Automatic Control of Nucleation and Crystal Growth Using Online Raman Analyzer

Abstract

The accurate determination of crystal formation during crystallization is crucial for obtaining crystal products with consistent quality and quantity. In this study, we aimed to identify the feasibility of using Raman spectroscopy to monitor the crystal growth stage in the crystallization process using cephalosporin intermediate 7-ACT as an example molecule. By observing the changes in the characteristic peak of the 7-ACT crystal (504 cm−1) and the characteristic peak of the solvent acetonitrile (914 cm−1), a correlation between the crystal growth stage and the change in the Raman intensity of the crystal solution was discovered. The determination of the optimal starting time for the crystal growth stage through a Raman analyzer significantly improves the consistency of crystal product quality. This led to a fivefold reduction in the variation in the weight and water content of the final 7-ACT crystal products compared to those obtained via manual control. In addition, our experiments also indicated that Raman monitoring could be more efficient at enabling the chemical synthesis reaction to be completed compared to manual control. Thus, our work demonstrates the potential of Raman spectroscopy in the real-time control of chemical synthesis reactions and crystallization processes.