This study demonstrates that the simple direct-compression process can be enabled for low-dose tablet manufacturing through the preparation of an optimal ordered mixture. By producing low-dose tablets containing a micron-sized active pharmaceutical ingredient (API), we showed that excellent content uniformity of a drug product can be accomplished through direct compression, when ordered mixing was introduced as part of the manufacturing process. To incorporate content uniformity into the final drug product, we systematically investigated the material attributes of API and excipients leading to the optimal ordered units. We discovered that excipients with round morphology and rugged surface, which enabled "depth-filling" pattern and multi-layer coverage of API on carrier particles, can give rise to ordered mixtures with greater carrier capacity, stronger adhesive forces, and reduced ordered unit segregation tendency. We developed a sample-saving, bench-scale diagnostic tool which can successfully evaluate the sifting-driven segregation tendency of powder blends. We further identified the conical screen milling process as a robust approach to produce stable ordered mixtures, due to the physical impact and mixing behavior involved in the milling process. This systematic approach, developed on the basis of mechanistic understanding of the critical material and process attributes for ordered mixing and segregation, allowed us to consistently manufacture tablets with high content uniformity both at 1-kg scale and 40-kg scale. Through this study, we demonstrated that common risks associated with the direct-compression process at production scale, such as content uniformity, can be mitigated by understanding and manipulating the particle-particle structures and interactions of the formulation components. (C) 2013 Elsevier B.V. All rights reserved.