The dehydration of nitrofurantoin monohydrate II was monitored under different isothermal conditions (100, 105, 110, 115, and 120 °C) using Raman spectroscopy in the low-(−300 to 15 and 15 to 300 cm −1 ) and mid-(300 to 1800 cm −1 ) frequency regions. Clear and subtle spectral differences were observed for Raman spectra in the respective domains for solidstate transformations. Multivariate curve resolution was used to extract the information on the solid-state forms present and their relative abundances during the isothermal dehydration experiments. Theoretical modeling of nitrofurantoin hydrates (nitrofurantoin monohydrates I and II) and anhydrous forms (α and β) was carried out using density functional theory with periodic boundary conditions to support the interpretation of low-energy vibrational modes. Midfrequency Raman spectroscopy detected the onset of the dehydration process (where observed) of nitrofurantoin monohydrate II ∼100−300 s before the low-frequency Raman spectral domain depending on the isothermal condition. This was attributed to the change of order during the process, where disruption of localized molecular arrangements within the monohydrate crystal structure is first expected to occur.
The solid-state landscape of carbamazepine during its dehydration was explored using Raman spectroscopy in the low- (−300 to −15, 15 to 300) and mid- (300 to 1800 cm−1) frequency spectral regions. Carbamazepine dihydrate and forms I, III, and IV were also characterized using density functional theory with periodic boundary conditions and showed good agreement with experimental Raman spectra with mean average deviations less than 10 cm−1. The dehydration of carbamazepine dihydrate was examined under different temperatures (40, 45, 50, 55, and 60 °C). Principal component analysis and multivariate curve resolution were used to explore the transformation pathways of different solid-state forms during the dehydration of carbamazepine dihydrate. The low-frequency Raman domain was able to detect the rapid growth and subsequent decline of carbamazepine form IV, which was not as effectively observed by mid-frequency Raman spectroscopy. These results showcased the potential benefits of low-frequency Raman spectroscopy for pharmaceutical process monitoring and control.
Surface-driven isothermal dehydration of model tablets containing citric acid monohydrate was investigated using spatially offset low-frequency Raman spectroscopy (SOLFRS). Experiments were carried out under different isothermal conditions (50 to 65 °C), and dehydration kinetics were monitored ex situ by sampling the tablets at different time points. Better SOLFRS data interpretation was facilitated by the use of multivariate curve resolution and complementary Raman microscopy analysis of tablet cross sections that enabled access to detailed information on spatial dehydration characteristics within the tablets. Additionally, theoretical characterization of Raman-active low-energy (phonon) modes of citric acid solid-state forms was carried out using periodic boundary density functional theory.
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