Cocrystal or Salt: Does It Really Matter?

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.
Keywords: Cocrystal; salt; hydrogen bonding; crystal lattice; crystal prediction