(22a) Predicting Temperature-mediated Solid Form Transformations in Small Molecule Crystals with Molecular Dynamics

Many pharmaceutical compounds can crystallize into more than one solid form, and the overall solubility and bioavailability of a therapeutic compound can vary markedly between different structures. Selecting a stable and soluble solid form is therefore an important 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 can reveal previously unobserved crystal structures and assist in selecting the appropriate form for commercial manufacturing. However, the current approaches for crystal structure predictions (CSP) often neglect the effects of temperature on solid form stability. Such approaches cannot capture temperature-mediated transformations that can occur during product manufacturing and storage.

In this work, we present a method to compute the temperature-dependent stability of small molecule crystals and capture temperature-mediated solid form transformations. All crystal structures of interest are heated from zero Kelvin up to ambient conditions using molecular dynamics simulations. The sets of simulations are combined to construct temperature-dependent free energy profiles for each structure. We demonstrate this technique on multiple polymorphic small molecules of pharmaceutical interest, and show that current point-charge potentials are capable of capturing the large entropy differences between forms which facilitates crystal transformations at high temperature.

In addition, we show that molecular dynamics simulations can yield visual insights into when crystalline systems undergo critical property changes as a result of a change in temperature. These changes include solid-solid transformations, order-disorder transitions, and lattice minima interconversions.