Cocrystals of Active Pharmaceutical IngredientsPraziquantel in Combination with Oxalic, Malonic, Succinic, Maleic, Fumaric, Glutaric, Adipic, And Pimelic Acids

The combination of racemic praziquantel, (<i>RS</i>)-PZQ, with aliphatic dicarboxylic acids of the homologous series HOOC–(CH₂)_<i>n</i>–COOH (with <i>n</i> = 0–8) and the unsaturated analogues of succinic acid as cocrystal formers via liquid-assisted grinding provided a total of nine 1:1 and 2:1 cocrystals with oxalic acid, malonic acid, succinic acid (two polymorphic phases), maleic acid, fumaric acid, glutaric acid, adipic acid, and pimelic acid. The cocrystalline phases were identified first by XRPD analysis and then structurally characterized by IR spectroscopy and, as far as possible, by single-crystal X-ray diffraction analysis. Crystals suitable for XRD analysis were obtained for seven cocrystals and, additionally, for (<i>RS</i>)-PZQ. The analysis of the supramolecular interactions in the crystal structures has shown that the dominant hydrogen bonding patterns within the cocrystals are heterodimeric motifs formed through O–H···O hydrogen bonds between PZQ and the dicarboxylic acids, which mostly contain additionally at least one secondary C–H···O contact. In all crystal structures, the PZQ molecules are connected with each other through cyclic homodimeric hydrogen bonding interactions formed mainly through C–H···O, but also through C–H···π contacts, giving overall 1D, 2D or 3D hydrogen bonded networks. The crystallographic study also allowed us to establish that there are two main rotational conformers for PZQ, which differ in the configuration of the CO groups in the piperazinone–cyclohexylcarbonyl segment. In the crystal structure of (<i>RS</i>)-PZQ, all four independent molecules in the asymmetric unit have the <i>syn</i>-conformation, which in the hemihydrates, viz. (<i>R</i>)-PZQ·0.5H₂O and (<i>S</i>)-PZQ·0.5H₂O, and all cocrystals except for one are switched to the <i>anti</i>-antagonist