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Multicomponent Crystal Forms of a Biologically Active Hydrazone with Some Dicarboxylic Acids: Salts or Cocrystals?

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journal contribution
posted on 08.11.2019, 18:04 by Liliana Mazur, Ilona Materek, Andrew D. Bond, William Jones
A multifunctional, biologically active hydrazone compound (BZH) has been cocrystallized with four aliphatic dicarboxylic acids of different carbon linkage. Multiple hydrogen-bond donor and acceptor sites on both the ligand and the coformers enlarge the spectrum of possible aggregation modes and facilitate the formation of different stoichiometric variations. The screening for multicomponent molecular complexes was performed applying both crystallization from solution and mechanochemical neat grinding (NG) and liquid-assisted grinding (LAG) techniques. The outcomes were identified and characterized by powder X-ray diffraction as well as thermogravimetric/differential scanning calorimetry (TG/DSC) analyses. Single-crystal X-ray analysis, supported by dispersion-corrected density functional theory (DFT) relative lattice energy calculations and CSD searches, has been performed to study the chemical nature (cocrystals vs salts) of new forms as well as synthon preferences in the resulting solids. The study reveals that the crystals are based on neutral or ionic carboxyl-pyridyl and carboxyl-amide heterosynthons. The same products were obtained under all tested experimental conditions: salts for malonic and succinic acids and a cocrystal for the larger glutaric acid. For the asymmetric mesaconic acid, two concomitant crystal forms, a 1:1 cocrystal and a 2:3 disordered solid form, were found after solution crystallization. A methanol solvate of the 1:1 cocrystal was also obtained. The LAG and NG techniques resulted in nonsolvated forms of the 1:1 and 2:3 cocrystals, respectively. The correlations between the protonation state of the components, intermolecular interactions, crystal packing features, and thermal stability of the resulting solids are discussed.