Cocrystal Dissociation under Controlled Humidity: A Case Study of Caffeine–Glutaric Acid Cocrystal Polymorphs

Caffeine–glutaric acid cocrystal polymorphs, Form I and Form II, are presented as a model system to study cocrystal dissociation under controlled humidity. On the basis of relative humidity (RH) data, it was observed that Form I transforms to Form II at high RH and that the rate of the polymorphic phase transformation increases with increasing RH, with the relative stability of the cocrystal following a trend similar to that of the coformer deliquescence point for other caffeine dicarboxylic acid cocrystals. In addition, reduction in particle size, change in crystal morphology with greater number of crystal faces exposed to surrounding atmosphere, and internal arrangement of molecules in the crystal structure are shown to influence cocrystal instability and favor dissociation under increased humidity.