The Phase Relationship Between the Pyrazinamide Polymorphs α and γ

23 December 2019, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Pyrazinamide is an active pharmaceutical compound for the treatment of tuberculosis. It possesses at least four crystalline polymorphs. Polymorphism may cause solubility problems as the case of ritonavir has clearly demonstrated; however, polymorphs also provide opportunities to improve pharmaceutical formulations, in particular if the stable form is not very soluble. The four polymorphs of pyrazinamide constitute a rich system to investigate the usefulness of metastable forms and their stabilization. However, despite the existence of a number of papers on the polymorphism of pyrazinamide, well-defined equilibrium conditions between the polymorphs appear to be lacking. This paper focusses on the phase behavior of the so-called a and g polymorphs of pyrazinamide, its liquid phase and vapor phase. The melting points and enthalpies of both solid phases have been determined. The equilibrium temperature between a and g was experimentally found at 392(1) K. Moreover, vapor pressures and solubilities of both phases have been determined, clearly indicating that form a is the more stable form at room temperature. High-pressure thermal analysis and the topological pressure-temperature phase diagram demonstrate that the g form is stabilized by pressure and becomes stable at room temperature under a pressure of 260 MPa.


vapor pressure
thermal expansion
solid-solid transition
specific volume
pressure-temperature phase diagram
Active pharmaceutical ingredient

Supplementary materials

Supplementary Materials-OA


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