A comprehensive model with all effective phenomena in drug release such as diffusion, swelling and erosion was considered. In this work, a mathematical model was developed to describe drug release from controlled release HPMC matrices as a favorable system in pharmaceutical industries. As a novel study, the impact of the MCC presence as a filler in tablet preparation process was considered in the mathematical model. In addition, we found that the volume expansion of these polymeric matrices did not follow the ideal mixing rule and we derived an equation for estimating the volume of hydrated matrix. Furthermore, some equations were derived to estimate the parameters of model (Kerosion, Deq) as well as the change in matrix volume based on the amount of polymer and filler in formulation. This investigation gave deeper insight into underlying drug release mechanisms. According to the results, Kerosion increases linearly and Deq increases exponentially with the increase in the amount of MCC in formulation. Application of this comprehensive mathematical model enables us to predict the behavior of HPMC-MCC based matrices. Furthermore, this model is able to represent the formulation for the desired drug release profile which is useful to design new controlled release matrix as well as improving the system geometry and dimensions of tablets. The presented model was validated by two independent tests: (a) predicting the behavior of matrix with certain MCC/HPMC ratio upon exposure to the release medium; (b) designing formulation of Bupropion hydrochloride extended release tablet.