CONTEXT The release of an encapsulated drug is dependent on diffusion and/or degradation/erosion processes. OBJECTIVE This work aimed to better understand the degradation mechanism of clonidine-loaded microparticles. METHODS Gel permeation chromatography was used to evaluate the degradation of the polymer. The water-uptake and the weight loss were determined gravimetrically. The swelling behaviour and the morphological changes of the formulations were observed by microscopy. The glass transition temperature and the crystallinity were also determined by differential scanning calorimetry and X-ray diffraction, respectively. The pH of the medium and inside the microspheres was assessed. RESULTS The microspheres captured a large amount of water, allowing a decrease in the molecular weight of the polymer. The pH of the medium decreased after release of the degradation products and the pH inside the microparticles remained constant due to the neutralization of these acidic products. CONCLUSION Clonidine and buffers both had an action on the degradation.