Effects of temperature and entropy in small molecule crystal structure prediction
Many pharmaceutical compounds can crystallize into more than one solid form with varying chemical and physical properties. Selecting a solid form that is stable, manufacturable, and bioavailable is therefore a critical step in the drug development process, and an unintended late-stage transformation into a new solid form can severely delay a therapeutic reaching the market. Computational models of a compound’s solid form landscape represent an inexpensive method to reveal previously unobserved crystal structures and assist in selecting the appropriate form to advance to commercial manufacturing. However, conventional approaches for crystal structure prediction (CSP) often neglect the effects of temperature and entropy on solid form stability, and the consequences of this assumption are not fully understood. Molecular Dynamics simulations were used here to introduce the effects of temperature and entropy into models of small molecule crystal structures. These simulations were used to estimate how solid form stability changes with temperature and more generally elucidate the consequences of temperature and entropy effects on the predicted polymorphic landscape. These simulations demonstrate that large entropy differences can exist between enantiotropically related polymorphs, and molecular dynamics is capable of capturing these temperature effects on thermodynamic stability in agreement with experiments. In addition, the dynamic simulations reveal when a crystal undergoes an order-disorder transition that can facilitate the stabilization of a higher-energy form over a lower-energy form at nonzero temperature. Finally, the results provide evidence for a long standing hypothesis that multiple lattice minima can exist within the same ambient-temperature free energy basin. The inclusion of temperature and entropy effects in future CSP models has the potential to significantly boost the accuracy and efficiency of predicting the crystals of pharmaceutical compounds.