This study focuses on understanding the physicochemical principles for the preparation of high drug-loaded microgranules with a desired size distribution and mechanical properties. Mesalamine was selected as a model drug, and microgranulation was performed using an extruder and a conical screen mill. Throughout the processes, factors including the binder to powder ratio, the shape of the impeller, and type and hole size of the screen significantly affected the size distribution of the microgranules. In particular, the number of milling stages made a noticeable difference, as the addition of a pre-milling stage could increase the yield of microgranules within the target interval by facilitating the particle escape from the screen. Moreover, the effect of three commonly used excipients, microcrystalline cellulose, dibasic calcium phosphate dihydrate, and lactose monohydrate, were investigated with the expectation of enhancing the mechanical properties of microgranules. Unexpectedly, however, the addition of excipients resulted in a rather negative effect on the friability of microgranules owing to the inhomogeneous distribution of the binder polymer. An attrition test was determined to be a suitable method for evaluating the mechanical properties of microgranules due to its dynamic test condition. In contrast, tests performed using a texture analyzer were static, which in turn distorted the strength of microgranules. As various active pharmaceutical ingredients and excipients have their own characteristics, investigation into their physicochemical fundamentals is an essential prerequisite for the successful preparation of a high drug-loaded microparticle system. (C) 2017 Elsevier B.V. All rights reserved.