Hiding in Plain Sight: Polymorphs of Riluzole†

Abstract

Riluzole is a glutamate modulator approved by the U.S. Food and Drug Administration in 1995 for treating amyotrophic lateral sclerosis. Although the drug is typically formulated as a solid in tablets for oral administration, little has been published about the crystallinity, structure, and polymorphism of the compound. We have found that riluzole can exist in at least three crystalline forms: a previously reported triclinic P1̅ Form I and two new monoclinic P2₁/c Forms II and III. The relative stability of the forms has been established, and the structure of the form used commercially has been determined. Our study illustrates the difficulty of characterizing polymorphic landscapes when different forms have close structural relationships, when crystallites tend to adopt preferred orientations that complicate the analysis of powder diffractograms, and when computational predictions of structures with high values of Z′ remain challenging. Because riluzole has a compact structure incorporating diverse functionality, including an aromatic core, fluorination, and a capacity for hydrogen bonding, its polymorphism is a subject of special interest at a time when the number of fluorinated drugs is growing rapidly.