24/7 BIOPHARMA - issue 1 / October 2024

LONZA

Lonza’s Small Molecules Division has developed an AI-enabled Route Scouting service to provide customers looking to make a new API with a rapid way to identify commercially- viable synthetic routes.

Back to the future

Despite the growing research focus on biologics, small molecules still make up the lion’s share of the medicines taken by patients every year. This is unlikely to change any time soon, as they make up about 90% of pharmaceutical sales. While research into new small molecule active pharmaceutical ingredients (APIs) continues, many of the ‘easy’ targets are already served by multiple marketed drugs and, as a result, the molecules being designed today are becoming ever more complex. This is often required to modulate targets that are considered difficult, or potentially even undruggable. The increase in molecular complexity introduces greater synthetic challenges, too. It is not uncommon for synthetic routes to be 15 or 20 steps long, or even more. The result is invariably lower overall yields, longer manufacturing times and increased costs. Process chemists are therefore faced with a growing challenge: creating a reliable manufacturing process for the API, while simultaneously considering the supply chains for both raw materials and intermediates. What is being done to improve the situation? Increasingly, the answer lies in applying in silico tools to the problem.

Retrosynthetic analysis is familiar to anyone who has studied organic chemistry. It was first developed by Harvard chemist E. J. Corey, who won the Nobel Prize in chemistry for his work on it in 1990. It’s a little like taking a complex Lego model, breaking it into pieces and then putting them back together again to remake the model. The chemist considers the complicated molecule and imagines how it might be assembled from smaller fragments. What chemical reactions could be used to make the bonds needed to put them back together again and how could you break those fragments down into even smaller pieces? This retrosynthetic process is repeated until all the pieces of the jigsaw are available. Of course, there are many, many ways a large and complicated molecule might be broken down into fragments and there lies the real challenge – which way is likely to be best? Which has the fewest steps? Which uses easy, safe, high-yielding reactions? Which minimises purification steps? Also, crucially, which is likely to be quickest and cheapest to run on a large scale?

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TWENTYFOURSEVENBIOPHARMA Issue 1 / October 2024