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
Why does the USP sometimes have more than
one dissolution test? For example, there are four
dissolution tests for Clarithromycin Extended-
Release Tablets?
A
USP monographs provide publicly accessible standards
for drug products. The monographs are categorized
according to API, dosage form, and performance
type (immediate, extended, or delayed release). The
monograph you cite describes public standards for several
products. This is almost typical for extended-release
solid oral dosage forms because many manufacturing
strategies exist to provide extended-release profiles in
vivo. For products marketed in the United States, the FDA
provides information on bioequivalence in the Orange
Book. USP monographs with multiple performance test
procedures indicate that at least one product exists for
which each particular test procedure is appropriate.
Because identification of the appropriate test will not be
possible given the information in the monograph, the
independent analyst depends on the product labeling to
determine the correct procedure.
Q
As part of doing robustness validation for a
dissolution test, I am evaluating the pH of the
dissolution medium. Can the standard solution for
this procedure be made in the regular dissolution
medium or must it be in the medium with the
changed pH?
A
In a robustness study, the elements of the procedure
are perturbed to estimate the sensitivity of the results to
normal variation in the procedure. For pH, this means that
the meter reading may be slightly incorrect, or the analyst
has prepared the medium so that the actual pH is not
spot on. When the pH of the medium may be a concern,
evaluating the effect of slight controlled variations of
pH on the dissolution rate as well as the precision and
accuracy of the analytical results is important. If a variation
around the desired pH of the medium makes no change
in the analytical response of the API, you might be safe in
making the assumption that the use of a single standard
solution is adequate for your study. However, best
practice makes use of a standard solution that is prepared
in a solvent that matches the solvent for the unknown
under test.
Q
Would we be required to perform disintegration
testing on an extended-release product if we are
already testing for dissolution? If disintegration of
such a product is needed, how is it evaluated?
A
Typically, where a dissolution test is in place, the
disintegration test is seen as redundant. Disintegration
is often part of the kinetics of dosage form dissolution.
The criterion used to evaluate disintegration is that any
residue of the unit, except fragments of insoluble coating
or capsule shell, remaining on the screen or adhering to
the lower surface of the disks, if used, is a soft mass having
no palpably firm core. Only orally disintegrating tablets
typically require both disintegration and dissolution tests.
For most orally disintegrating tablets, the drug substance
is coated to mask its possibly unpleasant taste. With these
products, the disintegration test demonstrates that the
product is rapidly disintegrating, while dissolution
confirms the release of drug from the formulation.
Q
What is the maximum concentration of surfac-
tant that can be added to dissolution media?
A
There are no official limits for the amount of surfactant
to be used in doing dissolution testing for poorly soluble
drugs, but because surfactants can mask problems with
the formulation, the amount used should be the smallest
possible. Sometimes the drug substance simply needs
to be wetted to start the dissolution process. Therefore,
a very small amount of surfactant will be sufficient. The
amount and type of surfactant used need to be justified.
For more details on the use of surfactants in dissolution,
see:
Noory, C.; Tran, N.; Ouderkikr, L.; Shah, V. Steps for development of a dissolution test for sparingly water-soluble drug products. Dissolution Technol. 2000, 7 (1), 16-21.
Park, S. H.; Choi, H. K. The effects of surfactants on the dissolution profiles of poorly water-soluble acidic drugs. Int. J. Pharm. 2006, 321, 35-41.
Q
We are evaluating a batch of tablets for
dissolution (Q is NLT 60%) and uniformity of dose.
We are finding about 85-96% of the drug dissolved
in the dissolution test and about 98-102% in the
uniformity of dose test. Why are the results lower
for dissolution?
A
Tests for dissolution and uniformity of dosage units
evaluate different properties of dosage forms. Dissolution
is going to measure the amount of drug substance
dissolved under controlled conditions in a defined period
of time. Uniformity of dose is going to quantify the total
amount of drug substance in each of the dosage units.
The tests are done in different ways. In the dissolution
test, the test conditions (medium composition,
apparatus, rotation speed, etc.) are selected to produce
discriminative results. The intention is for the test to
show differences in the dissolution rate if there are any
deviations (drug substance characteristics, manufacturing
process, etc.) in the product. The uniformity of dosage
units test is developed to quantitatively extract the drug
substance contained in each dosage form. This is going
to be achieved with efficient extraction procedures.
The results obtained from dissolution and uniformity
of dose tests should not be compared because they are
measuring different parameters of the dosage form.
The dissolution procedure can be modified to produce
samples useful in evaluating content uniformity. Usually
this is done after collecting the sample corresponding
to the last time point in the dissolution profile when the
rotation speed of the apparatus is increased to about
150 rpm for 30-60 min (this is sometimes referred to as
the infinity point or fast-stir), allowing the extraction of
any remaining drug substance contained in the dosage
form.
Q
We are working with gelatin capsules and are
finding that the amount of enzyme (3.2 g of pepsin/
L) in the simulated gastric fluid is too high. Is it
necessary to use all this pepsin?
A
Typically in USP, if simulated gastric fluid is used as a
dissolution medium, it is without enzyme. However, it is
perfectly acceptable to add enzyme if the gelatin is
presenting cross-linking. The amount of purified pepsin
to be added is mentioned in the USP General Chapter
Dissolution <711>, an amount that results in an activity
of 750,000 units or less per 1000 mL. The method for
determining the activity of purified pepsin is described
in the Reagents section of USP.
Q
What is the maximum upper limit and time for
the amount of drug dissolved for fast dissolving
tablets?
A
There are no official limits for the maximum amount
dissolved or for the testing time. It is up to the analyst
to define the dissolution conditions that are most
discriminative for a formulation. Discriminative conditions
are those that show different dissolution profiles if there
are any deviations in the product. These deviations can
be in the drug substance or excipient characteristics,
manufacturing process, or behavior of the product during
its shelf life. Ideally, the dissolution method should be
discriminative for deviations that will affect the in vivo
performance of the product.
Q
If it is necessary to go to Stage S3 in dissolution
testing, should we do the test in equipment that has
12 vessels, or is it acceptable to run the test twice in
equipment with 6 vessels?
A
The USP General Chapter Dissolution <711> does not
specify how to run the test. Twelve additional results are
needed in S3. These results can be obtained in a 12-vessel
assembly, if available in the lab, or they can be obtained
with two runs in a 6-8-vessel assembly.