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
The ICH guidance Q6A, Section 2.1 Periodic or
Skip Testing, indicates that for some tests (e.g.,
residual solvents and microbiological testing) for
solid oral dosage forms, skip-testing can be applicable.
Is it possible to justify skip-testing for dissolution?
A
No. If the dissolution test was well-developed, it is discriminative
for the critical quality attributes of the products. As
these attributes may change over time and affect the release
behavior of the dosage form, the dissolution test needs to be
done at batch release and at each time point in the accelerated
and normal stability studies.
Q
Regarding the USP General Chapter <1087> Apparent
Intrinsic Dissolution—Dissolution Testing Procedures
for Rotating Disk and Stationary Disk, how long
should the deaeration procedure be applied? We are
working with a drug substance that is still under development,
and we do not have large quantities available
to prepare the 150-mg compact for the evaluation of
intrinsic dissolution. Can we dilute the drug substance
with an excipient? Also, we would like to know what
the critical variables in this test are.
A
The dearation procedure described in footnote 1 in this
USP chapter can be used (filtration and subsequent stirring
above the test temperature with the application of vacuum).
A 5-min stirring time is described, but only following filtration.
The medium should be deaerated immediately before
use in the test. The chapter does not yet specify an amount
of material needed to prepare the compact; the design of the
apparatus may require 150 mg. One way of dealing with limited
sample is to dilute the active ingredient with an excipient.
Caution should be exercised with this approach because
the combination of the drug substance with an excipient may
produce a dissolution rate that is affected by an interaction
between the two compounds and not strictly an attribute of
the pure material. As the most valuable use of the procedures
in <1087> is in the comparison of the apparent dissolution
rates between two different materials representing different
sources of drug substances or its preparation, both samples
should be prepared with the same excipient in the same percentage.
In this way, a comparison can be made, but it would
be incorrect to state that the observed rate is a property of the
pure drug substance. The critical variables in intrinsic dissolution
are the stirring rate, the exposed surface area (apparatus
diameter), the medium, temperature, and compression pressure.
Q
Which apparatus can be used for the evaluation of
drug release from transdermal systems?
A
The apparatus that can be used in the drug release testing
of transdermal systems are described in the USP General
Chapter <724> Drug Release and in the European Pharmacopoeia
monograph 2.9.4 Dissolution Test for Transdermal
Patches.
Q
What is the temperature for the drug release testing
of transdermal systems?
A
For any dosage form applied to the skin, the temperature
should be 32 ± 0.5 °C. This is the temperature of the
site of application/introduction/administration of the dosage
form.
Q
How is the validation parameter, accuracy, evaluated
for a drug release test for transdermal systems
(TDS)?
A
Two possible approaches could be (1) spike the placebo of
the transdermal system with known amounts of the reference
standard of the active ingredient or (2) add the placebo of the
transdermal system to the dissolution medium, let them interact
for a certain period of time, remove the TDS from the
medium, and spike the medium with known amounts of the
reference standard of the active ingredient. The evaluation of
accuracy should be done for all the TDS strengths.
Q
When working with a UV-coupled online sampling
system in a dissolution test for an extended-release
dosage form, a bubble appeared in one of the flow cells,
and an aberrant reading was obtained at one sampling
time. How should this be addressed? If samples are collected
and archived, can the analyst run that one sample
again to obtain an accurate reading?
A
Collecting a backup sample is a good strategy. Where the
automated system has been proved equivalent to offline
analysis, the backup is representative of the missed sample so
there is no missing data if the analysis is done on the backup.
Without that luxury, that data point is missing. If the missing
data point invalidates only the results from the affected
vessel, could the test be repeated for that vessel alone on the
grounds that no probable cause can be assigned? If the answer
is yes, the test would be repeated only for that vessel but
effectively consumes, if not the total resources, then the time
needed to repeat the whole test. In that case and if there is no
limitation on samples, it is recommended to repeat the entire
run for all vessels just to make sure that a complete data set
is obtained. It may be easier to justify running the entire test
again than inserting data.
Q
Is it necessary to run a dissolution test for oral suspensions
at the time of reconstitution and also after a
certain period of days after the initial reconstitution?
A
The dissolution profiles of all the pilot samples and the
samples in accelerated and normal stability studies are evaluated
during product development. In the case of suspensions,
the samples need to be prepared following the instructions to
the patient/practitioner. The stability of the formulation on reconstitution
is part of the product development information.
Routine stability studies for a marketed product will typically
look at the attributes of the product as reconstituted. One
parameter that you need to check is the uniformity of dose
for this type of product in multiple-unit containers. See the
proposal for the new General Chapter <909> Uniformity of
Dose from Oral Suspensions in Multiple-Unit Containers published
in Pharmacopeial Forum 40 (4), available free of charge
at www.usppf.com.
Q
How can we deaerate dissolution medium that contains
surfactants?
A
If deaeration is necessary, the medium can be deaerated
before the addition of the surfactant.
Q
We are evaluating the dissolution of a tablet that
has a very low content of a particular drug. Is it possible
to use 10 tablets per vessel to facilitate the quantitation
of the drug released?
A
The USP General Chapter <711> Dissolution, under Procedure,
states to place one dosage unit in the apparatus. If the
product has a very low content of the active ingredient, a more
sensitive quantitative procedure will be needed. Another approach
is to work with a smaller volume of medium. This may
require a non-compendial apparatus such as the mini-paddle.
Q
Is it necessary to do a dissolution test for dry syrups?
A
Dry syrup is not a name accepted by USP for a dosage form.
It is an expression used for marketing purposes. The correct
name of the pharmaceutical dosage form is Powder for Oral
Solution or Powder for Oral Suspension. Any dosage form
that, when reconstituted according to the instructions to the
patient, results in a suspension needs a dissolution test. If it
results in a solution, a dissolution test typically would not be
required.
Q
What validation parameters should be applied to a
dissolution test for gelatin capsules when enzymes are
used because of potential cross-linking?
A
A complete validation of the dissolution procedure with
and without the enzyme is required. Also, if you have any
components in the dissolution medium that may inactivate
the enzyme, you need to develop a pretreatment step where
the enzyme is added to the medium without this component,
and the component is added to the medium later, after the
enzyme is able to digest the cross-linked gelatin. This pretreatment
needs to be completely validated. See more information
in the USP General Chapter <1094> Capsules—Dissolution
Testing and Related Quality Attributes, the Stimuli article Use
of enzymes in the dissolution testing of gelatin capsules and
gelatin-coated tablets—Revisions to Dissolution <711> and
Disintegration and Dissolution of Dietary Supplements, published
in Pharmacopeial Forum 40 (6) (available free of charge
at www.usppf.com), and in the paper Enzymes in the Dissolution
Testing of Gelatin Capsules AAPS PharmSciTech 2014, 15
(6), 1410-1416.
Q
What are the reasons that a USP dosage form monograph
would have multiple dissolution tests?
A
The dissolution, drug release, or disintegration tests in any
USP monograph are the tests approved by FDA for products
marketed in the United States. Because the dissolution performance
may be formulation-dependent for immediate-release
products with a poorly soluble drug substance or for products
with a modified-release mechanism, a single dissolution
test may not be suitable for all products covered by the USP
monograph.
Q
We measure the pH of the dissolution medium before
and after the dissolution test. Is there an acceptable
range for pH variation during the dissolution test?
A
There is no general acceptable range for pH variation during
the dissolution test. If a pH change is observed due to the
dissolution of the sample, its effect on the drug substance solubility
must be evaluated. Where the drug substance has low
solubility, the dissolution process will be slowed or completely
interrupted. This problem of pH change in the bulk medium
can be eliminated or minimized by increasing the buffer capacity
of the dissolution medium. Insight into the buffer used
for dissolution of weak acid or weak base substances can be
found in Dissolution Technologies 21 (4), Formulating Buffered
Dissolution Media for Sparingly Soluble Weak Acid and Weak
Base Drug Compounds Based on Microenvironmental pH0
Considerations.
Q
Is a USP capsule monograph applicable for soft and
hard gelatin capsules?
A
The monograph will be applicable to any type of capsule
approved by FDA to be marketed in the United States. It is
recommended to do a search in the FDA website for human
drugs (www.fda.gov/drugs)
to find more details about what
type of capsules are approved by the agency. If a particular
test is specific for a particular type of capsule, a mention will
be made in the monograph text stating in which cases the
test is applicable.
Q
How can the transdermal system (TDS) be fixed in
USP Apparatus 6 (rotating cylinder)? Can we cut the
TDS to accommodate it on the cylinder?
A
The USP General Chapter <724> Drug Release lists some
options on how to attach the TDS to the cylinder: glue, double-
faced adhesive tape, membrane, net, inert metal ring, or
polymer ring. Any possible interference with the quantitative
step should be evaluated. The recommendation is to not cut
the TDS. The cylinder for Apparatus 6 is available on the market
with an extension that can be used for larger TDS. Keep in
mind that the TDS needs to be covered with dissolution medium
during the entire test.
Q
We are working with a formulation that has an active
ingredient with a very high affinity for plastics. Is
there a suitable filter to be used in the dissolution testing
of such a formulation?
A
The best option will be to centrifuge the samples using
glass tubes. Even if the filter membrane is not a plastic,
it will be encased in a plastic support. You need to
determine the time and the speed for this centrifugation
experimentally.
Q
Should the paddle be running before the sample is
introduced in USP Apparatus 2?
A
The paddle should not be in motion, otherwise there is a
risk that the dosage form will hit the paddle and be damaged.
Running the paddle ahead of the start of the test will reintroduce
dissolved gas into deaerated medium.
Q
Should the sampling in USP Apparatus 1 and 2 be
done with the equipment running?
A
The sampling should be done with the equipment in motion.
This is especially important when multiple time points
are sampled.
Q
Is it mandatory to deaerate all dissolution media?
A
No. The need for deaerated dissolution medium is verified
case by case.
Q
Is there a general rule for the relation between
dissolution parameters of tablets and capsules containing
the same active ingredient. If we use USP Apparatus
2 at 50 rpm, 30 min, for tablets, can we use the
same conditions for capsules?
A
No, there are no general rules. Tablets and capsules are
considered different dosage forms even if the formulations
are very similar and they contain the same drug substance.
Most obviously, capsules may float where tablets will probably
sink. The critical quality attributes will be different, in
part due to different manufacturing processes. Also, if you are
working with gelatin capsules, you need to take into account
the potential for cross-linking in the gelatin. See the USP General
Chapter <1094> Capsules—Dissolution Testing and Related
Quality Attributes, <1092> The Dissolution Procedure—
Development and Validation, and <711> Dissolution.