In this case study, we showcase a few publications that utilized CSBio's peptide synthesizers in developing green SPPS methods.
Solid-phase peptide synthesis (SPPS) is essential for developing therapeutic peptides due to its ability to accommodate a wide range of modifications that are critical for enhancing peptide functionality, stability, and bioavailability. While recombinant synthesis, and alternative method for peptide manufacturing, is scalable and cost-effective, it often falls short in incorporating non-proteinogenic amino acids and complex chemical modifications, which are vital for optimizing therapeutic efficacy and addressing pharmacokinetic challenges such as stability and half-life. SPPS, on the other hand, excels in producing peptides with these necessary modifications. Additionally, recombinant synthesis of peptides has long development times with high upfront costs to establish the fermentation process; making SPPS especially suitable for producing peptides during early clinical phases, but also during later stage commercial manufacturing up to multi-kg production. Thus, despite the advantages of recombinant methods, SPPS remains a cornerstone in peptide drug manufacturing due to its versatility, reliability, and ability to meet diverse and complex pharmaceutical needs.
However, SPPS relies heavily on toxic solvents like N,N'-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), and dichloromethane (DCM), which are not only hazardous but also contribute to a high carbon footprint due to their vast consumption. The process mass intensity (PMI) for SPPS is notably high, making it an environmentally intensive practice. With regulatory bodies like the European Chemicals Agency moving towards restricting these harmful solvents, finding sustainable alternatives and reducing solvent usage towards Green SPPS is imperative for both environmental safety and compliance with upcoming regulations.
CSBio has established itself as a leader in peptide synthesis technology with a range of synthesizers that cater to different scales of operation—namely the CS136X, CS536X, and CS936 fully automated peptide synthesizers. These instruments have been instrumental in the development of greener peptide synthesis methods, as demonstrated in research over the recent years.
In a study published in Green Chemistry by the University of Bologna and Fresenius Kabi, the CSBio CS136X peptide synthesizer was utilized to explore green chemistry in solid-phase peptide synthesis (SPPS). The researchers focused on reducing environmental impact by identifying and testing greener alternatives for traditionally used solvents and reagents. Specifically, they investigated alternatives to piperidine for Fmoc removal, a common step in SPPS, as piperidine is toxic and subject to strict regulations. They tested various bases and solvents for their efficacy and environmental footprint, ultimately finding that certain alternatives could match the efficiency of piperidine while being less harmful.
Download the publication here: Replacing piperidine in solid phase peptide synthesis: effective Fmoc removal by alternative bases
A study by Bachem, Novo Nordisk, and Professor Fernando Albericio demonstrated the CS536X's ability to handle medium-scale synthesis while implementing new greener methodologies. They focused on identifying greener solvent alternatives to DMF, given its environmental and health hazards. In a series of studies, they explored binary solvent mixtures that could maintain the effectiveness of peptide bond formation while reducing toxicity and environmental impact. The binary mixtures studied, such as combinations of DMSO with DOL or 2-Me-THF, showed promise in matching or improving the efficiency of DMF in SPPS. This research is pivotal in moving towards more sustainable peptide synthesis practices, integrating green chemistry principles while maintaining or enhancing the performance of peptide synthesis.The study highlighted the synthesizer's flexibility and precision in handling complex peptide sequences, which is crucial for reducing waste and improving yield in peptide synthesis.
Download the publication here: Harnessing polarity and viscosity to identify green binary solvent mixtures as viable alternatives to DMF in solid-phase peptide synthesis
Novo Nordisk developed a method to enhance the environmental sustainability of solid-phase peptide synthesis (SPPS) where they focused on the spectrophotometric detection of residual piperidine using Oxyma. This method allowed for real-time monitoring of piperidine in the waste streams of peptide synthesis, aiming to reduce solvent use and improve safety by avoiding the need for manual sampling. In this study, the CSBio CS936 peptide synthesizer proved effective in automating the synthesis of peptides using green chemistries, while also specifically utilizing process analytical technology in the form of UV-Vis for automating the process of performing inline flow/percolation washing while measuring piperidine in real time. The CSBio CS936 peptide synthesizer automatically stopped the flow/percolation washing and continued to the next step after a user defined acceptance criterion pre-programmed into the synthesis recipe was reached by measuring piperidine in real time.
Download the publication here: Green Solid-Phase Peptide Synthesis: Oxyma-Triggered Spectrophotometric Monitoring of Residual Piperidine
CSBio's peptide synthesizers allow precise control over reaction conditions, which is crucial for implementing new greener reagents and methodologies. This control helps in minimizing the formation of unwanted byproducts and optimizing reaction conditions to increase yield and purity.
From small-scale laboratory experiments to large-scale production, CSBio synthesizers provide options suitable for all levels of peptide synthesis, making it easier to scale up successful green synthesis methods without significant modifications.
CSBio instruments are highly automated, reducing the need for manual intervention and thus minimizing exposure to hazardous chemicals. Automation also contributes to consistency and repeatability, which are vital for developing and standardizing greener synthesis protocols.
CSBio peptide synthesizers are designed for compatibility with green solvents, and can be user customized to implement new process analytical technologies with automated feedback. CSBio systems can be highly tailored and configured to work with any new green chemistries.
CSBio's range of peptide synthesizers is proving integral to the advancement of Green SPPS. Their ability to be used with novel, sustainable methodologies at various scales of production not only aligns with current environmental directives but sets the standard for peptide synthesizer needs today. As the demand for peptides continues to grow, the role of such technologies in ensuring sustainable production practices cannot be overstated. Reach out to CSBio today and discover how our systems can help your production of peptides for today and the green SPPS of tomorrow.
About CSBio: For over 30 years, CSBio, a leading peptide synthesizer manufacturing company located in Silicon Valley, California, has been providing automated peptide synthesizers and cGMP peptides to the global pharmaceutical community. CSBio’s peptide synthesizers can be found in production laboratories, universities, and pharmaceutical companies worldwide.
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CSBio is a leading peptide and instrumentation manufacturing company located in Silicon Valley, California.
CSBio provides nonGMP and cGMP peptides, peptide APIs, research scale peptide synthesizers, commerical scale peptide synthesizers, DNA/RNA oligonucleotide synthesizers, and preparative HPLC purification equipment.
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