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

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 P2₁ 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.