The objective of this work was to investigate the mechanism of release of active pharmaceutical ingredients (APIs) both small molecules (ketoprofen, indomethacin, coumarin-6) and macromolecules (human serum albumin, ovalbumin), from PLGA (50:50) nanoparticulates (400–700 nm), having drug loadings less than 10%. The nanoparticulates were prepared by emulsification/solvent evaporation methods and release determined in phosphate buffer pH 7.4 at 37 °C. The release profiles exhibited an initial burst release phase, a slower lag phase and a second increased release rate phase. The profiles were consistent with a model in which the first phase of the release reflects diffusion controlled dissolution of drug accessible to the solid/dissolution medium interface and the second phase reflects release of drug entrapped in the polymer, the release of which was dependent on the bulk degradation of the polymer. The burst phase tended to increase with increase in API loading and solubility. The polymer erosion related parameters also indicated that increased drug loading accelerated this phase of API release. Small acidic hydrophobic actives such as ketoprofen and indomethacin had a much greater effect on these parameters than the larger hydrophilic more neutral proteins, HSA and ovalbumin.