Real-Time Formation Monitoring of Cocrystals with Different Stoichiometries Using Probe-Type Low-Frequency Raman Spectroscopy

In the cocrystallization process, real-time monitoring is effective for obtaining cocrystal products with consistent quality. Low-frequency Raman spectra reflect the lattice vibrations derived from crystalline differences; therefore, it is expected to be useful for the monitoring of pharmaceutical cocrystals that are difficult to distinguish by Raman spectroscopy in the fingerprint region. In this work, we attempted to monitor the formation of cocrystals with 1:1 and 2:1 cocrystals consisting of carbamazepine and 4-aminobenzoic acid using probe-type low-frequency Raman spectroscopy. Real-time measurements were performed during stirring of a composition known to form 1:1 and 2:1 cocrystals by the reaction crystallization method, and the spectra derived from the cocrystals were confirmed after 5 min. To monitor the transition of the cocrystals toward a stoichiometry of 2:1 from 1:1 and toward a stoichiometry of 1:1 from 2:1, specified amounts of raw materials were added to the cocrystals suspended in ethanol. The cocrystals with different stoichiometries were transformed after 3 h.