(496e) Mechanistic Insights into the Enantiotropic Layer Slip Polymorphic Transition in Paracetamol

Reversible temperature mediated solid phase changes, otherwise known as Enantiotropic transformations, often occur in many molecular crystals. These transformations occur as a result of free energy stabilization through entropic contributions at finite temperatures. These phase transitions can often have significant implications on the quality, performance, and characteristics of crystalline solids. As such, understanding and predicting these transformations is of great importance.

In this study, we utilize molecular simulations to elucidate the mechanisms behind the enantiotropic layer slip phase transformation between the Paracetamol orthorhombic and monoclinic versions of Form III (Form III-m and III-o), as reported by Reiss et al.¹ Using standard molecular dynamics (MD) in addition to Crystal Adiabatic Free Energy Dynamics (Crystal-AFED)², an enhanced sampling approach, we demonstrate that the transformation from the monoclinic Form III-m to orthorhombic Form III-o is driven by localized and dynamic disorder within the structure rather than a perfect crystal to crystal transformation. These results suggest that the orthorhombic Form III structure does not exist as a perfect orthorhombic crystal with perfectly aligned layers, but rather as a collective ensemble average of various layer slipped structures. In addition, we demonstrate the utility of standard MD and Crystal-AFED to successfully map out the free energy profile of this enantiotropic transformation as a function of temperature, and also for incorporating dynamic structural disorder in crystal structure prediction.

RH, AM, and AS are employees of AbbVie and may own AbbVie stock. MT, LVM and EC are employees of New York University and have no additional conflicts of interest to disclose. AbbVie and NYU sponsored and funded the study; contributed to the design; participated in the collection, analysis, and interpretation of data, and in writing, reviewing, and approval of the final publication.

1. Reiss, C. A.; Mechelen, J. B. v.; Goubitz, K.; Peschar, R., Reassessment of paracetamol orthorhombic Form III and determination of a novel low-temperature monoclinic Form III-m from powder diffraction data. Acta Crystallographica Section C 2018, 74 (3), 392-399.
2. Yu, T.-Q.; Tuckerman, M. E., Temperature-Accelerated Method for Exploring Polymorphism in Molecular Crystals Based on Free Energy. Physical Review Letters 2011, 107 (1), 015701.