The aim of this study is to obtain swelling controlled release matrix tablets of captopril using the Quality by Design methodology (ICH Q8) and to know the transport mechanisms involved in captopril release. To obtain the area of knowledge, the design of experiments studying the effect of two components (HPMC K15M and ethylcellulose) at different levels has been applied, with the captopril dissolution profile as the product's most important critical quality attribute (CQA). Different dissolution profiles have been obtained with the design of experiments performed, which is a key factor in the development of controlled release matrix tablets. Kinetic analysis according to the equations of Higuchi and Korsmeyer-Peppas demonstrates that the release mechanism is a mechanism of erosion when the whole percentage of the polymer is ethylcellulose, and a diffusion mechanism when the whole percentage of the polymer is HPMC K15M. The physico-chemical characteristics of the gel layer determine the release rate of captopril. The thickness of the gel layer, the porosity which is formed in the matrix upon contact with water, pore size, the swelling rate, the erosion rate of the matrix, and the physico-chemical characteristics of captopril, are factors related to the kinetic equations described and that allow us to predict the release mechanism of captopril. A new relationship of the kinetic equations governing the in vitro behavior with the physical characteristics of the gel layer of the different formulations has been established. This study shows that the size of water-filled pores and the degree of crosslinking between the chains of HPMC K15M of the matrix are related to the exponent n of the Korsmeyer-Peppas equation and the type of transport of the captopril from within the matrix to the dissolution medium, that is, if the transport is only through water-filled pores, or if a combination of diffusion occurs through water-filled pores with a transport through continuous polymeric networks.