Crystal Polymorphs of Barbital: News about a Classic Polymorphic System

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 <b>I</b>⁰, <b>III</b>, <b>IV</b>, and <b>V</b>) 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 <b>I</b>⁰, <b>III</b>, and <b>V</b> are enantiotropically related to one another. Polymorph <b>IV</b> is enantiotropically related to <b>V</b> and monotropically related to the other two forms. The transition points for the pairs <b>I</b>⁰/<b>III</b>, <b>I</b>⁰/<b>V</b>, and <b>III</b>/<b>IV</b> lie below 20 °C, and the transition point for <b>IV</b>/<b>V</b> is above 20 °C. At room temperature, the order of thermodynamic stability is <b>I</b>⁰ > <b>III</b> > <b>V</b> > <b>IV</b>. The metastable modification <b>III</b> 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 <b>IV</b>

New Solvates of an Old Drug Compound (Phenobarbital): Structure and Stability

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 <b>III</b>, <b>II</b>, and <b>I</b>. At a low relative humidity (25 °C) the solvates transform to polymorph <b>III</b>, and at higher relative humidity the monohydrate and the metastable polymorphs <b>IV</b> and <b>VI</b> 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