Mechanisms by Which Moisture Generates Cocrystals

TLDR: The results show that deliquescence can transform API to cocrystal or reverse the reaction given the right conditions and the interplay between moisture uptake and dissolution determines the liquid phase composition, supersaturation, and cocystal formation rates.

Abstract: The purpose of this study is to determine the mechanisms by which moisture can generate cocrystals when solid particles of cocrystal reactants are exposed to deliquescent conditions (when moisture sorption forms an aqueous solution). It is based on the hypothesis that cocrystallization behavior during water uptake can be derived from solution chemistry using models that describe cocrystal solubility and reaction crystallization of molecular complexes. Cocrystal systems were selected with active pharmaceutical ingredients (APIs) that form hydrates and include carbamazepine, caffeine, and theophylline. Moisture uptake and crystallization behavior were studied by gravimetric vapor sorption, X-ray powder diffraction, and on-line Raman spectroscopy. Results indicate that moisture uptake generates cocrystals of carbamazepine−nicotinamide, carbamazepine−saccharin, and caffeine or theophylline with dicarboxylic acid ligands (oxalic acid, maleic acid, glutaric acid, and malonic acid) when solid mixtures with cocry...