Expanding the Supramolecular Toolkit: Computed Molecular and Crystal Properties for Supporting the Crystal Engineering of Higher-Order Molecular Ionic Cocrystals

Tamador Alkhidir,Zeinab M Saeed,Sharmarke Mohamed,Runyararo M Nyadzayo,Eman Abujami,Bhausaheb Dhokale,Abeer F Shunnar

doi:10.1021/acs.cgd.1c01107

Tamador Alkhidir, Zeinab M Saeed + Show 5 more

Open Access

https://doi.org/10.1021/acs.cgd.1c01107

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Abstract

Over the past 2 decades, significant progress has been made in developing a robust supramolecular toolkit for the crystal engineering of simple binary cocrystals. By contrast, crystal engineering of higher-order molecular ionic cocrystals (ICCs) is not well established. Here, we report the results of the most extensive survey of the molecular and crystal properties of ICCs reported to date and use the resulting data to propose a set of guiding principles to aid the crystallization of molecular ICCs sustained by charge-assisted hydrogen bonding interactions. Using a data set comprising a total of 94 ICC crystal structures, this work reveals that molecular ICCs are favored within a narrow range of the property landscape. Specifically, most of the ICCs in the data set are crystallized using molecules with significantly different polar surface areas. The data also highlight the importance of choosing molecules with a similar number of conformational degrees of freedom when targeting higher-order cocrystals. Molecular ICCs comprising conjugate acid–base fragments are more likely to be observed in crystallization screens when the difference in the ionization constants of the acid–base pair lie within the “gray” zone of the salt–cocrystal continuum. This work also reveals the hierarchy in the supramolecular heterosynthons of molecular ICCs. Finally, periodic dispersion-corrected density functional theory calculations on a limited subset of crystal structures reveals that most of the ICCs surveyed are driven to form on the basis of favorable energetics as indicated by a mean stabilization energy of −5 kJ mol–1.

Highlights

The discovery of new multicomponent crystals of organic compounds allows us to optimize the solid-state properties and performance characteristics of active pharmaceutical ingredients (APIs).[1]
A total of 94 molecular ionic cocrystals (ICCs) were retrieved from the Cambridge Structural Database (CSD), and a number of molecular and crystal properties were determined using a variety of computational methods including state-of-the-art DFT−D methods
Our work suggests that careful selection of the molecular fragments is required in order to target conjugate acid−base ICCs (CAB−ICCs)

Summary

INTRODUCTION

The discovery of new multicomponent crystals of organic compounds allows us to optimize the solid-state properties and performance characteristics of active pharmaceutical ingredients (APIs).[1]. There has been renewed interest in widening the supramolecular toolkit to cater for the crystal engineering of multicomponent crystals comprising more than two chemical fragments in the crystal The focus of this contribution is on a specific subclass of higher-order cocrystals (HOCs) that are known as ionic cocrystals (ICCs).[13−16]. Recent reports have shown that ICCs offer significant opportunities for optimizing a range of solid-state properties, most notably the solubility,[22] melting point,[18] and dissolution rate.[23,24] while the supramolecular toolkit has proven to be reliable in the design of binary cocrystals, the recent interest in ICCs has led us to question whether solid forms comprising three or more chemical units sustained by charge-assisted interactions can be engineered in the supramolecular sense.

RESULTS AND DISCUSSION

CONCLUSIONS

EXPERIMENTAL SECTION

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■ ACKNOWLEDGMENTS

■ REFERENCES