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 • • • OdC 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. † Dedicated to Emer. Prof. Maria Kuhnert-Brandsta ¨tter on the occasion of her 90th birthday.

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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.

The solvent formation of phenobarbital, an important drug compound with an unusually complex polymorphic behavior, was studied in detail. Monosolvates with acetonitrile, nitromethane, dichloromethane, and 1,4-dioxane were produced and characterized by single-crystal and powder X-ray diffraction, thermoanalytical methods, FT-IR, Raman, and solid-state NMR spectroscopy. Thermal desolvation of these compounds yields mainly mixtures of polymorphs III, II, and I. At a low relative humidity (25 °C) the solvates transform to polymorph III, and at higher relative humidity the monohydrate and the metastable polymorphs IV and VI can be present as additional desolvation products. These results highlight the potential complexity of desolvation reactions and illustrate that a tight control of ambient conditions is a prerequisite for the production of phase-pure raw materials of drug compounds. Transformation in aqueous media results in the monohydrate. Below room temperature, the 1,4-dioxane monosolvate undergoes a reversible single-crystal-to-single-crystal phase transition due to the ordering/disordering of 50% of its solvent molecules. Dipolar-dephasing NMR experiments show that the solvent molecules are relatively mobile. Deuterium NMR spectra reinforce that conclusion for the dioxane solvent molecules. The crystal structure of an elusive 1,4-dioxane hemisolvate was also determined. This study clearly indicates the existence of "transient solvates" of phenobarbital. The formation of unstable phases of this kind must be considered in order to better understand how different solvents affect the crystallization of specific polymorphs.

Barbital is a hypnotic agent that has been intensely studied for many decades. The aim of this work was to establish a clear and comprehensible picture of its polymorphic system. Four of the six known solid forms of barbital (denoted I0, III, IV, and V) were characterized by various analytical techniques, and the thermodynamic relationships between the polymorph phases were established. The obtained data permitted the construction of the first semischematic energy/temperature diagram for the barbital system. The modifications I0, III, and V are enantiotropically related to one another. Polymorph IV is enantiotropically related to V and monotropically related to the other two forms. The transition points for the pairs I0/III, I0/V, and III/IV lie below 20 °C, and the transition point for IV/V is above 20 °C. At room temperature, the order of thermodynamic stability is I0 > III > V > IV. The metastable modification III is present in commercial samples and has a high kinetic stability. The solid-state NMR spectra provide information on aspects of crystallography (viz., the asymmetric units and the nature of hydrogen bonding). The known correlation between specific N–H···O=C hydrogen bonding motifs of barbiturates and certain IR characteristics was used to predict the H-bonded pattern of polymorph IV.