The purpose of this study was to understand the impact of the poly (lactic-co-glycolic acid) (PLGA) molecular behavior in the feed solution on the drug release kinetics of PLGA microparticles prepared via spray drying. The PLGA molecular behavior in the feed solutions were characterized by using tube viscometry, which provides information about the polymer coil radius (R-coil), the Martin constant (K-m), and the overlap concentration (c*). The particle size and the drug surface enrichment were investigated by using scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS), respectively. The drug release profiles were characterized by using the USP paddle method and analyzed by using the Crank's diffusion model to calculate the kinetic parameters. Multivariate data analysis using principal component analysis (PCA) was employed to display the relationship between the PLGA molecular behavior, particle properties and the drug release kinetics from the spray dried PLGA microparticles. Rheological studies suggested that an increased molar ratio of a poor solvent (methanol) in the solvent system resulted in a decreased R-coil, the increase in K-m and c*. The higher effective diffusion coefficient of drug calculated by using the Crank's diffusion model was observed in the polymer matrix prepared at an acetone-to-methanol molar ratio of 69:31. The PCA models indicated that the drug surface enrichment and the K-m were directly proportional to the drug burst release, while the entanglement index was inversely correlated. Further, the particle size had a less significant impact on the drug burst release. This study implies that the polymer molecular behavior would influence the microscopic connectivity and diffusivity of polymer matrix, which eventually affects the drug release kinetics. (C) 2013 Elsevier Ltd. All rights reserved.