The surface activity of phenothiazine derivatives at the air-solution interface.

The surface activity of triflupromazine, chlorpromazine, promazine, promethazine, and chlorpromazine sulfoxide has been determined at the air-solution interface by the drop-volume method to measure surface tension. Differences in the abilities of the various phenothiazines employed to affect surface pressure development seem correlated with their relative nonpolarities. Anionic buffer ingredients appear to have an affect on surface activity at pH 5.0. Increasing concentrations of phthalate, citrate, and succinate buffers tend to increase surface activity, while increasing the concentration of the acetate buffer has the opposite effect. Raising the pH greatly increases surface activity of chlorpromazine and its sulfoxide, but the low solubility of the un-ionized form of chlorpromazine prevents it from exhibiting surface activity unless a significant amount of protonated form is also present. The un-ionized form of chlorpromazine sulfoxide is more soluble than chlorpromazine, and it exhibits marked surface activity at high pH. ACCUMULATION at various biological membranes of chlorpromazine and other pharmacologically active phenothiazines has been demonstrated by a number of studies in vitro recently reviewed by Guth and Spirtes.r Guth et al2 have also shown that chlorpromazine acts at rat liver membranes in vivo as well as in vitro. In addition, studies with lipid monomolecular films to simulate the oriented structure of membranes have demonstrated that phenothiazine derivativesaand other psychoactive drugs,5 in relatively low concentration, accumulate at the monolayer-solution interface. Whatever receptor surface or membrane may be involved in the action of the phenothiazines, it may be assumed that their widespread activity at membranes is dependent partially on their marked ability to “leave” an aqueous phase for a more nonpolar environment. The tendency of drugs to do this has often been correlated qualitatively with drug action by means of physical chemical measurements such as lipid solubility, p&, surface activity, and the ability to interact or complex with other molecules in solution. Measuring the adsorption of drugs at the air-solution interface offers many advantages for studying their escaping tendency from aqueous solution. Surface-tension measurements are extremely sensitive to factors which influence the properties of molecules in solution;6 and, since no chemically specific receptors are present, factors governing surface activity will be dependent on the relationship between solvent and drug. Thus, although the air-solution interface does not approach *The work was supported by Research Grant GM 12886-01, from the National Institutes of Health, Bethesda, Md.