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

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 com-bination 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 hydro-gen 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 O -H center dot center dot center dot O, N -H center dot center dot center dot O, and O -H center dot center dot center dot 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 fluores-cent 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 fol-lows 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 (c) 2022 Elsevier B.V. All rights reserved.