Structural Features, Phase Relationships and Transformation Behavior of the Polymorphs I−VI of Phenobarbital

Six of the more easily accessible forms of phenobarbital (Pbtl-I, II, III, IV, V, VI) were characterized by a variety of analytical methods (thermal analysis, solution calorimetry, X-ray diffraction methods, infrared, Raman and solid-state NMR spectroscopy), in order to get a clear picture of this complex polymorphic system and to eliminate severe inconsistencies in the existing data. On the basis of the thermochemical data and stability studies, we were able to clarify the thermodynamic relationships of the six forms with the aid of a semi-schematic energy/temperature diagram. The order of the thermodynamic stability at 20 °C was established as I > II > III > IV > V/VI, but forms I and II are energetically almost indistinguishable. This study provides a comprehensive description about the production, identification, and transformation pathways of the six polymorphs and discusses the structural origins for some of the unique solid-state phenomena of this important drug compound.