Aqueous solubility estimation from

Delaney JS. ESOL estimating aqueous solubility directly from molecular structure. J Chem Inf Comput Sci 2004 44 1000-5. 

Delaney, J. S. ESOL estimating aqueous solubility diredly from molearlar strurture. J. Chem. Inf. Comput. Sci. 2004, 44,1000-1005. 

This phase was first described by Birkenbach and Huttner [30BIR/HUT], who also estimated its aqueous solubility product from a one-point determination of [Ag ] in a saturated AgSeCN suspension to be log (AgSeCN, cr, 291 K) = — 15.4. 

An extensive series of studies for the prediction of aqueous solubility has been reported in the literature, as summarized by Lipinski et al. [15] and jorgensen and Duffy [16]. These methods can be categorized into three types 1 correlation of solubility with experimentally determined physicochemical properties such as melting point and molecular volume 2) estimation of solubility by group contribution methods and 3) correlation of solubility with descriptors derived from the molecular structure by computational methods. The third approach has been proven to be particularly successful for the prediction of solubility because it does not need experimental descriptors and can therefore be applied to collections of virtual compounds also. 

The Rvalues are partition coefficients. The assumption that these are real constants Is seldom completely true, of course, because equilibrium Is rarely achieved and because the equilibrium ratios generally are not the same for all concentration levels. Moreover, It Is difficult to find the needed Information, and one must often accept a single literature value as typical of a given Intermedia transfer. When the organic content of the soli Is known or can be accurately estimated, one can usually derive Kgw from a compound s aqueous solubility, S, or Its octanol/water partition coefficient, KQW (14) Values of Kpa, namely "bloconcentratlon factors" between feed and meat animals (15,16), can also be derived from S or KQW. Bloconcentratlon factors between water and fish are well documented (14) A considerable weakness exists In our perception of the proper estimates to use for partition coefficients between soli and edible crop materials. Thus, at one time, two of the present authors used a default value of Kgp = 1 for munitions compounds that are neither very soluble In water nor very Insoluble (4) at another time, a value of was assumed for compounds with very low values of Ksw, l.e., polybromoblphenyls (6). 

Estimated from poster data presented in Rapid screening of aqueous solubility by a nephelometric assay ,... 

QMPRPlus was used to generate in silico estimates of log P, aqueous solubility, and human jejunal permeability from 3D molecular structures. The predictive... 

In the multimedia models used in this series of volumes, an air-water partition coefficient KAW or Henry s law constant (H) is required and is calculated from the ratio of the pure substance vapor pressure and aqueous solubility. This method is widely used for hydrophobic chemicals but is inappropriate for water-miscible chemicals for which no solubility can be measured. Examples are the lower alcohols, acids, amines and ketones. There are reported calculated or pseudo-solubilities that have been derived from QSPR correlations with molecular descriptors for alcohols, aldehydes and amines (by Leahy 1986 Kamlet et al. 1987, 1988 and Nirmalakhandan and Speece 1988a,b). The obvious option is to input the H or KAW directly. If the chemical s activity coefficient y in water is known, then H can be estimated as vwyP[>where vw is the molar volume of water and Pf is the liquid vapor pressure. Since H can be regarded as P[IC[, where Cjs is the solubility, it is apparent that (l/vwy) is a pseudo-solubility. Correlations and measurements of y are available in the physical-chemical literature. For example, if y is 5.0, the pseudo-solubility is 11100 mol/m3 since the molar volume of water vw is 18 x 10-6 m3/mol or 18 cm3/mol. Chemicals with y less than about 20 are usually miscible in water. If the liquid vapor pressure in this case is 1000 Pa, H will be 1000/11100 or 0.090 Pa m3/mol and KAW will be H/RT or 3.6 x 10 5 at 25°C. Alternatively, if H or KAW is known, C[ can be calculated. It is possible to apply existing models to hydrophilic chemicals if this pseudo-solubility is calculated from the activity coefficient or from a known H (i.e., Cjs, P[/H or P[ or KAW RT). This approach is used here. In the fugacity model illustrations all pseudo-solubilities are so designated and should not be regarded as real, experimentally accessible quantities. 

As described earlier, Henry s law constants can be calculated from the ratio of vapor pressure and aqueous solubility. Henry s law constants do not show a simple linear pattern as solubility, Kqw or vapor pressure when plotted against simple molecular descriptors, such as numbers of chlorine or Le Bas molar volume, e.g., PCBs (Burkhard et al. 1985b), pesticides (Suntio et al. 1988), and chlorinated dioxins (Shiu et al. 1988). Henry s law constants can be estimated from ... 

Isnard, P., Lambert, S. (1988) Estimating bioconcentration factors from octanol-water partition coefficient and aqueous solubility. Chemosphere 17, 21-34. 

Pollutants with high VP tend to concentrate more in the vapor phase as compared to soil or water. Therefore, VP is a key physicochemical property essential for the assessment of chemical distribution in the environment. This property is also used in the design of various chemical engineering processes [49]. Additionally, VP can be used for the estimation of other important physicochemical properties. For example, one can calculate Henry s law constant, soil sorption coefficient, and partition coefficient from VP and aqueous solubility. We were therefore interested to model this important physicochemical property using quantitative structure-property relationships (QSPRs) based on calculated molecular descriptors [27]. 

Henry s Law constant (i.e., H, see Sect. 2.1.3) expresses the equilibrium relationship between solution concentration of a PCB isomer and air concentration. This H constant is a major factor used in estimating the loss of PCBs from solid and water phases. Several workers measured H constants for various PCB isomers [411,412]. Burkhard et al. [52] estimated H by calculating the ratio of the vapor pressure of the pure compound to its aqueous solubility (Eq. 13, Sect. 2.1.3). Henry s Law constant is temperature dependent and must be corrected for environmental conditions. The data and estimates presented in Table 7 are for 25 °C. Nicholson et al. [413] outlined procedures for adjusting the constants for temperature effects. 

Drouillard, K.G., Hiebert, T., Tran, P., Tomy, G.T., Muir. D.C.G., and Friesen, K.J. Estimating the aqueous solubilities of individual chlorinated n-alkanes (C10-C12) from measurements of chlorinated alkane mixtures. Environ. Toxicol. Chem., 17(7) 1261-1267, 1998. 

Transfer chemical potentials for the low-spin amine-diimine complexes [Fe(tsba)2] " with tsba = (8 were estimated from the solubilities of their perchlorate salts, in methanol-water mixtures.Solubility and transfer chemical potential data are also available for [Fe(Me2bsb)3] " " in several nonaqueous solvents. One of the main purposes in determining transfer chemical potentials for these iron(II)-diimine complexes is to enable dissection of reactivity trends into initial state and transition state components for base hydrolysis (see next section) in binary aqueous solvent mixtures. Systems for which this has been achieved are indicated in Table 8. 

P 5.4 Estimating Aqueous Solubilities Using Solubility Data of Structurally Related Compounds (adapted from Roberts, 1995). 

Estimate the liquid aqueous solubility of TeCIBP from its aqueous solubility using Tin (Eqs. 5-13 and 4-41). The resulting (L) value is 3.5 x 10 7 mol-L 1. Insert this value together with the above calculated x, Aroclor value and y Arodor = 1 into Eq. 7-19 to get the estimated aqueous concentration of TeCIBP ... 

Seawater contains dissolved inorganic salts. An aqueous solution of about 35 gL-1 NaCl is often taken as a model solution for seawater. The salt effect on the solubility of nonelectrolyte organic compounds has been investigated systematically by Sechenov [68] and by Long and McDevit [69]. Correlations between pure water solubility, Sw, and the solubility at different salt concentrations are compound dependent. For example, the seawater solubility, 5SW, of PAHs are from 30 to 60% below their freshwater solubilities [1], depending on the particular structure of the PAH. We concentrate our interest on the question if, for certain compound classes, Ssw can be estimated from known Sw without any input of further compound-specific parameters. 

Aqueous Solubility. Solubility of a chemical in water can be calculated rigorously from equilibrium thermodynamic equations. Because activity coefficient data are often not available from the literature or direct experiments, models such as UNIFAC can be used for structure—activity estimations (24). Phase-equilibrium relationships can then be applied to predict miscibility. Simplified calculations are possible for low miscibility, however, when there is a high degree of miscibility, the phase-equilibrium relationships must be solved rigorously. 

In the application of this expression to the solubility of temazepam in 29 solvents (Richardson et al., 1992), the predicted mole fraction solubilities were always of the same order of magnitude. When the Flory-Huggins correction was applied, a marked increase in overall predictive ability was observed. In the Lnal analysis, the predicted solubilities on the average were only off by 33% from the experimental solubilities. The results are presented graphically in Figure 2.4. It should be noted that the estimated aqueous solubility was low by only 12%. 

There are also empirical equations available that can be used for solubility estimation. Yalkowsky and Valvani (1980) developed the following equation by considering the transfer of a solute from the solid state to octanol followed by its transfer to the aqueous phase ... 

Keep in mind that this is an empirical method therefore, it is realistic to expect that it may work well for certain compounds but not for others. When the method was used to estimate aqueous solubility of the very insoluble compound cosalane, the results were in fair agreement with those from the facilitated dissolution method (Venkatesh et al., 1996). However, when the method was used to estimate the solubility of a series of prodrugs of 5-FU, the calculated water solubilities were one to three orders of magnitude too high and did not accuratelyatetrends in the series (Beall etal., 1993). 

---