Combining Real-Time Monitoring Using Raman Spectroscopy, Rotating-Bed Reactors, and Green Solvents to Improve Sustainability in Solid-Phase Peptide Synthesis

In response to the need for more sustainable practices in peptide synthesis, particularly in the context of solid-phase peptide synthesis (SPPS), this study introduces a transformative approach toward achieving sustainability. This work combines, for the first time, the use of Raman spectroscopy as a process analytical tool (PAT) for real-time monitoring and optimization of reaction steps and substitution of environmentally concerning N,N-dimethylformamide (DMF) with a green solvent mixture of dimethyl sulfoxide (DMSO) and ethyl acetate (EtOAc). Assuming that in SPPS, the synthetic intermediates are not isolated, the utilization of PAT provides robust and high-resolution analytics to enable precise control of reaction end points, which allows for timely adjustments, leading to accelerated development, reduction of waste generation, and enhanced reaction efficiency. Additionally, SpinChem, a unique design of a rotating bed reactor, is introduced as an alternative reactor, which also enables easy integration of PATs to perform solid-phase synthesis. This study provides valuable insights and practical strategies to advance sustainable peptide synthesis, offering promising solutions for a greener future in the pharmaceutical industry.