The interplay of phase inversion and membrane formation in the drug release characteristics of a cellulose acetate (CA) membrane-based delivery system has been examined. Drug encapsulated films were cast from solutions of naproxen (drug), CA (polymer), acetone (solvent), and water (nonsolvent). Membrane morphologies, drug release kinetics, and drug-polymer interactions were studied using scanning electron microscopy (SEM), USP apparatus 5 dissolution bath release rate measurements, and differential scanning calorimetry (DSC). The drug load (DL), drug-polymer compatibility, and water content in the casting solution has a significant effect on the membrane morphology and drug release rates. Naproxen was shown to inhibit the locking-in of the phase invertion structure by lowering the glass transition temperature (T.) of the naproxen/CA membrane. Interestingly, the burst effect for high DL films was avoided for membranes with the honeycomb structure. An interpretation of these results is discussed, and a quantitative model for the drug release mechanism is also given. (c) 2007 Elsevier B.V. All rights reserved.