Lipophilicity of zwitterionic sulphate conjugates of tiaramide, propranolol and 4′-hydroxypropranolol

Abstract

1. Metabolism of basic drugs may result in the formation of zwitterionic sulphate conjugates. The additional ionization introduced by the sulphate group into these compounds compared with the basic parent drug does not produce a corresponding increase in hydrophilic character.

2. Zwitterionic conjugates have constant lipophilicity between their pKa values. The opposite charges on the ionizing functional groups in this pH range appear to cancel the effect of each other on lipophilicity.

3. In the case of propranolol the O-sulphate derivative is more lipophilic than the parent compound at pH values below 7, despite the ionized character of the sulphate function.

4. The decrease in lipophilicity appears to be related to the separation in the molecular structure of the amino and sulphate groups.