The Solid-phase Peptide Synthesis (SPPS) technology is required to manufacture all kinds of chemically-modified therapeutic peptides. However, the repetitive Fmoc/tBu procedure involves the consumption of vast amounts of swelling, coupling, deprotection, washing, cleavage, precipitation, purification, and cleaning solvents. The manufacturing problem solved in this paper is whether there is any greener solvent system which could minimize the liquid burden without compromising the quality of crude peptides, accessibility of resins, solubility of reagents, solvent recovery, and compatibility of the system with the equipment. The comparison includes traditional DMF/NMP/DCM approach and solvent systems comprising propylene carbonate, N-butylpyrrolidinone (NBP), DMSO/2-MeTHF, DMSO/DOL, N-octylpyrrolidone/dimethyl carbonate (NOP/DMC), neat NOP, PolarClean/water, dipropyleneglycol dimethylether (DMM), anisole/NOP, and N-formylmorpholine/anisole. The quantitative information encompasses peptide-process PMI values of about 3000--15000 kg kg$^{-1}$ per the molecular mass of peptides of around 1000--5000 Da; contribution of solvents and washing to the total mass of process of about 80--90\%; NOP/DMC 8:2 crude purity of 97.5\% for Aib-enkephalin and $>$99\% for linear octreotide; purity of neat NOP of Aib-enkephalin of 97.7\% and 97.4\% on Wang and trityl chloride resins; purity of NBP of $>$99\% for AKDGYI-NH$_2$ at 45\,\si{\celsius}; purity of DMSO/2-MeTHF of bivalirudin of 70.7\%; purity of DMSO/DOL of bivalirudin of 72.7\%; and purity of PolarClean/water of 86\% for Leu-enkephalin amide. NOP/DMC is the best first choice for plant qualification due to the ability of the DMC fraction to reduce the viscosity of NOP; high peptide purity for both Aib-enkephalin and linear octreotide; and recovery of NOP, DMC, and piperidine. NBP, DMSO-based systems, PolarClean/water, DMM, anisole/NOP, and NFM/anisole retain the value for specific sequence classes and equipment. Nevertheless, their direct testing under resin-specific, impurity-specific, recovery-specific, cleaning-specific, and product contact-specific conditions is required.

Solid-phase peptide synthesis,green solvents,process mass intensity,materials compatibility,solvent recovery,peptide purification,resin swelling,Fmoc/tBu chemistry,product-contact qualification