Study On The Dehydration Process Of Isonicotinamide Monohydrate By Terahertz Spectroscopy

The different crystal polymorphism forms of drugs affect the properties of drugs,such as solubility,dissolution rate,bioavailability and physicochemical stability.When drug crystals form hydrates,they have poorer water solubility,dissolution rate and stability than those anhydrate.Therefore,the research on dehydrating behavior of drug crystals has become the focus of pharmaceutical industry.nuclei growth(Avrami-Erofeyev equations)and power law,geometrical contraction models,diffusion models and reaction-order models have been proposed to describe the dehydration behavior of hydrates at present.Although these models explain the kinetics of dehydration well,how the interactions vary during dehydration remains elusive.In this paper,isonicotinamide monohydrate I(INA-H I)was synthesized at room temperature and high humidity(Relative humidity>80%).The dehydration process of INA-H I was characterized by terahertz time-domain spectroscopy in situ whose results showed that the dehydration process of INA-H I had a significant change which went through two stages: peak shift and baseline decline.The first stage corresponds to the loss of water from the crystal lattice and the resulting contraction of the lattice structure of the intermediate,and the second stage corresponds to the transition of the intermediate to the stable Form I.On the basis of the variation of characteristic peak area,a two-step kinetic model including first order reaction and three dimensional nuclear growth was proposed,and the reaction rate constant was calculated.Based on solid state density functional calculation,the low frequency vibration characteristics of INA-H I were also discussed through terahertz characteristic peaks,showing that water molecules mainly exhibit translational characteristics in INA-H I low-frequency vibration mode,and there is translational and rotational coupling motion,so it is speculated that the low-frequency vibration of water molecules is likely to be the origin of hydrate dehydration.It is expected that a clear image of the trajectories of water molecules can be obtained through molecular dynamics during dehydration.