Relative Stability of Pyrazinamide Polymorphs Revisited: A Computational Study of Bending and Brittle Forms Phase Transitions in a Broad Temperature Range

Abstract

Pyrazinamide may exist in at least four known polymorphic forms, which were obtained experimentally. One of these polymorphs, (α), shows outstanding mechanical properties, demonstrating a significant anisotropic plasticity in a three-point bending test, while the δ form was brittle. Despite a δ → α transition as well as β and γ behavior being experimentally studied, the relative stability of pyrazinamide polymorphs remains unclear and even controversial. In this work we provide a pure computational study of the thermodynamic relationships between all four polymorphs as a function of temperature using periodic DFT calculations. It was shown that the β but not the δ form is the most stable at low temperatures. Moreover, the relative stability of the δ form in comparison to α is questioned, showing that the “brittle to bending” δ → α transition was kinetically hindered in the experiments. We show that α and γ polymorphs were stabilized at higher temperatures due to an entropy term. Finally, the calculated stability of the bending α form of pyrazinamide at room temperature was in perfect agreement with previous experiments, which showed a transformation of all other forms to α during six month storage or grinding.