The first objective of this study was to evaluate melatonin properties related with the release behavior of this substance in oral controlled release tablets. Melatonin was found as a highly soluble substance with a micronized particle size (D50=4.1µm) and recrystallization in the same polymorphic form. The second aim was to evaluate parameter which affect the release rate of melatonin from prolonged release erodible and non-erodible matrix tablets. Commonly used polymers, such as Methocel, Ethocel, Kollidon SR and Eudragit were employed. The release rate of melatonin was affected by polymer properties like viscosity, particle size and permeability, as well as parameter such as, loading, agitation rate and granulation previous compression. The third objective was to evaluate the effect of polymer loading on melatonin pulsatile release tablets based on a rupturable coating containing Compritol 888 ATO in two different pHs. The lag time was affected by the polymer loading in the formulation and the release after the lag time showed a slight difference in the two pHs, due to the presence of Ac-Di-Sol, the superdisintegrant employed in the formulation.