Co-crystals of pyrazinamide (PZA) with terephthalic (TPH) and trimesic (TMS) acids: Structural insights and dissolution study

Abstract

Two new co-crystals of pyrazinamide (PZA) with terephthalic (TPH) and trimesic (TMS) acids have been prepared and characterized by single-crystal and powder X-ray diffraction, spectroscopic and thermal analysis, and the corresponding dissolution curves are discussed. PZA-TPH co-crystal is formed by a combination of acid-py heterosynthons and amide-amide homosynthons, while in PZA-TMS co-crystal only amide-acid and acid-py heterosynthons were observed. These interactions are discussed based on hydrogen bonds and pairwise interaction energies calculated using B3LYP/6–31G(d,p) molecular wave functions. Hirshfeld surface analysis shows that the crystal structure is mainly controlled by short OH‧‧‧O, NH‧‧‧O, and OH‧‧‧N hydrogen bonds forming molecular sheets that induce preferred orientations in their powder samples. During single-crystal X-ray diffraction experiments, a sort of anisotropic X-ray induced fluorescent phenomenon was observed. PZA-TPH and PZA-TMS co-crystals present improved thermal stabilities compared to PZA. However, the solubility of co-crystals decrease compared to PZA which remarkably follows the proportionality of the conformer solubility rule. In the co-crystals, the lower solubility is due to the precipitation of the TPH and TMS acids, nevertheless, PZA molecules tend to retain a more stable concentration over time