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Extending the Range of Nitrofurantoin Solid Forms: Effect of Molecular and Crystal Structure on Formation Thermodynamics and Physicochemical Properties

Cite this: Cryst. Growth Des. 2022, 22, 4, 2569–2586
Publication Date (Web):March 11, 2022
https://doi.org/10.1021/acs.cgd.2c00044
Copyright © 2022 American Chemical Society

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    Abstract

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    In this work, four novel pharmaceutical cocrystals of nitrofurantoin, an antibacterial drug, with isonicotinamide, picolinamide, 2-hydroxybenzamide, and 2-aminobenzamide have been obtained and thoroughly characterized by various analytical techniques. The crystal structures of the solid forms have been elucidated by single-crystal X-ray diffraction, and the energy distribution of intermolecular interactions has been further quantified on the basis of QTAIMC analysis. Eight distinct supramolecular heterosynthons of hydrogen bonding have been identified in the studied crystals, and their relative stability has been ranked in terms of total interaction energies. The thermodynamics of the cocrystallization reactions has been systematically investigated using two independent experimental techniques, namely solution calorimetry and phase solubility diagram, which allowed us to assess both the enthalpic and the entropic contributions to the cocrystal formation driving force. The pH-solubility behavior of the cocrystals has been investigated at different pH values using eutectic concentrations of the components. Although all of the cocrystals reported here were found to be more soluble than the parent drug, their advantage in thermodynamic solubility did not translate into enhanced dissolution performance due to a rapid solution-mediated phase transformation in aqueous media. In addition, the effect of cocrystallization on other pharmaceutically relevant properties of nitrofurantoin, including photostability and membrane permeability, has been considered and analyzed.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.cgd.2c00044.

    • Crystallographic data for the cocrystals, details of the CSD analysis, periodic DFT and MEP calculations, illustrations of packing projections for the NFT cocrystals and results of thermal analysis, experimental results of the solution calorimetry study and phase solubility diagrams, details of aqueous solubility studies (eutectic concentrations) and PXRD patterns of residual materials after dissolution experiments, and details of diffusion and photostability investigations (PDF)

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    CCDC 21311652131168 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 6 publications.

    1. Alex N. Manin, Denis E. Boycov, Olga R. Simonova, Ksenia V. Drozd, Tatyana V. Volkova, German L. Perlovich. How Molecular Packing Affects the Thermodynamic Parameters of Cocrystal Formation: The Case of Carbamazepine Cocrystals. Crystal Growth & Design 2024, 24 (1) , 252-261. https://doi.org/10.1021/acs.cgd.3c00949
    2. Artem O. Surov, Anna G. Ramazanova, Alexander P. Voronin, Ksenia V. Drozd, Andrei V. Churakov, German L. Perlovich. Virtual Screening, Structural Analysis, and Formation Thermodynamics of Carbamazepine Cocrystals. Pharmaceutics 2023, 15 (3) , 836. https://doi.org/10.3390/pharmaceutics15030836
    3. Keitumetsi Ndlovu, Christina Kannigadu, Janine Aucamp, Helena D. Janse van Rensburg, David D. N'Da. Exploration of ethylene glycol linked nitrofurantoin derivatives against Leishmania : Synthesis and in vitro activity. Archiv der Pharmazie 2023, 92 https://doi.org/10.1002/ardp.202200529
    4. Denis E. Boycov, Ksenia V. Drozd, Alex N. Manin, Andrei V. Churakov, German L. Perlovich. New Solid Forms of Nitrofurantoin and 4-Aminopyridine Salt: Influence of Salt Hydration Level on Crystal Packing and Physicochemical Properties. Molecules 2022, 27 (24) , 8990. https://doi.org/10.3390/molecules27248990
    5. Ilma Nugrahani, Emy Susanti, Tazkia Adawiyah, Safira Santosa, Agnesya Namira Laksana. Non-Covalent Reactions Supporting Antiviral Development. Molecules 2022, 27 (24) , 9051. https://doi.org/10.3390/molecules27249051
    6. Noopur Pandey, Animesh Ghosh. An outlook on permeability escalation through cocrystallization for developing pharmaceuticals with improved biopharmaceutical properties. Journal of Drug Delivery Science and Technology 2022, 76 , 103757. https://doi.org/10.1016/j.jddst.2022.103757

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