The Future of API Synthesis
We need to produce molecules faster, more economically and with greater control. AI and protein engineering are effective tools to help with this mission.
David Entwistle, Oscar Alvizo |
This article was published in our sister publication, The Small Molecule Manufacturer, which celebrates the field of small molecule drug development and manufacturing with interviews and articles focusing on success stories, equipment, and new processing techniques.
Historically, given enough time and resources, almost any small molecule API will succumb to “total synthesis” – first in medicinal chemistry and then in process chemistry. The greatest challenge facing the process chemist, both then and now, is to produce the molecules under a state of control, with a reproducible impurity profile, in an economical fashion, and at increasing scale. These seemingly simple but high-level goals arguably cause the most problems and influence route design the most. In addition, the regulatory and toxicology landscape has changed and a much more rigorous approach to impurity control, especially of potential genotoxins, has emerged (and rightly so).
More recently, the industry has recognized that it needs to be able to produce its products in a sustainable manner. For example, in almost all cases, solvent use is the greatest contributor to waste during API syntheses, which adds not only cost to the process, but also an environmental burden that must be tackled – with solvent type and usage being the main areas of concern. As drug makers increasingly seek more potent, targeted and (often as a consequence) more complex molecules, the pressure on synthetic chemists to find cost-effective and sustainable routes to their drug candidates has grown.
In terms of challenging chemotypes, chirality is a heavily investigated area. In the early 1990s, the FDA specified that APIs should be produced in high isomeric purity. A command that resulted in many intermediates or APIs being classically resolved, resulting in at least a 50 percent increase in the cost of raw materials, increased waste, and potential impurity issues with residual off-isomers. As asymmetric catalytic methods (both chemo- and biocatalytic) have advanced, they have become indispensable tools in producing chiral APIs.
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