligands known to bind and deactivate nucleases are incorporated into the polymer phase, the nucleases will then partition into the heavy phase and be deactivated. Thus, this polymer–salt system is a useful tool for purifying DNA from a sample while simultaneously protecting it from nucleases.

Food industry

The PEG–NaCl system has been shown to be effective at partitioning small molecules, such as peptides and nucleic acids. These compounds are often flavorants or odorants. The system could then be used by the food industry to isolate or eliminate particular flavors. Caffeine extraction used to be done using liquid–liquid extraction, specifically direct and indirect liquid–liquid extraction (Swiss Water Method), but has since moved towards super-critical CO₂ as it is cheaper and can be done on a commercial scale.

Analytical chemistry

Often there are chemical species present or necessary at one stage of sample processing that will interfere with the analysis. For example, some air monitoring is performed by drawing air through a small glass tube filled with sorbent particles that have been coated with a chemical to stabilize or derivatize the analyte of interest. The coating may be of such a concentration or characteristics that it would damage the instrumentation or interfere with the analysis. If the sample can be extracted from the sorbent using a nonpolar solvent (such as toluene or carbon disulfide), and the coating is polar (such as HBr or phosphoric acid) the dissolved coating will partition into the aqueous phase. Clearly the reverse is true as well, using polar extraction solvent and a nonpolar solvent to partition a nonpolar interferent. A small aliquot of the organic phase (or in the latter case, polar phase) can then be injected into the instrument for analysis.

Purification of amines

Amines (analogously to ammonia) have a lone pair of electrons on the nitrogen atom that can form a relatively weak bond to a hydrogen atom. It is therefore the case that under acidic conditions amines are typically protonated, carrying a positive charge and under basic conditions they are typically deprotonated and neutral. Amines of sufficiently low molecular weight are rather polar and can form hydrogen bonds with water and therefore will readily dissolve in aqueous solutions. Deprotonated amines on the other hand, are neutral and have greasy, nonpolar organic substituents, and therefore have a higher affinity for nonpolar inorganic solvents. As such purification steps can be carried out where an aqueous solution of an amine is neutralized with a base such as sodium hydroxide, then shaken in a separatory funnel with a nonpolar solvent that is immiscible with water. The organic phase is then drained off. Subsequent processing can recover the amine by techniques such as recrystallization, evaporation or distillation; subsequent extraction back to a polar phase can be performed by adding HCl and shaking again in a separatory funnel (at which point the ammonium ion could be recovered by adding an insoluble counterion), or in either phase, reactions could be performed as part of a chemical synthesis.

Temperature swing solvent extraction

Main article: Desalination § Temperature_swing_solvent_extraction

Temperature swing solvent extraction is an experimental technique for the desalination of drinking water. It has been used to remove up to 98.5% of the salt content in water, and is able to process hypersaline brines that cannot be desalinated using reverse osmosis.

Kinetics of extraction

It is important to investigate the rate at which the solute is transferred between the two phases, in some cases by an alteration of the contact time it is possible to alter the selectivity of the extraction. For instance, the extraction of palladium or nickel can be very slow because the rate of ligand exchange at these metal centers is much lower than the rates for iron or silver complexes.

Aqueous complexing agents

If a complexing agent is present in the aqueous phase then it can lower the distribution ratio. For instance, in the case of iodine being distributed between water and an inert organic solvent such as carbon tetrachloride then the presence of iodide in the aqueous phase can alter the extraction chemistry: instead of ${\displaystyle D_{{\mathrm{I}}^{+2}}}$ being a constant it becomes

${\displaystyle D_{{\mathrm{I}}^{+2}}}$ = k[I₂ (organic)]/[I₂ (aq)][I⁻ (aq)]

This is because the iodine reacts with the iodide to form I₃⁻. The I₃⁻ anion is an example of a polyhalide anion that is quite common.

Industrial process design

In a typical scenario, an industrial process will use an extraction step in which solutes are transferred from the aqueous phase to the organic phase; this is often followed by a scrubbing stage in which unwanted solutes are removed from the organic phase, then a stripping stage in which the wanted solutes are removed from the organic phase. The organic phase may then be treated to make it ready for use again.

After use, the organic phase may be subjected to a cleaning step to remove any degradation products; for instance, in PUREX plants, the used organic phase is washed with sodium carbonate solution to remove any dibutyl hydrogen phosphate or butyl dihydrogen phosphate that might be present.

Liquid-liquid equilibrium calculations

In order to calculate the phase equilibrium, it is necessary to use a thermodynamic model such as NRTL, UNIQUAC, etc. The corresponding parameters of these models can be obtained from literature (e.g. Dechema Chemistry Data Series, Dortmund Data Bank, etc.) or by a correlation process of experimental data.

Equipment

While solvent extraction is often done on a small scale by synthetic lab chemists using a separatory funnel, Craig apparatus or membrane-based techniques, it is normally done on the industrial scale using machines that bring the two liquid phases into contact with each other. Such machines include centrifugal contactors, Thin Layer Extraction, spray columns, pulsed columns, and mixer-settlers.

Extraction of metals

The extraction methods for a range of metals include:

Cobalt

The extraction of cobalt from hydrochloric acid using Alamine 336 (tri-octyl/decyl amine) in meta-xylene. Cobalt can be extracted also using Ionquest 290 or Cyanex 272 {bis-(2,4,4-trimethylpentyl) phosphinic acid}.

Copper

Copper can be extracted using hydroxyoximes as extractants, a recent paper describes an extractant that has a good selectivity for copper over cobalt and nickel.

Neodymium

The rare earth element Neodymium is extracted by di(2-ethyl-hexyl)phosphoric acid into hexane by an ion exchange mechanism.

Nickel

Nickel can be extracted using di(2-ethyl-hexyl)phosphoric acid and tributyl phosphate in a hydrocarbon diluent (Shellsol).

Palladium and platinum

Dialkyl sulfides, tributyl phosphate and alkyl amines have been used for extracting palladium and platinum.

Polonium

Polonium is produced in reactors from natural ²⁰⁹Bi, bombarded with neutrons, creating ²¹⁰Bi, which then decays to ²¹⁰Po via beta-minus decay. The final purification is done pyrochemically followed by liquid-liquid extraction vs sodium hydroxide at 500 deg C.

Zinc and cadmium

Zinc and cadmium are both extracted by an ion exchange process, the N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) acts as a masking agent for the zinc and an extractant for the cadmium. In the modified Zincex process, zinc is separated from most divalent ions by solvent extraction. D2EHPA (Di (2) ethyl hexyl phosphoric acid) is used for this. A zinc ion replaces the proton from two D2EHPA molecules. To strip the zinc from the D2EHPA, sulfuric acid is used, at a concentration of above 170g/L (typically 240-265g/L).

Lithium

Lithium extraction is more popular due to the high demand of lithium-ion batteries. TBP (Tri-butyl phosphate) and FeCl₃ are mostly used to extract lithium from brine (with high Li/Mg ratio). Alternatively, Cyanex 272 was also used to extract lithium. The mechanism of lithium extraction was found differently from other metals, such as cobalt, due to the weak coordinating bonding between lithium ions and extractants.

Partition coefficient

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Partition_coefficient

In the physical sciences, a partition coefficient (P) or distribution coefficient (D) is the ratio of concentrations of a compound in a mixture of two immiscible solvents at equilibrium. This ratio is therefore a comparison of the solubilities of the solute in these two liquids. The partition coefficient generally refers to the concentration ratio of un-ionized species of compound, whereas the distribution coefficient refers to the concentration ratio of all species of the compound (ionized plus un-ionized).

In the chemical and pharmaceutical sciences, both phases usually are solvents. Most commonly, one of the solvents is water, while the second is hydrophobic, such as 1-octanol. Hence the partition coefficient measures how hydrophilic ("water-loving") or hydrophobic ("water-fearing") a chemical substance is. Partition coefficients are useful in estimating the distribution of drugs within the body. Hydrophobic drugs with high octanol-water partition coefficients are mainly distributed to hydrophobic areas such as lipid bilayers of cells. Conversely, hydrophilic drugs (low octanol/water partition coefficients) are found primarily in aqueous regions such as blood serum.

If one of the solvents is a gas and the other a liquid, a gas/liquid partition coefficient can be determined. For example, the blood/gas partition coefficient of a general anesthetic measures how easily the anesthetic passes from gas to blood. Partition coefficients can also be defined when one of the phases is solid, for instance, when one phase is a molten metal and the second is a solid metal, or when both phases are solids. The partitioning of a substance into a solid results in a solid solution.

Partition coefficients can be measured experimentally in various ways (by shake-flask, HPLC, etc.) or estimated by calculation based on a variety of methods (fragment-based, atom-based, etc.).

If a substance is present as several chemical species in the partition system due to association or dissociation, each species is assigned its own K_ow value. A related value, D, does not distinguish between different species, only indicating the concentration ratio of the substance between the two phases.

Nomenclature

Despite formal recommendation to the contrary, the term partition coefficient remains the predominantly used term in the scientific literature.

In contrast, the IUPAC recommends that the title term no longer be used, rather, that it be replaced with more specific terms. For example, partition constant, defined as

(KD)A = ⁠[A]org/ [A]aq⁠,

(1)

where K_D is the process equilibrium constant, [A] represents the concentration of solute A being tested, and "org" and "aq" refer to the organic and aqueous phases respectively. The IUPAC further recommends "partition ratio" for cases where transfer activity coefficients can be determined, and "distribution ratio" for the ratio of total analytical concentrations of a solute between phases, regardless of chemical form.

Partition coefficient and log P

An equilibrium of dissolved substance distributed between a hydrophobic phase and a hydrophilic phase is established in special glassware such as this separatory funnel that allows shaking and sampling, from which the log P is determined. Here, the green substance has a greater solubility in the lower layer than in the upper layer.

The partition coefficient, abbreviated P, is defined as a particular ratio of the concentrations of a solute between the two solvents (a biphase of liquid phases), specifically for un-ionized solutes, and the logarithm of the ratio is thus log P. When one of the solvents is water and the other is a non-polar solvent, then the log P value is a measure of lipophilicity or hydrophobicity. The defined precedent is for the lipophilic and hydrophilic phase types to always be in the numerator and denominator respectively; for example, in a biphasic system of n-octanol (hereafter simply "octanol") and water:

${\displaystyle \log P_{\text{oct/wat}}={\log }_{10}\left(\frac{[\text{solute}{]}_{\text{octanol}}^{\text{un-ionized}}}{[\text{solute}{]}_{\text{water}}^{\text{un-ionized}}}\right).}$

To a first approximation, the non-polar phase in such experiments is usually dominated by the un-ionized form of the solute, which is electrically neutral, though this may not be true for the aqueous phase. To measure the partition coefficient of ionizable solutes, the pH of the aqueous phase is adjusted such that the predominant form of the compound in solution is the un-ionized, or its measurement at another pH of interest requires consideration of all species, un-ionized and ionized (see following).

A corresponding partition coefficient for ionizable compounds, abbreviated log P ^I, is derived for cases where there are dominant ionized forms of the molecule, such that one must consider partition of all forms, ionized and un-ionized, between the two phases (as well as the interaction of the two equilibria, partition and ionization). M is used to indicate the number of ionized forms; for the I-th form (I = 1, 2, ... , M) the logarithm of the corresponding partition coefficient, ${\displaystyle \log P_{\text{oct/wat}}^I}$, is defined in the same manner as for the un-ionized form. For instance, for an octanol–water partition, it is

${\displaystyle \log P_{\text{oct/wat}}^{\mathrm{I}}={\log }_{10}\left(\frac{[\text{solute}{]}_{\text{octanol}}^I}{[\text{solute}{]}_{\text{water}}^I}\right).}$

To distinguish between this and the standard, un-ionized, partition coefficient, the un-ionized is often assigned the symbol log P⁰, such that the indexed ${\displaystyle \log P_{\text{oct/wat}}^I}$ expression for ionized solutes becomes simply an extension of this, into the range of values I > 0.

Distribution coefficient and log D

The distribution coefficient, log D, is the ratio of the sum of the concentrations of all forms of the compound (ionized plus un-ionized) in each of the two phases, one essentially always aqueous; as such, it depends on the pH of the aqueous phase, and log D = log P for non-ionizable compounds at any pH. For measurements of distribution coefficients, the pH of the aqueous phase is buffered to a specific value such that the pH is not significantly perturbed by the introduction of the compound. The value of each log D is then determined as the logarithm of a ratio—of the sum of the experimentally measured concentrations of the solute's various forms in one solvent, to the sum of such concentrations of its forms in the other solvent; it can be expressed as

${\displaystyle \log D_{\text{oct/wat}}={\log }_{10}\left(\frac{[\text{solute}{]}_{\text{octanol}}^{\text{ionized}}+[\text{solute}{]}_{\text{octanol}}^{\text{un-ionized}}}{[\text{solute}{]}_{\text{water}}^{\text{ionized}}+[\text{solute}{]}_{\text{water}}^{\text{un-ionized}}}\right).}$

In the above formula, the superscripts "ionized" each indicate the sum of concentrations of all ionized species in their respective phases. In addition, since log D is pH-dependent, the pH at which the log D was measured must be specified. In areas such as drug discovery—areas involving partition phenomena in biological systems such as the human body—the log D at the physiologic pH = 7.4 is of particular interest.

It is often convenient to express the log D in terms of P^I, defined above (which includes P⁰ as state I = 0), thus covering both un-ionized and ionized species. For example, in octanol–water:

${\displaystyle \log D_{\text{oct/wat}}={\log }_{10}\left(\sum _{I=0}^M{f}^I{P}_{\text{oct/wat}}^I\right),}$

which sums the individual partition coefficients (not their logarithms), and where ${\displaystyle f^I}$ indicates the pH-dependent mole fraction of the I-th form (of the solute) in the aqueous phase, and other variables are defined as previously.

Example partition coefficient data

The values for the octanol-water system in the following table are from the Dortmund Data Bank. They are sorted by the partition coefficient, smallest to largest (acetamide being hydrophilic, and 2,2',4,4',5-pentachlorobiphenyl lipophilic), and are presented with the temperature at which they were measured (which impacts the values).

Component	log POW	T (°C)
Acetamide	−1.16	25
Methanol	−0.81	19
Formic acid	−0.41	25
Diethyl ether	0.83	20
p-Dichlorobenzene	3.37	25
Hexamethylbenzene	4.61	25
2,2',4,4',5-Pentachlorobiphenyl	6.41	Ambient

Values for other compounds may be found in a variety of available reviews and monographs. Critical discussions of the challenges of measurement of log P and related computation of its estimated values (see below) appear in several reviews.

Applications

Pharmacology

A drug's distribution coefficient strongly affects how easily the drug can reach its intended target in the body, how strong an effect it will have once it reaches its target, and how long it will remain in the body in an active form. Hence, the log P of a molecule is one criterion used in decision-making by medicinal chemists in pre-clinical drug discovery, for example, in the assessment of druglikeness of drug candidates. Likewise, it is used to calculate lipophilic efficiency in evaluating the quality of research compounds, where the efficiency for a compound is defined as its potency, via measured values of pIC₅₀ or pEC₅₀, minus its value of log P.

Drug permeability in brain capillaries (y axis) as a function of partition coefficient (x axis)

Pharmacokinetics

In the context of pharmacokinetics (how the body absorbs, metabolizes, and excretes a drug), the distribution coefficient has a strong influence on ADME properties of the drug. Hence the hydrophobicity of a compound (as measured by its distribution coefficient) is a major determinant of how drug-like it is. More specifically, for a drug to be orally absorbed, it normally must first pass through lipid bilayers in the intestinal epithelium (a process known as transcellular transport). For efficient transport, the drug must be hydrophobic enough to partition into the lipid bilayer, but not so hydrophobic, that once it is in the bilayer, it will not partition out again. Likewise, hydrophobicity plays a major role in determining where drugs are distributed within the body after absorption and, as a consequence, in how rapidly they are metabolized and excreted.

Pharmacodynamics

In the context of pharmacodynamics (how the drug affects the body), the hydrophobic effect is the major driving force for the binding of drugs to their receptor targets. On the other hand, hydrophobic drugs tend to be more toxic because they, in general, are retained longer, have a wider distribution within the body (e.g., intracellular), are somewhat less selective in their binding to proteins, and finally are often extensively metabolized. In some cases the metabolites may be chemically reactive. Hence it is advisable to make the drug as hydrophilic as possible while it still retains adequate binding affinity to the therapeutic protein target. For cases where a drug reaches its target locations through passive mechanisms (i.e., diffusion through membranes), the ideal distribution coefficient for the drug is typically intermediate in value (neither too lipophilic, nor too hydrophilic); in cases where molecules reach their targets otherwise, no such generalization applies.

Environmental science

The hydrophobicity of a compound can give scientists an indication of how easily a compound might be taken up in groundwater to pollute waterways, and its toxicity to animals and aquatic life. Partition coefficient can also be used to predict the mobility of radionuclides in groundwater. In the field of hydrogeology, the octanol–water partition coefficient K_ow is used to predict and model the migration of dissolved hydrophobic organic compounds in soil and groundwater.

Agrochemical research

Hydrophobic insecticides and herbicides tend to be more active. Hydrophobic agrochemicals in general have longer half-lives and therefore display increased risk of adverse environmental impact.

Metallurgy

In metallurgy, the partition coefficient is an important factor in determining how different impurities are distributed between molten and solidified metal. It is a critical parameter for purification using zone melting, and determines how effectively an impurity can be removed using directional solidification, described by the Scheil equation Consumer product development

Many other industries take into account distribution coefficients, for example in the formulation of make-up, topical ointments, dyes, hair colors and many other consumer products.

Measurement

A number of methods of measuring distribution coefficients have been developed, including the shake-flask, separating funnel method, reverse-phase HPLC, and pH-metric techniques.

Separating-funnel method

In this method the solid particles present into the two immiscible liquids can be easily separated by suspending those solid particles directly into these immiscible or somewhat miscible liquids.

Shake flask-type

The classical and most reliable method of log P determination is the shake-flask method, which consists of dissolving some of the solute in question in a volume of octanol and water, then measuring the concentration of the solute in each solvent. The most common method of measuring the distribution of the solute is by UV/VIS spectroscopy.

HPLC-based

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 values.

An advantage of this method is that it is fast (5–20 minutes per sample). However, since the value of log P is determined by linear regression, several compounds with similar structures must have known log P values, and extrapolation from one chemical class to another—applying a regression equation derived from one chemical class to a second one—may not be reliable, since each chemical classes will have its characteristic regression parameters.

pH-metric

The pH-metric set of techniques determine lipophilicity pH profiles directly from a single acid-base titration in a two-phase water–organic-solvent system. Hence, a single experiment can be used to measure the logarithms of the partition coefficient (log P) giving the distribution of molecules that are primarily neutral in charge, as well as the distribution coefficient (log D) of all forms of the molecule over a pH range, e.g., between 2 and 12. The method does, however, require the separate determination of the pK_a value(s) of the substance.

Electrochemical

Polarized 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. The first is ITIES, "interfaces between two immiscible electrolyte solutions". The second is droplet experiments. 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.

Single-cell approach

There are attempts to provide partition coefficients for drugs at a single-cell level. This strategy requires methods for the determination of concentrations in individual cells, i.e., with Fluorescence correlation spectroscopy or quantitative Image analysis. Partition coefficient at a single-cell level provides information on cellular uptake mechanism.

Prediction

There are many situations where prediction of partition coefficients prior to experimental measurement is useful. For example, tens of thousands of industrially manufactured chemicals are in common use, but only a small fraction have undergone rigorous toxicological evaluation. Hence there is a need to prioritize the remainder for testing. QSAR equations, which in turn are based on calculated partition coefficients, can be used to provide toxicity estimates. Calculated partition coefficients are also widely used in drug discovery to optimize screening libraries and to predict druglikeness of designed drug candidates before they are synthesized. As discussed in more detail below, estimates of partition coefficients can be made using a variety of methods, including fragment-based, atom-based, and knowledge-based that rely solely on knowledge of the structure of the chemical. Other prediction methods rely on other experimental measurements such as solubility. The methods also differ in accuracy and whether they can be applied to all molecules, or only ones similar to molecules already studied.

Atom-based

Standard approaches of this type, using atomic contributions, have been named by those formulating them with a prefix letter: AlogP, XlogP, MlogP, etc. A conventional method for predicting log P through this type of method is to parameterize the distribution coefficient contributions of various atoms to the overall molecular partition coefficient, which produces a parametric model. This parametric model can be estimated using constrained least-squares estimation, using a training set of compounds with experimentally measured partition coefficients. In order to get reasonable correlations, the most common elements contained in drugs (hydrogen, carbon, oxygen, sulfur, nitrogen, and halogens) are divided into several different atom types depending on the environment of the atom within the molecule. While this method is generally the least accurate, the advantage is that it is the most general, being able to provide at least a rough estimate for a wide variety of molecules.

Fragment-based

The most common of these uses a group contribution method and is termed cLogP. It has been shown that the log P of a compound can be determined by the sum of its non-overlapping molecular fragments (defined as one or more atoms covalently bound to each other within the molecule). Fragmentary log P values have been determined in a statistical method analogous to the atomic methods (least-squares fitting to a training set). In addition, Hammett-type corrections are included to account of electronic and steric effects. This method in general gives better results than atomic-based methods, but cannot be used to predict partition coefficients for molecules containing unusual functional groups for which the method has not yet been parameterized (most likely because of the lack of experimental data for molecules containing such functional groups).

Knowledge-based

A typical data-mining-based prediction uses support-vector machines, decision trees, or neural networks. This method is usually very successful for calculating log P values when used with compounds that have similar chemical structures and known log P values. Molecule mining approaches apply a similarity-matrix-based prediction or an automatic fragmentation scheme into molecular substructures. Furthermore, there exist also approaches using maximum common subgraph searches or molecule kernels.

Log D from log P and pK_a

For cases where the molecule is un-ionized:

${\displaystyle \log D\cong \log P.}$

For other cases, estimation of log D at a given pH, from log P and the known mole fraction of the un-ionized form, ${\displaystyle f^0}$, in the case where partition of ionized forms into non-polar phase can be neglected, can be formulated as

${\displaystyle \log D\cong \log P+\log \left(f^0\right).}$

The following approximate expressions are valid only for monoprotic acids and bases:

${\displaystyle \begin{array}{rl}\log D_{\text{acids}}& \cong \log P+\log \left[\frac{1}{1+{10}^{\mathrm{p}H-\mathrm{p}{K}_a}}\right],\\ \log D_{\text{bases}}& \cong \log P+\log \left[\frac{1}{1+{10}^{\mathrm{p}{K}_a-\mathrm{p}\mathrm{H}}}\right].\end{array}}$

Further approximations for when the compound is largely ionized:

• for acids with ${\displaystyle \mathrm{p}\mathrm{H}-\mathrm{p}{K}_a>1}$, ${\displaystyle \log D_{\text{acids}}\cong \log P+\mathrm{p}{K}_a-\mathrm{p}\mathrm{H}}$,
• for bases with ${\displaystyle \mathrm{p}{K}_a-\mathrm{p}\mathrm{H}>1}$, ${\displaystyle \log D_{\text{bases}}\cong \log P-\mathrm{p}{K}_a+\mathrm{p}\mathrm{H}}$.

For prediction of pK_a, which in turn can be used to estimate log D, Hammett type equations have frequently been applied.

Log P from log S

If the solubility, S, of an organic compound is known or predicted in both water and 1-octanol, then log P can be estimated as

${\displaystyle \log P=\log S_{\text{o}}-\log S_{\text{w}}.}$

There are a variety of approaches to predict solubilities, and so log S.

Octanol-water partition coefficient

Main article: Octanol-water partition coefficient

The partition coefficient between n-Octanol and water is known as the n-octanol-water partition coefficient, or K_ow. It is also frequently referred to by the symbol P, especially in the English literature. It is also known as n-octanol-water partition ratio.

K_ow, being a type of partition coefficient, serves as a measure of the relationship between lipophilicity (fat solubility) and hydrophilicity (water solubility) of a substance. The value is greater than one if a substance is more soluble in fat-like solvents such as n-octanol, and less than one if it is more soluble in water.

Example values

Values for log K_ow typically range between -3 (very hydrophilic) and +10 (extremely lipophilic/hydrophobic).

The values listed here are sorted by the partition coefficient. Acetamide is hydrophilic, and 2,2′,4,4′,5-Pentachlorobiphenyl is lipophilic.

Substance	log KOW	T	Reference
Acetamide	−1.155	25 °C
Methanol	−0.824	19 °C
Formic acid	−0.413	25 °C
Diethyl ether	0.833	20 °C
p-Dichlorobenzene	3.370	25 °C
Hexamethylbenzene	4.610	25 °C
2,2′,4,4′,5-Pentachlorobiphenyl	6.410	Ambient