A New Insight into Pyrazinamide Polymorphic Forms and their Thermodynamic Relationships

Abstract

Screening of pyrazinamide polymorphs was carried out by crystallization from solvents differing in polarity and hydrogen bonding ability and also by sublimation and lyophilization. Pure samples of polymorphs α, δ, and γ could be prepared, and mixtures of the β form with one of the other polymorphs were also produced. These forms were fully characterized by infrared spectroscopy and two main profiles registered in the N−H stretching vibration region, clearly distinguishing polymorphs encompassing a dimeric pirazinamide unit, α, β, and δ, and where the dimer does not exist, the γ one. The thermal behavior of pyrazinamide polymorphs was also investigated using differential scanning calorimetry (DSC) and polarized light thermal microscopy, supported by powder X-ray diffraction and infrared spectroscopy. The α, β, and δ forms give rise on heating to the γ form, in endothermic transitions, with some superheating being observed. Also, the DSC peaks display an irregular shape. These observations suggest kinetic hindering of the solid−solid transitions. An endothermic phase transition of the δ form to the α one was observed only for samples seeded with this latter polymorph. The relative stability of the four pyrazinamide polymorphs was derived from the experimental observations.