Nitazoxanide Cocrystals in Combination with Succinic, Glutaric, and 2,5-Dihydroxybenzoic Acid

Combination of nitazoxanide (NTZ) with a total of 32 cocrystal formers gave cocrystals with succinic acid (NTZ-SUC, 2:1) and glutaric acid (NTZ-GLU, 1:1). Additionally, 2,5-dihydroxybenzoic acid provided a cocrystal solvate with acetonitrile (NTZ-25DHBA-CH₃CN, 1:1:1). All solid phases were characterized by X-ray powder diffraction analysis, IR spectroscopy, thermogravimetric analysis, differential scanning calorimetry, and single-crystal X-ray diffraction analysis. Single-crystal X-ray crystallography revealed that NTZ and the carboxylic acid cocrystal formers were linked in all three cocrystals through the same supramolecular heterodimeric synthon, C­(N)­NH···HOOC. Despite having different stoichiometries, the crystal structures of NTZ-SUC and NTZ-GLU showed similarities in the supramolecular organization, both containing two-dimensional layers formed by NTZ molecules, which were further interconnected by single (NTZ-SUC) and homodimeric entities (NTZ-GLU) of the cocrystal former. Basic physical stability tests showed that cocrystals NTZ-SUC and NTZ-GLU are stable at least for one month under standardized temperature/relative humidity stress conditions but decompose within 1 h into the corresponding physical phase mixtures, when exposed to aqueous solutions simulating physiological gastrointestinal conditions. Measurement of the dissolution rates gave small increases of the intrinsic dissolution rate constants when compared with NTZ. Pressure stability tests showed that the cocrystals support higher pressures (at least up to 60 kg/cm²) than NTZ

Nitazoxanide Cocrystals in Combination with Succinic, Glutaric, and 2,5-Dihydroxybenzoic Acid

Combination of nitazoxanide (NTZ) with a total of 32 cocrystal formers gave cocrystals with succinic acid (NTZ-SUC, 2:1) and glutaric acid (NTZ-GLU, 1:1). Additionally, 2,5-dihydroxybenzoic acid provided a cocrystal solvate with acetonitrile (NTZ-25DHBA-CH₃CN, 1:1:1). All solid phases were characterized by X-ray powder diffraction analysis, IR spectroscopy, thermogravimetric analysis, differential scanning calorimetry, and single-crystal X-ray diffraction analysis. Single-crystal X-ray crystallography revealed that NTZ and the carboxylic acid cocrystal formers were linked in all three cocrystals through the same supramolecular heterodimeric synthon, C­(N)­NH···HOOC. Despite having different stoichiometries, the crystal structures of NTZ-SUC and NTZ-GLU showed similarities in the supramolecular organization, both containing two-dimensional layers formed by NTZ molecules, which were further interconnected by single (NTZ-SUC) and homodimeric entities (NTZ-GLU) of the cocrystal former. Basic physical stability tests showed that cocrystals NTZ-SUC and NTZ-GLU are stable at least for one month under standardized temperature/relative humidity stress conditions but decompose within 1 h into the corresponding physical phase mixtures, when exposed to aqueous solutions simulating physiological gastrointestinal conditions. Measurement of the dissolution rates gave small increases of the intrinsic dissolution rate constants when compared with NTZ. Pressure stability tests showed that the cocrystals support higher pressures (at least up to 60 kg/cm²) than NTZ

A Twist in Cocrystals of Salts: Changes in Packing and Chloride Coordination Lead to Opposite Trends in the Biopharmaceutical Performance of Fluoroquinolone Hydrochloride Cocrystals

Fluoroquinolones are extensively used antibiotics that are generally prescribed as hydrochloride salts because the neutral forms display low solubility due to their zwitterionic character. Starting from the hydrochloride salts of ciprofloxacin (CiHCl) or (<i>S</i>,<i>S</i>)-moxifloxacin (MoHCl) and 4-hydroxybenzoic acid (4HBA) as a cocrystal former, two cocrystalline solids, CiHCl–4HBA and MoHCl–4HBA, were obtained in a salt/coformer stoichiometric ratio of 1:1. The cocrystalline phases were identified by X-ray powder diffraction analysis and further characterized by IR spectroscopy, thermogravimetric analysis-differential scanning calorimetry, and single crystal X-ray diffraction analysis. The novel solid phases could be formed using different methodologies, namely, solution-mediated phase transformation, solvent drop grinding, crystallization by solvent evaporation, and reaction crystallization. Pharmaceutically relevant properties such as phase stability, thermodynamic solubility, and dissolution rate were examined. All cocrystalline phases remained stable when suspended in acidic aqueous solutions and did not transform upon accelerated temperature/relative humidity exposition for 30 days. Interestingly, opposite trends in the thermal stability, solubility, and dissolution rate of the cocrystals were exhibited by the different fluoroquinolones in comparison to the parent starting salts. Upon heating, the CiHCl–4HBA cocrystal releases first the coformer before decomposing and displayed a lower solubility and dissolution rate in comparison to CiHCl·1.34H₂O. By contrast, the MoHCl–4HBA cocrystal melts in a single-phase transition process and showed enhanced solubility and dissolution rate when compared to the parent moxifloxacin salt. The similar composition of the cocrystals and the structural resemblance of the fluoroquinolones examined herein allowed for a detailed vis-à-vis comparison between the supramolecular structures in the solid-state and the physicochemical properties. The incorporation of 4HBA in the crystal lattice caused changes in the number, type, and strength of the intermolecular interactions between the ionic components (chloride and fluoroquinolinium cations), which could be related to the solubility and dissolution rate properties. While the cocrystal CiHCl–4HBA retained essential features of the supramolecular assembly found also for the starting hydrochloride and gave an overall three-dimensional hydrogen bonded network with the cocrystal former, MoHCl–4HBA showed a singular two-dimensional assembly, with linear chains formed between the 4HBA molecules and chloride ions through O–H···Cl^–···H–O hydrogen bonds in place of the usual charged-assisted N⁺–H···Cl^– interactions

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