Using Prenucleation Aggregation of Caffeine-Benzoic Acid as a Rapid Indication of Co-crystallization from Solutions

Co-crystal design is a convenient way to remedy the poor biopharmaceutical properties of drugs. Most studies focus on ex-perimental co-crystal screening or computational prediction, but hardly any work has been done towards fast, efficient and reliable prediction of solution crystallization for co-crystal formation. Here, we study the caffeine-benzoic acid co-crystal system, due to its reported difficulty to crystallise from the solution phase. With this work, we investigate whether there is a link between pre-nucleation aggregation in solution and co-crystal formation and how to harness this for crystallisation pre-diction. 1H and 13C NMR spectroscopy are used to study the pre-nucleation interaction between caffeine and benzoic acid in methanol, acetone and acetonitrile as examples of common solvents. In this system, crystallisation from methanol leads to no co-crystallisation, from acetone to concomitant crystallisation of co-crystal and caffeine, and from acetonitrile to pure co-crystal formation from solution. Strong heteromeric dimers were found to exist in all three solvents. Ternary phase dia-grams were defined and a solution-accessible co-crystal region was found for all solvents. For this system, the pre-nucleation clusters found in solution could be linked to the crystallization of the co-crystal. Crystallisation from DMSO did not yield the co-crystal and there were no detectable pre-nucleation aggregates. NMR spectroscopy to probe dimers in solution can thus be used as a fast, reliable and promising tool to predict co-crystallisation from specific solvents and to screen for suitable solvents for manufacturing and scale-up.