Gibbs Formation Energy of a Cocrystal that Dissociates into a Hydrate

Abstract

The Gibbs energy of formation, ΔG f, of a cocrystal is a fundamental property to determine its thermodynamic stability. One of the methods to determine ΔG f is from the eutectic composition of the components of the cocrystal in a given solvent. However, conventional methods to determine the ΔG f of a cocrystal from the eutectic composition in a given solvent are indicated to be valid when it dissociates into an unsolvated (or anhydrous) form of the components in that solvent. This article explores the condition when the ΔG f of a cocrystal may be calculated from its eutectic composition in a solvent where the thermodynamically stable form of one of the components is a hydrate. The theophylline–nicotinamide cocrystal, which dissociates into theophylline hydrate and nicotinamide in water, is used as the model cocrystal in this study. The calculated ΔG f values of the cocrystal from water are compared with those obtained from the eutectic composition of the cocrystal in nonsolvate forming solvents, namely, ethyl acetate and 2-propanol. The implication of the study in pharmaceutical development of cocrystal is discussed.

Synthetic Strategies toward Higher Cocrystals of Some Resorcinols

“…Whether or not hydration/solvation occurs because of a failure to obtain optimal packing and hydrogen bonding is a matter for further research, but previous studies do indicate that this might be the case. 63,64 This is why the hydrated/solvated structures are difficult to predict and engineer.…”

“…The general conclusion is that in these hydrogen-bonded structures with a high chemical diversity in the donors and acceptors in terms of acidity/basicity, and also taking into account the need to achieve a maximum number of hydrogen bonds, with or without a hydrogen bonding solvent, there will be an inevitable compromise in the interaction metrics. Whether or not hydration/solvation occurs because of a failure to obtain optimal packing and hydrogen bonding is a matter for further research, but previous studies do indicate that this might be the case. , This is why the hydrated/solvated structures are difficult to predict and engineer.…”