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

Abstract

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.

Influence of Bio-Isosteric Replacement on the Formation of Templating Methanol and Acetonitrile Solvates in Lophines

“…16 On the other hand, solvates represent a route to obtain novel unsolvated crystal forms, which are not accessible by direct crystallisation. [17][18][19][20][21][22] The inclusion of solvent molecules into crystal forms has been widely studied, not only in the pharmaceutical field. The influence of solvate formation has been studied in a co-crystal system that has been crystal-engineered to undergo photodimerisation.…”

Buthalital and methitural – 5,5-substituted derivatives of 2-thiobarbituric acid forming the same type of hydrogen-bonded chain

“…C-2 chains containing a 2 1 screw axis occur in polymorph III of phenobarbital (PHBARB09), the CH 2 Cl 2 solvate of the same compound (EPUDEA) (Zencirci et al, 2010(Zencirci et al, , 2014 and in 5-fluoro-5-phenylbarbituric acid (HEKTOG) (DesMarteau et al, 1994) as well as in (I). By contrast, the C-2 chains of 6oxocyclobarbital (OXCBAR) (Chentli-Benchikha et al, 1977) and polymorph III of pentobarbital (FUFTEG02) (Rossi et al, 2012) exhibit glide symmetry.…”

Crystal structure of 5-hydroxy-5-propylbarbituric acid

“…As part of a systematic investigation of solid-state properties of derivatives of barbituric acid (Gelbrich et al, 2015;Zencirci et al, 2014;Rossi et al, 2012), we are studying the polymorphism of a group of 5-monosubstituted barbituric acids. The title compound is an oxidation product of 5-propylbarbituric acid, formed during a crystallization experiment and the structure is reported herein.…”