In Situ Monitoring of Crystalline Transformation of Carbamazepine Using Probe-Type Low-Frequency Raman Spectroscopy

Crystallization is one of the most useful processes for the separation and purification of crystalline compounds. In crystallization processes, real-time monitoring is essential to obtain constant quality of crystalline compounds. This paper is the first to report in situ monitoring of crystalline transformations of active pharmaceutical ingredients by probe-type low-frequency Raman spectroscopy. In this study, carbamazepine was used as a model active pharmaceutical ingredient. We attempted to monitor the crystalline transformation of carbamazepine during heat treatment and the addition of solvent in a one-pot reaction. When carbamazepine form III was heated to 170 °C, the indicative spectrum of carbamazepine form I appeared over time. Subsequent addition of ethanol with heat treatment caused the carbamazepine form I spectrum to disappear. After cooling to room temperature, the spectrum of carbamazepine form III reappeared. To optimize the solvent ratio, we monitored carbamazepine form III as it dispersed into a mixture of ethanol/water with different compositions (75/25, 62.5/37.5, 50/50, 37.5/62.5, and 25/75 (v/v)). The spectra of carbamazepine dihydrate were observed in all solvent compositions. When the mixture of ethanol/water was 62.5/37.5 (v/v), the conversion time to carbamazepine dihydrate was fastest. Therefore, probe-type low-frequency Raman spectroscopy can be used for the in situ monitoring of crystalline transformation and may become a useful process analytical technology technique.