Alkane-water partitioning

One of the first studies to predict log P by using potential energy fields calculated using the GRID and CoMFA approaches was done by Kim [60]. The author investigated H, CH3 and H2O probes, and calculated the best models using the hydro-phobic probe H2O for relatively small series (20 or less compounds each) of furans, carbamates, pyridines and pyrazines. A similar study was performed by Waller [61] who predicted a small series of 24 polyhalogenated compounds. Recently, Caron and Ermondi [62] used a new version of Cruciani s software, VolSurf [63], to predict the octanol-water and alkane-water partition coefficients for 152 compounds with r = 0.77, q = 0.72, SDEP = 0.60 for octanol-water and r = 0.76, q = 0.71, SDEP = 0.85 for alkane-water. 

Figure 7.11 Intrinsic permeabilities versus alkane-water partition coefficients for drugs PAMPA filters soaked with alkane [509].

Figures 7.31a-c clearly show that after some critical soy content in dodecane, Pe values decrease with increasing soy, for both sink and sinkless conditions. [This is not due to a neglect of membrane retention, as partly may be the case in Fig. 7.23 permeabilities here have been calculated with Eq. (7.21).] Section 7.6 discusses the Kubinyi bilinear model (Fig. 7.19d) in terms of a three-compartment system water, oil of moderate lipophilicity, and oil of high lipophilicity. Since lipo-some(phospholipid)-water partition coefficients (Chapter 5) are generally higher than alkane-water partition coefficients (Chapter 4) for drug-like molecules, soy lecithin may be assumed to be more lipophilic than dodecane. It appears that the increase in soy concentration in dodecane can be treated by the Kubinyi analysis. In the original analysis [23], two different lipid phases are selected at a fixed ratio (e.g., Fig. 7.20), and different molecules are picked over a range of lipophilicities.

Faller and Wohnsland [18, 19] developed the PAMPA assay using phospholipid-free hexadecane, supported on 10 pm-thick polycarbonate filters, and were able to demonstrate interesting predictions. Their PAMPA method appeared to be a satisfactory substitute for obtaining alkane/water partition coefficients, which are usually very difficult to measure directly, due to the poor solubility of drug molecules in alkanes. Apparently, membrane retention was not measured. 

Wohnsland and Faller ([175] performed measurements using a thin (9-10 //in) supported, phospholipid-free hexadecane layer. To validate their model, they used 32 well-characterized chemically diverse compounds. The permeability values obtained with their model could be correlated with known human absorption values if the maximum permeability obtained at different pH was taken into account. However, several disadvantages are related to this method. For hydrophilic drugs, hexadecane by itself has an increased barrier function in comparison with membranes. In addition, the hexadecane layers are not very stable, which makes this assay difficult to apply as a routine screening method. The advantage of this PAMPA setup is that it appears to be a satisfactory substitute for obtaining alkane-water partition coefficients, which are usually very difficult to measure directly, due to the poor solubility of drug molecules in alkanes. 

Toulmin, A., Wood, J.M. and Kenny, P.W. (2008) Toward prediction of alkane/water partition coefficients. Journal of Medicinal Chemistry, 51, 3720-3730. 

Determination of alkane/water partition coefficients of polar compounds using hydrophilic interaction chromatography. Journal of Chromatography A, submitted. 

These equations make explicit the individual polar terms that are negatively related to lipophilicity and account for most polar interactions between a solute and the two solvent phases. In the case of the octanoi/water system (Eq. [6]), the main contributor to a solute s polarity is thus its H-bond acceptor basicity 0), and to a lesser extent its dipolarity/ polarizability (ir ). In contrast, the polar interactions expressed in alkane/ water partition coefficients (Eq. [7]) are the H-bond donor acidity (a) and the H-bond acceptor basicity 0), and again to a lesser extent the dipolarity/polarizability (ir ). 

With only few exceptions, most log P programs refer to the octanol-water system. Based on Rekker s fragmental constant approach, a log P calculation for aliphatic hydrocarbon-water partitioning has been reported [96]. Another more recent approach to alkane-water log P and log D is based on the program VolSurf [97]. It is believed that these values may offer a better predictor for uptake in the brain. 

A CRO may also allow for the in-house introduction of specialized lipophilic scales by transferring routine measurements. While the octanol-water scale is widely applied, it may be advantageous to utilize alternative scales for specific QSAR models. Solvent systems such as alkane or chloroform and biomimetic stationary phases on HPLC columns have both been advocated. Seydel [65] recently reviewed the suitabihty of various systems to describe partitioning into membranes. Through several examples, he concludes that drug-membrane interaction as it relates to transport, distribution and efficacy cannot be well characterized by partition coefficients in bulk solvents alone, including octanol. However, octanol-water partition coefficients will persist in valuable databases and decades of QSAR studies. 

It is also quite interesting that lipid model 4.0 may be used to obtain alkane partition coefficients at high-throughput speeds, as suggested by Faller and Wohnsland [509,554], It is also interesting to note that since our Pe are corrected for membrane retention, the slope in Fig. 7.11 corresponding to the dashed line (our data) is 1.0, whereas the data not corrected for retention (solid line) show a lesser slope. This may not matter if the objective is to obtain alkane-water log Kp values at high speeds. 

Seiler [250] proposed a way of estimating the extent of hydrogen bonding in solute partitioning between water and a lipid phase by measuring the so-called A log P parameter. The latter parameter is usually defined as the difference between the partition coefficient of a solute measured in the octanol-water system and that measured in an inert alkane-water suspension AlogP = log Kp oet — log Kp aik. 

A log P Difference between log P in octanol/water and alkane/water log D Logarithm of the distribution coefficient in octanol/water at pH 7.4 log P Logarithm of the partition coefficient in octanol/water (for neutral species)... 

Jonsson, J. A., Vejrosta, J., Novak, J. (1982) Air/water partition coefficients for normal alkanes (n-pentane to n-nonane). Fluid Phase Equil. 9, 279-286. 

FIGURE 2.2.5 Octanol -water partition coefficient versus Le Bas molar volume for alkanes. 

Trzilova, B., Horska, E. (1988) Biodegradation of amines and alkanes in aquatic environment. Biologia (Bratislava) 43, 209-218. Tse, G., Sandler, S.I. (1994) Determination of infinite dilution activity coefficients and 1-octanol/water partition coefficients of volatile organic pollutants. J. Chem. Eng. Data 39, 354—357. 

The studies with barbiturates revealed that the logarithm of the retention time is linearly related to the octanol/water partition coefficients [66,67]. It has been observed that the retention index of the drug is linearly related to the octanol/water partition coefficient (logP), and that results are very close to that of the 2-keto alkane standard (solid line in Fig. 15.9). 

The physical properties of -hexane (see Table 3-2) that affect its transport and partitioning in the environment are water solubility of 9.5 mg/L log Kow (octanol/water partition coefficient), estimated as 3.29 Henry s law constant, 1.69 atm-m3 mol vapor pressure, 150 mm Hg at 25 °C and log Koc in the range of 2.90 to 3.61. As with many alkanes, experimental methods for the estimation of the Koc parameter are lacking, so that estimates must be made based on theoretical considerations (Montgomery 1991). 

Among the large number of existing lipophilicity parameters [31], the descriptor frequently estimated by in silica methods is the partition coefficient of a solute between 1-octanol and water, expressed as log Poet [32]. However, lipophilicity determination in different solvent systems, such as alkane/water system, proved its utility in (Q)SAR studies and therefore some predictive methods also emerged in this field. Many publically available databases include numerous experimental values collected through the literature the quality of the experimental data represents the cornerstone of most of the models developed to predict lipophilicity. 

Illustrative Example 6.4 Estimating Air-Water Partition Constants by the Bond Contribution Method Problem Estimate the Kiavi values at 25°C of (a) n-hexane, (b) benzene, (c) diethylether, and (d) ethanol using the bond contribution values given in Table 6.4. Compare these values with the experimental air-water partition constants given in Table 3.4. Note that for a linear or branched alkane (i.e., hexane) a correction factor of +0.75 log units has to be added (Meylan and Howard, 1991). 

Within a given class of apolar or weakly polar compounds (e.g., alkanes, chlorobenzenes, alkylbenzenes, PCBs), the variation in the air-octanol partition constants (Kiao) is much larger than the variation in the air-water partition constants (Kiaw). For example, the Kim values of the chlorinated benzenes vary between 10 3 5 (chlorobenzene) and 10-7 (hexachlorobenzene, see Hamer and Mackay, 1995), whereas their A, aw values are all within the same order of magnitude (Appendix C). Try to explain these findings. 

Model of Bahnick and Doucette Molecular connectivity indices have been applied to establish structure-soil water partitioning relationships for various classes of compounds. Bahnick and Doucette [22] briefly review such models and present a new model for a variety of organic compounds, including halogenated alkanes, PAHs, chlorobenzenes, PCBs, and different pesticide classes. The model is... 

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