Opening Pandora’s Box: Chirality, Polymorphism, and Stoichiometric Diversity in Flurbiprofen/Proline Cocrystals

Natalia Tumanova, Nikolay Tumanov, Koen Robeyns, Franziska Fischer, Luca Fusaro, Fabrice Morelle, Voraksmy Ban, Geoffroy Hautier, Yaroslav Filinchuk, Johan Wouters, Tom Leyssens, Franziska Emmerling

Research output: Contribution to journalArticle

Abstract

Proline has been widely used for various cocrystallization applications, including pharmaceutical cocrystals. Combining enantiopure and racemic flurbiprofen and proline, we discovered 18 new crystal structures. Liquid-assisted grinding proved highly efficient to explore all the variety of crystal forms. A unique combination of state-of-the-art characterization techniques, comprising variable temperature in situ X-ray diffraction and in situ ball-milling, along with other physicochemical methods and density functional theory calculations, was indispensable for identifying all the phases. Analyzing the results of in situ ball-milling, we established a stepwise mechanism for the formation of several 1:1 cocrystals via an intermediate 2:1 phase. The nature of the solvent in liquid-assisted grinding was found to significantly affect the reaction rate and, in some cases, the reaction pathway.
Original languageEnglish
Pages (from-to)954-961
Number of pages8
JournalCrystal Growth & Design
Volume18
Issue number2
DOIs
Publication statusPublished - 4 Jan 2018

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  • Equipment

  • Datasets

    CCDC 1537401: Experimental Crystal Structure Determination

    Tumanova, N. (Contributor), TUMANOV, N. (Contributor), Robeyns, K. (Contributor), Fischer, F. (Contributor), FUSARO, L. (Contributor), Morelle, F. (Contributor), Ban, V. (Contributor), Hautier, G. (Contributor), Filinchuk, Y. (Contributor), WOUTERS, J. (Contributor), Leyssens, T. (Contributor) & Emmerling, F. (Contributor), Cambridge Crystallographic Data Centre, 1 Jan 2018

    Dataset

    CCDC 1537420: Experimental Crystal Structure Determination

    Tumanova, N. (Contributor), TUMANOV, N. (Contributor), Robeyns, K. (Contributor), Fischer, F. (Contributor), FUSARO, L. (Contributor), Morelle, F. (Contributor), Ban, V. (Contributor), Hautier, G. (Contributor), Filinchuk, Y. (Contributor), WOUTERS, J. (Contributor), Leyssens, T. (Contributor) & Emmerling, F. (Contributor), Cambridge Crystallographic Data Centre, 1 Jan 2018

    Dataset

    CCDC 1537408: Experimental Crystal Structure Determination

    Tumanova, N. (Contributor), TUMANOV, N. (Contributor), Robeyns, K. (Contributor), Fischer, F. (Contributor), FUSARO, L. (Contributor), Morelle, F. (Contributor), Ban, V. (Contributor), Hautier, G. (Contributor), Filinchuk, Y. (Contributor), WOUTERS, J. (Contributor), Leyssens, T. (Contributor) & Emmerling, F. (Contributor), Cambridge Crystallographic Data Centre, 1 Jan 2018

    Dataset

    Cite this

    Tumanova, N., Tumanov, N., Robeyns, K., Fischer, F., Fusaro, L., Morelle, F., Ban, V., Hautier, G., Filinchuk, Y., Wouters, J., Leyssens, T., & Emmerling, F. (2018). Opening Pandora’s Box: Chirality, Polymorphism, and Stoichiometric Diversity in Flurbiprofen/Proline Cocrystals. Crystal Growth & Design, 18(2), 954-961. https://doi.org/10.1021/acs.cgd.7b01436