A structural analysis of over 80 salts and cocrystals synthesized from equimolar amounts of carboxylic acids and N-heterocycles demonstrates that salt formation as a result of proton transfer from the acid to the base frequently (11/24; 45%) results in a lattice with an unpredictable chemical (solvate) or stoichiometric composition. However, if no proton transfer takes place and the result is a molecular cocrystal, a crystal lattice with an unexpected chemical content or stoichiometry is much less likely (3/61; 5%). These results indicate that the process of converting a neutral carboxylic acid into a carboxylate anion can have important structural consequences that make structure prediction and targeted supramolecular synthesis of salts much more difficult than of cocrystals. Consequently, cocrystals may offer new opportunities for producing a greater diversity of solid forms of drug substances that exhibit the appropriate balance of critical properties for development into a viable and effective drug product.

The molecules presented here provide a test-bed for competitive supramolecular chemistry, and on the basis of five crystal structures a ranking of the relative structural importance and influence of competing weak/strong hydrogen bonds and weak/strong halogen bonds has been achieved.

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Through a combination of structural chemistry, vibrational spectroscopy, and theory, we have systematically examined the relative structure-directing importance of a series of ditopic halogen-bond (XB) donors. The molecular electrostatic potential surfaces of six XB donors were evaluated, which allowed for a charge-based ranking. Each molecule was then co-crystallized with 21 XB acceptors and the results have made it possible to map out the supramolecular landscape describing the competition between I/Br-ethynyl donors, perfluorinated I/Br donors, and I/Br-phenyl based donors. The results offer practical guidelines for synthetic crystal engineering driven by robust and directional halogen bonds.