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
I would like to have an explanation with details on how to perform
manual sampling during the dissolution test.
A
Sampling should be done with the paddles or baskets
in motion. The sample is withdrawn from a zone midway
between the surface of the dissolution medium and the
top of the rotating basket or blade, not less than 1 cm from
the vessel wall. Our suggestion is to use large volume
glass or plastic syringes with a stainless steel cannula bent
in an L shape and available from a number of sources. This
facilitates taking the sample at the appropriate sampling
point even for vessels at the back of the equipment.You
should determine if there is any interference from the
syringe material in the analysis. The specimens are to be
withdrawn at the stated times,within a tolerance of ±2%.
In order to comply with this time requirement,you may
introduce the capsules or tablets into the dissolution
vessels at staggered times leaving enough time between
sample introductions to compensate for the sample withdrawal
and filtration. In some cases,you may need to
contact the manufacturer of your dissolution equipment
to determine any modifications needed to allow the
motion of the baskets or paddles to be started after the
sample is introduced into each vessel. The samples should
be filtered promptly after being removed. The filter should
be evaluated for adsorption of the drug substance and for
possible leaching of substances that could interfere with
the analysis. Analysts need to be very well trained to
ensure the reproducibility of the sampling procedure.
Q
I deaerated the dissolution medium according to
the procedure described in the document that
comes with the USP calibrator tablets.How should I
transfer this hot medium to the dissolution vessel?
Can I use graduated cylinders or volumetric flasks?
A
Since the volume of medium specified in the USP dissolution
test is measured at room temperature, and the test is
performed with medium that has been heated,you must
take into account the density of the medium at room
temperature. One way to determine the rough density is
to weigh the amount of medium that will fill a 1- or 2-Liter
volumetric flask to the mark. The approximate density is
the ratio of the mass of room temperature medium to the
nominal volume of the flask. Multiply the target volume
(generally 900 mL) by the ratio expressed as grams per mL
to get the mass of hot medium needed.
Q
What procedure is used to validate filters used in
the dissolution test?
A
Either a 100% standard solution or a dissolved sample
solution (e.g.,prepared as a typical dissolution sample in a
dissolution vessel or as a sample in a beaker that is stirred with
a magnetic stirrer for one hour) is filtered at least three times.
For the standard solution,compare the filtered solution
response to that of the unfiltered solution. For the dissolved
sample,filter a portion of the dissolved sample solution and
compare response to that of a portion of the sample solution
which has been centrifuged. For the filter to be acceptable for
use,the response of the filtered portions should be within
98% to 102% of the response of the unfiltered standard solution
(first case) or the centrifuged sample solution (second
case). If the filters are unacceptable,the evaluation might be
repeated,with a volume of filtrate discarded before collection
of the sample for analysis begins. Based on the acceptability
of the filtered sample,the discard volume may need to be
increased. If an acceptable discard volume is not found,then a
change to another type of filter is recommended.
Q
Is the replacement of dissolution medium after
each sampling mandatory? How should I do this
replacement? How can not replacing the dissolution
medium influence the dissolution profile? Is there
any calculation I should use to make any corrections?
USP also allows the test to be continued without replacement
of the sampled volume if replacement can be shown to
be unnecessary. In this case the calculation will reflect the
amount of medium actually present at sampling. The mass of
active taken in previous aliquots must still be included in the
calculation of cumulative amount released.
The dissolution rate of drug from its dosage form can be
influenced by the energy available from the moving medium.
The energy input from the apparatus should remain constant.
However,with less mass of medium and different boundary
conditions (lower medium surface) the energy available will
change.The mixing pattern of the solution can also change.
The effect of these changes must be evaluated.
A
USP recommends that the sample volume taken be
replaced with fresh medium heated to 37°±0.5° for multiple
sampling times. If this is done,the calculation of amount
dissolved will use the nominal volume and will account for
the mass of active taken in previous aliquots. The replacement
volume should be added carefully so as not to disturb
the flow in the vessel or the dosage form residue.