Prediction of Distribution

One of the most useful concepts for present purposes is that of the ideal solution. There are four important characteristics of such solutions, all interrelated  

Mixing of the constituents causes no change in the average inter-molecular forces of attraction. 

The volume of the solution is an additive property of the volume of the constituents over the entire range of composition. 

Mixing of the constituents in any proportion results in neither absorption nor evolution of heat. 

The total vapor pressure of the solution is a linear function of the 

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Gsizmadia, F., Tsantili-Kakoulidou, A., Panderi, L, Darvas, F. Prediction of distribution coeffident from structure. 1. Estimation method. J. Pharm. Sci. 1997, 86, 865-871. 

Govers, H.A.J., Evers, E.H.G. (1992) Prediction of distribution properties by solubility parameters description of the method and application to methylbenzenes. Chemosphere 24, 453 -64. 

Campbell, J.R., Luthy, R.G., and Carrondo, M.J.T. Measurement and prediction of distribution coefficients for wastewater aromatic solutes, Environ. Sci. Technol., 17(10) 582-590, 1983. 

Although theories of solution (this chapter) and formation of extractable complexes (see Chapters 3 and 4) now are well advanced, predictions of distribution ratios are mainly done by comparison with known similar systems. Sol-vatochromic parameters, solubility parameters, and donor numbers, as discussed in Chapters 2-4, are so far mainly empirical factors. Continuous efforts are made to predict such numbers, often resulting in good values for systems within limited ranges of conditions. It is likely that these efforts will successively encompass greater ranges of conditions for more systems, but much still has to be done. 

Fig. 5.3. FREZCHEM model prediction of distribution of water during seawater freezing along the Ringer-Nelson-Thompson pathway. Reprinted from Marion and Grant (1994) with permission...

Reymond, F. Steyaert, G. Carrupt, P.A. Testa, B. Girault, H. Ionic partition diagrams a potential-pH representation. J. Am. Chem. Soc. 1996,118, 11,951-11,957. Tsantili-Kakoulidou, A. Panderi, I. Csizmadia, F. Darvas, F. Prediction of distribution coefficient from structure, II. Validation of prologD, an expert system. J. Pharm. Sci. 1997, 86, 1173-1179. 

Extensive research has established the relationship between the extent of distribution of compounds and their physicochemical properties. With this information, Vdss can be quite successfully predicted using in silico models [27-30], In silico prediction of distribution is based on physicochemical properties that relates to passive transmembrane diffusion and tissue binding, and it only predicts Vdss. The other factors that contribute to distribution, such as transporter-mediated distribution, were not taken into account. These algorithms are based on the assumption that all compounds will dissolve in intra- and extracellular tissue water, and the unionized portion will partition into the neutral lipids and neutral phospholipids located within tissue cells. For compounds categorized as a strong base (at least one basic group (p/fa >7), an additional mechanism of electrostatic interaction with tissue acidic phospholipids is incorporated. Acids and weak bases are assumed... 

Concentration Units. Predictions of distribution thus far described are based on mole fraction concentration units. It should be noted that distribution coefficients in terms of weight fractions are different from those in terms of mole fractions, although ordinarily the direction of distribution is the same for both unit systems. In a few cases, where there is an unusual combination of molecular weights, this will not be the case. For example, in the system ethanol-ethyl acetate-water, higher concentrations of ethanol are in the water-rich layer on a weight basis but in the ester layer on a mole basis. Where the ternary-solubility curve is available, corrections from one system to another can easily be made. If the distribution is estimated from data on the binaries alone, then at zero concentration of C,... 

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