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      Efficient Screening for Ternary Molecular Ionic Cocrystals Using a Complementary Mechanosynthesis and Computational Structure Prediction Approach

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          Abstract

          The discovery of molecular ionic cocrystals (ICCs) of active pharmaceutical ingredients (APIs) widens the opportunities for optimizing the physicochemical properties of APIs whilst facilitating the delivery of multiple therapeutic agents. However, ICCs are often observed serendipitously in crystallization screens and the factors dictating their crystallization are poorly understood. We demonstrate here that mechanochemical ball milling is a versatile technique for the reproducible synthesis of ternary molecular ICCs in less than 30 min of grinding with or without solvent. Computational crystal structure prediction (CSP) calculations have been performed on ternary molecular ICCs for the first time and the observed crystal structures of all the ICCs were correctly predicted. Periodic dispersion‐corrected DFT calculations revealed that all the ICCs are thermodynamically stable (mean stabilization energy=−2 kJ mol −1) relative to the crystallization of a physical mixture of the binary salt and acid. The results suggest that a combined mechanosynthesis and CSP approach could be used to target the synthesis of higher‐order molecular ICCs with functional properties.

          Abstract

          Spot on predictions! The mechanosynthesis of ternary molecular ionic cocrystals (ICCs) with significantly different physicochemical properties has been achieved in less than 30 min of grinding. The crystal structures of the ICCs were successfully predicted by using computational methods. The results pave the way for the efficient screening of higher‐order multicomponent crystal forms with functional properties (see figure).

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          Author and article information

          Contributors
          sharmarke.mohamed@ku.ac.ae
          Journal
          Chemistry
          Chemistry
          10.1002/(ISSN)1521-3765
          CHEM
          Chemistry (Weinheim an Der Bergstrasse, Germany)
          John Wiley and Sons Inc. (Hoboken )
          0947-6539
          1521-3765
          24 March 2020
          09 April 2020
          : 26
          : 21 ( doiID: 10.1002/chem.v26.21 )
          : 4752-4765
          Affiliations
          [ 1 ] Department of Chemistry Khalifa University of Science and Technology P.O. Box 127788 Abu Dhabi UAE
          [ 2 ] New York University Abu Dhabi P.O. Box 129188 Abu Dhabi UAE
          [ 3 ] Molecular Systems Engineering Group Centre for Process Systems Engineering Department of Chemical Engineering Imperial College London London SW7 2AZ UK
          [ 4 ] Department of Biomedical Engineering Center for Membrane and Advanced Water Technology Khalifa University of Science and Technology Masdar Campus P.O. Box 127788 Abu Dhabi UAE
          Author information
          http://orcid.org/0000-0002-0763-6066
          http://orcid.org/0000-0001-7520-4727
          http://orcid.org/0000-0001-5956-6496
          http://orcid.org/0000-0001-7173-1829
          http://orcid.org/0000-0003-2416-6569
          http://orcid.org/0000-0002-5195-2533
          Article
          CHEM201904672
          10.1002/chem.201904672
          7187361
          31793669
          d60d9758-b284-42c6-9ca0-ffac011c9d77
          © 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

          This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

          History
          : 13 October 2019
          Page count
          Figures: 11, Tables: 1, References: 123, Pages: 14, Words: 0
          Funding
          Funded by: Khalifa University of Science, Technology and Research , open-funder-registry 10.13039/501100004070;
          Award ID: CIRA-2018-068
          Categories
          Full Paper
          Full Papers
          Crystal Structure Prediction
          Custom metadata
          2.0
          April 9, 2020
          Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.1 mode:remove_FC converted:28.04.2020

          Chemistry
          crystal engineering,crystal structure prediction,green chemistry,mechanosynthesis,molecular ionic cocrystals,x-ray diffraction

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