Cocrystallization of Caffeine with Carboxylic Acids and Flavonoids: In Vitro Study to Control the “Caffeine Crash”

Caffeine is a psychoactive substance that is used to increase alertness and vigilance. High-dose single administration, such as in coffee-based beverages, leads to a significant number of adverse effects like nervousness or rapid and unexpected drops in beneficial effects ("Caffeine crash"). In order to increase the performance of caffeine, especially in the case of sleep deprivation, it is crucial to control its delivery, which is usually modulated by complex formulations. In a different approach, in this work, we have addressed this issue by the cocrystallization of caffeine with five different small molecules to influence the solubility, dissolution rate, and permeability. In particular, the caffeine-xinafoic acid cocrystal reduces the solubility of caffeine by approximately 80% and reduces the dissolution rate up to 30% in the first 20 min while increasing the permeability (3-fold). Overall, the cocrystallization leads to better control of the in vitro release of caffeine while guaranteeing the membrane diffusion of the drug and its advantageous effects. These effects were attributed to interactions between caffeine and the coformer in solution. Supporting evidence comes from density functional theory (DFT) calculations, which indicate that the heterocomplex is more stable than caffeine-caffeine aggregates. Overall, these results suggest that molecular complexation plays a key role in modulating the effects of caffeine.