The release kinetics of indomethacin (IND) and hydrochlorothiazide (HCT) from drug/PLGA formulations with different copolymer composition and molecular weight of PLGA were measured in vitro by using a rotating disk system (USP II). The release mechanism of IND and HCT from their PLGA formulations was analyzed using a chemical-potential-gradient model combined with the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). Furthermore, the release kinetics of IND and HCT from the PLGA formulations with different copolymer composition and molecular weight of PLGA were correlated and predicted in good accordance with the experimental data. It was found that the chemical-potential-gradient model combined with the PC-SAFT helped to understand the drug release mechanism from the drug/PLGA formulations. It also well correlated and predicted the drug release kinetics as function of copolymer composition and molecular weight of PLGA as well as of drug type. It helps to save time and costs for determination of the long-term drug release kinetics, especially for sustained drug release as obtained from the drug/PLGA formulations in this work. (c) 2016 American Institute of Chemical Engineers AIChE J, 62: 4055-4065, 2016