Drugs with different water-solubility and molecular weights were microencapsulated in cellulose acetate phthalate, using an emulsion-solvent evaporation technique with a continuous oil-phase. The mean size of the particles was approximately 600 μm, and they were non-porous. The capacity of the microspheres to retain the drugs was evaluated by in vitro release studies in acidic medium. For low molecular weight compounds the release rates increased with solubility: for thiamin hydrochloride and phenacetin, a highly and a poorly soluble compound respectively, the percentages released at 60 min were 90 and 10%. Drugs with molecular weights above approximately 700 Da were retained in the microspheres. The above dependence on solubility was corroborated by release studies in ethanol, and by modelling the release of phenacetin in acidic media. Microspheres with a different polymer matrix, Eudragit® RS PO, were also prepared by a similar technique, and these particles prolonged the release of thiamin for over 6 h, under simulated GI conditions.