(139b) Understanding the Effect of Changing Complexities of Potential Energy Functions on the Entropic Contribution to Free Energy Differences of Organic Polymorphs

Accurate and fast computational methods to predict the free energy differences of crystals can greatly impact the pharmaceutical industry. Experimental approaches to capture all polymorphs are costly and time consuming. Current computational methods are able to exhaustively search for the lattice minimum structures, but fail to include entropic effects. Our group has been focused on the testing and development of methods that include the entropic behavior of crystalline materials to determine the free energy ranking at temperatures of interest.

We compare the free energy differences of 13 polymorphic pairs of organic molecules using the OPLS-AA point charge potential and the AMOEBA polarizable potential, . using full molecular dynamics (MD) simulations as well as lattice dynamic (LD) approaches using isotropic expansion to compute the free energy differences. For the small and rigid crystalline systems, we find that there is little deviation (< 0.1 kcal/mol) between MD and LD approaches up to 300K, with somewhat larger differences for flexible molecules. Including anisotropy to the expansion in LD does not significantly improve the match to MD, suggesting that the deviations between the methods are because of fundamental anharmonicity in the free energy landscape.

We also calculate the free energy differences using isotropic lattice dynamics for the 13 polymorphic pairs at DFT-D3 levels of theory, and compare these free energy differences between the three different potential energy functions.