Chadha, Harpreet Singh; (1994) Application of solute descriptors to chemical and biological phenomena. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A new general solvation equation developed by Abraham and Whiting has been investigated and its applicability to a number of very important phenomena has been studied. The general solvation equation is: log SP=c+rR₂+sπᴴ₂+aΣαᴴ₂+bΣβᴴ₂ +νVx where SP is the measured solute dependent property, the solute descriptors are R₂ an excess molar refraction, πᴴ₂ the dipolarity/polarisability, Σαᴴ₂ and Σβᴴ₂ the effective hydrogen-bond acidity and basicity, and Vx the characteristic volume of McGowan and the equation constants relate to the properties under investigation. The equation has successfully been applied to chemical phenomena - high performance liquid chromatographic data (SP=κ') - octanol-water and alkane-water partitioning (log SP=log P), as well as Seiler's hydrogen bond descriptor (log SP=Δlog P). The solute factors that influence these processes have been ascertained. The equation has also been applied to biological phenomena; application of the equation to blood-brain equilibrium distribution measurements (SP=BB) for the first time yields the factors controlling the distribution: log BB(All)=-0.038+0.198R₂-0.687πᴴ₂-0.715Σαᴴ₂-0.698Σβᴴ₂+0.995Vx, n=57 p=0.9522 sd=0.197 F=99.2. Similarly application to skin (stratum corneum) permeation (SP=kp) and partition data (SP=Km) leads to an understanding of the exact factors that influence these processes. In the former case the derived equation is: log kp=-5.201-0.782πᴴ₂- 0.408Σαᴴ₂-3.393Σβᴴ₂+2.004Vx, n=46 p=0.9757 sd=0.266 F=203.2. Many solute descriptors used in this work have been obtained by a novel techniques, these are illustrated. In addition, the application of the log Pplus approach has been described, whereby the well known octanol-water partition coefficient has been combined with solute descriptors to yield a high quality yet simplified correlative tool.

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