Solubility-partition Coefficient Relationships

Solubility-Partition Coefficient Relationships A critical review on the applicability of empirically derived solubility -Kow models has been given by Yalkowsky et al. [24], Isnard and Lambert [26], Lyman [1], and Muller and Klein [27]. Equations 10.4.3 to 10.4.5 are examples of solubility-Kow models. Isnard and Lambert developed a model based on 300 structurally diverse compounds. The model equation for liquids (Tm 25°C) is 

If these equations are applied in combination with structure-based methods to estimate Kow, then only Tm or merely the information of liquidity is required as input to 11.4.11 or 11.4.10, respectively. 

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Yalkowsky, S.H., Valvani, S.C. (1979) Solubilities and partitioning 2. Relationships between aqueous solubilities, partition coefficients, and molecular surface areas of rigid aromatic hydrocarbons. J. Chem. Eng. Data 24, 127-129. 

Yalkowsky, S.H. and S.C. Valvani. 1979. Solubility and Partitioning 2 Relationships Between Aqueous Solubility, Partition Coefficients, and Molecular Surface Areas of Rigid Aromatic Hydrocarbons. /. Chem. Eng. Data. 24 127-129. 

As a rule it has to be stated that halogenated alkylphenols are more active and broader in effectiveness than the alkylphenols. It is therefore in no way astonishing that some of the most important phenol derivatives in practical application are found in this class of phenolics. Among others Klarmann et al. (1933) have carried out systematic examinations of the relationship between chemical structure and antimicrobial activity with regard to halogenated alkylphenols. However, one should not overestimate the value of the data obtained when decisions and selections have to be made for practical application, as other properties of the microbicidal compounds, such as water-solubility, partition coefficient, activity in the presence of interfering factors encountered in practice, and toxicity, are of the same or of even more importance. Although there are available a lot of data and experience, often the optimum compound and formulation must be determined by experiment. 

Physico-chemical properties of the active substance influence to a large extent the administration routes and dosage forms that are feasible. Relevant properties include solubility, partition coefficient (log P), pKa, membrane passage, metabolic stability, and half-life. Conversely, the administration route and formulation influence safety and efficacy of the active substance. This cause-effect relationship implies that formulations designed for different or even the same route of administration may not be interchangeable. Chapters 4—14 discuss these (im)possibilities in more detail, for different administration routes. 

Two approaches to quantify/fQ, i.e., to establish a quantitative relationship between the structural features of a compoimd and its properties, are described in this section quantitative structure-property relationships (QSPR) and linear free energy relationships (LFER) cf. Section 3.4.2.2). The LFER approach is important for historical reasons because it contributed the first attempt to predict the property of a compound from an analysis of its structure. LFERs can be established only for congeneric series of compounds, i.e., sets of compounds that share the same skeleton and only have variations in the substituents attached to this skeleton. As examples of a QSPR approach, currently available methods for the prediction of the octanol/water partition coefficient, log P, and of aqueous solubility, log S, of organic compoimds are described in Section 10.1.4 and Section 10.15, respectively. 

In 1868 two Scottish scientists, Crum Brown and Fraser [4] recognized that a relation exists between the physiological action of a substance and its chemical composition and constitution. That recognition was in effect the birth of the science that has come to be known as quantitative structure-activity relationship (QSAR) studies a QSAR is a mathematical equation that relates a biological or other property to structural and/or physicochemical properties of a series of (usually) related compounds. Shortly afterwards, Richardson [5] showed that the narcotic effect of primary aliphatic alcohols varied with their molecular weight, and in 1893 Richet [6] observed that the toxicities of a variety of simple polar chemicals such as alcohols, ethers, and ketones were inversely correlated with their aqueous solubilities. Probably the best known of the very early work in the field was that of Overton [7] and Meyer [8], who found that the narcotic effect of simple chemicals increased with their oil-water partition coefficient and postulated that this reflected the partitioning of a chemical between the aqueous exobiophase and a lipophilic receptor. This, as it turned out, was most prescient, for about 70% of published QSARs contain a term relating to partition coefficient [9]. 

Despite the work of Overton and Meyer, it was to be many years before structure-activity relationships were explored further. In 1939 Ferguson [10] postulated that the toxic dose of a chemical is a constant fraction of its aqueous solubility hence toxicity should increase as aqueous solubility decreases. Because aqueous solubility and oil-water partition coefficient are inversely related, it follows that toxicity should increase with partition coefficient. Although this has been found to be true up to a point, it does not continue ad infinitum. Toxicity (and indeed, any biological response) generally increases initially with partition coefficient, but then tends to fall again. This can be explained simply as a reluctance of very hydrophobic chemicals to leave a lipid phase and enter the next aqueous biophase [11]. An example of this is shown by a QSAR that models toxicity of barbiturates to the mouse [12] ... 

Hansch, C., Quinlan, J. E., Lawrence, G. L. The linear free-energy relationship between partition coefficients and the aqueous solubility of organic liquids. 

Essentially, extraction of an analyte from one phase into a second phase is dependent upon two main factors solubility and equilibrium. The principle by which solvent extraction is successful is that like dissolves like . To identify which solvent performs best in which system, a number of chemical properties must be considered to determine the efficiency and success of an extraction [77]. Separation of a solute from solid, liquid or gaseous sample by using a suitable solvent is reliant upon the relationship described by Nemst s distribution or partition law. The traditional distribution or partition coefficient is defined as Kn = Cs/C, where Cs is the concentration of the solute in the solid and Ci is the species concentration in the liquid. A small Kd value stands for a more powerful solvent which is more likely to accumulate the target analyte. The shape of the partition isotherm can be used to deduce the behaviour of the solute in the extracting solvent. In theory, partitioning of the analyte between polymer and solvent prevents complete extraction. However, as the quantity of extracting solvent is much larger than that of the polymeric material, and the partition coefficients usually favour the solvent, in practice at equilibrium very low levels in the polymer will result. 

Chiarini, A. Tartarini, A. Fini, A., pH-solubility relationship and partition coefficients for some anti-inflammatory arylaliphatic acids, Arch. Pharm. 317, 268-273 (1984). 

Also in Table 3.4 are some solubility relationships (including partition coefficients) and one transport property. In these cases, the molecule in question is interacting with other kinds, and the product vo-2ot is found to be of less importance. Instead, cr2ot, cr2, and a2 often appear in the equations, along with terms involving molecular size. 

Bocek K. 1976. Relationships among activity coefficients, partition coefficients and solubilities. In Tichy M, ed. Quantitative structure-activity relationships. Basel and Stuttgart Birkhauser Verlag, 231-240. 

Another feature of the process is that the sorption capacity of type II organoclays is inversely related to the aqueous solubility of the NOCs (Chiou 1989). For example, the affinity of HDTMA-smectite for various phenols increases in the order phenol < chlorophenol < dichlorophenol < trichlorophenol since phenol is the most water-soluble while trichlorophe-nol is the most hydrophobic (Mortland et al. 1986, Lo et al. 1998). The relationship between the distribution (partition) coefficient in a type II organoclay and water-solubility is illustrated in Fig. 5 for a range of nonionic organic pollutants. 

Fig. 5. Relationship between the distribution (partition) coefficient on dimethyl dihydrogenated tallow montmorillonite for a range of non-ionic organic pollutants and their corresponding solubility in water. BHC is benzene hexachloride, the y-isomer of which is known as lindane aroclor 1232 and aroclor 1252 denote mixtures of polychlorinated biphenyls containing about 32 and 52% chlorine, respectively. After Beall (2003).

Briggs GG (1981) Theoretical and experimental relationships between soil adsorption, octanol-water partition coefficients, water solubilities, bioconcentration factors, and the parachor. J Agric Food Chem 29 1050-1059... 

Such relationships have been applied to solubility, vapor pressure, Kow, KAW, KOA, Henry s law constant, reactivities, bioconcentration data and several other environmentally relevant partition coefficients. Of particular value are relationships involving various manifestations of toxicity, but these are beyond the scope of this handbook. These relationships are valuable because they permit values to be checked for reasonableness and (with some caution) interpolation is possible to estimate undetermined values. They may be used (with extreme caution ) for extrapolation. 

There is a continuing effort to extend the long-established concept of quantitative-structure-activity-relationships (QSARs) to quantitative-structure-property relationships (QSPRs) to compute all relevant environmental physical-chemical properties (such as aqueous solubility, vapor pressure, octanol-water partition coefficient, Henry s law constant, bioconcentration factor (BCF), sorption coefficient and environmental reaction rate constants from molecular structure). 

Several workers have explored the linear relationship between octanol-water partition coefficient and solubility as a means of estimating solubility. 

The plot between Henry s law constant and molar volume (Figure 1.7.4) is more scattered. Figure 1.7.5 shows the often-reported inverse relationship between octanol-water partition coefficient and the supercooled liquid solubility. 

Boublik, T., Fried, V., Hala, E. (1984) The Vapor Pressure of Pure Substances, 2nd revised Edition, Elsevier, Amsterdam, The Netherlands. Bowman, B. T., Sans, W. W. (1983) Determination of octanol-water partitioning coefficient (KqW) of 61 organophosphorus and carbamate insecticides and their relationship to respective water solubility (S) values. J. Environ. Sci. Health B18, 667-683. Bradley, R. S., Cleasby, T. G. (1953) The vapour pressure and lattice energy of some aromatic ring compounds. J. Chem. Soc. 1953, 1690-1692. 

Bruggeman, W. A., van der Steen, J., Hutzinger, O. (1982) Reversed-phase thin-layer chromatography of polynuclear aromatic hydrocarbons and chlorinated biphenyls. Relationship with hydrophobicity as measured by aqueous solubility and octanol-water partition coefficient. J. Chromatogr. 238, 335-346. 

Hawker, D. W. (1989) The relationship between octan-l-ol/water partition coefficient and aqueous solubility in terms of solvatochromic parameters. Chemosphere 19, 1586-1593. 

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