Finite-Temperature Mechanical Properties of Organic Molecular Crystals from Classical Molecular Simulation

The mechanical properties of crystalline materials can have an impact on different aspects of solid dosage form design and manufacturing. Experimental determination of these quantities is known to pose difficulties and can be time-consuming. Instead, first-principles predictions of such materials have the potential for accelerating drug formulation development. We calculated elastic constants and several derived mechanical properties for the crystalline phase of a set of 18 small organic molecules with available experimental data, using molecular dynamics simulations based on the widely used GAFF2 force field. Attempts to further improve the accuracy of the predicted mechanical properties were made by fitting the force field parameters to the energies and forces determined by DFT calculations. We determine that DFT-based optimization of the force field parameters were unable to improve the accuracy of the mechanical property predictions over the currently established GAFF2 force field, which already provides reasonably accurate results with mean unsigned errors of individual elastic constants of around 2-3 GPa, or lower, in the majority of cases. Also, the elastic anisotropy is correctly predicted, at least qualitatively. The method used here can be a simple and fast means for the approximate determination of mechanical properties of a crystalline drug powder─material properties that can be used to guide decisions during formulation development.