The inability to obtain a crystal form that has previously been reliably prepared is an important concern for industrial solid-state scientists. In the present study, we extend further the evidence that such a phenomenon also applies to cocrystals. Specifically, we report further on the apparent "disappearing polymorphs" of a cocrystal composed of caffeine and citric acid. This study commenced at the University of Cambridge with the initial aim of gaining insight into the mechanisms associated with the mechanochemical formation of the known caffeine:citric-acid cocrystal, namely Form I. A second polymorph, Form II, was soon after prepared mechanochemically through neat grinding, making it seemingly impossible to reproduce Form I in the same laboratory.Subsequent studies also resulted in the mechanochemical formation of another polymorph, Form III, for which no structural characterization has yet been possible. We therefore also focus on the understanding of the factors contributing to the inability to reproduce Form I after another polymorph has been obtained. Experiments that were extended to two other laboratories within different UK universities (De Montfort University Leicester and University College London) revealed that, depending on the "apparent" level of contamination of a specific laboratory, different polymorphs can be obtained, but only one of them at any period of time. The inability to predict, control and undertand disappearing polymorphs remains a frustrating experience-even 25 years after Dunitz and Bernstein first stated that "we are far from being able to present a theory of disappearing polymorphs". In this context, we reason that a first step forward would consist of reporting comprehensive and detailed accounts for every example of apparently disappearing polymorphs, with the hope of finding similarities that can subsequently result in a better understanding and possible rationalization of the puzzling phenomenon of disappearing polymorphs. We here report what we know so far of the intriguing caffeine:citric-acid cocrystal system.
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