Nondestructive Spatial Dehydration Analysis of Crystalline Hydrates in Pharmaceutical Solid Dosage Forms Using Spatially Offset Low-Frequency Raman Spectroscopy

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 degrees 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.