The Phase Behaviour of Tetramorphic Pyrazinamide
Résumé
The phase behaviour of pyrazinamide has long been difficult to resolve,[1-3] in particular because of the strong hysteresis between the phase transitions. Vapour pressure data has allowed to improve our understanding resulting in the phase diagram below. Uncertainties in the transition temperatures between the phases and and the phases and still exist as they have not been measured directly. It is however likely that the equilibrium temperature of the - phase equilibrium is found between 0 and 25°C. At room temperature both solids must have the same solubility, as their vapour pressures are virtually the same. Because phase transformations are not observed at room temperature and is also stable above room temperature up to 120°C[1], stability-wise it would be the most logical form to use in formulations.
The form possesses a more pronounced thermal expansion than the other polymorphs. This result is most likely due to its layered structure held together by weak interactions, which also leads to a large compressibility observed by synchrotron X-ray diffraction. Interestingly, forms and , which both exhibit uniaxial negative thermal expansion to some level, are only stable at low pressures.
The high compressibility of the form possibly leads to a considerably curved - equilibrium with a temperature minimum in the equilibrium line (not indicated in the figure below). Such curvature presents a challenge to the topological approach with the aim of constructing phase diagrams with only ordinary pressure data (P 0 MPa) and the Clapeyron equation. From a large number of high-pressure studies,[4] it can be concluded that most solid-solid equilibria are straight lines in the pressure-temperature plane implying that compressibilities between polymorphs do not differ much; thus, the current finding appears to be a rare case.