Pharmaceutical Cocrystallization: Engineering a Remedy for Caffeine Hydration

A systematic crystal engineering study was performed on the model pharmaceutical compound caffeine
to prepare a cocrystal that, unlike caffeine, is physically stable at all relative humidities (RH). Six cocrystal materials
containing caffeine with one of several dicarboxylic acids are described herein. Methods of cocrystallization included
solution growth, neat solid-state grinding, and grinding with solvent-drop addition. Crystal structures are reported
for a total of five cocrystals containing caffeine (with oxalic acid, malonic acid, maleic acid, and glutaric acid), including
two recently reported polymorphic caffeine cocrystals. In each of these structures, a predicted intermolecular hydrogen-bonding motif is observed. The stability with respect to RH is evaluated for the six cocrystal materials. The cocrystal
with oxalic acid exhibits complete stability to humidity over a period of several weeks. Other cocrystals demonstrate
lesser degrees of stability with respect to humidity.