Quality by Design Approach to the Optimization of Cohesive Powder Blending in Direct Compression

Background/Objectives: Direct compression of cohesive powders is often challenged by poor flow, blend heterogeneity, and variable tablet quality. This study investigated how mixing time, fill level, and rotational speed affect the blending behavior and tablet properties of a sodium naproxen–calcium carbonate formulation and aimed to define a robust operating space for process optimization. Methods: Powder blends were prepared in a V-type mixer according to a central composite design and analyzed using response surface methodology. The effects of the three process parameters were evaluated through powder flow descriptors (angle of repose, angle of fall, and angle of difference) and tablet quality attributes, including thickness, mass, active pharmaceutical ingredient (API) content, and abrasiveness. Statistical significance was assessed by ANOVA, and a design space was established using predefined acceptance criteria. Results: Mixing time significantly affected the angle of difference, indicating changes in blend cohesiveness and flow uniformity, whereas fill level significantly influenced API content. Tablet thickness and mass remained relatively stable across the tested conditions. Abrasiveness showed the greatest numerical variability and tended to increase at high fill levels combined with short mixing times. Response surface analysis identified two acceptable operational regions that satisfied the quality criteria for blend homogeneity, API content, and abrasiveness. Conclusions: The studied process variables exerted selective, property-specific effects rather than uniform changes across all quality attributes. The results support QbD-based process design for cohesive direct-compression systems and show that robust tablet manufacture can be achieved within more than one operating window.