Partition coefficients P

Two parameters are commonly used to represent lipophilicity, namely the partition coefficient (P) and the lipophilicity substituent constant (it). The former parameter refers to the whole molecule whilst the latter is related to substituent groups. 

The nature of the relationship between P and drug activity depends on the range of P values obtained for the compounds used. If this range is small the results may be expressed as a straight line equation having the general form  

Lipophilic substituent constants are also known as hydrophobic substituent constants. They represent the contribution that a group makes to the partition coefficient and were defined by Hansch and co-workers by the equation  

Lipophilic constants are frequently used when dealing with a series of analogues in which only the substituents are different. This usage is based on the assumption that the lipophilic effect of the unchanged part of the structure is similar for each of the analogues. 

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There are many other applications. They include detemiination of the ratios of the partition coefficients P IPq) of solutes B and C in two different solvents by using the themiodynamic cycle ... 

Solubilisation is usually treated in terms of the pseudophase model, in which the bulk aqueous phase is regarded as one phase and tire micellar pseudophase as another. This allows the affinity of the solubilisate for the micelle to be quantified by a partition coefficient P. Different definitions of P can be found in the literature, differing in their description of the micellar phase. Frequently P is... 

The kinetic data are essentially always treated using the pseudophase model, regarding the micellar solution as consisting of two separate phases. The simplest case of micellar catalysis applies to unimolecTilar reactions where the catalytic effect depends on the efficiency of bindirg of the reactant to the micelle (quantified by the partition coefficient, P) and the rate constant of the reaction in the micellar pseudophase (k ) and in the aqueous phase (k ). Menger and Portnoy have developed a model, treating micelles as enzyme-like particles, that allows the evaluation of all three parameters from the dependence of the observed rate constant on the concentration of surfactant". ... 

The partition coefficient P, defined as the equilibrium concentration of the compound in n-octanol divided by that in the aqueous phase, has been measured for pyrazole and indazole (B-79MI40416). It was found that log F = 0.13-0.26 for pyrazole and 1.82 for indazole, clearly showing the greater hydrophobicity (lipophilicity) of the indazole ring, due to the benzenoid moiety. 

The comparison of predicting capabilities of two kinds of hydrophobicity evaluations is of interest. For these purpose partition coefficients P and P for a number of benzodiazepines gidazepam (I), medazepam (II), nitrazepam (III), oxazepam (IV), lorazepam (V) and diazepam (VI) were determined. 

Several Hansch-Leo n substituent parameters denved from octanol-water partition coefficients (P), = log p (ce sX) - log P (C H ), are hsted m Table 9... 

Table 11. Solvent Effects on Solvent-Water Partition Coefficients (P) [49]...

A relative scale of the standard Gibbs energies of ion transfer or the standard ion transfer potentials can be established based on partition and solubility measurements. The partition eqnilibrium of the electrolyte can be characterized by a measnrable parameter, the partition coefficient P x-... 

Clog P Calculated hydrophobicity of the whole molecule (calculated logarithm of partition coefficient (P) in M-octanol/water) ji Calculated hydrophobicity of the substituent... 

The quantitative descriptor of lipophilicity, the partition coefficient P, is defined as the ratio of the concentrations of a neutral compound in organic and aqueous phases of a two-compartment system under equilibrium conditions. It is commonly used in its logarithmic form, logP. Whereas 1-octanol serves as the standard organic phase for experimental determination, other solvents are applied to better mimic special permeation conditions such as the cyclohexane-water system for BBB permeation. Measurement of log P is described in Chapters 12 and 13 as well as in Ref [22]. 

The partition coefficient of a substance between several Immiscible solvent pairs can be combined with retention time data to confirm the identity of a substance when a pure standard is available [706]. Devised by Bowman and Beroza, the substance specific partition coefficient ("p-value") was defined as the fractional amount of substance partitioning into the less polar phase of an equal-volume, two-phase system. Only nanogram quantities of sample are required for the measurement and p-values are often sufficiently characteristic to distinguish between closely related substances. 

The distribution ratio D is used only in the context of ionizable molecules [229,270-276]. Otherwise, D and P are the same. The partition coefficient P, defined in Eq. (4.2), refers to the concentration ratio of a single species. In contrast,... 

If the permeating molecule is sufficiently bulky, of course, the degree to which it can partition into the polymer (dissolve in, with partition coefficient P = CQ and its mobility... 

The widely used term log P refers to the logarithm of the partition coefficient P of the unionized species, which is P° for a base with no acidic functions, and P1 for a monoprotic acid or an ordinary ampholyte. Log P is equal to log D at any pH remote from the pKa where the molecule exists entirely in its unionized form. Log D at any pH is equal to log P for a non-ionizable molecule. 

Equations have been published [16] which relate pKa and p0Ka values to partition coefficient (P) values for monoprotic acids and bases, and diprotic acids, bases and ampholytes. For example, P1 for a monoprotic acid is calculated from... 

Brooke, D.N., Dobbs, A.J., Williams, N. (1986) Octanol/water partition coefficients P measurement, estimation, and interpretation particularly for chemicals with P > 106. Ecotoxicol. Environ. Saf. 11, 251-260. 

As mentioned before, the hydrophobicity and the partition coefficient can be related to the solubility of the solutes in water (also see Section 15.8.4). The partition coefficient (P) between octanol and water can be described as the 7r-constant of Hansch or the logP values of Rekker. The logP values calculated from the fragmental constant are then used for the optimization of RPLC. However, this method is not adequate to develop an optimization system for the mixtures of different types of compounds [71]. 

The partition coefficient P = [concentration in C8Fi7H]/[concentration in 1-decene],... 

PARTITION COEFFICIENTS (P ), RETENTION FACTOR (K) AND MOBILITY DATA OF DYE INTERMEDIATES MEASURED WITH A PHOSPHATE-(TTAB) BUFFER AT PH 5.0 ... 

It assumes that there are no significant solute-solute interactions and no strong solute-solvent interactions which would influence the distribution process. Concentrations are expressed as mass/unit volume, and usually C1 refers to an aqueous phase and C2 to a non-aqueous phase. The equilibrium constant (P or K) defining this system is referred to as the partition coefficient or distribution ratio. The thermodynamic partition coefficient (P ) is given by the ratio of the respective mole fractions as follows ... 

The partition coefficient (P) is a measure of how a drug partitions between a water-immiscible lipid (or an organic phase) and water. It is defined as follows ... 

Monomer concentrations as a function of total surfactant concentration. Experimental CMC s are marked by arrows. At 0.01 o total surfactant levels, the monomer concentrations will be approximately given by the CMC values except for Cj E g whose CMC is 0.06.. Inset shows absorption profile if values of partition coefficient (P) shown apply. From Florence (1982). 

Fischer, R.G. and Ballschmiter, K. Determination of vapor pressure, water solubility, gas-water partition coefficient Pgw, Henry s law constant, and octanol-water partition coefficient P of 26 alkyl dinitrates, Chemosphere, 36 (14) 2891 -2901,1998a. 

Bennett and Larter (1997) also studied the solvation of alkylphenols in crude oil-water systems at equilibrium to obtain partitioning coefficients under variable temperature, pressure, and water salinity concentration. Alkylphenol depletion from crude oil, expressed by phenol, cresols, and 3,5 dimethyl phenol, versus temperature in a range of 25-125°C, is given in terms of partition coefficient (P) values (Fig. 16.22). Partition coefficient values increase with addition of alkyl groups to the phenol nucleus. Note that the alkylphenol partition coefficient curves for different isomers tend to converge at higher temperatures and, as a consequence, differences between phenol and p-cresol decrease with increases in temperature. Similar results for oil-deionised water and oil-brine experiments show that increasing temperature leads to a decrease in partition coefficient values. 

Fig. 16.23 Plot of partition coefficients, P, for alkylphenol (shaded symbols) and o-cresol (open symbols) at 25 (O), 200 (O), and 340 ( ) bar pressure versus temperature after 1 1 Miller oil/brine (20g/L NaCl) equilibration. Reprinted from Bennett B, Barter SR (1997) Partition behaviour of alkylphenols in crude oil brine systems under subsurface conditions. Geochim Cosmochim Acta 61 4393-4402. Copyright 1997 with permission of Elsevier...

Polarity term, mainly related to hydrogen bonding capability of a solute Logarithm of the partition coefficient (P) of neutral species Logarithm of the distribution coefficient (D) at a selected pH, usually assumed to be measured in octanol/water... 

For an organic compound, Hpophilicity can be described in terms of its partition coefficient P (or log P as it is generally expressed). This is defined as the ratio of concentrations of the compound at equilibrium between the organic and aqueous phases ... 

Figure 3. Effect of partition coefficient (P) on availance within a multilaminate septum in which detoxifying reactions occur with rate constants (k) = 1 and (k) = 0.04. Redrawn from Hartley and Graham-Bryce (13).

Provided, therefore, the additive contributions for different structural components can be quantified, the partition coefficient can be readily computed, A long established and convenient means for such quantification is already available in the form of the parachor, which is equivalent to the molar volume of a substance when its surface tension is unity. Parachor is primarily an additive property and there are extensive tabulations of parachor equivalents for various structural elements, such as that by Quayle (30). Parachor (H) can be related to partition coefficient (P) using the relationship of McGowan (3I) -... 

A measure of the capability of a solute for hydrophobic interactions, based on the partition coefficient P for the distribution of the solute between 1-octanol and water. 

The Menger-Portnoy model is closely related to the Berezin model employing partition coefficients instead of equilibrium constants.For the case where only two pseudophases (bulk water and micelle) are considered, the partitioning of the reactant is given by the partition coefficient P. This leads to Equation (4) describing observed rate constants as a function of surfactant concentration. 

As indicated earlier (Section 3.1.1) the sorption of organic compounds onto dissolved matter can significantly increase the solubility of the compound. This can in turn affect the fate of these chemicals in the environment. We can use physicochemical parameters such as distribution coefficients (log D), aqueous acid dissociation constants (pAia), and octanol-water partition coefficients (p/to )-These attributes are also linked to the acidity and alkalinity of the environment as well as lipohilicity of the compound. The mathematical relationships between these attributes are outlined below to explore how each of these impacts the fate of PPCPs in the environment. 

Several studies attempted to relate the partition coefficient P of a solute in a liquid chromatographic or a gas chromatographic system with the composition of the two phases, one of which has a varying composition [19-23]. Tijssen et al. [24] and Schoenmakers [25] derived a relation between the partition coefficient and a binary mobile phase in reversed-phase HPLC from the solubility parameter theory of Hildebrand et al. [26]. Similarly, a relation can be derived for liquid-liquid extraction with extraction liquids composed of three components ... 

Summarising, to optimise the partition coefficient P of a solute i, P, should be maximised by mixing three solvents in the correct proportions. The use of mixture design statistical techniques with the natural logarithm of the partition coefficient as response criterion is a valid way to achieve this. 

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