Integration of a Raman spectroscopic platform based on online sampling to monitor chemical reaction processes

During the pharmaceutical synthesis process, it is essential to control the reaction time to avoid by-product formation and the reduction of yield. In this study, a Raman spectroscopic platform based on online sampling was integrated to collect Raman spectra in real time and realize process monitoring. Considering its attractive features of strong light transmittance and resistance to acids, alkalis and high temperatures, polyfluoroalkoxy (PFA) tubes rather than cuvette-type flow cells or similar devices were used to transfer solutions and as a flow cell for collecting Raman spectra, therefore not requiring an <i>in situ</i> Raman probe, and significantly reducing the cost of equipment. The peristaltic pump is controlled by the sampling software to realize automatic sampling, and it automatically pushes the reaction solution back into the reaction vessel after the spectra are collected. Taking the aspirin synthesis reaction as an example, the platform was employed to monitor the chemical reaction in real-time. The internal standard method was adopted to minimize the interference of spectral oscillation and baseline drift during online monitoring. The characteristic peak of the PFA tube at 731 cm^-1 was selected as the internal standard peak, which formed the relative intensity ratio <i>R</i> with the characteristic peak of the product acetylsalicylic acid at 1606 cm^-1. The endpoint of the reaction was identified based on the trend of the relative intensity ratio with the reaction time. The results indicate that the method is feasible for monitoring the aspirin synthesis reaction and provides a research basis for real-time monitoring of other pharmaceutical processes.