5:09 PM
Feb 15, 2018
 |  BC Innovations  |  Strategy

Pfizer’s chemistry machine

How Pfizer is bringing continuous flow to medicinal chemistry

With the goal of creating a step-change in the optimization of small molecules in discovery research, Pfizer Inc. has built a continuous flow machine that rapidly tests thousands of chemical reactions using submilligram quantities of starting material. The goal is to bring the optimization process upstream in drug development and reduce the amount of reinventing the wheel on compound synthesis that occurs later in CMC.

Although combinatorial chemistry has become commonplace throughout the industry and enabled construction of large compound libraries, the standard methods still limit the options available to medicinal chemists for optimizing molecules early in drug discovery.

Most systems rely on generalizable coupling strategies to link chemical building blocks, but designing efficient methods that will scale is limited by the availability of starting material. In particular, dialing in the right solvent, temperature, pressure, catalyst and other conditions for the couplings can take many iterations.

Consequently, chemists often make small molecules for research under suboptimal conditions that don’t easily scale. Some reactions never get solved under any conditions, limiting the chemical space.

Last month in Science, Pfizer published a study outlining a continuous flow system to accelerate compound optimization and enable bench-scale reactions normally beyond reach.

“Over the last 20 years, spurred by the combinatorial revolution, we started to run 10-20 reactions per day. Our paper reports 1,500 mini reactions per day. The miniaturization allows us to do optimizations we couldn’t do before,” said principal investigator Neal Sach, an associate research fellow at Pfizer who was one of the machine’s architects.

He said the miniaturization already yielding benefits. “We can iron problems out before we get to the difficulty of being on a timeline to make large amounts under pressure,” he said.

“In discovery, we may have 100 mg of precious reagent available to us. With this system we can still run thousands of combinations against that. In the past, we would have needed tens of grams,” he said.

“We need to expedite the route to the clinic by making scalable chemistry. That’s where the instrument comes to bear.”

Paul Richardson, Pfizer Inc.

Sach told BioCentury the machine can be constructed for about $22,000, plus the cost of liquid chromatography/mass spectrometry (LC/MS) analysis, an instrument many labs already have.

Martin Burke, a professor of chemistry at University of Illinois, said the technology represents an important advance in the miniaturization and automation of synthesis and is likely to rescue difficult projects. Burke published on his own small molecule synthesis machine in 2015, which he licensed to Revolution Medicines Inc., a natural products discovery company.

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