Predicting and Mitigating Sticking in High-Drug-Load Acetaminophen Tablets Using a Powder Rheology-Compression Approach: Evaluation of Glidant Type and Punch Metal Selection

Tablet sticking remains a persistent manufacturing challenge in solid oral dosage forms, particularly for high-drug-load formulations, where increased API surface exposure promotes adhesion to tablet punches. Generally, glidants are used to improve powder flow; their role in tablet sticking remains insufficiently understood. This study presents a material-sparing and predictive framework that utilizes powder rheology to calculate cohesion and adhesion forces. The predicted sticking rank order was experimentally validated through tablet compression studies. We systematically investigated the effects of glidant type (Aerosil® 200, Syloid® 244, and talc), concentration (0–2.0% w/w), and five distinct punch surfaces (Chromium Nitride (CrN), Hard Chromium (HCr), Zirconium Nitride (ZrN), S7 tool steel (S7), and Böhler M340 premium stainless steel (M340) on high-drug-load acetaminophen as a model drug. Formulations were characterized using shear-cell testing, wall-friction testing, flow-function analysis, and permeability measurements, followed by validation through tablet compression studies. Among the glidants investigated, Aerosil® 200 showed the greatest effectiveness by reducing sticking propensity, improving flowability, crushing strength, minimizing air entrapment, and tablet weight variability. Syloid® 244 exhibited moderate effectiveness, while talc showed the least benefit. Punch surfaces further influenced sticking behavior, with M340 exhibiting the lowest sticking tendency and ZrN the highest. The combination of 2.0% w/w Aerosil® 200 and the M340 punch surface has the lowest Sticking Index (0.25) and the longest time to stick on the punch (659 ± 9 s). Statistical analysis confirmed that increasing the glidant from 1.0% to 2.0% did not significantly affect tablet sticking, suggesting a threshold effect. Overall, this material-sparing framework provides a mechanistic link between powder rheology and compaction outcomes, enabling early prediction of tablet sticking and rational selection of glidants and punch materials during formulation development.