Group contribution approaches partition coefficient

Platts, J. A., Abraham, M. H., Butina, D., Hersey, A. Estimation of molecular linear free energy relationship descriptors by group contribution approach. 2. Prediction of partition coefficient. J. Chem. Inf. Comput. Sci. 2000, 40, 71-80. 

Klopman, G., J.-Y. Li, S. Wang, and M. Dimayuga. 1994. Computer Automated log P Calculations Based on an Extended Group Contribution Approach. J. Chem. Inf. Comput. Sci. 34, 752-781. Klopman, G., and S. Wang. 1991. A Computer Automated Structure Evaluation (CASE) Approach to Calculation of Partition Coefficients. J. Comput. Chem. 8 1025-1034. 

Aqueous solubility prediction continues to be an active area of research, with a wide variety of approaches being applied to this important and challenging area. To date, group contribution approaches as well as correlation with physicochemical properties (partition coefficient) appear to be the most promising (29, 32). It is important to keep in mind that correlations that are developed from structurally related analogs would consistently yield more accurate predictions. 

The X values used for the solutes in Table III came from a variety of sources (2,3) and it should be noted that solute solubilities at near ambient conditions are available in the literature for a variety of compounds (18,19). The recent compendium of Yalkowsky and He (20) contains over 16,000 data entries for 4,000 organic compounds in water - many over a range of temperatures between ambient and the bp of water. Such data provide a range of X values to estimate solubilities (X2) in sub-H20. Other experimental data, such as activity coefficients, Henry s law constants, and/or octanol/water (0/W) partition coefficients can be converted into X values, and provide another source of estimating solute solubilities over an extended temperature range. These data bases like the 0/W values can be combined with a group contribution approach... 

Therefore, logarithmic partition coefficients exhibit a rather linear behavior with respect to surface-composition or group-contribution variables, and many approaches of this kind have proved to be quite successful. 

We recommended two of these methods for general use, estimation from octanol-water partition coefficient and a group contribution method named AQUAFAC. Three other methods are also valuable under certain circumstances, the connectivity, UNIFAC, and sol-vatochromic approaches. 

Two methods are recommended for routine use for estimating solubility the correlation with octanol water partition coefficient method and the AQUAFAC group contribution method. When possible, use both approaches and compare the results. Insights can also be obtained if solubility data are available for structurally similar compounds. Both methods are illustrated below. 

Here k f k2f and kare microscopic ionization constants defined in section 4.6. From this it was possible to calculate and plot variation in Dnoh with pH for pentazocine as shown in Figure 2. The fourth partition coefficient was obtained by structural group contribution to the measured partition coefficient of a reference compound (morphine). This was done following the Hansch approach. 

With the widespread application of lipophi-licity and partitioning to biophysical processes, a wide variety of tools is currently available to estimate partition coefficient. Several recent reviews of programs and methods that are commercially available have been published (25-28). Predictive methods may be broken down into the following basic approaches to partition coefficient estimation (i) group contribution methods, by use of molecular fragments (2) group contribution, by use of atom-based contributions (5) conformation-dependent or molecular methods (4) combined fragment and atom-based methods and (5)other physicochemical methods. 

Laboratory measurements of S and can be costly and difficult. Various methods, including group contribution technique and quantitative structure (or property) property relationships (QSPRs or QPPRs), are available to estimate S, and S, from which a values can be derived. A direct approach of predicting o has also been established based on the dependence of cosolvency on solute hydrophobicity. Among a number of polarity indices, octanol/water partition coefficient, was initially chosen by Yalkowsky and Roseman for correlation with a, due mainly to die abundance of available experimental data and... 

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