Speciality Chemicals Magazine MAR / APR 2026 | Page 25

PEPTIDES & PROTEINS that process mass intensity( PMI) in industrial SPPS can reach 5,000 – 20,000 kg / kg API, primarily due to solvent usage in washing cycles. 2 Strategies like inline solvent recycling and lowswelling resins have demonstrated > 50 % solvent reduction without compromising yield.

For larger peptides(> 30 aa), hybrid SPPS – LPPS routes offer improved atom efficiency. By coupling shorter fragments synthesised on resin through solution-phase ligations, companies can balance automation with scalability. Such strategies, coupled with orthogonal protecting group schemes like Fmoc / t-Boc hybrids improve yields while reducing solvent usage by up to 30 %. 1

Digital integration through process analytical technologies( PAT)— real-time infrared and massspectrometric monitoring— enables the dynamic control of coupling completion, minimising the overaddition of reagents. In silico design of experiments( DoE) for coupling kinetics and resin behaviour allows predictive optimisation, as seen in Novo Nordisk’ s semaglutide production programme. 2

Green chemistry & solvent minimisation

Solvent use contributes up to 90 % of the environmental impact of SPPS. Traditional solvents like DMF, DCM and NMP are reprotoxic and pose regulatory challenges. The green transition focuses on substituting these with greener dipolar aprotic solvents such as dimethyl carbonate( DMC), propylene carbonate or γ-valerolactone. 3

Novo Nordisk successfully validated a DMF-free SPPS for GLP-1 analogues using N-butylpyrrolidone( NBP) and 2-methyltetrahydrofuran( 2-MeTHF) as primary solvents, achieving equivalent coupling efficiency while improving biodegradability and lowering toxicity.

The E-factor and complete E-factor( cEF) are core indicators. Pawlas et al. have calculated that substituting conventional linkers and optimising solvent recovery in the exenatide CEPS process reduced the cEF from 1,700 to 350 and carbon intensity by 75 % relative to benchmark SPPS. 4

Closed-loop distillation and membrane nanofiltration can recover ~ 90 % of acetonitrile and ethanol. Novartis and Boehringer Ingelheim reported similar solvent-recycling efficiencies in internal green chemistry audits. 1

Peptide bond-formation typically relies on carbodiimides like DIC and DCC or uronium salts like HATU and HBTU. These generate significant urea or guanidinium waste. Greener coupling systems based on ethyl cyanoglyoxylate oxime( Oxyma Pure) and COMU have demonstrated reduced racemisation and improved atom economy. Emerging microwaveassisted SPPS and solvent-free ballmilling peptide synthesis represent radical steps toward solventminimised manufacturing.

Process intensification and continuous flow peptide synthesis platforms significantly reduce energy demand. Continuous microreactor set-ups allow precise temperature control and improved mixing, yielding up to 80 % shorter cycle times compared with batch SPPS. 2

Biotechnological & enzymatic innovations

Chemo-enzymatic peptide synthesis( CEPS) merges solid-phase fragment preparation with enzymatic ligation. Pawlas et al. demonstrated the use large-scale CEPS for exenatide using engineered omniligase-1( derived from subtilisin BPN’) for fragment condensation. 4

At optimised pH 7.5 and ambient temperature, the process yielded 53 g of exenatide API with superior purity and a ten times lower carbon footprint than conventional SPPS. This case exemplifies CEPS as a commercially viable, environmentally preferable route. It reduces dependence on hazardous reagents and circumvents side reactions like racemisation or epimerisation, enhancing overall process robustness.

Next-generation ligases, notably sortases, butelases and engineered peptide ligases, can expand the scope of enzymatic fragment coupling. Their high chemoselectivity allows aqueous reactions at mild conditions, minimising solvent loads and energy consumption. Sadatshojaei et al. demonstrated the use of low-toxicity co-solvents, such as glycerol or ionic liquids, for enzyme stabilisation, achieving comparable yields to organic solvent systems while reducing environmental hazard. 5

Recombinant expression of bioactive peptides in E. coli, Pichia pastoris or cell-free transcription – translation systems represent another frontier. Genetic fusion to carrier proteins and subsequent cleavage( e. g. inteinmediated release) makes scalable bioproduction possible.

Table 2- Metrics of green performance in peptide manufacture

MAR / APR 2026 SPECCHEMONLINE. COM

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