Low-temperature polymorphs of lacosamide

Abstract

Lacosamide is used in the adjunctive treatment of partial-onset seizures and diabetic neuropathic pain. Up-to-date, only one polymorph has been described. Our aim was to explore the thermal phase behavior of this compound. When heated, no transformations are observed until the melting point. A very different situation is observed, when lacosamide is cooled. With the use of variable-temperature X-ray diffraction, we were able to detect two phase transformations. The crystal structures of the two new polymorphs were determined by single-crystal and powder X-ray diffraction. We also offer a redetermination of the room temperature polymorph with the explicitly described disorder and the correct chirality. All three polymorphs were analyzed from the point of the conformation of the lacosamide molecule, the non-bonded interactions, the crystal packing and the transformations between them. The structures are positively distinct, but surprisingly similar. Especially the two low-temperature polymorphs are almost identical, with the only major difference between them being the monoclinic angle. The transformations between lacosamide polymorphs are fully reversible and do not exhibit any hysteresis, which are important findings for the manufacturing and storage of the lacosamide drug product.