Octanol/water distribution coefficient

S. W. Karickhoff and D. S. Brown, determination of Octanol Water Distribution Coefficients, Water Solubilities, and Sediment/Water Partitions Coefficientsfor Hydrophobic Organic Pollutants, EPA-600/4-79-032, report, EPA, Washington, D.C., 1979. 

MD simulations in expHcit solvents are stiU beyond the scope of the current computational power for screening of a large number of molecules. However, mining powerful quantum chemical parameters to predict log P via this approach remains a challenging task. QikProp [42] is based on a study [3] which used Monte Carlo simulations to calculate 11 parameters, including solute-solvent energies, solute dipole moment, number of solute-solvent interactions at different cutoff values, number of H-bond donors and acceptors (HBDN and HBAQ and some of their variations. These parameters made it possible to estimate a number of free energies of solvation of chemicals in hexadecane, octanol, water as well as octanol-water distribution coefficients. The equation calculated for the octanol-water coefficient is ... 

Tetko, I. V., Bruneau, P. Application of ALOGPS to predict 1-octanol/water distribution coefficients, log P, and log D, of AstraZeneca in-house database. 

Fig. 16.2 Octanol-water distribution coefficient versus pH for a weak acid with pfC=4, logPHA=4 and logP =0 (solid line) or 2 (dashed line).

While there are plenty of methods to predict 1-octanol-water partition coefficients, logP (see Chapters 14 and 15), the number of approaches to predict 1-octanol-water distribution coefficients is rather limited. This is due to a lower availability of log D data and, in general, higher computational complexity of this property compared to that of log P. The approaches to predict log D can be roughly classified into two major categories (i) calculation of log D at an arbitrary pH and (ii) calculation of log D at a fixed pH. 

Although traditional octanol/water distribution coefficients are still widely used in quantitative structure-activity relationships (QSAR) and in ADME/ pharmacokinetic (PK) studies, alternatives have been proposed. To cover the variability in biophysical characteristics of different membrane types, a set of four solvents has been suggested - sometimes called the critical quartet [49-51], The 1,2-dichloroethane (DCE)/water system has been promoted as a good alternative to alkane/water due to its far better dissolution properties [50, 51], but it may be used only rarely due to its carcinogenic properties. 

Using a pPLC system, log P for one unknown compound was determined in less than 1 hr. It is important to note that the excess capacity provided by the system (24 columns are available for simultaneous analysis) allows simultaneous determination of log P for six additional compounds. The same study required 5 hr using conventional HPLC, and consumed 300 mL of solvent, equivalent to 15 times the volume of solvent used for the evaluations via jtiPLC. A similar approach can be used to evaluate log D, the octanol-water distribution coefficient—a measure of the distribution ratios of all combinations (ionized and unionized) of octanol and pH-buffered water. 

Holten Liitzhoft, H.-C., Yaes, W. H. J., Freidig, A. P., Halling-Sorensen, B. and Hermens, J. L. M. (2000). 1-Octanol/water distribution coefficient of oxolinic acid influence of pH and its relation to the interaction with dissolved organic carbon, Chemosphere, 40, 711-714. 

The lipophilicity of a substance, that is, the tendency of a substance to become dissolved in a lipid, is often measured by the tendency of a substance to become dissolved in a nonpolar solvent, for example, by the n-octanol-water distribution coefficient. The lipophilicity of a substance is inversely proportional to its water solubility. 

The use of capillary electrophoresis (CE) during the synthetic drug development is described from the preclinical development phase to the final marketed stage. The chapter comprises the determination of physicochemical properties, such as acid—base dissociation constants (pKJ, octanol—water distribution coefficients (logP), and analysis of pharmaceutical counterions and functional excipients. 

Karickhoff, S. W., and Brown, D. S. (1979). Determination of octanol/water distribution coefficients, water solubilities, and sediment/water partition coefficients for hydrophobic organic pollutants. EPA/600/4-79/032 (Order No. PB80-103591). 

Hafkenscheid, T.L., Tomlinson, E. (1983) Correlation between alkane/water and octanol/water distribution coefficients and isocratic reversed-phase liquid chromatographic capacity factor of acids, bases and neutrals. Int. J. Pharm. 16, 225-240. 

For example, the ratio of the n-octanol/watcr distribution coefficient of the nondissociated species to that of the ionic species is nearly 10,000 for 3-methyl-2-nitrophenol, but only about 1000 for pentachlorophenol because of the greater significance of the hydrophobicity of the ionized form of pentachlorophenol. The logarithm of the -octanol/water distribution coefficient of pentachlorophenol as the phenolate is about 2 (determined at pH 12, and 0.1 M KC1), which indicates significant distribution of the ionized form into the n-octanol phase [8,37], Extraction of such highly hydrophobic ionogenic organic compounds can result from mixed-mode mechanisms that incorporate both the hydrophobic and ionic character of the compound. 

In the case of a structurally inhomogeneous series of antihistamines, the sedative side-effects were found to be much better described by their octanol-water distribution coefficient at pH 7.4, log D, than by Alog P0ct.-aik. or their hydration capacity, Aalkane [b7[. 

Apart from the hydrophobic interactions provided by the alkyl part of the molecule, octanol has also hydrogen-bond acceptor and donor functions like lipid membranes have. This property of n-octanol made the octanol-water distribution coefficient that widely used. However, n-octanol or reversed phase materials cannot mimic the interfacial character of the bilayer structure. The ionic interactions between membrane phospholipids and solute are also not represented in the properties of octanol or reversed phase materials. To overcome this issue, alternative stationary phases... 

Figure 9.28. The distribution of nonpolar organic substances between aquatic solids and water (as given by the distribution coefficient Kp) is dependent upon the lipophilicity of the compound and the organic C content of the adsorbing material (foe = weight fraction). The solid phases considered here are coastal sea and lake sediments, river sediments, solids from aquifers and biomass (activated sludge). The octanol/water distribution coefficients are, respectively 500, 2400, 11,200 and 52,000 for chlorobenzene, 1,4-dichlorobenzene, 1,2,4-trichlorobenzene and 1,2,4,5-tetrachlorobenzene. (Modified from Schwarzenbach and Westall, 1980).

Figure 9.29. The lipophilicity of a substance, as measured by the octanol-water distribution coefficient, is an essential parameter for predicting biomagnification (biostorage and accumulation in the food chain) (Calculated from data by Chiou et al., 1977.)...

Fraction of organic carbon Octanol-water distribution coefficients Tetrachlorethylene Tetrachlorobenzene... 

When two immiscible phases in contact with each other reach equilibrium, the solute distributes between the two immiscible phases with a different concentration in each phase. For instance, if acetone (the solute) is equilibrated between octanol and water, the acetone s octanol concentration, C, and water concentration, C, are related by the octanol/water distribution coefficient, in L of water per L of organic phase ... 

However, experimental determination of logP does include correlation with such properties. For example, the ElogD method developed by Lombardo et al. [67] uses RP-HPLC retention data to determine octanol-water distribution coefficients at pH 7.4 for neutral and basic drugs in Pfizer. Moreover the authors used the same method to determine ElogD at pH 6.5, thus calculating important parameters for intestinal absorption [68],... 

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