Bridging Material Variability and Tablet Performance: Optimization of Direct Compression Using Tensile Strength–Ejection Stress Mapping

<b>Objectives</b>: The current study presents a sequential strategy for the development of directly compressible powder formulations relying on Design of Experiments (DoE) and Compactibility-Ejection stress plots. <b>Methods</b>: Compression analysis was used to evaluate the impact of changing the sort of microcrystalline cellulose (MCC), dicalcium phosphate (DCP), the diluent ratio, lubricant type, and the inclusion of an API from different suppliers. <b>Results</b>: The effect of DCP particle size on the ejection stress was efficiently mitigated in the placebo formulations by lubrication. However, the initial differentiation between sorts was highlighted at a smaller scale when the active pharmaceutical ingredient (API) was included in the formulation. For MCC, the tensile strength was positively correlated with the level of plasticity and tabletability capacity of different sorts. The particle size was a critical attribute for the API, influencing the detachment and ejection stress values. Fine particles (d50 = 30 µm) presented increasing stress values once the compression force rose, while for coarser particles (d50 = 50 µm) these effects were limited. <b>Conclusions</b>: Material-related variability must be understood to design products and processes with adequate performance. The proposed strategy enables early identification of critical material attributes, supporting rational formulation and supplier selection to ensure consistent quality during manufacturing.