What do we really mean by “complex chemistry?”

INTRODUCTION

Dear Community,

Welcome to Issue 7 of Synthesis. This month, we explore complexity in just some of its many guises.

Let’s start with the big picture. Historically, the pharmaceutical industry has been divided into two distinct camps: “small molecules” and “biologics” (a large chunk of that latter segment being represented by monoclonal antibodies).

In more recent times, we’ve seen the striking emergence of a continuum that runs from fully synthetic to fully biologic and covers an increasing diversity of powerful yet complex modalities in the middle ground; for example, mAbs conjugated to small molecules, radioactive nuclei tethered via a synthetic compound to proteins or peptides, oligo-protein and peptide conjugates, and so on.

On paper, these innovative entities look promising and sound exciting. But when it comes to both analytical testing and manufacturing, this continuum presents significant complexity and poses challenging questions. How can we best bridge the divide? What should the manufacturing plant of the future look like? What advanced technologies do we need to accommodate this important shift?

I believe the need to answer these questions will dominate discussions for the next 5–10 years.

What I can say now with certainty is that complexity is here to stay and will continue to present itself in unexpected ways, as evidenced by both THE LEAD REACTION and ANALYZE THIS below. I am also confident that complexity will only grow as humanity explores novel ways to tackle the intractable.

Here at Cambrex, we’re passionate about keeping our finger on the scientific pulse so that we can offer the most innovative solutions to complex chemistry challenges today and prepare ourselves for the complexity of tomorrow.

How might complexity present itself to you? Please let us know so that we can start working on potential solutions.

Until next time,

Matt Bio

THE LEAD REACTION

Bubble Trouble

Development and scale-up of new chemical processes is rarely a straight road. Fortunately, cross-discipline collaboration and rich data can help ease the way through the twists and turns, explains Cambrex Senior Scientist Jenna Humke in a recent webinar.

Presenting a case study from Cambrex Charles City, Jenna describes how process chemists and engineers joined forces to develop a new biocatalytic process. Early in lab-scale development, the team needed to address the production of a volatile, catalyst-inhibiting byproduct. The introduction of subsurface sparging (bubbling gas through the reaction mixture) effectively removed the byproduct, but it led to an unexpectedly voluminous side effect.

All appeared calm for the first four hours of the reaction, which was left to continue overnight. But come morning, scientists were greeted by the hints of a runaway reaction and a fresh challenge to tackle. To find out what was happening, the team connected a camera to Cambrex’s LabOS™ platform to track the reaction 24/7. Put simply, LabOS is a data collection and automation tool that allows Cambrex scientists to remotely control and monitor experiments across a wide range of instruments. Having captured photos every five minutes for the entire reaction, the team identified significant foam production from 6 hours (peaking at around 9 hours) before completely dissipating at 12 hours.

Evidently, the conditions needed for optimum vapor-liquid mass transfer – high gas flow, small bubbles, and agitation – are also the perfect recipe for producing large quantities of foam.

To balance bubbles and byproduct removal, the team again relied on LabOS to closely track parameters, including flow rate, agitation and antifoam additives. The resulting wealth of data enabled a design of experiments (DOE) approach to identify the “sweet spot” for effective conversion without the after-hours foam party – dubbed Phase 1 by the team.

Once the foam was under control, they moved on to DOE “Phase 2” to boost throughput and establish potential critical process parameters and design space.

In the second portion of the webinar, Engineering Fellow Mark Stevens describes how the process was taken from demo scale (5 L) to pilot scale (1100 L). The team was delighted to see not only excellent conversion rates from the very first batches but also zero foam. Mark also details practical scale-up developments, including dramatically reducing nitrogen consumption by introducing a vacuum.

Overall, the team more than doubled the output per batch to 733 kg, while simultaneously addressing manufacturing sustainability goals (process mass intensity was reduced from 58 to 20).

The project is now moving into small-scale validation, and the team is applying LabOS across the board to allow smart, data-informed process development and scale-up.

Watch the full webinar.

ANALYZE THIS

Rapidly Reacting to Unexpected Impurities

What do you do when an unknown peak pops up on a routine chromatogram during accelerated stability studies?

“Identifying impurities can be complex,” says Darryl A. LeBlanc, Senior Fellow, Analytical Services, which is why Cambrex’s facilities boast state-of-the-art instrumentation (including UPLC, HRMS, and NMR). But if you need a rapid response to the unexpected, the deep collaboration that naturally occurs between a team of analytical chemists and a team of synthetic chemists working together can be a game-changer.

When a client came to Cambrex with the discovery of an impurity that exceeded the qualification limit set forth by ICH guidelines, this dual-team approach was deployed. First, expert chemists enriched the analyte through forced degradation. The proposed structure of the impurity was handed to synthetic chemists who simultaneously evaluated four possible synthetic routes. To satisfy the urgent request, the teams delivered a confirmed structural identity in just 10 days, allowing the client to provide regulatory evidence: the toxicology profile of the product had not been compromised. The newly synthesized material was qualified as a reference standard, with quantitative analyses revealing an impurity concentration of 0.1%, which is below the ICH Qualification threshold.

“The client minimized interruption to ongoing studies by providing evidence of the impurity identification to the FDA,” says Darryl. “And they are now equipped with a qualified reference standard to evaluate the presence of this impurity in their drug product in the future.”

Complexity made simple!

Read the full case study here.

THE CATALYST

What we are reading…

Every year, the Journal of Medicinal Chemistry publishes a perspective on the synthetic approaches to new drugs approved. This year’s perspective published in June¹ looked back at the 39 new small molecule drugs approved worldwide in 2024. A glance at the structures is enough to drive home the complexity of these new drugs.

¹J. Med. Chem. 2026, 69(13), 15045-15091. DOI: 10.1021/acs.jmedchem.6c00287.

The caged structure of crisugabalin (pictured above) struck me as particularly complex. The synthesis of this 12 carbon tricyclic amino acid described in the review utilizes a thermal 2+2 reaction to construct the skeleton. The overall synthesis reported relies on a classical resolution to deliver the purified enantiomer crisugabalin. Devising an enantioselective route is left to the reader as an exercise…

THE SIDEBAR

Solving complex chemistry through continuous innovation

The complexity of API molecules is increasing dramatically. Multimodality, including ADCs, peptides, polymer drugs, is adding more complexity. And yet development timescales are being driven down. We hire the most talented scientists to solve the most challenging problems.