The relation between twinning and disorder in the gamma form of pyrazinamide

Abstract

International audiencePyrazinamide (PZA), an active pharmaceutical ingredient (API) is a first-line drug for the treatment of tuberculosis. Its molecular structure is shown in the figure below. Pyrazinamide possesses at least four known polymorphs, named alpha (P21/n), beta (P21/c), gamma (Pc) and delta (P1 ̅). Among these polymorphs, the gamma form exhibits a distinctively different packing from the other three polymorphs as one intermolecular hydrogen bond (N-H...N) links the amide group with the pyrazine ring forming linear chains of single H-bonded molecules. Moreover, crystals of the gamma form are very often twinned.Single crystals of gamma can be obtained by sublimation. In the literature, disorder has been reported in crystals of the gamma form [1,2], which takes the form of two molecular orientations in which the pyrazine ring and the amide moiety of the disordered molecules have been exchanged. Although the crystal structure of the gamma form explicitly including disorder had been found to be energetically quite close to the ideally ordered crystal structure [2], it has not been clear until now whether the disorder is static or dynamic and how twinning may be related to the disorder.Disorder and twinning of the gamma form of PZA have been investigated experimentally. Single crystal X-ray diffraction as a function of temperature has led to results that demonstrate that the disorder site occupancy is independent of the temperature, thus suggesting that the disorder is static. For twinned crystals, the morphology of each domain of the twinned crystals are different from that of single crystals. The twin interface is found to be (100). This is shown in the figure on the right in which the 100 faces are facing each other, while the orientation of the molecules at the twin boundary are shown below. The orientation of ‘disordered’ molecules and the orientation of the molecules on the twin boundary are the same, implying that both phenomena are closely related