Process Scale-Up and Solvent Recycling Mechanism Study of Continuous Flow Liquid-Phase Peptide Synthesis (CF-LPPS)
DOI:
https://doi.org/10.70088/9peadk12Keywords:
Continuous flow synthesis, Liquid-phase peptide synthesis, Process scale-up, Solvent recycling, Membrane separation, Green manufacturingAbstract
Continuous flow liquid-phase peptide synthesis (CF-LPPS) has emerged as a transformative technology for large-scale peptide manufacturing, addressing the inherent limitations of conventional batch solid-phase peptide synthesis (SPPS) including high solvent consumption, low productivity, and scale-up challenges. This work presents a comprehensive investigation into the process scale-up principles and solvent recycling mechanism of CF-LPPS. A hydrodynamic scale-up model based on residence time distribution (RTD) and dimensionless analysis was developed, maintaining constant Damköhler number (Da) and Bodenstein number (Bo) across scales from 5 mL to 50 L reactor volumes. The solvent recycling system integrates nanofiltration membrane separation, distillation, and adsorption purification, achieving an overall solvent recovery rate of 94.7% with N,N-dimethylformamide (DMF) purity exceeding 99.2%. Mechanistic studies revealed that membrane fouling is primarily governed by concentration polarization and peptide oligomer adsorption, which can be mitigated by crossflow velocity optimization and periodic backwashing. Techno-economic analysis demonstrates that the scaled-up CF-LPPS process reduces solvent cost by 87.3% and carbon footprint by 79.1% compared with batch SPPS. The scale-up framework and solvent recycling mechanism established herein provide critical engineering fundamentals for the industrial implementation of continuous peptide manufacturing.References
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Copyright (c) 2026 Xiaofan Li (Author)
This work is licensed under a Creative Commons Attribution 4.0 International License.
