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 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.