Partitioned total surface area

The Partitioned Total Surface Areas and Their Potential Application in the Drug Discovery Process... 

Although various computational approaches for the prediction of intestinal drug permeability and solubility have been reported [219], recent computer-based absorption models utilize a large number of topological, electronic, and geometric descriptors in an effort to take both aqueous drug solubility and permeability into account. Thus, descriptors of partitioned total surface areas [168], Abraham molecular descriptors [220,221], and a variety of structural descriptors in combination with neural networks [222] have been shown to be determinants of oral drug absorption. 

This led to the concept of fragmentation of the total molecular surface area in combination with multivariate analysis (Stenberg et al. 2001) towards predictive models of drug permeability for more complex datasets. Permeability models were established based on so-called partitioned total surface area (PTSA) descriptors. Each of the PTSA descriptors corresponds to the surface of a certain atom type, differentiated by hybridisation, which results in individual descriptors for e.g. sp3, sp2, and sp carbon atoms. The resulting permeability model based on 19 descriptors finally consisted of oxygen, nitrogen and polar hydrogen surfaces, while the main contribution for prediction of Caco-2 permeability was attributed to PSA. In addition some more lipophilic contributions... 

Considering the importance of the surface interactions of solute and solution, Bergstrom developed partitioned total surface area (PTSA) as an extension of PSA (polar surface area) [20], PTSA calculates surface areas corresponding to particular types of atoms (i.e., sp, sp2, and sp3 hybridized... 

The introduction of more complex datasets used for model development has pointed at the need for several descriptors and multivariate data analysis (Table 16-3). For instance, combinations of PSA and nonpolar surface area (NPSA) proved to predict the permeability of a series of peptides when PSA alone failed [41], Moreover, the introduction oflarger structures and structures with larger flexibility showed that the partitioned total surface areas (PTSAs), that is, the surface area of the molecule occupied by a specific atom, and/or descriptors related to the flexibility of the molecule are in the permeability predictions [42, 43],... 

Fig. 15.3. Examples of partitioned total surface comprised of PTSAs of oxygen atoms, nitrogen areas (PTSAs) included in the multivariate data atoms and hydrogen atoms bound to these analysis. The PTSAs represent the surface heteroatoms. All other atom types are included...

Hydrophohicity-related the logarithm of the octanol-water partition coefficient, LogP [30], included in GlogP [31] and ELogP [24] the logarithm of the (molar) aqueous solubility [32, 33], included in ELogSw [25] the nonpolar surface area, both in Pf (NPSA) and normalized to the total surface area (%NPSA) ... 

The approach to calculate the van der Waals and cavity terms from the molecular surface areas can be used for the calculation of partition coefficients. The results show that for the distribution of hydrocarbons between water and n-octanol the calculated partition coefficient is linear in carbon number. Qualitatively similar data are obtained for the distribution between other solvents and water and the results can be used to predict the retention in liquid>liquid chromatography. On the other hand, if retention in RPC occurs due to reversible binding at the surface of the stationary phase, the significant parameter is not the total surface area of the eiuite but rather the net decrease in the molecular surface area of the stationary phase ligates and that of the eiuite upon binding, i.e., the contact area in the complex. 

Note that in Eq. 11-3, in contrast to the equation used for describing bulk phase partitioning, CA, is not the total surface area (TSA,) of the organic molecule. Rather it reflects the contact area between the molecule and the surface. But as a first approximation, we will assume that CA, is proportional to TSA,. By doing so, we neglect any special steric aspects that may affect the ability of a sorbate to closely approach the surface moieties with which it interacts. 

Study by Lohmann et al. (2000) who examined partitioning of PCBs in the atmosphere of Manchester also drew the similar conclusion. On the contrary, Harner and Bidleman (1998) concluded that the Koa-based model is more suitable for PCBs compared to the Junge-Pankow model. Chen et al. found that Koa absorption model predicted better for most of PBDE congeners while Junge-Pankow model tended to overestimate the fractions of PBDEs in particle phase in a Chinese study (Chen et al. 2006). The prediction results may vary signihcantly with the assumption of different OM content and total surface area of particles (Shoeib et al. 2004 Chen et al. 2006 Cetin and Odabasi 2008). 

TABLE 1 gives the reported values or ranges of the physical-chemical properties of chlorobenzenes (CBs), polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (PCDDs). Fugacity ratios were obtained from a single estimated entropy of fusion of 56 J mol °K (Yalkowsky 1979), molar volumes were calculated by the Le Bas method, an additive group contribution method (Reid et al. 1977). Total surface area (TSA) values were obtained from Yalkowsky et al. (1979 a,b). Solubilities, vapour pressures and octanol/water partition coefficients (Andren et al. 1986 Shiu and Mackay 1986 Bobra et al. 1985) are also tabulated. Henry s law constants were calculated as PSl/C and the octanol solubility Q as C Kq, . 

TABLE 1 Selected physical-chemical properties of the chlorobenzenes, polychorobiphenyls, and polychlorodiben-zo-p-dioxins, at 25° C. Given are molecular weight (MW) melting point (mp), fugicity ratio (F), total surface area, aqueous solubility of solid (Cg) and subcooled liquid (Cl), vapour pressure of solid (Pg) and subcooled liquid (Pl), Henry s law constant (H), log octanol/water partition coefficient (log Kq ), and the product Q = Cg log Kq -... 

Where K is the surface partition coefficient and A is the total surface area of the polymer powder in the chromatographic column. Thermodynamically, the molar free energy of adsorption,.AGi , of solute on the polymer layer can be related to Vg by the following relationship ... 

De Bruijn, J., Hermens, J. (1990) Relationships between octanol/water partition coefficients and total molecular surface area and total molecular volume of hydrophobic organic chemicals. Quant. Struct.-Act. Relat. 9, 11-21. 

Doucette, W. J., Andren, A. W. (1987) Correlation of octanol/water partition coefficients and total molecular surface area for highly hydrophobic aromatic compounds. Environ. Sci. Technol. 21, 521-524. 

Dickhut, R.M., Miller, K.E., Andren, A.W. (1994) Evaluation of total molecular surface area for predicting air water partitioning properties of hydrophobic aromatic chemicals. Chemosphere 29, 283-297. 

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