Capturing Entropic Contributions to Temperature-Mediated Polymorphic Transformations Through Molecular Modeling

Solid materials with multiple observable phases can restructure in response to a change in temperature, fundamentally altering the materials’ properties. This temperature-mediated solid transformation occurs primarily because of a difference in entropy between the two crystal forms. In this study, we examine for the first time the ability of classical point-charge molecular dynamics simulations to compute entropy and enthalpy differences between solid forms of a range of organic molecules and ultimately predict temperature-mediated restructuring events. Twelve polymorphic organic small molecule systems with known temperature-mediated transformations were modeled with the point-charge OPLS-AA potential. Relative entropies and free energies between different solid forms were estimated by computing the stability as a function of temperature from 0 K up to ambient conditions using molecular dynamics simulations. These simulations correctly found the experimental high temperature solid form to have an entropy larger than that of the low temperature form in all systems examined. The magnitude of the temperature/entropy contributions to the free energy at ambient conditions is generally larger than the change in enthalpy difference. We also find that free energy differences between polymorphs computed with a less expensive quasi-harmonic approximation are within 0.07 kcal·mol –1 at all temperatures up to 300 K in the small rigid molecules examined. However, the molecular dynamics free energies deviate from the quasi-harmonic approximation in the more flexible molecules and systems with disordered crystals by as much as 0.37 kcal·mol –1 . Finally, we demonstrate that at ambient conditions multiple lattice energy minima can convert into the same crystal ensemble due to easily kinetically accessible transitions between similar structures when thermal motions are present.