Hydrophobicity Parameter of Diazines IV: A New Hydrogen‐Accepting Parameter of Monosubstituted (Di)azines for the Relationship of Partition Coefficients in Different Solvent Systems

Abstract

We recently proposed a new hydrogen‐accepting scale, SHA, for each member of the substituted (di)azine series on the basis of the heat of formation calculated under various dielectric environments by the COSMO method. In this paper, the SHA scale was used to examine relationships between log PCL (PCL: CHCl3/H2O partition coefficient) and log Poct (Poct: 1‐octanol/H2O partition coefficient) for each of the 2‐substituted pyridine (I), monosubstituted pyrazine (II), and pyrimidine (III) series. This SHA parameter worked nicely, representing the hydrogen‐accepting effect of the solute molecule. A correlation equation with excellent quality, such as log PCL = a log Poct + sSHA + constant, was obtained for each series. We further defined the parameter SHA/PY, derived from SHA values for the heterocyclic series by shifting the reference points to unsubstituted pyridine, to unify separately derived correlation equations. Thus, the correlation between log PCL and log Poct for all combined data of three series was derived by using a single equation as log PCL = a log Poct + sSHA/PY + constant. The SHA parameters were reasonably considered as being free‐energy related, and the rationale for the hydrogen‐bond‐acceptor scale was presented. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89:1505–1517, 2000