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

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

doi:10.1002/chem.201904672

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.

Highlights

The ability to select the optimal crystal form of an active pharmaceutical ingredient (API) has important economic, regulatory, and clinical consequences.[1]
Solution crystallization of ternary molecular ionic cocrystals (ICCs) is complicated by the differences in the solubilities of the reactants, which if significant can lead to undesired products or a physical mixture of the starting reactants
We set out to test the potential for the rapid mechanochemical screening of ICCs by using 4-DMAP and the set of acid coformers shown in Scheme 1

Summary

Introduction

The mechanosynthesis of CABICCs and NCAB-ICCs reported exclusively from solution crystallization screens[14,18] were targeted as a validation of our proposed mechanochemical rapid-screening protocol This was followed by mechanosynthesis experiments targeting a novel CAB-ICC of 2-chlorobenzoic acid and 4-dimethylaminopyridine using a coformer replacement strategy based on molecular size-matching. Despite the proven value of computational crystal structure prediction (CSP) methods in facilitating the discovery of previously unknown solid forms,[4c,19] molecular solids comprising three or more chemical entities are not routinely studied in such work. We test the success of the computational model in reproducing the crystal structures of known CAB-ICCs and NCAB-ICCs displaying rigid molecular conformations This is followed by a more extensive blind[21] CSP study on two conformationally flexible systems: A binary salt and a ternary CABICC derived from 2-CLBZAH and 4-DMAP. We test the hypothesis that the crystallization of ternary molecular ICCs is under thermodynamic control,[22] and that the use of dispersion-corrected density functional theory (DFT-D) energies is diagnostic enough to guide the experimental discovery of ternary molecular ICCs

Results and Discussion

Conclusion

Conflict of interest