Kinetics and Mechanism of the Thermal Dehydration of a Robust and Yet Metastable Hemihydrate of 4‑Hydroxynicotinic Acid

Abstract

Hydrates are the most common type of solvates and certainly the most important ones for industries such as pharmaceuticals which strongly rely on the development, production, and marketing of organic molecular solids. A recent study indicated that, in contrast with thermodynamic predictions, a new hemihydrate of 4-hydroxynicotinic acid (4HNA·0.5H₂O) did not undergo facile spontaneous dehydration at ambient temperature and pressure. The origin of this robustness and the mechanism of dehydration were investigated in this work, through a combined approach which involved kinetic studies by thermogravimetry (TGA), crystal packing analysis based on X-ray diffraction data, and microscopic observations by hot stage microscopy (HSM), scanning electron microscopy (SEM), and atomic force microscopy (AFM). The TGA results indicated that the resilience of 4HNA·0.5H₂O to water loss is indeed of kinetic origin, c.f., due to a significant activation energy, <i>E</i>_a, which increased from 85 kJ·mol^–1 to 133 kJ·mol^–1 with the increase in particle size. This <i>E</i>_a range is compatible with the fact that four moderately strong hydrogen bonds (typically 20–30 kJ·mol^–1 each) must be broken to remove water from the crystal lattice. The dehydration kinetics conforms to the Avrami-Erofeev A2 model, which assumes a nucleation and growth mechanism. Support for a nucleation and growth mechanism was also provided by the HSM, SEM, and AFM observations. These observations further suggested that the reaction involves one-dimensional nucleation, which is rarely observed. Finally, a statistical analysis of Arrhenius plots for samples with different particle sizes revealed an isokinetic relationship between the activation parameters. This is consistent with the fact that the dehydration mechanism is independent of the sample particle size