Sustained-Release Dual-Drug Ternary Salt Cocrystal of Piperazine Ferulate with Pyrazinamide: Synthesis, Structure, and Hirshfeld Surface Analysis

A novel dual-drug ternary salt cocrystal of piperazine ferulate (PRZ–FLA) with pyrazinamide (PRA), namely, PRZ–FLA–PRA, has been synthesized and characterized. Single-crystal X-ray diffraction reveals that the cocrystal has a formula of (PRZ2+)·(FLA–)2·(PRA)2, in which the PRZ2+ and FLA– ions form a one-dimensional chain by the strong charge-assisted hydrogen bonds and then interacts with neutral PRA molecules through hydrogen bonds, constructing a three-dimensional supramolecular network. As far as we know, this is the first example of a dual-drug ternary salt cocrystal simultaneously containing both a nephrosis-treating drug and antituberculous agent. The solubility and dissolution rate studies of the cocrystal are conducted under various physiological pH environments to assess the effects of cocrystallization on in vitro release behaviors of PRZ–FLA, and the outcomes suggest that the intrinsic dissolution rate and solubility of PRZ–FLA in the cocrystal are slowed and lowered, respectively, in comparison with the parent drug. The present work not only provides an alternative approach to reduce the release rate, which is in favor of solving issues with the short half-life of PRZ–FLA, but also offers a potential synergistic therapeutic application as a promising combination drug to treat the symptoms of complications from tuberculosis and renal injury.