Multicomponent cocrystal

Since both cocrystals and salts are multicomponent crystalline forms, it is clear that the distinction between the two depends on the degree of proton transfer between the donor and the acceptor. In this view, salts would be characterized by effectively complete proton transfer, while cocrystals would exhibit proton sharing with little or no transfer [17,18]. In a survey study of over 80 salts and cocrystals prepared by the interaction of carboxylic acids and N-heterocyclic compounds, it was reported that structure prediction and targeted synthesis appeared to be more difficult for salts than for cocrystals [19]. 

Crystal structure prediction can give insights into molecular packing and the relevant solid-state interactions of cocrystals [46,47] but is yet too time consuming to be of practical use for flexible, multicomponent systems, or even for the screening over several coformers. 

Surveys of the CSD " have indicated that the prevalence of polymorphism in single-component organic molecules (circa 1.4%) is about the same as exhibited by all organic multicomponent crystals sustained by hydrogen bonding (circa 1.9%), and that the tendency of each class to form multiple crystal forms is significantly less than exhibited by APIs. The working hypothesis is that cocrystal... 

Crystal engineering is a scientific area in constant flux, which helps explain why unambiguous definitions have not yet been developed and/or accepted. The term cocrystal is not well defined, and the existing literature contains terms such as molecular complexes, multicomponent solids, cocrystals, molecular adducts, molecular salts, clathrates, and inclusion compounds that frequently describe one and the same family or type of chemical compounds. We will not attempt to add to the ongoing discussion, and we limit our overview to structurally homogeneous crystalline materials containing two or more neutral building blocks that are present in definite stoichiometric amounts and that are made from reactants that are solids at ambient conditions [1] (therefore hydrates and other solvates are excluded from this overview). In addition, we do not discuss... 

One of the most useful applications of solid-state grinding and kneading is undoubtedly the preparation of cocrystals. In the following, we have adopted the liberal view of cocrystal as a multicomponent molecular crystal even though the exact definition of a cocrystal is still matter of debate. The flexible definitions allow us to include solvates and hydrates and also the cases where the difference between salts and neutral systems will depend on the extent of proton transfer along a hydrogen bond. ... 

Already, more than 25 years ago, Toda et al. reported the mechanochemical preparation of crystalline host-guest inclusion compounds and of charge-transfer (CT) systems. CT systems have also been studied by Kuroda et al., who were able to obtain multicomponent systems based on racemic bis-)8-naphtol, benzoquinone, and anthracene the cocrystal formation could be easily followed by the change in color of the solid mixtures. Importantly, this material was not accessible from conventional solution crystallization procedures and required structure determination from X-ray powder diffraction. ... 

The application of mechanochemistry in supramolecular synthesis has been extensively used in the past 10 years for obtaining multicomponent molecular crystals in particular in the pharmaceutical field [5, 7]. The production of new solid forms, especially cocrystals is of utmost importance as it provides a way to derivatize active pharmaceutical ingredients (APIs), by modifying their solid-state arrangements rather than their internal molecular structures. Modification of the crystal... 

Here we aim to present some of the recent advances in crystal engineering concerning the synthesis of metastable solid tautomers by design, usually by complexation with suitable counter-molecules (later called coformers), forming the multicomponent molecular solids. We will also discuss the methods and supramolecular rules that can be used for design and controllable synthesis of such solids. Finally, we will present some of the most illustrative examples of cocrystal systems comprising more tautomeric forms reported to date. 

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