77 – Process Chemistry: From Bench to Plant (S6E2)

Okay, so picture this. You're in a lab surrounded
by all this delicate glassware, and there's this
scientist meticulously working with these tiny
amounts of liquid. It's like the classic image
of a scientific discovery. Yeah, the eureka moment.
But here's the thing that I always kind of think
is so interesting. What happens when a promising
molecule that's found in that lab setting needs
to actually become a medicine for millions and
millions of people? Yeah. It's such a fascinating
transition. It is. It's a pivotal moment and,
you know, the initial breakthrough is often celebrated,
but the pathway to actually making that medicine
widely available involves a crucial and often
unseen discipline. Totally. Welcome to this deep
dive. The learner, you shared some material that
touched on this whole big picture of drug development.
And we thought it would be so valuable to really
kind of zoom in on this one specific make or
break phase process chemistry. We're going to
unpack how processed chemists take a reaction
that works on a lab bench and adapt it for the
totally different demands of commercial manufacturing.
It's like scaling up a recipe that you perfected
at home to feed an entire stadium. Oh, wow. Yeah.
It's not just about multiplying the ingredients.
No, no. It's way more complex than that. For
you, the learner understanding this stage is
key to really appreciating the immense effort
and ingenuity that goes into making medicines
accessible. It's not a simple matter of just,
like you said, multiplying ingredients. It's
really about tackling a whole new set of challenges
that emerge when you go to that scale of production.
Absolutely. We're going to uncover some of the
surprising details and the clever problem solving
involved in this whole world of process chemistry.
OK. You've got optimizing these reaction conditions,
figuring out the right kind of equipment, overcoming
all the hurdles that come with making things
huge. Right. I think there are some really interesting
nuances here that most people don't realize.
I agree. So where does this journey from small
scale to large scale really begin? Well, it usually
starts with a reaction that a medicinal chemist
has very carefully designed and optimized on
a small scale in the lab. Right. But what performs
well in a small flax doesn't always translate
effectively when you scale it up to a reactor
that's thousands of times larger. Yeah. In the
lab, you've got such precise control, you can
fine tune temperatures. Exactly. You can stir
things exactly as needed. Right. You can use
all this specialized equipment. When you're dealing
with these industrial size volumes, it's a whole
different ballgame. Totally different. Just take
something fundamental like reaction conditions,
temperature pressure makes these behave in fundamentally
different ways in large quantities. Yeah, the
physics of it changes when you go to a different
scale. So how do process chemists even begin
to tackle that? Well, they have to essentially
re -engineer the reaction for its new environment.
They have to meticulously investigate and optimize
these conditions, specifically for the large
-scale equipment. And there's the scientific
journal called Organic Process Research and Development,
or OPRND. It's a key resource in this field.
And they provide a lot of great examples of this
kind of optimization. We see instances where
they're doing temperature screening, but they're
doing it in tube reactors, which is very different.
from how you'd heat a small flask in a lab. Yeah,
totally different setup. Or even something as
seemingly straightforward as needing forced convection
ovens for reactions that have to happen above
140 degrees Celsius. Because the oil baths that
are commonly used in labs, they become impractical
and potentially even unsafe at that scale. I
see that makes sense. So, you know, it's really
interesting to see how they adapt these techniques.
And it's not even just about reaching the right
temperature. Right. It's also about maintaining
that temperature uniformly throughout a huge
volume. Exactly. I was reading one of those OPRND
papers and they were talking about reaction kinetics.
Yes. And just because a reaction happens quickly
in a small flask doesn't guarantee that it's
going to behave the same way in a massive reactor.
Absolutely. And that has to do with the way heat
is transferred in a larger system. Right, so
tell me a little bit more about that, like why
is that such a big deal? Well, the relationship
between the surface area and the volume of the
reaction mixture changes dramatically as you
scale up. This affects how efficiently heat can
be added or removed. For example, heat generated
in the bulk of the reaction in a big reactor
can't dissipate as quickly through the reactor
walls as it does in a small flask. Yeah, that
makes sense. So this can lead to what are called
hot spots. Hot spots. Where certain areas of
the reaction mixture get much hotter than others.
And that's bad. Well, it's bad because it can
reduce the yield of the desired product. OK.
And it can even create safety risks because some
reactions can become very dangerous if they get
too hot. Right. Run away. Exactly. So understanding
those underlying kinetics is crucial for process
chemists to anticipate and manage these effects
in larger reactors. And that's where this deep
understanding of chemistry comes in. Absolutely.
It's not just about the practical aspects. It's
about really understanding the molecules and
how they're behaving. Exactly. And let's not
overlook the role of solvents. Right. That seems
like such a basic component. It is. But choosing
the right solvent system is really crucial for
scale up. It is, and OPRND has some great examples
of how the selection of a unified solvent system.
A unified solvent system, what does that mean?
It means finding a single solvent that works
well across multiple steps of a synthesis. So
instead of having to switch solvents between
each step, which can be time consuming and generate
a lot of waste, they find one solvent that can
be used for several consecutive reactions. This
can shorten the production time, reduce the amount
of solvent needed, and increase the overall productivity.
So it's all about streamlining and making the
process more efficient. Exactly. Okay, so you
figured out the optimal conditions you found
your solvent system. Now you have to actually
do the reaction on this massive scale. Right.
And that's where the equipment comes in, which
is a completely different world compared to the
glassware in a lab. Totally. You go from those
beautiful elegant glass flasks you see in a chemistry
lab to these huge industrial reactors that can
hold thousands of liters. Yeah. And these are
often made of very specialized materials like
stainless steel or glass line steel. Right. And
these materials have different properties in
terms of heat transfer and chemical compatibility.
Right, because glass and steel don't behave the
same way when it comes to heat. Exactly, and
they don't react with chemicals in the same way
either. So all of this can influence the reaction
itself. It's almost like the reaction itself
has to adapt to its new, much larger container.
In a way, yes. I was reading about continuous
flow reactors and microreactor technology in
some of the OPRND papers. Yes. That sounds like
a pretty significant shift from the traditional
way of doing things in batches. It is a shift
towards greener and more efficient methodologies.
Okay, so explain that a little bit more. Like,
why is that better? Well, continuous flow reactors,
particularly microreactors, allow for much more
precise control over the reaction parameters
because you're dealing with much smaller volumes
flowing through these narrow channels. This can
lead to higher yields, less waste, and it can
even allow you to safely conduct reactions that
might be too hazardous in large batch reactors.
Oh, I see. Because you can control the heat better.
Exactly. If a reaction generates a lot of heat,
you can more easily remove that heat in a continuous
flow system, preventing a dangerous buildup.
So instead of having one big pot where everything's
reacting at once, it's more like this continuous,
carefully controlled stream. Exactly. And OPRND
has examples where switching from batch to flow
chemistry has actually resolved some pretty serious
safety concerns and reduced the environmental
impact. That makes a lot of sense. So it's a
really promising area of research. And it must
change how you monitor the reaction as well,
right? Yes, that's right. In a lab, you can just
take a sample, but in a huge industrial setup,
that's... Not so easy. That's where Integrated
Process Analytical Technology, or PT, comes in.
PT? Yes. At large scale, real -time monitoring
is essential. So PAT -E involves using various
sensors and analytical tools right in the reactor.
Oh, wow. So it's built in. Yes. It allows you
to continuously track things like temperature
pressure, pH, even the concentrations of the
reactants and products as the reaction is happening.
Wow. So it's like having a constant health check
on the reaction as it's going. Exactly. That's
incredible. It gives you much tighter control
over the process and the ability to make adjustments
on the fly, which is often not practical in early
stage lab work. Makes sense. So we've talked
about optimizing conditions, the different equipment.
Right. But I'm guessing that scaling up also
introduces a whole new set of problems. It does.
That you just wouldn't encounter at bench scale.
Absolutely. We call these scale -related issues,
and they can be pretty significant. Well one
of the biggest challenges is managing heat and
mass transfer. OK, we touched on that a little
bit before. We did. And it becomes even more
important at large scale. OK. Getting heat into
or out of that reaction mixture becomes much
more challenging in these big vessels. Right.
If you can't remove heat efficiently from an
exothermic reaction, you risk what we call a
runaway reaction. Right, where it gets too hot.
Exactly. Or you get the formation of unwanted
byproducts because the heat is driving the reaction
in the wrong direction. And on the flip side,
if you need to heat the reaction. Right. making
sure that heat is distributed evenly is a challenge.
Absolutely. You need to ensure that the reactants
are uniformly mixed and distributed throughout
the whole volume. So you don't end up with some
parts of the batch reacting faster or slower
than others? Exactly. And I imagine safety becomes
an even greater concern when you're dealing with
tons of chemicals. Oh, absolutely. The potential
hazards increase significantly with scale, especially
when you're dealing with chemicals that are reactive
or flammable. There's an interesting example
in OPR &D where they were looking at the residues
left over after a distillation. OK, the stuff
you usually just discard. Exactly. They use techniques
like DSC and ARC. DSC and ARC. Yeah, differential
scanning calorimetry and accelerating rate calorimetry
to analyze these residues. And they found that
they could undergo exothermic decomposition.
Exothermic decomposition meaning? Meaning they
release a lot of heat when they break down. Okay.
And this could happen at surprisingly low temperatures.
So even the stuff you think is harmless could
be dangerous at a large scale. Exactly. Which
is why you need specialized safety protocols.
Right. Like pressure relief systems. OK. And
very rigorous control of the operating conditions.
Wow. It's amazing how many things you have to
think about. It is. So we've talked about safety.
What about the actual drug substance itself?
Right. Is scaling up ever affect its purity?
It can. Sometimes scaling up can lead to different
types and amounts of impurities forming. This
can happen because of subtle shifts in reaction
kinetics or the emergence of minor side reactions
that weren't really a big deal at lab scale.
I see. So the purification methods that worked
well for small batches might need to be completely
reevaluated and adapted for the larger quantities.
Because you're dealing with different impurities
now. Exactly. You need to make sure that the
final drug substance still meets those those
very strict quality standards required for pharmaceuticals.
And are there ways to deal with that? Yes, there
are. OPRND has lots of examples of where purification
techniques like chromatography or crystallization
needed to be significantly optimized for large
-scale production. So it's not a one -size -fits
-all approach? Definitely not. And I remember
reading something about different physical forms
a drug can take. Right. You mentioned polymorphs
earlier. Yes, different polymorphs of the same
drug molecule can have different properties,
like solubility, stability, even how they behave
during manufacturing. So the form that works
well in the lab might not be the best for large
-scale production? Exactly. So process chemists
need to ensure that the chosen solid form is
robust and reproducible at commercial scale.
That's fascinating. So it's not just about making
more of the drug. Right. It's about making sure
it has the right physical characteristics at
that larger scale. Precisely. And I can only
imagine there are some very practical, almost
mundane issues that can arise just from working
with much larger equipment. Oh, there are definitely
some practical challenges that you don't encounter
at bench scale. Like what? Well, OPRND even mentions
things like potential clogging in continuous
flow reactors. Clogging? How does that happen?
If you have even a small amount of solid particles
forming during the reaction, they might not cause
any problems in a lab flask, but they could easily
block those narrow channels of a flow reactor
at an industrial scale. Oh, because the space
is so much smaller relatively. Exactly. So you
might need to adjust the reactor design or the
process parameters to prevent that. So it's like
every little detail matters. It really does.
It's amazing how many different angles process
chemists have to consider. It's a very multifaceted
field. It's not just about the chemical transformation
itself. Right. It's about engineering safety
purity. Yeah. Even the physical properties of
the final product. Exactly. It all comes together
in process chemistry. And I think it would be
really helpful to look at some specific examples
from the OPRND literature. I agree. to really
illustrate these challenges and the solutions
that have been developed. Absolutely. Let's delve
into some real world examples of process chemistry
in action. OK, so what are some instances where
you've seen process chemistry successfully tackling
these scale up challenges? Well, we already talked
about switching from batch to flow chemistry.
There was one really interesting case in OPRD
involving a formulation reaction. Formulation?
Yeah, it's a common reaction in organic chemistry.
OK. The original batch process for this reaction
was kind of risky, and it generated a lot of
waste. By switching to a continuous flow approach
for the formulation step, they were able to make
the process much safer and more environmentally
friendly. So that's a win -win. Definitely a
great example of how a creative approach can
lead to substantial improvements. What other
examples come to mind? Well, there are a lot
of cases where optimizing the reaction conditions
was key. For example, there was one reaction
involving a carbon -nitrogen bond formation,
and when they tried to scale it up, they ran
into problems. Like what kind of problems? They
were getting low conversion rates. Meaning not
all the reactants were being converted to product.
Right. And they were getting a lot of unwanted
byproducts. Which then makes purification harder.
Exactly. And more expensive. Right. But by carefully
tweaking the base and solvent system, they were
able to significantly improve both the yield
and the purity of the product at manufacturing
scale. So it's really about fine tuning. those
details. It is, and those details can make a
huge difference when you're producing large quantities.
Right, because a small inefficiency at lab scale...
Exactly. ...becomes a big problem at manufacturing
scale. Exactly, it all multiplies. What other
cool examples are there? Well, there's also a
lot of work being done on developing continuous
flow processes for multi -step synthesis. Oh
wow, so instead of doing each step separately...
Right. ...you're making it all flow together.
Exactly, the reaction mixture just... flows seamlessly
from one reactor to the next. That's amazing.
It's a very efficient approach. Yeah. It reduces
the need for manual handling and purification
between steps. So less time, less waste. Exactly.
It's pretty impressive. It's like a miniature
chemical factory. I love that. Yeah, it's pretty
cool. So it seems like process chemistry is all
about finding these clever modifications and
optimizations to make the process more robust
and efficient at a large scale. Exactly. It's
about taking what works in the lab and translating
it to the real world of manufacturing. And it's
not always a straightforward path, right? No,
it's often an iterative process. Meaning? Meaning
you try something, it doesn't quite work. Right.
You analyze the problem, you come up with a solution,
you try again. So it's a lot of trial and error.
In a way, yes, but it's very informed trial and
error. Right, you're using your knowledge of
chemistry and engineering to guide those experiments.
Exactly. Okay, so let's step back for a second.
Sure. It sounds like process chemistry is this
absolutely essential but often unseen step in
the journey of making medicines. It's the bridge
between the discovery of a promising molecule,
and the ability to actually produce it on a scale
that can help people. And it's far more than
just making larger amounts of something. Right.
It's about fundamentally adapting and re -engineering
these chemical reactions to meet the very different
demands of commercial manufacturing. And it requires
a very specific skill set. Right. So what kind
of skills does the process chemist need? Well,
they need a deep understanding of chemistry,
of course. OK. But they also need a strong foundation
in engineering. They need to be aware of safety
considerations. And they need to be very good
problem solvers. Because every time you scale
up, you're going to encounter new problems. Exactly.
And you need to be able to think on your feet
and come up with creative solutions. And that's
what those real -world examples from OPRND show
us. They do. They highlight the ingenuity and
the meticulous attention to detail that characterizes
this field. So for you, the learner, I hope this
deep dive has given you new appreciation for
the complexity of drug development. I hope so
too. It's not just about finding a magic bullet
in the lab. Right. It's about all the steps that
come after that. Absolutely. To make sure that
that drug can actually reach the people who need
it. It's a team effort for sure. And it's a reminder...
that while the initial drug discovery often gets
all the attention, it's the process chemists
who really make those breakthroughs a reality.
I like to think of them as the unsung heroes
of the pharmaceutical industry. That's a great
way to put it. They take those initial discoveries
and turn them into something tangible, something
that can actually help people. It's really amazing
when you think about it. And it makes you wonder
what other scientific disciplines play these
equally vital but less visible roles. Yeah. What
other unsung heroes are out there? And considering
all the intricate steps and problem -solving
we've talked about, what questions does this
raise for you, the learner, about the accessibility
and the cost of medications? That's a good question
to ponder. Because all this effort, all of this
expertise, it doesn't come cheap. No, it doesn't.
So it's something to think about. Definitely
something to consider. Food for thought. Absolutely.
Thanks for joining us on this deep dive, The
Learner. It was my pleasure. We'll see you next
time. Until then.