Crystallization of Metastable Polymorphs of Phenobarbital by Isomorphic Seeding

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). Pbtl-VII was obtained as a stabilized intermediate phase from the system dipropylbarbital/Pbtl. Pbtl-VIII occurs on seeding with alphenal (Alp) form I. The structure analysis of this orthorhombic Alp modification revealed the presence of N−H···OC hydrogen bonded layers. Pbtl-IX and X show isomorphic relationships to a rich variety of different barbiturate structures, all based on the same pair of H-bonded ribbon chains. The packing features of Pbtl-IX were deduced from the isomorphic structures of amytal-II and soneryl-I. Pbtl-X is isomorphic to both amytal-I and phanodorm-II. The existence of form XI was confirmed via the solid solutions of Pbtl/Alp and Pbtl/dipropylbarbital. This study conveys some of the basic principles of isomorphic additives on the formation of specific polymorphs or the stabilization of unstable crystal forms, which are not detectable in solvent or melt crystallization experiments of the pure compound.