Applications of Raman Spectroscopy in Solvent Distillation and Exchange During Early-Phase Chemical Synthesis

Applications of Raman spectroscopy in monitoring the concentration of solvents in various distillation and solvent exchange steps in chemical synthesis are discussed. Two case studies from early-phase active pharmaceutical ingredient (API) process development, one each from the distillation and the solvent exchange operations, are presented. The results are compared to respective conventional techniques. Sampling, measuring, and building models using appropriate chemometric tools are described in detail. A list of 70 different pairs of commonly used solvents and reactants, where Raman spectroscopy models could be successfully developed and employed, is provided with the corresponding range of quantitation. The advantages of Raman spectroscopy, such as rapid and nondestructive analysis, suitability for process analytical technology (PAT)-based applications for real-time monitoring, and ease of automation, are highlighted over traditional approaches. Some practical challenges of the technique towards its implementation are also discussed.