Monitoring of mannitol phase behavior during freeze-drying using non-invasive Raman spectroscopy

In this study, the feasibility of using Raman spectroscopy as a fast, non-invasive, non-destructive technique to monitor crystallization and polymorphic transformations during freeze-drying is assessed using mannitol as the model compound. In-line process monitoring was achieved by interfacing a Raman spectrometer with a fiber-optically coupled, long-working-distance probe to a freeze-drier. By analyzing the process data using principal component analysis, it was possible to extract valuable information pertaining to ice and mannitol crystallization points, the polymorphic form of mannitol, and dehydration of the mannitol hydrate. In conclusion, Raman spectroscopy is a potentially useful technique to monitor physical changes during freeze-drying.