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
USP General Chapter <724> Drug Release states
that the qualification of USP Apparatus 5 (paddle over
disk) should be done in the same way as directed for
USP Apparatus 2 (paddle) in <711> Dissolution. Should
we carry out this qualification with the disk assembly?
A
The qualification of USP Apparatus 5 should be done
using the procedure stated for USP Apparatus 2 in the
General Chapter <711> Dissolution without the disk
assembly. The paddle in USP Apparatus 5 is the same as
that in USP Apparatus 2.
Q
The monograph for Thyroxin Sodium Tablets in the
British Pharmacopoeia mentions the use of two tablets
per vessel. Can we use multiple tablets per vessel in the
case of very low product label claim?
A
We do not know the rationale for using two tablets in
the monograph for Thyroxin Sodium Tablets in the British
Pharmacopoeia. According to USP, only one unit should be
introduced in each vessel or cell. If the product has a very
low strength, a quantitative analytical procedure with
high sensitivity should be used. If more than one unit is
used in each vessel, the interaction between the product
and the dissolution medium will be compromised and a
higher variability in the results may be found.
Q
In the USP General Chapter <711> Dissolution,
Apparatus, Apparatus 2 (Paddle Apparatus) is written,
“The dosage unit is allowed to sink to the bottom of
the vessel before rotation of the blade is started.” Does
this mean that the sample must be introduced before
mixing or may the sample be introduced after mixing
starts?
A
The dosage form should be at the bottom of the
dissolution vessel before the paddle starts its motion. If
the dosage form is introduced with the paddle in motion,
it may hit the paddle and be damaged, invalidating the
test.
Q
Are there any USP monographs, official or proposed,
that call for USP Apparatus 4 (flow-through cell)?
A
At this time, the only USP monograph that calls for
the use of USP Apparatus 4 is Rufinamide Tablets. It can
be seen in the FDA dissolution methods database (
http://www.accessdata.fda.gov/scripts/cder/dissolution/index.cfm
) that the agency has already approved other
products that use the flow-through cell in the dissolution
test.
Q
Until some years ago there was a recommendation
in USP to run pooled sample with six tablets or capsules
in one of the six vessels. I was not able to find this
information in the current edition of USP. We need
to run the dissolution test for a particular product
according to the USP monograph, but the text does not
indicate how many tablets should be placed in each
vessel. Has the number of dosage units per vessel any
relationship with the sensitivity of the quantitative
procedure?
A
USP has never recommended the use of more than
one unit per dissolution vessel. This is written in the USP
General Chapter <711> Dissolution, under Procedure,
Apparatus 1 and Apparatus 2, Immediate-Release
Dosage Forms. The pooled sample procedure described
in the same chapter should not be confused with testing
multiple units in a vessel. If the USP monograph calls
for the pooled sample, one unit is placed in each vessel,
the aliquots of the six vessels are combined in just
one solution, and this solution is used to quantify the
amount of drug substance dissolved. The limitation of
the analytical method is not a justification for testing
multiple units in a single vessel. In all cases, only one unit
is introduced in each vessel or cell. If the product has a
very low label claim, a quantitative procedure with high
sensitivity should be used.
Q
USP General Chapter <701> Disintegration does
not state to use disks, but rather to use them only if
mentioned in the specific USP monograph. Does this
mean that disks are not recommended for tablets and
capsules? At the time of disintegration testing of hard
gelatin capsules, should we evaluate the disintegration
of only the capsule or the disintegration of the capsule
filling? Sometimes a powder filled in a capsule becomes
a “lump” and remains on the screen. Shall we wait for
complete disintegration of powder lumps?
A
The chapter says, “if prescribed, add a disk.” That
means that the use of a disk is not common and needs
to be part of the procedure in the monograph. If the
use of a disk is not part of the explicit procedure in the
monograph, it is not used. Only a few monographs
have disks as part of the explicit procedure. An example
of a monograph with the disk used for disintegration
testing is Phenelzine Sulfate Tablets. The chapter states,
“For the purposes of this test, disintegration does not
imply complete solution of the unit or even of its active
constituent. Complete disintegration is defined as that
state in which any residue of the unit, except fragments
of insoluble coating or capsule shell, remaining on the
screen of the test apparatus or adhering to the lower
surface of the disk, if used, is a soft mass having no
palpably firm core.” This allows some residue to remain
at the end of testing but restricts the allowable residue to
a soft mass having no palpably firm core. If the powder is
not firm to the touch, it will pass this criterion.
Q
The USP General Chapter <1092> The Dissolution
Procedure: Development and Validation, under
Validation, Accuracy, states that in the cases of poor
drug solubility, it may be appropriate to prepare a stock
solution by dissolving the drug substance in a small
amount of organic solvent (typically not exceeding 5%)
and diluting to the final concentration with dissolution
medium. Is this common practice during validation
of dissolution procedures where the quantitative
determination is by spectrophotometric techniques
(UV-vis range)
A
If the drug substance has low solubility in the
dissolution medium, you can either prepare a stock
solution using organic solvent then make the further
dilutions with dissolution medium or you can dissolve
the drug substance in a small amount of organic solvent
(typically NMT 5% of the volume of the first dilution) and
then dilute to volume with dissolution medium. You can
use this strategy during method development, method
validation, and in routine analysis regardless of the
technique used in the quantitative step in the dissolution
procedure.
Q
Regarding the amount of pepsin to be used in the
dissolution testing of gelatin capsules that present
cross-linking, we carried out the assay test on the
pepsin, and we obtained an activity value of 1205 for
2.5 mg of pepsin. Would this be a typical activity value
for this amount? Also, how would you calculate the
quantity required to give 750,000 U/L?
A
There is no typical value for the pepsin activity; it
depends on the activity of the pepsin you bought. The
activity varies from supplier to supplier and even within
the same supplier from batch to batch. This is the reason
for the recommendation of determining the activity in
your lab. Also, keep in mind that enzymatic activity may
change with time. To calculate the amount of pepsin to be
used, you need to know the activity per mg of enzyme. If
the pepsin has an activity of 2000 units per mg, you could
use up to 375 mg in a liter of dissolution medium.
Q
I would like to know what could be a suitable
dissolution medium for cilnidipine.
A
Based on information available in the literature,
cilnidipine is a BCS Class 2 compound; it has poor
solubility in aqueous solvents in the physiological pH
range. To select the most appropriate dissolution
medium for this compound, you need to determine
the solubility of the drug substance you will use in your
formulations in different media within the physiological
pH range at 37 °C. As different formulation strategies
may be used to increase the solubility of BCS Class 2
compounds, the dissolution test will be formulation
dependent. Therefore, you need to discuss with your
formulation/development group how the drug product
will be formulated. Depending on the formulation, you
may need to use surfactants in the dissolution medium.
You can find a recommendation on how to select the
appropriate surfactant in the February 2000 issue of
Dissolution Technologies.
Q
Based on the results obtained during the validation
of a dissolution procedure, I needed to go to S2 stage.
Do I need to justify the reasons for going to S2?
A
During the validation of dissolution procedures, no
parameter is validated against the acceptance criteria.
Therefore, there is no reason for going to S2 or S3 stages.
In the validation of dissolution procedures, the entire
dissolution profile should be considered.
Q
If a failing dissolution test result is obtained at L2
and an additional 12 tablets need to be run, can two
different apparatus be used so that the 12 tablets are
run at the same time or should the tablets be run on the
same apparatus, which means that only six tablets will
be run on that apparatus at a time and the data from a
total of 12 tablets will be obtained?
A
There are no official rules or guidelines to be used
in a situation like the one you described. Based on the
method validation and the performance qualification
of the assemblies, you can run 12 units in two separate
dissolution apparatus or you can do two runs of six units
in the same apparatus.
Q
According to the USP Dissolution Toolkit version from
22 March 2010 (
http://www.usp.org/sites/default/files/usp_pdf/EN/dissolutionProcedureToolkit2010-03.pdf
), when degassing the dissolution medium by
vacuum, “the measured vacuum should be less than
100 mbar,” while in the current USP General Chapter
<711> Dissolution, only “vacuum” is required. It
this parameter critical, and if so, what would be the
appropriate range for 100 mbar?
A
The tool kit is not official USP text. It is only a
recommendation and is intended to help you perform
the PVT. The official text is the one in USP-NF. In <711>,
there is only one procedure to deaerate dissolution
medium. Other procedures can be used if validated.
See the paper Comparison of Effectiveness of Various
Deaeration Techniques (
http://www.dissolutiontech.com/DTresour/200402Articles/DT200402_A01.pdf
).