125 - Dissolution Testing & Bioequivalence (S9E5)

Ever wonder how a generic pill can really be
considered the same as like the original brand
name version? Well, it's a great question. And
there's a lot of science that goes into ensuring
that. And one of the most important tests is
called dissolution testing. Dissolution testing.
It's kind of a mouthful, but it's actually super
fascinating. OK, so in this deep dive, we're
going to be talking about dissolution testing.
That's right. We'll be taking a behind the scenes
look at how scientists use this in vitro test
to basically predict what happens in vivo, you
know, inside a living organism. Yeah, exactly.
So what sources are we going to be using for
this? So our primary source is actually a transcript
from season nine, episode five of this very podcast.
It's called Dissolution Testing and Bioequivalence.
Okay, and is there anything else that we'll be
referencing? Well, we also have some snippets
from season three on basic pharmacokinetics and
a little bit from season five, which focused
on pharmaceutical product development and something
called in vitro in vivo correlation. All right,
so today we're going to be looking at essentially
how drugs get absorbed in the body. Yeah, that's
a big part of it. We're going to specifically
focus on dissolution testing, different types
of equipment, why the liquid or medium used in
these tests is so important and how those results
are interpreted. Okay, and you said that this
was vital in regulating the approval of new drugs.
Yeah, it's super important for both new drugs,
like NDAs, new drug applications, and also generic
drugs, which go through what's called an ANDA,
an abbreviated new drug application. Okay, so
how about we start with the basics? Can you explain
the link between this thing called dissolution
and buyer availability? Sure. So bioavailability
essentially refers to how much of a drug actually
reaches the bloodstream and how quickly it gets
there. Okay. And for solid dosage forms, like
the tablets or capsules that many of us take,
the rate at which that dissolves, that solid
form dissolves, really impacts how well it gets
absorbed in the GI tract, the gastrointestinal
tract. So does that mean that a pill that dissolves
quickly is going to be absorbed more quickly
than one that dissolves slowly? Exactly. And
that absorption rate directly affects affects
the drug's bioavailability. It determines how
much of the drug actually gets into your system
to do its job. That makes sense. So are we essentially
saying that dissolution testing is like a predictor
of how well a drug will actually work in the
body? You got it. In fact, in 1998, researchers
Dressman and his colleagues actually described
dissolution testing as a prognostic tool for
oral drug absorption. That phrase really captures
its importance. A prognostic tool, huh? That
sounds pretty serious. So are there different
ways to carry out these dissolution tests? There
are. A variety of specialized apparatus are used
to kind of simulate what happens in our stomachs
and intestines. So it's not just like dropping
a pill in a glass of water. No, not at all. These
are carefully controlled environments. Different
apparatuses are used depending on the type of
dosage form you're testing. Like an immediate
relief tablet versus a capsule versus a suspension
will all be tested slightly different. So Walk
me through this. What are some of the key things
that scientists consider when they're setting
up a dissolution test? Like what kind of things
can affect how a drug dissolves? Sure. So first,
there are the properties of the drug substance
itself. Think about its solubility, for example.
Some drugs are more soluble in water than others.
Then there's the dosage form itself. how the
tablet or capsule is made. Right. And this includes
the inactive ingredients or excipients that are
used. These can influence things like how quickly
a tablet breaks apart or disintegrates. Oh, I
see. And then, of course, there's the environment
of the gastrointestinal tract. Right, like the
stomach acid and all that. Exactly. The pH of
the stomach is very acidic, while the intestines
are more alkaline. And all of these factors together,
the drug substance, the dosage form, and the
GI environment play a role in how a drug dissolves.
So it sounds like choosing the right liquid for
these dissolution tests, you know the medium,
is super important. It's crucial. The dissolution
medium is carefully selected to mimic the fluids
in the GI tract. Like the stomach acid we talked
about. Exactly. For example, they might use a
solution with a very low pH, like around one
or two, to simulate the acidic stomach environment.
Wow, that's pretty acidic. It is. Or they might
use buffered solutions with a pH closer to 4
.5 or 6 .8 to represent different parts of the
intestines. Got it. And how does the pH actually
affect the drug dissolving? Well, the pH can
have a huge impact on a drug's solubility. Some
drugs dissolve much better in acidic conditions,
while others need a more basic or alkaline environment.
So choosing the wrong pH could really mess up
the results? It absolutely could. It wouldn't
accurately reflect how the drug would behave
in the body. And we actually have an example
of this in one of our sources. They talk about
how some natural and synthetic gums, which are
often used as binders in tablets. Binders. Yeah,
binders are inactive ingredients that basically
help hold the tablet together. OK. So these gums
can actually form these kind of viscous solutions
in gastric fluid, like a gel almost. And that
can slow down the dissolution process. So even
something that seems as simple as the binder
in a tablet can influence how the drug is released.
Exactly. It all comes down to carefully selecting
the right dissolution medium to really get a
good prediction of what's going to happen in
the body. OK, so let's say they've run the dissolution
test. They've got all their data. How do scientists
actually interpret those results? What are they
looking for? Well, the results are usually presented
as what's called a dissolution profile. It's
basically a graph that shows the percentage of
the drug that's dissolved over time. A graph,
okay. So, are they looking for a specific shape
or pattern in that graph? Well, they're looking
at the rate and the extent of dissolution. How
fast and how much of the drug is released from
the dosage form. And how does this relate to
the idea of bioequivalence? Well... When you're
comparing, let's say, a generic drug to a brand
-name drug, one of the key things you want to
see is that their dissolution profiles are similar.
So if the graphs for the generic and the brand
-name drug look pretty much the same, that's
a good sign. Exactly. It suggests that they're
both releasing the drug in a similar way, which
supports the idea that they'll be bioequivalent,
meaning they'll have the same therapeutic effect.
So dissolution testing is like a key piece of
evidence that the FDA would look at when they're
deciding whether to approve a generic drug. It's
a very important piece of evidence. It helps
them ensure that the generic drug is truly comparable
to the brand name drug in terms of how it behaves
in the body. And there's actually a specific
regulatory expectation that lots of different
batches of a drug. Right. even those that are
at the upper and lower limits of what's allowed
for dissolution, they should ideally be bioequivalent.
So they're not just testing one batch. They're
making sure that any batch of that drug is going
to be consistent. Precisely. It's about ensuring
consistent quality and performance across the
board. And this whole concept of bioequivalence
is really at the heart of the regulatory process
for NDAs, abbreviated new drug applications,
which is what generic drugs go through. Right,
so for a generic drug to get approved, it has
to prove that it's essentially the same as the
brand name drug. That's the main goal. They have
to demonstrate bioequivalence. And dissolution
testing is often a major part of that demonstration.
Okay, now what about new drugs? You mentioned
NDAs earlier. Does dissolution testing play a
role there as well? It does. For new drugs, dissolution
testing is crucial for characterizing the drug
product. It helps scientists understand how the
drug is released from that specific formulation
and how it might behave in the body. So for a
new drug, it's not about comparing it to something
else. It's about understanding its own unique
property. Exactly. It's about building a solid
foundation of knowledge about that particular
drug product. And this data is important for
things like setting quality control specifications
during manufacturing. So they can make sure that
every batch of the new drug is consistent. That's
right. And it also helps support the overall
efficacy and safety profile of the new medication.
OK, so we've talked about the principles dissolution
testing. We've talked about how it's used in
the regulatory process. Do you have any real
world examples of how this testing has actually
made a difference? Like, has it ever led to changes
in how a drug is formulated or helped get a generic
drug approved? You know, it's interesting. The
sources that we have for this episode don't really
delve into specific named case studies, but we
can definitely talk about some hypothetical scenarios
that are very realistic and reflect how dissolution
testing works in the real world. OK, I like hypothetical
scenarios. Let's hear one. All right, so imagine
a company that's developing a new tablet. They're
in the early stages of development. They've got
this promising drug compound. But when they do
their initial dissolution test, they find a big
problem. The drug is just not releasing from
the tablet very well. Oh, no. Yeah, it's dissolving
too slowly in the simulated gastric fluid. And
that's a red flag because it suggests that the
drug might not be absorbed very well in the stomach
when someone actually takes it. So what do they
do? Well, This is where dissolution testing really
guides the development process. They know they
need to go back and tweak the formulation. They
might experiment with different excipients, different
inactive ingredients, maybe try a different disintegrant,
which is something that helps the tablet break
apart more easily, or they might try a different
binder. So they're using the results of the dissolution
testing to improve the actual design of the tablet.
Exactly. It's an iterative process. They'll make
changes. retest, make more changes, retest until
they find a formulation that releases the drug
at the desired rate. That's really cool. It shows
how this testing isn't just a box to check. It's
actually driving innovation. Absolutely. And
now let's think about a hypothetical example
for generic drugs. Let's say a company is developing
a generic version of a popular medication. They've
created their formulation and now they need to
prove to the FDA that their version is bioequivalent
to the original. OK. So they're going to conduct
a bunch of dissolution tests comparing their
generic drug head to head with the brand name
drug. They'll use carefully chosen dissolution
media, the right apparatuses. Everything's got
to be just right to mimic the conditions in the
body. Makes sense. And if the results show that
the generic drug dissolves in a very similar
way to the brand name drug, then they have strong
evidence to support their claim of bioequivalent.
And that's ultimately what gets them approved.
That's a big part of it. The FDA needs to be
confident that the generic drug will essentially
work the same way as the brand name drug. And
dissolution testing is a key piece of that puzzle.
This has been super interesting. So as we wrap
up, can you just give us like the big picture
takeaway? messages about dissolution testing.
Sure. I think the main thing to remember is that
dissolution testing is a bridge. It connects
what happens in the lab with what happens in
the human body. A bridge. I like that. It allows
scientists to predict how a drug is going to
behave once it's taken. And that's essential
for ensuring the quality, consistency, and ultimately
the effectiveness of our medications. And it's
important for both. brand new drugs and generic
drugs. Absolutely. It plays a vital role in the
approval process for both, helping to guarantee
that patients have access to safe and effective
treatments. You know, it's amazing to think about
all the science and the testing that goes on
behind the scenes just to make sure that the
pills we take actually work the way they're supposed
to. It's pretty remarkable. And it makes you
wonder what other tests are out there that we
don't even know about, all working to ensure
the quality and safety of our medicines. It's
something to think about. Thanks for joining
us for this deep dive into dissolution testing
and bioequivalence. Thanks for having me. This
has been the deep dive. Bye.