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
In the performance verification (PVT) testing
with prednisone tablets, our mean values satisfy
the specification given in Table 1 of the certificate
that comes with the tablets (
prednisonelotq1l136.pdf
). We would like to know
if the individual values obtained with each vessel
must satisfy this specification as well. The individual values that we obtained are 56, 55, 67, 63, 57, 63,
and 61, and the geometric mean (GM) is 60.
A
From your data, we assume that you are testing the basket
apparatus and that you are performing the first stage
of the two-stage test with seven vessels. For this condition,
the acceptance criterion is a GM between 58% and 72%,
and the limit for acceptable %CV (coefficient of variation) is
9.2%. Your data give a GM of 60% and a %CV of 7.3%. Both
of these values are within the acceptable ranges. You indicate
that individual values lie outside the acceptable range
for the GM, and that is correct. The test is set up to limit the
GM and not individual values. Therefore, your concern is unwarranted.
Instead of establishing a limit to the acceptable
range of individual values, the distribution of the values is
controlled by the %CV. Again in your case, the %CV that you
observed is within the acceptable range.
Q
We are carrying out a dissolution test according
to the USP monograph. However, we are having
slightly lower dissolution values by following the
USP dissolution test, and with peak vessels, the
dissolution is improving. Can we use peak vessels
in this case?
A
Peak vessels are not compendial apparatus, and they
should only be used after you have tried other compendial
conditions. They can only be used with very good
justification. In most cases, increasing the rotation speed
of the paddles gives results similar to those obtained
with peak vessels. Be careful with the evaluation of your
results. If the dissolution test was appropriate for your
product in the past and now you are seeing differences
with your dissolution results, this may be an indication
that something is different with your product and you
need to investigate.
Q
In one of the USP monographs for orally disintegrating
tablets, there are two disintegration tests
with different acceptance criteria, one is NMT 10 s
and the other is NMT 30 s. What are the reasons for
different acceptance criteria?
A
Orally disintegrating tablets can be manufactured by
two processes: (1) lyophilization, which produces a very soft
and fragile "tablet" that disintegrates in just a few seconds
and (2) use of super disintegrants, which produces a harder
tablet. We might expect case 1 to produce a product that
would disintegrate faster than tablets made according to
case 2. This is the reason for the two Disintegration Tests.
The procedure for the test is described in the USP General
Chapter <701> Disintegration. The acceptance criteria for
disintegration of orally disintegrating tablets may be formulation
dependent, so you will need to define the appropriate
acceptance criteria for your formulation. Typically, orally
disintegrating tablets need to have a disintegration and a
dissolution test. For the FDA guidance for orally disintegrating
tablets, see
UCM070578.pdf
.
Q
Our product is a tablet containing a drug substance
that belongs to BCS Class 2. The recommendation
in the FDA guidance for establishing
the dissolution acceptance criteria is to choose
two time points, one at 15 min and the other at
a time when the release is equal to or greater
than 85%. However, our product contains more
than 10% in weight of coating, and at 15 min,
we are obtaining only 10% of drug released. In
this case, is 15 min reasonable as the first time
point? Should we choose the second time point
at 30 min (30% released) or 45 min (60% released)?
A
The acceptance criteria are selected from the dissolution
profiles obtained from all batches evaluated during
product development (pilot batches, batches with deviations
in the key quality attributes, bio-batch, etc.) including
the batches under stability studies. We cannot speak to
the FDA expectations. From a compendial point of view,
two-point dissolution test procedures are not mandatory
for immediate-release products. From your experience,
you need to verify the sampling times and criteria that add
information and that are the most discriminative for the
key quality attributes.
Q
In one of the USP monographs, a dissolution
test states to deaerate the dissolution medium
with helium. How is this done?
A
This procedure is done by bubbling helium directly into
the dissolution medium for a certain period of time. Helium
is very expensive and not readily available everywhere.
Other deaeration procedures can be used. A description
of a deaeration procedure that uses heat and vacuum is
in the USP general chapter. Also, have a look at the paper
"Comparison of the Effectiveness of Various Deaeration
Techniques" in Dissolution Technol. 2004, 11 (1), available at
www.dissolutiontech.com.
Q
The FDA guidance recommends the use of 12
units of the dosage form for the comparison of the
dissolution profile of the reference and the generic
products. To obtain the results from the 12 units,
can we run the test three times with four units?
A
Most of the dissolution equipment available on the
market has six or more vessels. To obtain 12 results, you just
need to do two runs of six units with each product. As far as
we know, there are no rules on how to obtain the 12 results,
but most labs do two runs with six vessels.
Q
How is the dissolution sample solution determined?
We find that in some tests, the samples
withdrawn from the vessel need to be diluted as
part of the quantitative procedure.
A
The final concentration of the sample solution depends
on the linearity of the method and the analytical technique.
Sometimes you will need to dilute the sample solutions to
be within the linear range of the technique and the detector.
Adjust the calculated result based on any dilutions done.
Q
What cell path length should be used in the
Dissolution Test 2, Buffer Stage, in the USP monograph
for Omeprazole Delayed-Release Capsules?
A
If the text does not mention the cell path length, it is
assumed that a 1-cm cell should be used. The text will mention
the cell size only if it is different from 1 cm.
Q
We validated a dissolution method for a tablet
using USP Apparatus 1. There was a modification
in the compression step of this tablet, and the
basket apparatus is not appropriate anymore. We
changed the method to use paddles with all the
other parameters remaining the same. Is it necessary
to revalidate the method?
A
The change that was made is very critical. The modified
method is considered a new method. You will need to
demonstrate that the modified method is discriminative
and justify the selection of all parameters and acceptance
criteria. The modified method requires full validation.
Q
We are trying to use Dissolution Test 4 in the
USP monograph for Pantoprazole Sodium Delayed-
Release Tablets, which specifies the use of sinkers. If
we use this test without the sinkers, should we validate
the method or just verify it? In our experience,
some enteric coatings have adhesive behavior with
sinkers and slow the dissolution of the product.
A
Sinkers are very critical, and they can have a big impact
on the dissolution profile. Depending on their design, they
can even prevent the disintegration of the dosage form. The
selection of the sinker design is formulation dependent. Each
formulation will require a specific type of sinker. Sinkers are
used if the dosage form floats or if it sticks to the vessel wall.
First you need to verify that your formulation requires the use
of sinkers. If it does, you need to select the most appropriate
type and size for your formulation. There are several designs
and types of sinkers, made of different materials, available on
the market. If the procedure in the monograph is changed in
any way, you will need to validate the new dissolution test.
Q
Is the USP monograph for Isotretionin Capsules
applicable for hard or soft capsules? Why there are
three different dissolution tests in this monograph?
A
The USP monograph is applicable to any Isotretinoin
Capsules approved by FDA for the U.S. market regardless
of the type of capsule shell (hard or soft, gelatin, starch
derivative, or cellulose derivative) and the type of filling
(solid, liquid, or semisolid). Isotretinoin is practically insoluble
in aqueous solvents. Each company uses a different
formulation strategy to minimize or overcome this problem.
Consequently, each formulation is going to have its own
dissolution test. Each dissolution test in this monograph is
specific for a particular product approved by FDA for the
U.S. market.
Q
If the assay test is done by HPLC or by spectrophotometry
and the dissolution test uses the same
quantitative method, can it be assumed that the
validation of the assay test can be used for the dissolution
test?
A
No, the sample is treated in very different ways in the
assay and dissolution tests, and each test needs to be
validated separately. The required analytical range and the
influence of excipients will be different for each test. In the
case of spectrophotometric methods, there is chance that
the blanks may be different for each test. For dissolution, it is
especially necessary to check for filter interference.
Q
I am designing a new apparatus for the in vitro
release of floating drug delivery systems. Do I
need to have a procedure for the performance
verification (PVT) of this new apparatus?
A
You will need detailed drawings of this new apparatus
with all the measurements and tolerances and a description
of the materials of construction. All documentation
needs to be written in such a way that the apparatus can
be replicated in any facility. In addition, you need to determine
the critical attributes of your apparatus and their
impact on the drug release determinations, and specify
acceptable tolerances. Confirming that the apparatus conforms
to specified dimensions and operational parameters
such as flow rate or rotation speed will be an important
part of the qualification. Finally, the purpose of the apparatus
is to produce a sample representing the in vitro
performance of a dosage form. Given that purpose, suitable
performance of an apparatus will be demonstrated
from acceptable dissolution results using a standardized
sample material.
Q
We are investigating the solubility of several
drug substances under different pH conditions
for the development of veterinary pharmaceutical
feed additives. The FDA Guidance for
Industry Waiver of In Vivo Bioavailability and
Bioequivalence Studies for Immediate-Release
Solid Oral Dosage Forms Based on a Biopharmaceutics
Classification System (BCS) (
ucm070246.pdf
) says to verify the
pH of the solution after the addition of the drug
substance to a buffer. It is necessary to have
constant monitoring of the pH of the solution
throughout the solubility determination?
A
The pH range may be selected based on the animal
species to which the product will be administered.
Depending on the animal species, the pH ranges in the
BCS guidance may not be applicable. The pH range in
the BCS guidance may be suitable for dogs. Papers that
discuss this topic are "Solubility Criteria for Veterinary
Drugs—Workshop Report" in Pharmacopeial Forum, 39(4)
[Jul.-Aug. 2013], "Solubility Criteria for Veterinary Drugs"
in Pharmacopeial Forum 38(4) [Jul.-Aug. 2012], and
"Veterinary Application of In Vitro Dissolution Data and
the Biopharmaceuticals Classification System." All are
available at
keyissue-standards-veterinary-drugs
.
Determine the pH of the solution before adding the drug substance, after adding the drug substance, and at the end of the solubility experiment to verify that the buffer capacity of the selected buffer is adequate. Certain compounds may react with the medium to alter the pH, possibly affecting the solubility of the compound.
Q
Please explain the statement "Validation studies
should address the variations associated with
different profile time points" found in the USP
General Chapter <1092> The Dissolution Procedure:
Development and Validation.
A
When running a dissolution profile, in most cases higher
variability in the dissolution results is seen at the initial
timepoints. The variability should decrease with time. Additionally,
the possibility of interference from the excipients
may be different over the dissolution profile as the formulation
interacts with the dissolution medium.
Q
Why are there three different dissolution tests
in the USP monograph for Glimepiride Tablets?
How should the correct one be selected for use?
A
Glimepiride is practically insoluble in aqueous solvents.
To overcome or minimize this problem, each company will
formulate the product using a different strategy based on
available technology or patent issues, cost analysis, and so
forth. The dissolution test for each formulation will reflect
those differences. The dissolution tests in USP monographs
have been approved by FDA for products marketed in the
United States. They may not be appropriate for products
sold in other regions. The dissolution tests in the USP monograph
can be used as a starting point in the development of
dissolution tests for new formulations.
Q
We are evaluating the dissolution of esomeprazole
delayed-release capsules and are finding
evidence that possibly 20-30% is released in the
acid-stage testing. Esomeprazole is unstable in
acid medium. How can we evaluate any release in
the acid medium?
A
Acid-resistant formulations should release very little drug
in the acid stage. The USP General Chapter <711> Dissolution
limits release in the acid stage to not more than 10% of the
product label claim. If you are finding high values released in
the acid stage, you should discuss your observations with your
formulators or product development group. If the drug substance
is unstable in acid medium, as is the case of omeprazole,
lansoprazole, esomeprazole, and other drug substances
from the same family of compounds, you can determine the
amount that remains in the dosage form after it has been submitted
to the acid-stage test. You can do this using the assay
or the quantitative procedure from the uniformity of dose test.
Q
Can mini vessels be used in the dissolution of tablets?
A
Mini vessels are not compendial apparatus, and the marketplace
is not standardized. They should be used only with
proper justification such as demonstrating that they bring an
advantage to your dissolution method when compared with
the compendial apparatus. Since they are not standardized,
you need to describe the vessels (dimensions, shape, supplier,
and catalog number) to be used in your method.
Q
In the USP monograph for Atenolol Tablets, the
acceptance criterion for the dissolution test is NLT
80% (Q) in 30 min. The manufacturer's specification
is NLT 85% in 30 min. Is this specification in
compliance with USP?
A
The USP monograph for Atenolol Tablets gives a dissolution
tolerance with the Q value of 80%. Acceptance Table 1
in the USP General Chapter <711> Dissolution shows that
at Stage 1, testing 6 units, no unit result is less than 85%
(Q + 5%). The manufacturer may mean that its specification
is set at the S1 level as presented in Acceptance Table 1.
That would partially conform with USP. The general chapter
describes the dissolution test as having three stages of testing,
S1, S2, and S3, with a possible total of 24 units tested.
The Q value is used in different ways as the testing proceeds
through all the stages. At the S2 level with 12 units tested,
Q is the limit for the average result with Q - 15% as the limit
for individual results. If the manufacturer simply means
that Q is 85% for its atenolol tablets, then it is applying a
more stringent requirement than the USP monograph test.
That may be done as a control on the product in its hands;
however, it is not required for products labeled as USP or
claiming to meet USP monograph requirements.
Q
In the USP monograph for Oxybutynin Chloride
Extended-Release Tablets under Dissolution Test 4
is the recommendation for a specific sinker with its
catalog number and a possible supplier for it. The
web site for this supplier mentions that sinkers
are for capsules, and the USP monograph uses the
same sinker for a tablet. Is this correct? Can other
types of sinker be used?
A
Sinkers can be used with either capsules or tablets if
they float or if they stick to the vessel walls (see USP General
Chapter <1092> The Dissolution Procedure: Development
and Validation). The type of sinker can have a big impact on
the dissolution profile; depending on its design, it can even
prevent dosage form disintegration. Therefore, the type of
sinker used should be carefully evaluated, and sinker selection
should be done on a case-by-case basis.
Q
There is a discrepancy between the temperature
for the deaeration procedure in the USP
General Chapter <711> Dissolution (41 °C) and in
the certificate that comes with the USP Prednisone
Tablets RS (41-45 °C). What are the reasons for this
discrepancy? Is there a difference in the deaeration
of the medium at a temperature of 41 or 45 °C?
A
The underlying principle is that the water solubilities of
atmospheric gases decrease with increasing temperature
and decreasing pressure. The medium is heated above the
test temperature, and then vacuum is applied with filtration
and stirring to decrease the dissolved gas content below
saturation. Exposed to the atmosphere, the dissolved gas
content is will increase as the medium cools and time goes
by. Studies in the USP laboratory have demonstrated that
good performance verification testing (PVT) results will not
likely be obtained if the dissolved oxygen (as a marker for dissolved
atmospheric gases) is much greater than 6 ppm. It has
been our experience that degassing water at a temperature
between 41 and 45 °C can produce an acceptable medium
for the PVT. In acknowledgment of the fact that the degassed
medium must cool to the test temperature before the start
of the dissolution PVT experiment, we performed studies in
our lab to determine a minimum degassing temperature
that would allow the medium to remain above the 37 °C test
temperature during subsequent vacuum treatment, transfer
to the vessels, and placement in the dissolution test assembly
while requiring minimal additional time for thermal equilibration.
It was observed that 41 °C fulfills that expectation.
However, in acknowledgment of the ability of a laboratory
to control the medium temperature during its preparation,
a range of 41-45 °C is practicable. Remember that once the
medium cools down to 37 °C and time passes, the dissolved
gas content will increase to saturated values. Therefore, before
the dissolution run, care must be taken not to let the medium
stand for any length of time and not to stir or agitate (such as
by pouring the medium with no regard to the potential for
mixing atmospheric gas) the medium unnecessarily.