Chemicals & raw materials
A diagram showing the step- by-step process of solid-phase peptide synthesis.
Resin Deprotection Cleavage
Peptide Synthesis Cycle
Coupling Amino acid
industrial manufacturing processes and has strong economies of scale to support the demand and bring down the cost. “To reach that point is not so easy, but if you change the
Activation
resin, you’re in a position where you can use standard green solvents,” Cabri adds. This means options like ethyl acetate, which is available at a reasonable cost but is not currently viable for use with the industry standard resins, could become viable.
Peptide
two main reasons for this; the first is that the original SPPS method developed by Merrifield was designed around the solvent. “All the resin, the reagents, the protective groups, the activation systems are based on DMF,” says Cabri. The second reason is more grounded in the risk tolerance of manufacturers, given the high cost of certain reagents. “When you have a reactor that’s doing solid phase synthesis, and you have in your reactor a molecule with a value of one or two million, you want to have an absolutely reliable technology,” Cabri adds. Given the level of automation applied to large-scale peptide synthesis, not having this reliability could be disastrous. “There is no correction you can use while you’re processing. That is why [manufacturers] are reluctant to move away from DMF,” explains Cabri. This reluctance remains even after the plethora of papers proposing green alternatives to DMF, and it has provided an impetus for the team at Bologna to attack the problem from a different angle. “The resin is an area we are investigating by discussing with polymer chemists, in order to have resins that don’t require swelling and have good reactivity,” says Cabri. Tolomelli adds that the departmental group is working with the industry to achieve this goal. “If we can find a resin that is able to open up with almost every solvent, we can select a green solvent based on what we need for reactivity,” she explains. The importance of this step isn’t just to do with the green credentials of the solvent either, because it’s one thing finding a new solvent or mixture that can lower the PMI of peptide production, but quite another to do so on a scale that’s cost effective – and that’s the bottom line for businesses. “The struggle is always the same. If you’re not able to reach a certain scale, the cost is not going down and you’re going to pay a price for that,” explains Cabri. He adds that the price for DMF is roughly £1 per kilogram, largely because it’s found in many
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Moving to liquid-phase synthesis Finding a universally applicable resin would be a game changer for green peptide chemistry. But what Cabri and Tolomelli see as the gold standard is removing SPPS completely, in favour of solution- phase synthesis, also known as liquid-phase synthesis. “We are now deeply involved in solution- phase synthesis because the final target is to produce peptides using a flow approach,” says Cabri. “So, a very rapid approach in order to have, instead of three or four couplings a day, 20 couplings a day.”
Flow chemistry is a fairly recent ambition among experts in chemical synthesis, and essentially refers to a chemical reaction run in a continuously flowing stream, rather than in batch production. But one reason that SPPS has been preferred over liquid- phase synthesis is the speed of production, and to make the latter viable for a flow chemistry approach to peptide manufacturing, each step in the process must happen fast. “We’ve already published a paper where we show that we are able to get the coupling in five minutes,” says Cabri. “If we’re able to get the deprotection in five minutes without generating much waste, we’re on the way there.” Of course, the elephant in the room is peptide quality and the purity of the final product, which is uncertain given that the method isn’t mature enough to be tested at the industrial level. There’s also the fact that as of right now, a solution-phase approach is only viable for shorter amino acid chains, and the need for a step to couple longer fragments outside of the solution-phase approach has the potential to kill any efficiency gained using it to build them.
Optimising the process to overcome these barriers will be a herculean task, but with regulators cracking down on the use of DMF, Cabri and Tolomelli are optimistic that an increasing use of solution-phase synthesis will be part of an evolution in peptide synthesis, starting over the next five years with the adoption of resins that make green solvents viable, and ending with a fully contained flow chemistry method that leaves SPPS in the dust. ●
World Pharmaceutical Frontiers /
www.worldpharmaceuticals.net
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