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

Abeer F. Shunnar, Bhausaheb Dhokale, Durga Prasad Karothu, David H. Bowskill, Isaac J. Sugden, Hector H. Hernandez, Panče Naumov, Sharmarke Mohamed

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)4752-4765
Number of pages14
JournalChemistry - A European Journal
Volume26
Issue number21
DOIs
StatePublished - Apr 9 2020

Keywords

  • X-ray diffraction
  • crystal engineering
  • crystal structure prediction
  • green chemistry
  • mechanosynthesis
  • molecular ionic cocrystals

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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