Low-temperature polymorphs of lacosamide

• Published in: Journal of crystal growth 2021-05, Vol.562, p.126085, Article 126085
• Main Authors: Skořepová, Eliška, Rohlíček, Jan, Chatziadi, Argyro, Zvoníček, Vít, Jirát, Jan, Čejka, Jan, Ridvan, Luděk, Šoóš, Miroslav
• Format: Article
• Language: English
• Subjects: A1. Crystal structure; A1. Phase transformation; A1. Polymorphism; A1. X-ray diffraction; A2. Low-temperature phase; B2. Pharmaceutical; Chemical bonds; Chirality; Crystal structure; Crystals; Low temperature; Melting points; Phase transitions; Room temperature; Seizures; Single crystals; X ray powder diffraction; X-ray diffraction
• ISSN: 0022-0248; 1873-5002
• DOI: 10.1016/j.jcrysgro.2021.126085

The crystal structures of two low temperature polymorphs of a pharmaceutical compound lacosamide are reported in addition to the room temperature form I. The transformations were studied by variable-temperature XRPD. [Display omitted] •The pharmaceutical compound lacosamide was found to have three polymorphs.•Two of the polymorphs exist at low temperatures.•The crystal structure of the room temperature form I has been corrected.•The three crystal structures are unusually similar in most respects.•The transformations between the polymorphs were studied by variable-temperature X-ray powder diffraction. 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.