Water-soluble drugs were encapsulated within anionic acrylic resin (Eudragit(R) S100) microspheres by water in oil in oil (w/o/o) double emulsion solvent diffusion method. Dichloromethane and corn oil were chosen as primary and secondary oil phases. respectively. The presence of internal water phase was essential in forming stable emulsion droplets and it accelerated the hardening of microspheres. Tween 80 was used as a surfactant for stabilizing internal water phase and Span 80 was used for stabilizing corn oil phase. The optimum concentration of Tween SO was 0.25% (v/v) and that of Span 80 was above 0.02% (v/v). The temperature of continuous phase affected stability of emulsion and the morphology of microspheres. As the volume of continuous phase increased. the size of microspheres decreased. The loading efficiency was >80% except for acetaminophen, due to its lower solubility in water and higher solubility in corn oil. The release profile of the drug was pH dependent. In acidic medium. the release rate was much slower. however, the drug was released quickly at pH 7.4. Tacrine showed unexpected release profiles, probably due to ionic interaction with polymer matrix and the shell structure and the highest release rate was obtained at pH 2.0. The prepared microspheres had a sponge-like inner structure with or without central hollow core and the surface was dense with no apparent poles. (C) 2000 Published by Elsevier Science B.V. All rights reserved.