We Must Rethink The Solvents We Use For Peptide Synthesis
Peptides as a class of drug have been around for several decades. GLP-1s, peptide receptor agonists, are synthetic peptides that mimic the action of the natural hormone glucagon-like peptide-1. They stimulate insulin secretion, inhibit glucagon release, and slow gastric emptying, making them effective for managing blood sugar levels and promoting weight loss. GLP-1 has been used for type 2 diabetes for a long time but thanks to its indication for weight loss, the use of and outlook for GLP -1s have changed completely. Often, one hears about the astonishing growth numbers, with projections such as $100 billion by 2030 and up to $471.1 billion by 2032, reflecting compound annual growth rates between 10.3% and 33.2%. This expansion stems from clinical successes in weight management, with drugs like Ozempic and Wegovy demonstrating significant reductions in body weight and cardiovascular risks. While the effectiveness of GLP-1 in weight loss is good news, there are growing pains behind the scenes that need to be addressed. One such pain is the use of organic solvents in the GLP-1 synthesis and purification process. This article highlights the need for the industry to invite potential solutions and discussion.
The 3 Common Methods For GLP-1 Production
1. Solid-phase peptide synthesis (SPPS)
SPPS is the go-to method for making GLP-1 peptides. In this process, the peptide is built one amino acid at a time on a solid resin support. It’s popular for a reason — it is efficient, letting machines handle much of the work, which cuts down on time and labor. The step-by-step assembly keeps impurities to a minimum, and it scales up easily for industrial production.
2. Liquid-phase peptide synthesis (LPPS)
Unlike SPPS, liquid-phase peptide synthesis happens in solution instead of on a resin. Although it is not as common for GLP-1 production, LPPS has its perks. It’s flexible and works well for shorter peptides or fragments. It’s also a more budget-friendly option since it doesn’t need as much specialized equipment. Often, LPPS is combined with SPPS in hybrid approaches, where peptides made in solution are later assembled on a solid support to make the process even more efficient.
3. Microbial fermentation method
Engineering microorganisms to produce GLP-1 peptides, this approach offers several advantages. It’s cost-effective, cutting out the need for pricey chemicals. It’s also scalable, as fermentation can churn out peptides in huge quantities.
Of the above three methods, SPPS is considered the mainstream way to make peptides, although the other two methods may be gaining prominence as well. But SPPS requires a lot of solvents like dimethylformamide (DMF) and N-Methyl-2-pyrrolidone (NMP). GLP-1 production heavily depends on solvents like DMF and NMP. These are polar aprotic, meaning they can dissolve a wide range of reagents and support efficient reactions without interfering in the process. In SPPS, DMF and NMP are essential for dissolving amino acids and coupling agents, enabling the sequential assembly of GLP-1 peptides. Their stability ensures consistent results, while their compatibility with various chemicals makes them indispensable.
As production of GLP-1 drugs has grown, so has the use of organic solvents such as DMF and NMP, creating a sustainability problem for the industry to address.
The Ideal Solution
The obvious solution would be to eliminate the use of organic solvents and use water as a solvent or even adopt a solventless system. SPPS relies on amino acids, coupling agents, and other reagents — many of which are poorly soluble in water — making it difficult to use water as a solvent. Without the right solvent, achieving the necessary reactivity and efficiency becomes significantly harder.
Industry also has explored friendlier solvents such as ethyl acetate and TamiSolve. While these solvents hold promise, they are a long way from solving the problem and being a mainstream solution. Developing a more environmentally friendly alternative will require collaboration among the entire value chain, including pharma companies and solvent producers.
The Practical Near-Term Solution
Replacing DMF and NMP is not a simple swap — it requires a complete rethinking of peptide synthesis methods. Any alternative solvent would need to match or exceed their performance while addressing environmental and safety concerns. Additionally, current equipment and procedures are optimized for these solvents, meaning a transition would demand new technologies, protocols, and validation processes.
Thinking from the ground up is necessary to identify sustainable yet effective substitutes. Hence, the focus should also be on how best to recycle the solvents used in peptide synthesis.
Recycling DMF And NMP
Both of these solvents are often thought of as commodity chemicals and usually would not be a subject of technical discussion and scrutiny. Given the nature of multistep peptide synthesis, it is not straightforward to recycle these solvents. There are several challenges with recycling:
- During this process, they become contaminated with reaction byproducts, including unreacted reagents and impurities, making purification complex and costly.
- The physical properties of DMF and NMP further complicate recycling. They are hygroscopic, meaning they absorb moisture from the environment, which can alter their composition and reduce their efficacy for reuse.
- Given the strict quality requirements for pharmaceutical-grade solvents, recycling must ensure complete removal of contaminants without compromising solvent purity.
Despite the above challenges, recycling DMF and NMP is an area for the industry to make technical advancements since it could be a near-term solution for the growing pain. Finding ways to recycle DMF and NMP is a valuable opportunity for the pharmaceutical and chemical industries to cut costs, lower environmental impact, and meet rising regulatory expectations. Achieving this, however, requires close collaboration between manufacturers and solvent suppliers.
Solvent suppliers have the specialized knowledge and tools needed to develop advanced recycling methods. By working together, the two industries can explore cutting-edge solutions like fractional distillation, advanced filtration, and custom solvent recovery processes designed to meet pharmaceutical-grade standards. This kind of partnership could pave the way for scalable, cost-effective systems that recycle DMF and NMP while maintaining the high levels of purity required.
Collaboration also can drive innovation by focusing on the development of more environmentally friendly alternatives. Solvent manufacturers, alongside industry players, could work toward creating recyclable or biodegradable substitutes that perform as well as DMF and NMP. This would ensure that sustainability doesn’t come at the expense of productivity
As sustainability becomes a priority for regulatory agencies, companies adopting solvent recycling initiatives can position themselves as leaders in environmental stewardship. Beyond meeting compliance requirements, these efforts could enhance the industry’s reputation, improve supply chain efficiencies, and achieve significant cost savings. Partnering with solvent manufacturers is a strategic step toward a more sustainable and innovative future.
About The Author:
Rajendran (Raj) Arunagiri has been in the pharma industry for a decade and has successfully developed and launched a new excipient. He is a co-author of technical articles and is an invited speaker at conferences focused on excipients and drug delivery. He specializes in the area of poorly soluble APIs and modified release. Arunagiri welcomes you to reach out to him for questions, comments, and collaboration ideas at raj.gceb@gmail.com.