Octanol/water distribution

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. 

Fig. 3.1 Octanol-water distribution (log Don) versus pH profile for pindolol, based on data reported by Barbato et al. [70]. The pCEL-X computer program (plON) was used to...

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. 

Here, APsuv is the absorption potential measured from the distribution in small unilamellar vesicles (SUV) at pH 6.8, the solubility was measured at pH 6.8 in simulated intestinal fluid, V is the volume of intestinal fluid, and dose is a mean single oral dose. Liposome partitioning is only partly correlated with octanol/water distribution. 

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. 

Figure 11. Uptake rates of inorganic Hg (a) and of methylmercury (b) by a marine alga as a function of the octanol-water distribution ratio of the Hg-species under various conditions of pH and chloride concentrations. The neutral species HgCl and CH5HgClH diffuse through the membranes. Reprinted with permission from [79] Mason, R. P. et al. (1996). Uptake, toxicity, and trophic transfer in a coastal diatom , Environ. Sci Technol., 30, 1835-1845 copyright (1996) American Chemical Society...

ZZoW Apparent octanol-water distribution ratio at ... 

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. 

However, as the number of H-bonding functions in a molecule rises, octanol/ water distribution, in isolation, becomes a progressively less valuable predictor. For such compounds desolvation and breaking of H-bonds becomes the rate-limiting step in transfer across the membrane [7]. 

Figure 3. Octanol/water distribution of salicylic acid over a range of pH values ...

In contrast to air-water partitioning, the situation may be a little more complicated when dealing with organic solvent-water partitioning of organic acids and bases. As an example, Fig. 8.9 shows the pH dependence of the n-octanol-water distribution ratios, D,ow (HA, A"), of four pesticides exhibiting an acid function ... 

Figure 8.9 The pH dependence of the /z-octanol-water distribution ratio of pentachlorophenol (PCP, pKj = 4.75), 4-chloro-a-(4-chlo-rophenyl) benzene acetic acid (DDA, pKb = 3.66), 2-methyl-4,6-dinitrophenol (DNOC, pKia = 4.46), and 2,4,5-trichlorophenoxy acetic acid (2,4,5-T, pKia = 2.83). (from Jafvert et al., 1990).

Figure 8.10 Calculated octanol-water distribution ratio of 2,4-dini-tro-6-methylphenol (DNOC, p= 4.46) as a function of pH and K+ concentration (adapted from Jafvert et al. 1990).

Figure 10.14 Log octanol-water distribution ratios (log D,ow, broken lines) and log L-a-dioleylphos-phatidylcholine liposome-water distribution ratios (log Dflipsw, solid lines) of pentachlorophenol (PCP) and 2-sec-butyl-4,6-dinitrophenol (dinoseb) as a function of pH at 25°C and 100 mM ionic strength. Data from Escher et al. (2000).

Figure 10.15 Plot of log 1 /LCi50 for guppies versus (a) log octanol-water distribution ratio (log Z),ow, Eq. 10-41), and (b) log liposome-water distribution ratio (log Z),lipsw, Eq. 10-41) at pH 7 for a series of chlorinated benzenes (o) and chlorinated phenols ( ) as well as for the herbicide 2-.9ec-butyl-4.6-dinitrophenol (dinoseb) (v). The liposomes used were L-a-dimy-ristoyl-phosphatidylcholine (chlorinated benzenes) and L-a-dioleyl-phosphatidylcholine (chlorinated phenols and dinoseb). The pH dependence of D/ow and D,lipsw of pentachlorophenol (PCP) and dinoseb is shown in Fig. 10.14. Data from Saarikoski and Viluskela (1992), Gobas et al. (1988), Escher and Schwarzenbach (1996), and Gunatilleka and Poole (1999).

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