Predicting milling performance of pharmaceutical crystals from elastic modulus

Predicting pharmaceutical milling outcomes from intrinsic material properties remains an unresolved challenge, with current approaches relying on empirically fitted population balance parameters or powder-scale mechanical testing that obscures the role of crystal-level mechanics. This work establishes that a solitary nanoindentation-derived property, the reduced elastic modulus (E_r), measured on individual API single crystals, quantitatively predicts jet milling particle size reduction across chemically diverse pharmaceutical systems. Ten API single crystals spanning E_r = 6.3 to 19.0 GPa were characterized by nanoindentation and jet-milled under identical conditions. A Hertzian contact mechanics framework reveals that stiffer crystals generate higher peak contact stresses during particle-particle collisions, activating a greater fraction of pre-existing flaws and producing finer comminution products. Simple linear regression models achieve leave-one-out cross-validated errors below 5% while blind validation on withheld API systems yields relative errors of 1.5-4.2%, confirming genuine predictive capability beyond the training set. Crucially, the model extends to eight external literature systems spanning E_r = 7.2 to 43.3 GPa, encompassing five different studies with diverse milling equipment, and independently determined modulus values with mean relative errors below 5% for systems within the calibration range. A complementary fracture mechanics analysis demonstrates that coarse particle reduction (Δd₉₀%) is governed by the brittleness index (H/K_IC) rather than E_r, delineating two mechanistically distinct comminution regimes: crack initiation-limited (fines, Er-governed) and crack propagation-limited (coarse tail, H/K_IC-governed). This dual-regime framework provides the first physics-grounded, single-crystal-based predictive tool for pharmaceutical milling, requiring only milligrams of crystalline material.