Dissolution An Overview of Dissolved Gasses in Disso Testing

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An Overview of Dissolved
Gasses in Dissolution Testing
Published on April 14, 2022
Ken Boda
Dissolution Product Specialist at Agilent Technologies
59 articles
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When performing dissolution testing, one of the biggest headaches is
dealing with dissolved gasses. Removing dissolved gasses can be one
of the biggest headaches in the lab, and when not done properly is one
of the most common causes of dissolution failures. I’ve written about
this topic previously, but I thought it was worth a revisit since the cost
of helium is on the rise again and is leading to some labs re-evaluating
how they choose to deal with dissolved gasses. As always, this article is
based on my experience and opinions and don’t reflect those of my
employer.
First of all, why are dissolved gasses such an issue in

dissolution? Dissolution is essentially a sample preparation device, but
a sample preparation that occurs under very controlled
conditions. When performing dissolution, one needs to make sure that
your alignment and accessories are correct so that you have a
reproducible mixing (or hydrodynamics) in the vessels. The dissolution
analyst needs to ensure the right temperature, media, sampling position,
filtration, etc. are all right and reproducible as well. The dissolution
also needs to minimize variability occurring from other sources which
include vibration and dissolved gasses. Dissolved gasses can lead to
significant variability in dissolution, or skew results high or low.
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How can dissolved gasses in the vessel lead to different results? Air
bubbles can act on the dissolution environment or your dosage form in
several ways which can lead to issues. Bubbles can form on your basket
sides or bottom leading the basket to be clogged with air and decrease
the interaction of your product with the dissolution media and lead to
lower results. The same can happen with transdermals. Bubbles can
also form on your dosage form itself and either block dissolution or act
as an additional force to erode your product (effervescent tablets are an
excellent way to have a rapid dissolution after all). In disintegrating
dosage forms or beaded formulations, the air bubbles can agglomerate
particles or pull them to the surface of the media and slow the
dissolution. Air bubbles can form on the vessels, paddle blade, etc. and
alter the hydrodynamics in the vessel. These are just some of the ways
that air bubbles can impact a dissolution sample.
Given all the way that air bubbles can impact the dissolution test, it
would seem like removing these dissolved gasses through de-aeration
would be mandatory, but this isn’t necessarily so. Some methods and
products are not sensitive to dissolved gasses. If you can show through
a validation that this is the case, then you can choose to not de-aerate
with that method. Before we discuss that, let’s talk about the proper
ways to remove dissolved gasses.
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De-aeration can be done in several ways in the lab. The primary
method to remove dissolved gasses is the method described in USP
<711>. This method involves heating the media to 41-45 C, pulling this
through a 0.45um PVDF filter with a vacuum, and then holding this
under vacuum for an additional 5 minutes once the media has all been
vacuum filtered. If you’re doing this approach, I prefer heating closer to
41 C so that there is less time needed for the media to cool so that you
can start your dissolution run. So, how does this work to remove
air? This approach is decreasing the air pressure so that you are boiling
the media and removing those dissolved gasses. This approach can be
time consuming if using a single layer filter, so many labs would prefer
not to use this approach. I have in the past used a multi-layer filter
which made quick work of degassing.
Alternate de-aeration methods that a lab wants to use must be compared

to the USP degassing procedure and validated to show that they get
similar results. This comparison can be done through product testing
with the USP degassing approach and alternate degassing approach,
and showing the results are equivalent through an f2. The comparison
can also be done to show that the alternate degassing approach can get
<6 ppm dissolved gasses using a total dissolved gasses meter. These
alternate degassing methods include helium sparging, superheating,
media degassing stations, etc. Helium sparging has1 been the most

common approach for years, however, there are challenges associated
with this. First, helium has become variable in price and there have
been issues with supply shortages over the last several years. Secondly,
helium sparging is often not properly defined in methods and I’ve seen
many failures due to chemists not sparging for long enough or at a high
enough flow. Media degassing stations are used as well, and I’ve seen
labs use these successfully. Superheating can work as well, basically
heating at a higher level without a vacuum, but require a longer cool
down time before the dissolution can be started. Unacceptable means to
de-aerate include nitrogen sparging which actually super-aerates the
media, and sonication which is ineffective for aqueous only solutions.
Another approach is to not de-aerate the dissolution media. This is

something that I recommend should be evaluated for every new
method. What would be done here is to perform the dissolution with the
USP degassing approach and compare those results to media which
hasn’t been de-aerated. This is usually an f2 comparison of n=12
degassed vs. n=12 non-degassed media. There are some rules of thumb
I have found where samples tend to be less likely to need de-
aeration. First are Apparatus 3 (Bio-Dis) runs, the Apparatus 3 never
requires media de-aeration as it is such a robust mixing
1
environment. Another are methods with media containing surfactants
are less likely to require de-aeration. The reason for this is that media
with surfactants re-aerate more quickly than media without surfactants
– fully re-aerating in as little as 15 minutes. Finally, extended release
products that are non-disintegrating also tend to be less impacted by
dissolved gasses and worth looking into seeing if dissolved gasses need
to be removed.
If your product does require de-aeration, then there are some additional
things to be aware of in order for your method to be
successful. Degassed dissolution media is not in a state of
equilibrium! Once your media is de-aerated, then you need to move
quickly and carefully to ensure that the dissolution media stays de-
aerated. Pour your de-aerated media carefully so that you don’t re-
introduce excessive dissolved gasses back into the media. Weighing
dissolution media directly into vessels can reduce the number of times
you pour your media and offer great volume accuracy. You also want to
use your media as soon as possible after it has been de-aerated. Media
with surfactants can re-aerate fully in 15 minutes, media without
surfactant may re-aerate fully in 30-60 minutes. Once media is de-
aerated – it isn’t the time to go to lunch, check e-mails, or go to a
meeting. If performing the USP method of de-aeration, the media will
typically be about 39-41 degrees when you pour it 1into the vessels and
you should be at 37 C +/- 0.5C within about 5-10 minutes. Take that
time to get your sampling cannulas, filters, etc. together or label your
sample tubes/vials and you’ll be ready to drop in no time.
In summary, proper media de-aeration is critical for many products to

have a proper and reproducible dissolution test. The USP procedure of
heating to 41-45 C under vacuum is the primary approach, but there are
other acceptable de-aeration procedures. Not all products require de-
aeration, and you can check and validate this through comparative
testing. If your method does require de-aeration though, this is a media
which is not under equilibrium and proper care must be taken to still
have that media adequately de-aerated when starting the dissolution
run.
Thanks for reading. If you’ve got questions, suggestions, corrections,

etc. let me know in the comments.
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Ken Boda 59 articles Following
Published • 6h
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Dissolved gasses in dissolution testing are a frequent source of questions from my
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gasses so problematic? How do you remove them? When can you choose not to? What are
some common issues with media degassing?
#dissolution #
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Laura Filla, Ph.D. •

2nd 2h
Staff Analytical Chemist at Mallinckrodt Pharmaceuticals
Good read. Would you say it's best practice to not start the paddles/baskets
rotating until the run starts? I sometimes turn them on before I drop the dosages
so the media warms up faster.
Like · 1 Reply · 3 Replies
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1 1h
Ken Boda • Following
Laura Filla, Ph.D. I think the re-aeration increasing is possible too, but I’ve
never seen this be tested anywhere.
Like Reply
Shawn Wyatt •
2nd 6h
Owner at Scout Scientific LLC
“Another approach is to not de-aerate the dissolution media.”
Often overlooked in development and not evaluated as an option.
“Once media is de-aerated – it isn’t the time to go to lunch, check e-mails, or go to

a meeting.”
Hah! So true….yet it happens. “I de-gassed it this morning….it’ll be fine…”. 😳
Like · 1 Reply · 1 Reply
Ken Boda • Following 6h

Yup. I often have times talking with analysts about their methods and ask
why are you doing some additional step and get “well, we always do it this
way”. I’m always a big fan of validating your way out of extra work and cost!
Like Reply
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4/15/22, 5:04 AM (1) An Overview of Dissolved Gasses in Dissolution Testing | LinkedIn

Home My Network Jobs Messaging Notifications Me Work

First of all, why are dissolved gasses such an issue in

Alternate de-aeration methods that a lab wants to use must be compared

media degassing stations, etc. Helium sparging has1 been the most

Another approach is to not de-aerate the dissolution media. This is

In summary, proper media de-aeration is critical for many products to

Thanks for reading. If you’ve got questions, suggestions, corrections,

Like Comment Share 35 · 8 comments

Laura Filla, Ph.D. •

Like · 1 Reply · 3 Replies

Load previous replies

“Another approach is to not de-aerate the dissolution media.”

Often overlooked in development and not evaluated as an option.

“Once media is de-aerated – it isn’t the time to go to lunch, check e-mails, or go to

Hah! So true….yet it happens. “I de-gassed it this morning….it’ll be fine…”. 😳

Like · 1 Reply · 1 Reply

Ken Boda • Following 6h

More from Ken Boda

Researching for Dissolution Method

Ken Boda on LinkedIn

Ken Boda on LinkedIn

Home My Network Jobs Messaging Notifications Me Work

Ken Boda on LinkedIn

Tips to Make Dissolution Testing

Ken Boda on LinkedIn

See all 59 articles

About Accessibility Talent Solutions Questions? Select Language

Privacy & Terms

LinkedIn Corporation © 2022

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