Thermodynamic and Kinetic Mechanism of the Phase Transition from Aztreonam Dihydrate to Anhydrates

In this work, two anhydrates (form A and form B) and one dihydrate (form C) of aztreonam were found and were characterized by powder X-ray diffraction (PXRD), thermogravimetric analysis, differential thermal analysis, and Fourier transform infrared spectroscopy. Dynamic vapor adsorption and variable-temperature PXRD experiments were carried out to study their thermal stability and moisture absorption stability. Furthermore, the critical water activity of aztreonam at 10–45 °C was determined, and it was found that the water activity determines the dehydration process of form C. The solubility of form A and form B in methanol solvent was measured at 10–45 °C to decide the thermodynamic stability of the polymorphs, and it was found that form B is thermodynamically stable below 28 °C, while form A is thermodynamically stable above 28 °C. The competitive suspension experiments further proved that form A and form B are enantiotropic polymorphs. In addition, the solution-mediated phase transition (SMPT) process of aztreonam form C was in situ monitored using Raman spectroscopy. The results show that the SMPT process is jointly controlled by the dissolution of the dihydrate and the nucleation of anhydrates, in which temperature plays a very important role. Finally, the SMPT mechanism of the dihydrate form is proposed.