The objective of this study was to determine the effect of drug stability on the analysis of in vitro release data from controlled release microspheres. Amoxicillin was chosen as a model drug and its stability in various media determined. The in vitro release of amoxicillin from PLGA microspheres was investigated in phosphate buffered saline (PBS) containing either Tween-80 or Tween-80 + Na-azide. Drug concentration in the media and the amount remaining inside the microspheres were analysed using HPLC. Amoxicillin degraded rapidly in PBS. The rate of degradation was reduced in the presence of Tween 80 and Na-azide. Drug release from the microspheres was analysed with and without considering the drug degradation rate. Mass balance between released drug, drug remaining in the microspheres and initial drug loading was only achieved when drug degradation was accounted for. Drug stability should be considered in analysis of in vitro extended release data, since released drug may degrade with time. These results have implications for in vitro release studies for controlled release products that include drugs and other compounds which are susceptible to degradation during the course of the release study.