The effect of the chemical nature of the drug on matrix degradation and drug release behavior of degradable polymers was studied, using lidocaine as a model drug in base and salt forms. We show in this study that the drug in the base form has a substantial effect on the release characteristics, through an accelerating effect on matrix degradation. Study of drug release from PdlLGA shows that lidocaine salt follows a three-phase release pattern, in contrast to the biphasic release of the lidobase. However, PlLA shows a different drug release pattern, with only a single diffusion phase exhibited for both lidobase and lidosalt. We also demonstrate that the crystallinity of matrix plays an important role on drug release profiles: a crystalline matrix (PlLA IV=2.04) releases the drug at a much slower rate compared to its amorphous counterpart of similar molecular weight (PdlLA IV=2.4). The details of the study of different factors influencing the drug release may have important implications for the control of delivery of potent drugs in various therapeutic windows.