Mechanochemical preparation of molecular and ionic co-crystals of the hormone melatonin

Two co-crystals of melatonin with piperazine and (1,4-diazabicyclo[2.2.2]octane), DABCO, and a hydrated ionic co-crystal with CaCl2 were obtained directly in the solid-state via kneading of the solid mixtures with a few drops of ethanol. The structure of the DABCO co-crystal, mel2·DABCO, was determined by single crystal X-ray diffraction, while those of the piperazine co-crystal, mel2·pip, isomorphous with the DABCO one, and the ionic co-crystal, mel2·CaCl2·2H2O, were determined from powder data. In the case of the ionic co-crystal with CaCl2, solubility measurements indicate that melatonin solubility in water increases by an order of magnitude with respect to the pure substance.