Enabling Cocrystallization of Challenging Systems: Passing through a Stable Cocrystal Solvate as a Pathway to Strenuous Cocrystal Forms

Caffeine and maleic acid can form various cocrystal forms, which is a potential route to avoiding hydration issues of caffeine. This particular system was intensively studied as it not only shows cocrystal polymorphism but also stoichiometrically diverse cocrystals with a 1:1 maleic acid: caffeine (MC) and a 1:2 maleic acid:caffeine (MC 2 ) form already identified. A cocrystallization process for MC was already developed. However, a process leading to pure MC 2 remained a challenge, as the stability zone of the MC 2 suspension is very narrow in most solvents. In this paper, we propose an alternative crystallization pathway toward this crystal form, passing through a stable solvate. Indeed, we identified a novel cocrystal solvate of MC 2 (MC 2 ·MeCN) in acetonitrile at 9 °C. This cocrystal solvate is characterized by a large stability zone in the ternary phase diagram, and consequently, a crystallization process leading to this form can easily be devised. Upon filtration, and exposure to ambient atmosphere, MC 2 ·MeCN is quickly desolvated leading to the pure MC 2 cocrystal phase. In this contribution, we therefore show that cocrystal phases, which are seemingly strenuous to crystallize from solution, can be accessed by thinking out-of-the-box and using the properties of unexpected alternative phases.