The resurgence of LPPS for large-scale manufacturing
Dr Eric Fang of Cambrex highlights the use of liquid-phase peptide synthesis in modern drug manufacturing
For most chemists and biologists, peptide synthesis is typically associated with solid-phase peptide synthesis( SPPS) or recombinant DNA expression in Escherichia coli or mammalian cell lines. Liquidphase( or solution-phase) peptide synthesis( LPPS) is far less familiar, despite its foundational role in the early history of peptide chemistry and its growing relevance to modern large-scale peptide manufacturing.
Historically, LPPS predates SPPS. In the mid-1960s, Chinese scientists reported the total chemical synthesis of bovine insulin, a 51-amino-acid peptide, using solution-phase chemistry. This achievement demonstrated that chemically synthesised peptides could adopt biologically active conformations.
However, the process suffered from extremely low overall yields(< 1 %), high cost and limited scalability. Coupled with geopolitical and historical factors, this work had little immediate industrial impact, and LPPS was largely set aside as a manufacturing strategy.
The landscape changed with Bruce Merrifield’ s invention of SPPS in the 1960s. By anchoring a growing peptide chain to a polymeric resin, SPPS eliminated the need for intermediate isolation and enabled repetitive coupling deprotection washing cycles.
Continuous improvements in coupling reagents, protectinggroup strategies and automation transformed SPPS into a dominant platform for peptide discovery and early development. SPPS also enabled the synthesis of peptides incorporating non-natural amino acids, stereochemical inversions and backbone modifications, capabilities that were difficult or impossible using recombinant expression.
Despite its success in discovery, SPPS has remained poorly suited for high-volume commercial manufacturing. Prior to the 2000s, commercial-scale SPPS was confined to a small number of specialised manufacturers.
Meanwhile, recombinant DNA technologies rapidly displaced chemical synthesis for many native peptides, including human insulin, due to their superior scalability and economics. However, recombinant expression remains fundamentally constrained to the 20 genetically encoded amino acids and offers limited flexibility for the chemical modifications that now define modern peptide therapeutics.
Manufacturing constraints of SPPS
As peptide drugs transition from niche indications to mass-market therapies, the limitations of SPPS as a commercial manufacturing platform have become increasingly apparent. First, SPPS is extremely solventand reagent-intensive. Each coupling cycle requires large excesses of activated amino acids and repeated wash steps, typically using polar aprotic solvents such as DMF. Producing one kilogram of peptide API via SPPS may consume more than ten tonnes of organic solvent, orders of magnitude higher than typical small-molecule processes.
Second, SPPS is inherently difficult to scale. Peptide resin slurries exhibit non-Newtonian, gel-like rheology and are highly sensitive to shear. As reactor size increases, washing and filtration steps become
Figure 1- Structure of tirzepatide( Zepbound)
Note- Highlighted non-coded amino acid currently can be expressed by recombinant DNA technology
30 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981