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

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.

Crystal Engineering of Pharmaceutical Cocrystals in the Discovery and Development of Improved Drugs

“…The interplay of hydrogen bonding and halogen bonding to modulate drug properties will involve a deeper understanding and more subtle interplay of these intermolecular interactions. The long-range synthon Aufbau model will guide in the design and stepwise assembly of binary cocrystals with multiple functional groups and beyond to build ternary and complex higher -order cocrystals through mechanochemistry . In effect, complex multicomponent supramolecular systems designed through an understanding and control of synthon hierarchy will be possible.…”

“…The long-range synthon Aufbau model will guide in the design and stepwise assembly of binary cocrystals with multiple functional groups and beyond to build ternary and complex higher -order cocrystals through mechanochemistry. 428 In effect, complex multicomponent supramolecular systems designed through an understanding and control of synthon hierarchy will be possible. Fluorinated coformers 429−431 and excipients may emerge as a new class of pharmaceutical additives.…”

Synthesis of Ternary Cocrystals, Salts, and Hydrates of Acefylline with Enhanced Dissolution and High Permeability

“…A sequential method for the synthesis of HOCs was recently reported during the period of this manuscript revision and repetition of our experiments. Our results add to the sequential supramolecular synthesis of HOCs (ternary and quaternary) from lower-component binary systems , for the category of pharmaceutical cocrystals and salts. Our preliminary results show that the role of “crystal seeds” should be considered when planning mechanochemical grinding experiments of multicomponent crystals.…”

“…The subject of multicomponent cocrystals (MCCs), also referred to as higher-order cocrystals (HOCs) and sometimes ionic cocrystals (ICCs), is growing, as is evident from several recent publications in Crystal Grown & Design and a leading ACS Editorial on crystal engineering and drug delivery. 50 In a very recent survey of 94 ICCs, Mohamed and co-workers 51 showed the hierarchy of supramolecular heterosynthons in the buildup from binary cocrystals/salts to HOCs−ICCs and classified the frequent synthons into three types. Thakur and Thakuria 52 discussed the factors that affect the physical stability of hygroscopic forms of APIs and coformer selection for the design of multicomponent cocrystals and salts that are stable at ambient/high humidity.…”

Controlling Thermal Expansion in Supramolecular Halogen‐Bonded Mixed Cocrystals through Synthetic Feed and Dynamic Motion

“…[1] Changing the molecular structure of the components is one strategy that often proves successful in changing the solid-state structure and resulting properties. [2] Another strategy is to synthesize a multicomponent solid such as a metal-organic framework, [3] salt, [4] cocrystal, [5] or host-guest complex, [6] wherein each component dictates structural assembly and influences the property of the solid. [7] An area of solid-state materials that is underexplored is a class of materials called mixed cocrystals.…”