The Rich Solid-State Phase Behavior of L-Phenylalanine: Disappearing Polymorphs and High Temperature Forms

HM Cuppen and MMH Smets and AM Krieger and JA van den Ende and H Meekes and ERH van Eck and CH Gorbitz, CRYSTAL GROWTH & DESIGN, 19, 1709-1719 (2019).

DOI: 10.1021/acs.cgd.8b01655

After years of controversy over the solid state structure of the essential amino acid L-phenylalanine, four different polymorphic forms were published recently. The common form I has symmetry P2(1) with four molecules in the asymmetric unit (Z' = 4), similar to form III, but with a different arrangement of molecular bilayers. Form II, obtained from the hydrate at very low humidity, is unrelated to forms I and III, as is the high-density form IV. The present investigation demonstrates that this prototype aromatic amino acid has two additional high-temperature phases Ih and IIIh obtained from form I and form III above 458 and 440 K, respectively, when flipping between two alternative side-chain conformations becomes dynamic and causes pairs of molecules, initially crystallographically independent, to become equivalent above a sharp transition temperature. These abrupt and reversible phase changes occur with a reduction of Z' from 4 (low T) to 2 (high T) and modified crystal symmetry. We furthermore experienced an example of disappearing polymorph for form I which after growing form III in one of our laboratories could no longer be crystallized at room temperature. In contrast, form III crystals may be irreversibly converted to form I crystals as a result of sliding of molecular bilayers in the crystal at elevated temperature. No conversions between the high-temperature forms Ih and IIIh were found. The remarkable crystallographic results are here corroborated by Molecular Dynamics and metadynamics simulations of the form I - form III system.

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