Mechanisms by Which Moisture Generates Cocrystals

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 cocrystal reactants deliquesce. Microscopy studies revealed that the transformation mechanism to cocrystal involves (1) moisture uptake, (2) dissolution of reactants, and (3) cocrystal nucleation and growth. Studies of solid blends of reactants in a macro scale show that the rate and extent of cocrystal formation are a function of relative humidity, moisture uptake, deliquescent material, and dissolution rates of reactants. It is shown that the interplay between moisture uptake and dissolution determines the liquid phase composition, supersaturation, and cocrystal formation rates. Differences in the behavior of deliquescent additives (sucrose and fructose) are associated with moisture uptake and composition of the deliquesced solution. Our results show that deliquescence can transform API to cocrystal or reverse the reaction given the right conditions. Key indicators of cocrystal formation and stability are (1) moisture uptake, (2) cocrystal aqueous solubility, (3) solubility and dissolution of cocrystal reactants, and (4) transition concentration.

Characterization and Quality Control of Pharmaceutical Cocrystals

“…59) This cocrystallization usually slowly proceeds through successive absorption, dissolution, nucleation, and crystal growth steps on the solid surface via the same mechanism observed in slurries and aqueous dispersions. 58,60) Storage of some tablets containing hydrated API or coformer crystals, such as theophylline monohydrate-anhydrous citric acid formulations, have also produced cocrystals.…”

Cocristais: uma estratégia promissora na área farmacêutica

“…[63][64][65][73][74][75] O teor lipídico presente nos alimentos e a presença de sais biliares também podem melhorar o desempenho de um fármaco lipofílico/hidrofóbico in vivo. [111][112][113][114][115] No entanto, o efeito destes agentes de solubilização na solubilidade do cocristal geralmente não é tão simples.…”

Solid-State Characterization and Interconversion of Recrystallized Amodiaquine Dihydrochloride in Aliphatic Monohydric Alcohols

“…Relative humidity in the environment may vary according to the differences in geographical locations and seasons, which, in turn, could affect the stability of solid-state forms of drugs (26,27). Therefore, the ability of water to adsorb on the surface of each solid-state structure was evaluated by isothermal DVS at 30°C within controlled relative humidity range of 0-100%RH.…”