Insights into the Polymorphic Structures and Enantiotropic Layer-Slip Transition in Paracetamol Form III from Enhanced Molecular Dynamics

Abstract

Reversible temperature-mediated solid phase changes, otherwise known as enantiotropic transformations, occur in many molecular crystals. These transformations take place as a result of the free-energy stabilization through entropic contributions at finite temperatures and can often have significant implications for the properties of crystalline solids. As such, understanding and predicting these transformations is of great importance. In this study, we utilize molecular simulations to elucidate the mechanism behind the enantiotropic layer-slip phase transformation between the orthorhombic and monoclinic versions of paracetamol form III (form III-m and III-o). Using standard molecular dynamics (MD) in addition to crystal adiabatic free-energy dynamics, an MD-based enhanced sampling approach for crystalline systems, we demonstrate that the transformation from the monoclinic form III-m to the orthorhombic form III-o is driven by localized and dynamic disorder within the structure rather than a perfect crystal-to-crystal transition. These results suggest that the orthorhombic form III-o structure does not exist as a perfect orthorhombic crystal with fully aligned layers, but rather, as an entropy-stabilized collective ensemble average of various misaligned layer-slipped structures. Overall, these simulation approaches, which explicitly treat dynamic structural disorder, allowed us to map out the free-energy landscape of this enantiotropic transformation as a function of temperature and extract critical insights into the underlying mechanism of the transformation.