The mode of association of amphiphilic drugs in aqueous solution

Abstract

The structural features of amphiphilic drug molecules which influence their association pattern in aqueous solution are identified from a survey of published work. Flexibility of the hydrophobic group, as in the large number of drugs with a diphenylmethane structure, leads to a closed or micellar association. Drugs possessing a rigid planar aromatic or heteroaromatic ring system to which an ester group or charge-bearing N atom is directly attached or which include a pyridine-like N atom, have an open or continuous association pattern. Several association models used to describe the association of these drugs are reviewed. The self-association of the large group of tranquillising drugs which have their charge localised at the end of a short side chain attached to a phenothiazine ring system is discussed in detail. The association pattern in water and dilute electrolyte is complex with discontinuities in solution properties at several critical concentrations. Evidence from a variety of experimental techniques indicates limited association in dilute solution leading to the formation of a stable aggregate at the first critical concentration. NMR studies of the changes in the chemical shifts of aromatic protons and carbon atoms over a wide concentration range have suggested an offset, concave-to-convex vertical stacking of the molecules within these aggregates, with the alkyl side chains on alternate sides of the stack. The association of several phenothiazines in the presence of high concentrations of added electrolyte (0.2 to 0.8 mol kg −1 sodium chloride) has been described by an association scheme in which a primary unit of 3 to 4 monomers is formed below the critical concentration by a continuous association process and grows with increasing solution concentration by the stepwise addition of monomers.