Exploring the Crystal Landscape of 3-Methyl-2-phenylbutyramide: Crystallization of Metastable Racemic Forms from the Stable Conglomerate

In the solid state, (±)-3-methyl-2-phenylbutyramide 1 spontaneously resolves into a conglomerate (Form I) that crystallizes in a racemic form (Form II) upon melting followed by vapor crystallization, a rarely reported phenomenon. An additional racemic polymorph, Form III, has been characterized, and the thermodynamic relationship between the three forms established by a variety of computational and experimental methods including grinding, slurry crystallization, and seeding techniques. Both racemic Forms II and III are metastable and readily convert to the more stable conglomerate, Form I. Density functional theory calculations of the different polymorphs of 1 show that the enantiomers of 1 (R & S) are more stable than both racemic forms.