Crystallization of Metastable Polymorphs of Phenobarbital by Isomorphic Seeding

Abstract

Six metastable polymorphs (V, VII−XI) of phenobarbital (Pbtl) were produced by melt crystallization via seeding with corresponding isomorphic barbiturate homologues, following the teachings of earlier thermoanalytical studies of isopolymorphic relationships and utilizing the melting phase diagrams of Pbtl admixtures with various 5,5-substituted barbituric acid derivatives. The Pbtl forms and their solid solutions were analyzed with hot-stage microscopy, powder X-ray diffraction, and infrared spectroscopy. The crystal structures of several isomorphic homologues were determined to assess the structural features of the metastable Pbtl polymorphs. In contrast to Pbtl-V, VIII, and IX, which could be isolated as a single component phase, Pbtl-VII, X, and XI could only be stabilized in the presence of one of the isomorphic additives. Form Pbtl-V, the most stable form among the six metastable polymorphs, is structurally similar to Pbtl-IV and was crystallized by seeding with co-crystals of Pbtl/rutonal (3:1). Pbt...