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 (MC2) form already identified. A cocrystallization process for MC was already developed. However, a process leading to pure MC2 remained a challenge, as the stability zone of the MC2 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 MC2 (MC2·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, MC2·MeCN is quickly desolvated leading to the pure MC2 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.