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
Which solvents can be employed to prepare the
standard solution to be used in the quantitative
procedure in dissolution testing? Is it mandatory to
use the dissolution medium?
A
There is no general answer to this question. The
conditions will be defined in a case-by-case approach
depending on the quantitative procedure characteristics. Once the dissolution sample is filtered, provided
the filtration step was properly validated, you can do
whatever is necessary to have reliable quantitative
results. Depending on the case, additional dilutions can
be made using any solvent, such as the mobile phase,
or a derivatization reaction can be done to generate a
compound for which a specific detector has higher sensitivity, or a chemical reaction can be done to remove an
interference, and so forth.
Q
During a multimedia dissolution study of our formulation, we found an irregular peak shape for the
active ingredient in 0.1 N hydrochloric acid because
the dissolution medium was not compatible with
chromatographic conditions. Consequently, the
criteria for peak symmetry, theoretical plates, and
relative standard deviation could not be met. A second dilution in water was made and injected into
the chromatograph, and a better peak shape was
obtained. Can other diluents, other than the dissolution medium, be used to prepare the samples in
the dissolution testing?
A
See the answer to the previous question.
Q
Is it necessary to run a dissolution test for an effervescent tablet?
A
If using the tablet according to the label instructions results in a solution, the dissolution test is not needed. Other
quality parameters, such as completeness of solution, may
need to be evaluated. If the tablet produces a suspension,
then a dissolution test needs to be developed.
Q
Should the evaluation of accuracy/recovery in
the validation of a drug release test for a transdermal system be done at 50% of label claim or 50%
of the lowest amount of drug released during the
experiment?
A
When doing an accuracy/recovery evaluation of dissolution procedures (regardless of the dosage form type
or dissolution apparatus), most companies select at least
three concentrations from the linearity range of the
method. For the highest concentration, the upper limit is
defined by the allowable range from uniformity of dosage
units. Most transdermal systems (TDS) have two label
claims, one is the total drug load present in the TDS (TDS
have a labeled overage to provide the appropriate drug
delivery over the treatment period) and a second label
claim for delivered dosing profile of drug released. The
value used in all calculations for TDS will be based on the
dose released from the TDS.
Q
The linearity range was defined for the validation of the drug release test for a transdermal
system (TDS), but what is the lowest concentration
level to be used for the accuracy evaluation?
A
The range for accuracy comes from the range for linearity. At least three concentrations from the linearity range
should be used in the accuracy evaluation. If the product
has different doses, all of them must be considered when
establishing the linearity range and defining the concentrations to be used to evaluate accuracy.
Q
We are thinking of buying some new vessels for
our dissolution apparatus. We are trying to decide
what type of vessels to buy, round-bottom vessels
(that we are using now) or Peak vessels. Since we
have no experience with Peak vessels, we would
like to know their advantages and disadvantages
compared with round-bottom vessels. Is there any
regulation that says we should not use Peak vessels
in some cases (e.g., dissolution profile comparison)?
If we buy Peak vessels, should we revalidate all of
our dissolution methods? What is meant when USP
vessels are specifically mentioned in some literature
articles? Is this a round-bottom vessel or some other
type, or is does this mean any vessel that complies
with USP requirements?
A
Peak vessels were developed in an attempt to minimize
perceived problems in the dissolution tests due to the
presence of a cone of granulate or particles on the bottom
of the round-bottom vessels. Peak vessels should be used
with caution because the issue of coning can be solved in
most cases by increasing the rotation of the paddle. Peak
vessels are not compendial apparatus. They are not included in the USP or European Pharmacopoeiaor Japanese
Pharmacopoeiageneral chapters on dissolution. They are
not standardized. They can only be used in very special
situations with very good scientific justification. Keep in
mind that cone formation can be reduced or eliminated
by increasing the paddle rotation. If you have dissolution
methods developed with round-bottom vessels, you cannot change these methods to use Peak vessels. Peak vessels have a very specific application and can only be used
with very good justification. USP vessels are the vessels
described in the USP General Chapter <711> Dissolution.
They are round bottom, and they can have volumes of 1 L,
2 L, and 4 L.
Q
What should be the paddle and basket heights
when using a Peak vessel?
A
There are only two USP monographs that use Peak vessels, praziquantel tablets (veterinary use) and galantamine
tablets, and both use the paddle at 2.5 cm.
Q
During the evaluation of dissolution results in
a stability study for an immediate-release dosage
form, is it necessary to go to Stage 2 when only one
unit is below the acceptance criterion or when more
than one unit fails Stage 1 (S1)?
A
The dissolution test is performed in three stages, if
needed. The test can be concluded when the results
conform at any stage. The S1 criteria require that results
are not less than Q + 5%. If that condition is not true, then
the testing proceeds to the next stage. The USP standard
applies over the shelf life of the product.
Q
Which reference solution concentration should
be used during the performance verification testing
for USP Apparatus 1 and 2?
A
The USP General Chapter <851> Spectrophotometry
and Light Scatteringrecommends that the standard
solution have a concentration within about 10% of
the test solution. When the standard and test solution
concentrations are in a linear range with respect to
the absorbance (Beer–Lambert relationship obeyed),
the differences can be greater. The USP Dissolution
Toolkit, available at
http://www.usp.org/sites/default/files/usp_pdf/EN/dissolutionProcedureToolkit201003.pdf, recommends that a standard solution of 0.01 mg/
mL prednisone be used. This corresponds to 50% of
the 10-mg prednisone Reference Standard Tablet (RS
tablet) dissolved in 500 mL of medium. The certificate
provided with the RS tablet just recommends the use
of a standard solution of known concentration. The response of prednisone solutions in water is established
for concentrations relevant to the PVT. However, the
performance of the spectrophotometer in your lab is a
variable that should be evaluated, so you should check
that you are getting a linear response in the concen-tration range of interest. Once you establish linearity,
you should choose a concentration appropriate to
the analysis of the prednisone solutions obtained in
your PVT experiments. Standardization of procedure is
viewed favorably, and documentation of your decisions
is part of good practices.
Q
We are developing a dissolution method for
a combination product containing cefixime and
azithromycin. The USP monographs give individual
dissolution media for each drug. How is a dissolution medium selected for a combination product?
A
You need to verify experimentally the best dissolution
conditions for this type of product. One of the major players in helping select the conditions is the solubility of each
drug substance in dissolution media within the physiological pH range at 37 °C. For combination products, there are
no specific rules. You can have the same dissolution conditions for both drug substances, you can have the same
dissolution conditions but different acceptance criteria, or
you can even have two separate dissolution procedures
for each one of the active ingredients.
Q
We are developing suppositories containing
paracetamol, and we found that a high speed (175–
200 rpm) should be used to release approximately
90–95% of the active ingredient in 1 h. Is this high
speed acceptable?
A
The dissolution test is a way to evaluate the performance, in vitro, of the dosage form. The main objective of the dissolution test is not to release the total
amount of drug present in the dosage form. The dissolution test should be discriminative for the critical
quality attributes associated with the product. If there
is any deviation in any of these critical attributes, the
dissolution profiles should show some differences. At
the early stages of development of a dissolution test,
the target should be to release around 70–80% of the
product label claim. The final acceptance criterion will
be selected as the point in the dissolution profile determined to be the most discriminative. Often a slower
dissolution profile may produce a more discriminative
dissolution test.
Q
I am preparing a film containing sumatriptan.
How should I select the composition of the dissolution medium?
A
The composition of the dissolution medium depends
on the physiological properties of the route of administration of the product (oral, topical, injection, etc.), the region
in the body where most of the absorption will occur
(mouth, skin, stomach, etc.), and the solubility of the active ingredient in the conditions (temperature, pH, etc.) of
the route and region of absorption.
Q
We are running a dissolution test for gelatin
capsules, and we need to add pancreatin to the
dissolution medium because the capsules are showing cross-linking. We used the information on the
product label to calculate the amount of enzyme
needed, and we added the calculated amount to
each vessel. Is this the right way of defining the correct quantity?
A
The information on the product label is just the manu-facturer specification, and it is not the enzymatic activity
of the particular batch of pancreatin that is going to be
used in your lab. You have two options: (1) contact the
reagent supplier and ask for the enzymatic activity of the
particular lot you plan to use and the method that was
used to determine its activity (it should be the protease
activity determined according to the USP monograph
for Pancreatin), or (2) determine the protease activity in
your lab using the procedure in the USP monograph for
Pancreatin. The medium containing the enzyme should
be prepared in bulk rather than by adding the enzyme to
each vessel. Preparing the enzyme-containing medium
in bulk will reduce the variability in the results by homogenizing the medium.