William Brown and Margareth Marques
The following questions
have been submitted by readers of Dissolution Technologies. Margareth
Marques, Ph. D. and Will Brown, United States Phamacopeia, authored
responses to each of the questions.
*Note: These are opinions and interpretations of the authors,
and are not necessarily the official viewpoints of the USP
Email for correspondence:
web@usp.org
Q
Is it necessary to run a dissolution test for a
product packed in a sachet?
A
It depends on the type of product packed in the sachet.
If the contents of the sachet are reconstituted according
to the instructions to the patient and the result is a solu-tion, then a dissolution test is not needed. If the result is a
suspension, then a dissolution test should be developed.
The major points to consider in the development of a dis-solution test for a suspension are: (1) the sample should be
reconstituted as directed in the instructions for the patient,
(2) the sample should be equivalent to the highest dose
that can be administered, and (3) the procedure to intro-duce the sample into the vessel should be evaluated and be
well described in the final method.
Q
What is the maximum sampling volume that can
be withdrawn from the dissolution vessel at each
time point in a dissolution profile?
A
The volume is defined case-by-case, and it is going
to be different for each product. The amount of sample
withdrawn from the dissolution vessel depends on the
analytical procedure that is going to be used to quantify
the amount of drug dissolved. The linearity and the limit
of quantification of the analytical method, and the filtra-tion procedure should be taken into consideration when
defining the amount of dissolution medium that is going
to be removed from the vessel at each time point. The
effect on the dissolution process of removal of a volume
of the test medium is a consideration. The USPGeneral
Chapter <711> Dissolution recommends that the vol-ume not deviate more than 1% from what is given in the
monograph test. This is a fair starting point in determining
whether the volume sampled should be replaced with
fresh medium.
Q
We are developing a fixed combination prod-uct containing two anti-cholesterol drugs. One
is sparingly soluble in water, and the other is
insoluble in water. The products containing only
the individual drugs have different dissolution
media. One uses pH 6.6 0.05 M sodium citrate
buffer, and the more insoluble one has 0.45%
sodium lauryl sulfate in pH 4.5 acetate buffer as
medium. Which medium should be used for the
combination product?
A
There are no general rules for a case like this one. Be-cause the solubilities of the two drug substances are very
different, it may be necessary to have a separate dissolution
method for each drug.
Q
Why is the dissolution medium volume usually
500 mL, 900 mL, or 1000 mL? How is this volume
defined?
A
These volumes are the ones most commonly used, but
the volume of dissolution medium is defined based on the
sink condition. The solubility of the drug substance is deter-mined in several dissolution media within the physiological
pH range. The volume of dissolution medium necessary to
obtain a saturated solution considering the highest dose
that is going to be marketed is calculated using the solubili-ty data. Sink condition can be defined as at least three times
the volume to obtain a saturated solution. A discriminative
method is the goal, and this is determined experimentally.
Sometimes, a more discriminative test is obtained by violat-ing sink conditions.
Q
My product has a dissolution acceptance crite-rion of not less than 80% (Q) in 45 min. How should
I report the dissolution results?
A
The way you are going to report the results depends on
how you are going to use this information. There are no
general rules; it is up to your lab to decide how to report
them. If you want to evaluate the variability of the product,
you may report the six individual results (or all the other
results if you go to the other stages listed in the appropriate
acceptance table in USPGeneral Chapter <711> Dissolution
or in the product specification), the standard deviation, and
the average of the six results. Another way would be to list
the lowest and highest values, the average, and the stan-dard deviation. Other approaches may be used depending
on how the information is going to be evaluated.
Q
I am testing a gelatin capsule product, and the
dissolution medium is water. The gelatin seems to
form a pellicle during the test, and my dissolution
results are very low. I have run all three stages of
the test in <711> Dissolution. I measured the pH
of the water to be 6.9. The two-tier test allows the
addition of pancreatin for media with pH not less
than 6.8 but says that pepsin needs to be used if
the pH is less than 6.8. I know that the activity of
pepsin is better in acid media than in media above
pH 4. Can I use pancreatin for my dissolution test?
A
The wording of the chapter makes it clear that if the me-dium is water, pepsin is used in the second-tier testing of
gelatin capsules. USP understands that pepsin has a lower
activity from pH 4 to 6.8 than from pH 1 to 4. An Expert
Panel has been formed to look at this issue and suggest a
solution. However, at this time, you will be limited to follow
the procedure found in the chapter.
Q
USPChapter <711> allows pepsin to be used in
dissolution testing of gelatin capsules. Does USP
give some recommendation of a supplier?
A
USPgives no recommendation regarding a source
of supply. USPReagent Specifications section gives
the requirements for purified pepsin that is used in the
second tier of the dissolution test. An enzyme activity
determination method is described. Enzyme activity is
dependent on test conditions and substrate. At present,
we do not have a conversion factor that might be applied
to a product that displays activity against a substrate and
under conditions differing from those given in USP. You
would do well to determine the activity of the material in
your hands and confirm continuing activity for material
that has been stored.
Q
Is it mandatory to develop a dissolution test
that releases 100% of the product label claim?
A
No, the main characteristic of a dissolution test is that it
should be discriminative for critical quality attributes. The
test should be developed in such a way that if there are any
deviations in any of the critical quality attributes (particle
size, polymorph forms, amount of key excipients, etc.) for
a particular product, the dissolution test is going to show
a difference in the dissolution profile. At the early stages
of dissolution, method development the timing of the test
should correspond to the dissolution profile where release
is about 75–80% of the product label claim.