Revealing slip behavior in organic molecular crystals: AFM nanoindentation of acetaminophen

Molecular crystals are subjected to mechanical stress that can alter their slip planes which are structural features that play a critical role in governing mechanical behaviors such as milling, that requires fundamental insight for the successful manufacturing and performance of solid oral dosage forms. Milling is a critical unit operation in the manufacturing of pharmaceutical dosage forms. During this process, slip planes may become disrupted and dislocations can form, potentially inducing plastic deformation and significantly altering the physicochemical properties of active pharmaceutical ingredients (API). While slip, a dominant mechanism of plasticity, is well characterized in inorganic crystals, its behavior in organic molecular crystals remains poorly understood due to their low symmetry and anisotropic nature. In this study, we investigate plastic deformation in a model organic crystal, acetaminophen, using atomic force microscopy (AFM) nanoindentation. Distinct pile-up patterns forming parallel facets around indentation sites were observed and systematically analyzed. These pile-ups were experimentally confirmed to align with specific crystallographic slip planes. Based on this, a geometry-based strategy was developed to automatically identify, and index slip planes from indentation pile-up features. This method may offer new insights into the deformation behavior of organic crystals and serves as a broadly applicable tool for investigating slip systems across a wide range of pharmaceutical and molecular materials.