(136c) Capturing the Role of Temperature and the Sensitivity to Energy Function Complexity in Crystal Polymorph Stability Using Molecular Modeling

Solid materials with more than one polymorph can restructure in response to a change in external conditions, fundamentally altering material properties like solubility and hardness. Such restructuring events have hindered pharmaceutical solid form development in numerous therapeutic candidates and have led to costly market recalls. Computer modeling has the potential to identify all observable solid forms and predict relevant restructuring events in the early stages of development. However, standard crystal structure prediction methods neglect the effect of temperature on relative crystal stabilities, which is vital for predicting temperature-mediated polymorphic transformations. In addition, discussions on the level of complexity to use in the energy function have focused on the effects on crystal lattice energies, rather than crystal free energies. In this study, we use molecular dynamics simulations to capture the effects of temperature and entropy on the stabilities of numerous polymorphic materials at different levels of energy function complexity.

Twelve small molecule organic systems with known temperature-mediated transformations were modeled with the point-charge OPLS-AA potential. Our simulations correctly identify the high temperature solid form as having a larger entropy than the low temperature form in all systems examined. The estimated entropy differences in the classical point-charge potential are significantly closer to experimental measurements than estimated enthalpy differences. This result suggests that entropy difference estimates are less sensitive to the complexity of the simulation potential than the corresponding enthalpy estimates.

We further probe the energy function sensitivity by directly computing the added effects of a more accurate polarizable Hamiltonian on polymorph free energies. We show that the change in free energy to the more complex potential comes predominately from enthalpic rather than entropic contributions in the system examined.