Structure-Lipophilicity Relationships of Neutral and Protonated b-Blockers Part I Intra- and Intermolecular Effects in Isotropic Solvent Systems by Giulia Caron a ), Guillaume Steyaert a ), Alessandra Pagliara a ), Fre Âde Âric Reymond b ), Patrizia Crivori a ), Patrick Gaillard a ), Pierre-Alain Carrupt a ), Alex Avdeef b ), John Comer c ), Karl J. Box d ), Hubert H. Girault b ), and Bernard Testa a )* a ) Institut de Chimie The Ârapeutique, Section de Pharmacie, Universite  de Lausanne, CH-1015 Lausanne b ) Laboratoire dElectrochimie, Ecole Polytechnique Fe Âde Ârale de Lausanne, CH-1015 Lausanne c ) pION Inc, 127 Smith Place, Cambridge, MA 02138, USA d ) Sirius Analytical Instruments Ltd., Riverside, Forest Row Business Park, Forest Row, East Sussex RH185DW, UK The objectives of this study were to validate new experimental techniques used to measure the log P of protonated drugs, and to investigate the inter- and intramolecular forces influencing the partitioning behavior of b-blockers in isotropic biphasic solvent systems. The lipophilicity parameters of a number of b-blockers were measured by two-phase titration, centrifugal partition chromatography (CPC) , and cyclic voltammetry (CV) in one or more of the following solvent systems : octanol/water, 1,2-dichloroethane/water, and dibutyl ether/water. CV proved to be a promising technique for measuring the lipophilicity of protonated b-blockers. Derived parameters such as Dlog P (difference between log P in two different solvent systems, a parameter valid for a given solute in a given electrical form) and diff (difference between log P of two different electrical forms of a given solute, in the same system) yielded insights into inter- and intramolecular interactions characteristic of b- blockers. The relevance of these parameters in structure-permeation relationships is explored. 1. Introduction. ± b-Blockers are widely used in the treatment of various cardiovascular diseases such as hypertension, angina pectoris, and cardiac arrhythmias [1][2] ( Fig. 1). This series of drugs having the common structural elements of one or more aromatic rings, and a b-aminoethanol or 3-amino-2-hydroxypropoxy side chain (pK a around 9.5) exists mostly as cations at physiological pH. In many studies, the lipophilic characteristics of b-blockers were examined in connection with their pharmacokinetic properties [3], although the lipophilic contribution of the cationic forms have been neglected [4 ± 7]. Today, however, the significance of the lipophilicity of ionized forms is well recognized, not only in anisotropic media [8 ± 10] but also in isotropic systems [11]. For complex compounds such as most drugs, the traditional octanol /H 2 O system is not always a very good indicator of biodistribution, mainly because all biological membranes do not possess the same biophysical characteristics. Thus, four solvents, known as the critical quartet, each encoding a different balance of intermolecular forces assessed by the so-called solvatochromic parameters (a  H-bond donor acidity ; b  H-bond acceptor basicity; p*  dipolarity/polarizability, and V W  calculated Van Helvetica Chimica Acta ± Vol. 82 (1999) 1211