Octanol standard system

It is our opinion that, among isotropic systems, alongside the standard octanol-water, the alkane-water system (partihoning between water and different alkanes is relahvely independent of the alkane used [14]) is the only system that can be successfuUy used in ADMET predichon, because of its completely different nature from octanol-water. The situahon is much more confused for arhsohopic systems (see Ref. [7] for a brief review) since no standard system has been defined to date. 

Bouchard, G., Galland, A., Garrupt, P. A., Gulaboski, R., Mirceski, V., Scholz, F., Girault, H. H. Standard partition coefficients of anionic drugs in the n-octanol/water system determined by voltammetry at three-phase electrodes. Phys. Chem. Chem. Phys. 2003, 5, 3748-3751. 

The LFER that results when correlating partitioning in the octanol-water system and the humic substances-water system Implies that the thermodynamics of these two systems are related. Hence, much can be learned about humic substances-water partitioning by first considering partitioning In the simpler octanol-water system. The thermodynamic derivation that follows is based largely on the approach developed by Chlou and coworkers (18-20), Miller et al. (21), and of Karickhoff (J, 22). In the subsequent discussion, we will adopt the pure liquid as the standard state and, therefore, use the Lewls-Randall convention for activity coefficients, l.e., y = 1 if the mole fraction x 1. 

Since there are at least 20 solvent systems in common use in partitioning work and since any one of them can be compared with any other in an equation such as (1), it is important to choose one system as a standard to develop a uniform frame of reference. We have chosen the octanol/water system as Pi for a number of reasons, one of the more important being that the greatest number of biologically interesting solute types have been measured in it. 

The transfer free energy (as measured by the slope value) for any solute in an alcohol/water system should decrease as the chain length of the solvent alcohol is shortened. Of course the same effect ought to be observed if we hold the oil phase constant and make the aqueous phase less hydrophilic. The equations in Table V show that for a limited set of barbiturates partitioned between diethyl ether and a 50-50 mixture of water and dimethylformamide, the slope, compared with the octanol standard, is only 0.4 whereas the ether/water system gives a slope for the donor solute group of 1.13. Thus, a 50% reduction in the protic character of the polar phase reduces the sensitivity of the system by a factor of 2.8. 

Recent comparative studies by Abraham et al. [99] demonstrated that reversed-phase HPLC systems with PS-DVB phases could be used to determine water-alkane partition coefficients, whereas the modem electrostatically shielded octadecylsilica phase produces retention parameters correlating better to the standard log P from the octanol-water system. 

Log P values can be measured experimentally or predicted from molecular structure. Experimental approaches run the gamut from the highly reliable and traditional shake-flask method to newer methodologies such as electrokinetic chromatographic methods that are rapid, accurate and precise, and can be automated. However, for validation purposes, partition coefficient data of large, structurally diverse datasets obtained from such systems should be compared with that from the standard octanol/water system. 

Several hundreds of linear relationships between various kinds of (mostly nonspecific) biological data and n-octanol/water partition coefficients have been published e.g. [18, 182]). However, the choice of n-octanol/water as the standard system for drug partitioning must be reconsidered in the light of some recent results. Principal component analysis of partition coefficients from different solvent systems [188 —190] shows that lipophilicity depends on solute bulk, polar, and hydrogen-bonding effects [189] isotropic surface areas, i.e. areas where no water molecules bind and hydrated surface areas, were correlated with the first and the second principal components of such an analysis [190]. 

Lipophilicity represents the affinity of a molecule or a moiety for a lipophilic (= fat-loving) environment and is commonly measured by the partition coefficient, (where aaa represent a generic biphasic system, e.g. oct indicates the standard octanol-water). P is valid for a single electrical species, to be specified (P for neutral forms and P for ionized species). The distribution coefficient, expressed as is a pH-dependent descriptor (Eq. 3) for ionizable solutes and results from the weighted contributions of all electrical forms present at this pH ... 

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]. 

Valko et al. [37] developed a fast-gradient RP-HPLC method for the determination of a chromatographic hydrophobicity index (CHI). An octadecylsilane (ODS) column and 50 mM aqueous ammonium acetate (pH 7.4) mobile phase with acetonitrile as an organic modifier (0-100%) were used. The system calibration and quality control were performed periodically by measuring retention for 10 standards unionized at pH 7.4. The CHI could then be used as an independent measure of hydrophobicity. In addition, its correlation with linear free-energy parameters explained some molecular descriptors, including H-bond basicity/ acidity and dipolarity/polarizability. It is noted [27] that there are significant differences between CHI values and octanol-water log D values. 

The distribution of solutes between the two phases can be estimated by measurement of the relative solubility of the reagent in each phase of the system under given physical conditions. Water and 1-octanol have become a standard solvent mixture for this [21], although other pairs of solvents may be used to produce, for example, a scale of preference for fluorous versus organic solvents, as described below. The quantity P, known as the partition coefficient, is defined as... 

Solvents can cause enzyme inactivation (decrease the number of active enzyme molecules). The exact mechanisms are not so well known, but it is clear that solvent polarity plays an important role. Several solvent parameters have been used to try to rationalise the influence of solvents on enzymes. The parameter which has been used most for this purpose is the log P value, which is defined as the logarithm of the partition coefficient of a substance in the standard 1-octanol/water two-phase system (Table 9.4). Log P values can be determined experimentally by measuring the partitioning of the solvent between octanol and water. Alternatively, log P values... 

Table 17-1. Average and standard error for Ap and of benzene and phenol in water and n-octanol calculated from 100-ps MD run of the solution system and 50-ps MD run of the pure solvent system. Ap and are expressed in units of kcal/mol...

In order to determine a partition coefficient, equilibrium between all interacting components of the system must be achieved, and the concentrations of the substances dissolved in the two phases must be determined. Octanol and water are standard solvents for the equilibrium experiments. They are readily available and allow equilibrium experiments with good repeatability and reproducibility. 

---