RESUMO
The ability to encode and embed desired mechanical properties into active pharmaceutical ingredient solid forms would significantly advance drug development. In recent years, computational methods, particularly dispersion-corrected density functional theory (DFT), have come of age, opening the possibility of reliably predicting and rationally engineering the mechanical response of molecular crystals. Here, many-body dispersion and Tkatchenko-Scheffler dispersion-corrected DFT were used to calculate the elastic constants of a series of archetypal systems, including paracetamol and aspirin polymorphs and model hydrogen-bonded urea and π-π-bound benzene crystals, establishing their structure-mechanics relations. Both methods showed semiquantitative and excellent qualitative agreement with experiment. The calculations revealed that the plane of maximal Young's modulus generally coincides with extended H-bond or π-π networks, showing how programmable supramolecular packing dictates the mechanical behavior. In a pharmaceutical setting, these structure-mechanics relations can steer the molecular design of solid forms with improved physicochemical and compression properties.
