Solvent-water Partition Research Articles

Prediction of Phospholipid-Water Partition Coefficients of Ionic Organic Chemicals Using the Mechanistic Model COSMOmic.

The partition coefficient of chemicals from water to phospholipid membrane, K(lipw), is of central importance for various fields. For neutral organic molecules, log K(lipw) correlates with the log of bulk solvent-water partition coefficients such as the octanol-water partition coefficient. However, this is not the case for charged compounds, for which a mechanistic modeling approach is highly necessary. In this work, we extend the model COSMOmic, which adapts the COSMO-RS theory for anisotropic phases and has been shown to reliably predict K(lipw) for neutral compounds, to the use of ionic compounds. To make the COSMOmic model applicable for ionic solutes, we implemented the internal membrane dipole potential in COSMOmic. We empirically optimized the potential with experimental K(lipw) data of 161 neutral and 75 ionic compounds, yielding potential shapes that agree well with experimentally determined potentials from the literature. This model refinement has no negative effect on the prediction accuracy of neutral compounds (root-mean-square error, RMSE = 0.62 log units), while it highly improves the prediction of ions (RMSE = 0.70 log units). The refined COSMOmic is, to our knowledge, the first mechanistic model that predicts K(lipw) of both ionic and neutral species with accuracies better than 1 log unit.

Analysis of the solubility of betaine: calculation of descriptors and physicochemical properties

We have previously constructed equations for the estimation of water–solvent partition coefficients of neutral molecules and of ions, in terms of properties or descriptors of the solute. We convert known solubilities of betaine in water and solvents into water–solvent partition coefficients and use the previous equations to determine descriptors for betaine. We show that equations for neutral compounds do not yield realistic results, but equations that include ionic terms allow descriptors for betaine to be determined. These indicate that betaine, although a very ‘polar’ molecule is not at all as polar as ion-pairs. From the determined descriptors, solubilities in further solvents and further water–solvent partition coefficients may be predicted.

Physicochemical and biochemical properties for the dialkyl phthalates

Abraham descriptors for 40 phthalate esters have been calculated from a variety of experimental data, including water–solvent partition coefficients, high performance liquid chromatographic and gas chromatographic retention times. These descriptors can then be used to calculate a large number of physicochemical and biochemical properties of the esters; values are given for dinonyl phthalate as an example. Once the Abraham descriptors have been obtained for a given phthalate ester, no more than simple arithmetic is needed to calculate values of a huge range of properties. The ‘three solubility method’ yields data that are consistent for a particular physicochemical property, but not necessarily correct data. Previous literature values for air–water partition coefficients for the higher phthalates are likely to be incorrect by several orders of magnitude.

Descriptors for the Prediction of Partition Coefficients of 8-Hydroxyquinoline and its Derivatives

Literature data on water-solvent partition coefficients have been used to obtain Abraham descriptors for 8-hydroxyquinoline and a large number of its derivatives. From these descriptors and known equations for water-solvent partitions, it is possible to predict partition coefficients for 40 derivatives of 8-hydroxyquinoline in 51 water-solvent systems with an error of about 0.05 log units. The method is entirely transparent and requires no more than simple arithmetic to implement.

On the solubility of quercetin

There is a considerable disagreement over the solubility of quercetin in water. Experimental values of log Cw with Cw in mol/L range from −2.52 to −5.89, a difference of over three log units. We have applied a methodology based on linear free energy equations for water-solvent and gas-solvent partitions to study solubilities. These are related to partition coefficients through Ps=Cs/Cw where Cs and Cw are solubilities of a given solute in a solvent and in water. We find that known solubilities of quercetin in methanol and ethanol at 298K and a known water-solvent partition coefficient can be accommodated in the same model if the water solubility at 298K, as log Cw, is taken as −3.90, that is near to the middle of the range of experimental values. Our model successfully predicts solubilities of quercetin in water–ethanol mixtures near to the ethanol rich mixtures.

An Improvement to COSMO-SAC for Predicting Thermodynamic Properties

A modified COSMO-SAC model is presented to calculate thermodynamic properties of pure fluids and mixtures using statistical thermodynamics and the surface charge density of each compound obtained from a quantum mechanics (QM) calculation. The main differences from the previous models are that the new model includes a dispersion contribution in the mixture interaction, and is reparametrized using measured pure and mixture thermodynamic data simultaneously. With a single set of universal parameters, the new model provides higher accuracy than our previous models for predicting mixture thermodynamic properties while maintaining the same accuracy for pure compound thermodynamic properties. The overall root-mean-square deviation (RMSD) in the logarithms of partition coefficients for 992 octanol–water partitioning systems and 829 other solvent–water partitioning systems with this new model is reduced by about 10% compared to the results from previous models. Also, the agreement between the predicted and measure...

DESCRIPTORS FOR ARTEMISININ AND ITS DERIVATIVES; ESTIMATION OF PHYSICOCHEMICAL AND BIOCHEMICAL DATA

Properties, or descriptors, of artemisinin and some of its derivatives have been obtained from known solubilities and water-octanol partition coefficients. These descriptors can then be combined with already known equations to yield water-solvent partition coefficients and solubilities in a very large number of solvents, so that it is now possible to select suitable solvents for purification, etc. Combination of the descriptors with known equations for blood-tissue partitions enables partition coefficients to be estimated for partitions from blood to brain, muscle, liver, lung, kidney, heart, skin and fat. Where data on blood-tissue partitions exist, there is agreement with experiment.

Determination of solvation descriptors for terpene hydrocarbons from chromatographic measurements

Gas chromatographic retention data on 107 terpene hydrocarbons from the literature together with other data have been used to obtain a set of Abraham descriptors for these 107 compounds. For 88 aliphatic cyclic terpene hydrocarbons, a fragmentation scheme was constructed that allows key descriptors to be estimated just from structure. The total set of descriptors, including those estimated by the fragmentation schemes, were then used to predict water–octanol partition coefficients for the 88 compounds, there being good agreement with values calculated from a number of well-known programs. For a small number of terpene hydrocarbons, there was good agreement between predicted and experimental values of nasal pungency thresholds, and predicted and experimental gas–blood, gas–oil, and gas–water partition coefficients. It is suggested that the descriptors obtained for the 107 terpene hydrocarbons can be used to predict water–solvent partition coefficients, gas–solvent partition coefficients, and partition coefficients in a number of biological systems.

Determination of partition coefficients of refrigerants by gas liquid chromatographic headspace analysis

Gas–water partition coefficients, Kw, and gas–solvent partition coefficients, Ks, have been determined for chlorodifluoromethane and for 1,1,1,3,3,3-hexafluoropropane by headspace analysis, using a very simple experimental procedure. These partition coefficients then yield water–solvent partition coefficients, Ps. Where comparisons can be made there is excellent agreement with literature values for Kw and Ps. The obtained values of Ks and Ps can be used to obtain physicochemical properties, or descriptors, for the refrigerants. Combination of these descriptors with previous equations we have developed enables partition coefficients to be obtained for a host of systems.

Prediction and Experimental Evaluation of Soil Sorption by Natural Hormones and Hormone Mimics

Surface runoff from manure-fertilized fields is a significant source of endocrine-disrupting compounds (EDCs) in the environment. Sorption by soils may play a major role in the environmental fate of manure-borne EDCs, including 17α- and 17β-estradiol (17α-E2 and 17β-E2), estrone (E1), melengestrol acetate (MGA), 17α- and 17β-trenbolone (17α-TB and 17β-TB), trendione (TND), and zeranol (α-ZAL). As a measure of sorption behavior, the organic carbon-normalized partition coefficients (K(OC)) of 17β-E2, E1, MGA, and α-ZAL were experimentally determined for three agricultural soils with initial EDC concentrations spanning from ∼0.01 to >1 μM. Sorption isotherms were linear for most solute-soil combinations. Measured K(OC) values were compared to those predicted using a suite of single-parameter and polyparameter linear free energy relationships (sp- and pp-LFERs). Sp-LFER models were based on experimentally determined octanol-water partition coefficients (K(OW)), whereas pp-LFER solute descriptors were calculated indirectly from experimentally determined solvent-water partition coefficients or the program ABSOLV. Log K(OC) predictions by sp-LFERs were closest to the experimentally determined values, whereas pp-LFER predictions varied considerably due to uncertainties in both solute and sorbent descriptors determined by ABSOLV or estimates using the partition coefficient approach.

Gas–solvent and water–solvent partition coefficients of the tetraphenyl compounds of group (IV)

Literature data on solubilities in organic solvents and vapor pressures at 298 K have been used to obtain gas to solvent partition coefficients for Ph4M (M = C, Si, Ge, Sn, Pb). These partition coefficients together with known equations that relate partition coefficients to Abraham descriptors have been used to calculate the Abraham descriptors E, S, A, B, V and L. It is shown that for tetraphenylmethane the dipolarity/polarizability descriptor, S, is much smaller than anticipated. From the descriptors it is possible to calculate partition coefficients from water to the organic solvents, and from these together with solubilities in organic solvents finally to deduce the aqueous solubility, Cw in mol dm−3, of the Ph4M compounds. The solubilities we calculate for Ph4C and Ph4Ge, log Cw = −10.93 ± 0.58 and −11.12 ± 0.58 respectively, are far smaller than those obtained previously by experiment, log Cw = −7.8 and −7.77, so that our values for water–solvent partition coefficients are much larger than previously suggested. A number of important physico-chemical properties of the Ph4M compounds are also calculated.

Solvation thermodynamics and the physical–chemical meaning of the constant in Abraham solvation equations

Abraham solvation equations find widespread use in environmental chemistry. Until now, the intercept in these equations was determined by fitting experimental data. To simplify the determination of the coefficients in Abraham solvation equations, this study derives theoretical expressions for the value of the intercept for various partition processes. To that end, a modification of the description of the Ben-Naim standard state into the van der Waals volume is proposed. Differences between predicted and fitted values of the Abraham solvation equation intercept for the enthalpy of solvation, the entropy of solvation, solvent–water partitioning, air-solvent partitioning, partitioning into micelles, partitioning into lipid membranes and lipids, and chromatographic retention indices are comparable to experimental uncertainties in these values.

Sorption and desorption of 17β-estradiol to natural sediment

The sorption and desorption of 17β-estradiol (E2) to various natural sediment were investigated. First, the quantitative solvent-water partition indices were measured. Significant differences were found between the n-octanol-water partition coefficient (K(OW)) and the n-hexane-water partition coefficient (K(HW)) of E2. The value of K(HW) (Log K(HW) = 0.07) is lower than those of two to four ring polyaromatic hydrocarbons (PAHs), while the value of K(OW) (Log K(OW) = 3.99) and that of organic matter-water partition coefficient (K(OC)) onto humic acid (Log K(OC) = 4.30) were similar to those of the PAHs. Five natural sediments of various characteristics and origins were selected for sorption and desorption experiments. Linear isotherms were obtained for sorption and desorption. The equilibrium partitioning coefficients of E2 were well-correlated with their values of weight fraction of organic carbon in sediments (f(OC)). Results suggest that E2 is sorbed mainly onto the organic portion of sediments and that its sorption coefficient can be estimated from K(OW) and f(OC), as in the case of non-polar PAHs. However, because of its polarity, the sorption mechanism of E2 onto sediments cannot be explained solely by the hydrophobic interaction.

The lipophilicity and hydrogen bond strength of pyridine-N-oxides and protonated pyridine-N-oxides

Water–solvent partition coefficients for 4-nitropyridine-N-oxide have been determined in six solvent systems, and solubilities measured in water and 37 solvents. The combined data are used to obtain Abraham descriptors for 4-nitropyridine-N-oxide as follows: E = 0.934, S = 1.92, A = 0.21, B = 0.76, V = 0.9082 and L = 5.246; literature data on partition coefficients were used to calculate descriptors for 11 other pyridine-N-oxides as well as quinoline-N-oxide and isoquinoline-N-oxide. In all cases, the N-oxides were shown to be stronger hydrogen bond bases than the corresponding pyridines, thus leading to a decrease in lipophilicity. An unexpected observation is that of the hydrogen bond acidity of the N-oxides due, we suggest, to the positive nitrogen atom in the moiety N(+) → O(−). This leads to an even sharper decrease in the N-oxide lipophilicity in non-polar solvents. We have also used literature data to determine the 1 ∶ 1 hydrogen bond basicity, βH2, of a number of pyridine-N-oxides; again, this basicity is significantly larger than that of the corresponding pyridines. Protonation of pyridine-N-oxides removes all hydrogen bond basicity (B = 0.00), but the protonated compounds are strong hydrogen bond acids. For protonated pyridine-N-oxide itself, E = 0.514, S = 2.62, A = 1.51, B = 0.00, V = 0.7555 and the ionic descriptor J+ = 0.894; protonated 4-nitropyridine-N-oxide with A = 2.05 is a very strong hydrogen bond acid indeed.

Prediction of Soil Sorption Coefficients using Model Molecular Structures for Organic Matter and the Quantum Mechanical COSMO-SAC Model

The soil sorption coefficient, K(OC), is an important property affecting the environmental fate of organic molecules. Difficulties associated with measuring K(OC) have led to many attempts to predict this property, but most rely on empirical descriptors for the soil phase determined from correlations with measured K(OC) data, and are thereby limited by the data quality and diversity. A new method is presented to predict K(OC) for nonionic organic compounds that requires only molecular structures. No calibration is performed. Using model humic acid (HA) and fulvic acid (FA) molecular structures from the literature, the soil organic matter is modeled as an organic solvent composed of HA or FA molecules. K(OC) is predicted as an organic solvent-water partition coefficient using the quantum mechanics-based model COSMO-SAC. The log K(OC) values for a set of 440 diverse, environmentally relevant chemicals are predicted with a root-mean-square error of 0.84-1.08, depending on which model HA or FA is used.

ChemInform Abstract: Model Solvent Systems for QSAR. Part 2. Fragment Values (“f-Values”) for the “Critical Quartet”.

A data matrix has been prepared of log P values for 103 compounds distributed across four highly contrasted solvent–water partitioning systems: the ‘critical quartet’ of octanol (amphiprotic), alkane (inert), chloroform (proton donor) and propylene glycol dipelargonate (PGDP; proton acceptor). Here ‘alkane’ is defined as the straight-chain sequence from hexane to octane and (possibly) higher; it is shown that cyclohexane is out of line. In principle, these log P values can now be used to construct a comparative table of fragment values (f-values) for all four systems. In practice, those for non-polar substituents must first be established. Here the key quantity is f(CH2). This has been re-determined, and in the process its variability rationalised, for 24 water-saturated solvent systems; here the key factors (dry solvents are different) turn out to be the molarity, in the organic phase, of water and the solvent's own functional group. There results an almost complete data matrix of 82 f-values for all four solvents, about 25% of which are derived from the linear solvation energy relationship (LSER) equations of Part 3.7 It is shown that these four sets are very distinct, a fact that misleading statistical treatments can easily disguise. How the medicinal chemist might use these contrasting data sets is critically discussed, with particular reference to the rationalisation of biological selectivity.

Spectroscopic analysis of naphtholazobenzimidazole in organised solution

Micelle–water partition coefficient (Kx ) of naphtholazobenzimidazole dye (NAB) in aqueous solutions of cetyltrimethylammonium bromide (CTAB) and sodium dodecyl sulphate (SDS) has been determined spectrophotometerically. Changes in absorption patterns of dye caused by surfactants and solvents were quantified in terms of dye–surfactant ratio (n D/n S) and solvent water partition coefficients (P), respectively. Multiple residence sites have been suggested for dye molecules within micelles, based on shifts in azo-hydrazone tautomeric equilibrium. Micelle–water partition coefficients were used to evaluate the influence of dye on critical micelle concentration of CTAB and SDS. At same micelle concentration, M, the relative solubility of NAB was greater in cationic surfactant CTAB than in anionic surfactant SDS.

Water–Solvent Partition Coefficients and Δ Log P Values as Predictors for Blood–Brain Distribution; Application of the Akaike Information Criterion

It is shown that log P values for water–alkane or water–cyclohexane partitions, and the corresponding Δ log P values when used as descriptors for blood–brain distribution, as log BB, yield equations with very poor correlation coefficients but very good standard deviations, S from 0.25 to 0.33 log units. Using quite large data sets, we have verified that similar S‐values apply to predictions of log BB. A suggested model, based on log P for water–dodecane and water–hexadecane partition coefficients, has 109 data points and a fitted S = 0.254 log units. It is essential to include in the model an indicator variable for volatile compounds, and an indicator variable for drugs that contain the carboxylic group. A similar equation based on water–chloroform partition coefficients has 83 data points and a fitted S = 0.287 log units. We can find no causal connection between these log P values and log BB in terms of correlation or in terms of chemical similarity, but conclude that the log P descriptor will yield excellent predictions of log BB provided that predictions are within the chemical space of the compounds used to set up the model. We also show that model based on log P(octanol) and an Abraham descriptor provides a simple and easy method of predicting log BB with an error of no more than 0.31 log units. We have used the Akaike information criterion to investigate the most economic models for log BB. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2492–2501, 2010

The hydrogen bond acidity and other descriptors for oximes

The solvation descriptors for cyclohexanone oxime and acetone oxime have been obtained from measurements on water–solvent partitions, and gas–liquid chromatographic retention data. These yield values of 0.33 and 0.37 for the Abraham hydrogen bond acidity, A, in reasonable agreement with a value of 0.37 for cyclohexanone oxime obtained by our recent NMR method. The other descriptors E, S, B, L and V have also been obtained for cyclohexanone oxime and acetone oxime, and have been estimated for a number of other oximes as well. The value for A, the overall or effective hydrogen bond acidity of the oximes is reasonably close to the 1 : 1 hydrogen bond acidity, α2H = 0.39 to 0.46, that can be deduced from previous literature measurements on oximes, and to the 1 : 1 hydrogen bond acidity, α2H = 0.43 for another NOH compound, N,N-dibenzylhydroxylamine, that again can be deduced from literature measurements.

Improved Prediction of Octanol−Water Partition Coefficients from Liquid−Solute Water Solubilities and Molar Volumes

A volume-fraction-based solvent-water partition model for dilute solutes, in which the partition coefficient shows a dependence on solute molar volume (V), is adapted to predict the octanol-water partition coefficient (K(ow)) from the liquid or supercooled-liquid solute water solubility (Sw), or vice versa. The established correlation is tested for a wide range of industrial compounds and pesticides (e.g., halogenated aliphatic hydrocarbons, alkylbenzenes, halogenated benzenes, ethers, esters, PAHs, PCBs, organochlorines, organophosphates, carbamates, and amides-ureas-triazines), which comprise a total of 215 test compounds spanning about 10 orders of magnitude in Sw and 8.5 orders of magnitude in K(ow). Except for phenols and alcohols, which require special considerations of the K(ow) data, the correlation predicts the K(ow) within 0.1 log units for most compounds, much independent of the compound type or the magnitude in K(ow). With reliable Sw and V data for compounds of interest, the correlation provides an effective means for either predicting the unavailable log K(ow) values or verifying the reliability of the reported log K(ow) data.