The discovery of molecular ionic cocrystals (ICCs) of active pharmaceutical ingredients (APIs) widens the opportunities for optimizing the physicochemical properties of the API 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 that mechanochemical ball‐milling is a versatile technique for the reproducible synthesis of ternary molecular ICCs in less than 30 minutes of grinding with or without solvent. Computational crystal structure prediction (CSP) calculations were performed on ternary molecular ICCs for the first time and the observed crystal structures of all ICCs were correctly predicted. Periodic DFT‐D calculations reveal that all 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.
Shunnar, A. F., Dhokale , B., Karothu, D. P., Bowskill, D. H., Sugden, I. J., Hernandez, H. H., Naumov, P., & Mohamed*, S. (Accepted/In press). Efficient Screening for Ternary Molecular Ionic Cocrystals using a Complementary Mechanosynthesis and Computational Structure Prediction Approach. Chemistry - A European Journal, doi.org/10.1002/chem.201904672.. https://doi.org/doi.org/10.1002/chem.201904672