Dehydration and Rehydration Mechanisms of Pharmaceutical Crystals: Classification Of Hydrates by Activation Energy.

Dehydration strongly influences the stability of hydrate drug substances. Consequently, the ability to predict dehydration of crystalline hydrate using the intermolecular interactions of water molecules contained in the crystals is essential for drug development. The conventional method employed to predict the propensity for dehydration uses the dehydration temperature, which is related to how tightly water molecules are bound in the crystal lattice. However, it is difficult to predict the dehydration propensity of a particular hydrate using only the dehydration temperature because other kinetic factors affect dehydration behavior, such as intermolecular interactions, and drug-substance-to-water molar ratio in a hydrate. In this study, we explored the use of the dehydration activation energy E and rehydration behavior to classify 11 pharmaceutical hydrates into three classes according to their kinetic behavior related to the thermodynamic factors of hydrates. There is good agreement between these classes and hydrate crystal structures determined from single-crystal X-ray diffraction, and thus, the classification reflects their crystal structural features. We compared E to the dehydration temperatures for each class and found that E plays a crucial role and is better than the temperature for quantitative differentiation of the dehydration propensities in these hydrates.