Dehydration kinetics and mechanism of the stable isonicotinamide hydrate revealed by terahertz spectroscopy and DFT calculation.

The dehydration behavior of pharmaceutical hydrates has a great influence on its physiochemical properties such as stability, dissolution rate and bioavailability. However, how the intermolecular interactions vary during dehydration process remains elusive. In this work, we employed terahertz time-domain spectroscopy (THz-TDS) to probe the low-frequency vibrations and the dehydration process of isonicotinamide hydrate I (INA-H I). Theoretical solid-state DFT calculation was conducted to reveal its mechanism. Vibrational modes which are responsible for the THz absorption peaks were decomposed for better understanding the characters of these low-frequency modes. The result suggests translational motion is the dominant component for water molecules in THz region. Evolution of the THz spectrum of INA-H I during dehydration provides direct evidence of the variations of crystal structure. Based on the THz measurements, a two-step kinetics mode including first-rate reaction and three-dimensional nuclei growth is proposed. And we figure that the low-frequency vibrations of water molecules are the origin of dehydration process of hydrate.