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
When running dissolution tests for products with
very low strength,is it acceptable to use multiple
dosage units in each vessel?
A
The use of multiple dosage units in each dissolution vessel
is not recommended because it is very difficult to assure that
all units will be in contact with the dissolution medium in the
same way.The contact interface between the dosage unit
and the medium will not be the same for all units in all vessels,
presenting a very high variability in the results .There are
other approaches that are more appropriate:(1) the use of
200-mL vessels with mini paddles,just keep in mind that
because this apparatus is not compendial,you need to justify
its use,demonstrate that it brings an advantage to the test,
validate it,and develop a verification procedure;(2) use of an
analytical technique with more sensitivity. Some companies
are using liquid chromatography coupled with mass spectrophotometry
to quantify the low amounts of drug typically
released from drug-eluting stents.
Q
We are observing failing results when we are
doing the equipment verification with USP Prednisone
Tablets RS.We carried out the test with and
without sinkers,and we observed the failure just with
the use of sinkers.Do you have any comments?
A
Sinkers are used only when the dosage form floats.The
USP Prednisone Calibrator Tablets do not float.Therefore,the
use of sinkers is unnecessary.As in your case,the use of sinkers
can have an influence on the dissolution test results. In fact,
the particular sinker design that is used should be specified.
Thus,sinkers,when needed,will be specifically included in the
procedure with a description of the design that must be used.
The procedures for dissolution apparatus performance verification
are available at http://www.usp.org/
referenceStandards/useAndStorage/calibrators.html.
Q
Regarding the dissolution test of extendedrelease
dosage forms,can we claim that our product
is USP if we have our own tolerance test that is
different from those stated in a particular USP monograph?
A
No. In order to claim that your product is USP,it needs to
meet the acceptance criteria in all tests included in a particular
USP monograph. For a test like dissolution,several procedures
with associated acceptance criteria might be included.
Each marketed product would have to indicate in its labeling
the particular procedure and criteria that apply.What could
be done for your product is to request the inclusion of an
additional dissolution test procedure and acceptance criteria
in the USP monograph.As USP represents products that have
been approved by the FDA,your request for revision of the
monograph dissolution test should include a copy of your
dissolution test,its validation report,and a copy of the FDA
approval letter.
Q
Are other procedures for degassing the dissolution
medium,other than the one described in USP,
acceptable?
A
Yes,in the USP general chapter <711> Dissolution,page
2679 of USP 29,there is a footnote describing one possible
procedure for degassing dissolution medium. In this footnote
is stated that �other validated deaeration techniques for
removal of dissolved gases may be used.�Please refer to the
following papers:Griffith,M. F.,Curley,T. E.,Marting,G. P.,
Considerations in choosing a deaeration technique for dissolution
media. Dissolution Technol.,February 1997,pages
16�17;Degenhardt,O. S.,Waters,B.,Cameirao,A. R.,Meyer,A.,
Brunner,H.,Toltl,N. P.Comparison of the effectiveness of
various deaeration technique. Dissolution Technol.,February
2004,pages 6�11;Fliszar,K. A.,Forsyth,R. J.,Li,Z.,Martin,G. P.
Effects of dissolved gases in surfactant dissolution media.
Dissolution Technol.,August 2005,pages 6�10. See pages
15�18 in this issue.
Q
Could an orally-disintegrating tablet be classified
as a chewable tablet? Could the same dissolution
procedure be applicable for both dosage forms?
A
Chewable and orally-disintegrating tablets are formulated
in different ways,and they have different performances.
Chewable tablets are intended to have the active participation
of the patient who,by chewing the tablet,facilitates the
act of swallowing it.There is no guarantee that the patient will
follow the instructions completely,and swallowing the whole
tablet is a possibility.Therefore,the dissolution test for this
dosage form is done in the same way as for simple tablets.
Orally-disintegrating tablets are a more recent technical
breakthrough.Typically,these dosage forms are designed to
disintegrate rapidly in the presence of liquid to facilitate their
administration.As the rapid disintegration is a special characteristic
of this dosage form,a disintegration test is necessary.
Typically,drugs have bad taste;to overcome this in an orallydisintegrating
tablet,the drug is coated. Release of the drug
from the coated particles must be demonstrated.Therefore,a
dissolution test is also included in the specification of this
dosage form.
Q
How should the acceptance criteria in the Acceptance
Table 2 in the USP general chapter <711>
Dissolution be interpreted,mainly regarding the
statement "none is more than 10% of labeled content
outside each of the stated ranges"?
A
Acceptance Table 2 in <711> Dissolution is used to evaluate
the results for extended-release dosage forms.The Q
value and all the percentage values mentioned in the tolerances
of dissolution tests and in the acceptance tables are
expressed in the same terms as percentages of the labeled
amount of the drug. In the statement,outside means both
above and below the range endpoints. For instance,suppose
that for the timepoint 1 hour you have a range of between
20% and 30% of the drug released.Applying the statement in
the acceptance table,you will end with the new range of
between 10% (20% minus 10%) and 40% (30% plus 10%).