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
At the time of sampling in a dissolution test, is it
appropriate to increase the speed of the paddle to
250 rpm for a few seconds in order to get better
homogenization?
A
No, the speed of the basket or paddle must remain
constant during the entire dissolution test. The USP
General Chapter <711> Dissolution, on page 278 of USP
30, states, “A speed-regulating device is used that allows
the shaft rotation speed to be selected and maintained
at the rate specified in the individual monograph,
within ± 4%.” In addition, the discriminative power of the
test will be lost at such a high speed. The expectation of
the dissolution test is to determine the release rate under
controlled conditions. It is not an assay of the contents
where total recovery of the drug from the dosage unit is
the goal.
Q
Are there any justifications for getting lower
results at the later time points when doing a
dissolution profile?
A
Possible reasons are (1) the calculation formula may
not be appropriate, a correction must be done to account
for the volume of medium removed and replaced and the
amount of analyte removed; (2) the drug substance may
not be stable in the dissolution medium and is degrading
during the test; and (3) the concentration of the drug
substance released to the medium may be close to the
saturation concentration and the drug substance still
present in the dosage form is not being solubilized.
Q
Where can I find information about running
dissolution or drug release tests for suppositories?
A
The use of suppositories is more popular in Europe
than in the United States. The European Pharmacopoeia
has a general chapter, 2.9.42 Dissolution for Lipophilic
Solid Dosage Forms, that describes an apparatus, a flowthough
cell (USP Apparatus 4) with a special cell, and the
method that can be used to evaluate the drug release
from suppositories. Lipophilic and hydrophilic suppositories
will typically require different test conditions. Also, you
can find papers in the literature with more information at
the site www.NCBI.NLM.NIH.GOV (access free of
charge). This is a chapter on suppositories in the new
dissolution book out called “Dissolution Theory,
Methodology and Testing,“ Edited by A. Palmieri�see ad
on page 32.
Q
Some dissolution equipment are fitted with
eight dissolution vessels. Is it possible to do
dissolution runs in this type of equipment
combining different product batches? As an
example, could six vessels be used with one batch
and the other two vessels with the second batch?
A
The procedure described for dissolution does not
specifically forbid testing more (or less) than six units at a
time. In USP, a procedure for one unit is given followed by
the statement, “Repeat the test with additional dosage
form units.” A consideration of the effect of intermediate
precision on the results should be given for units within
the same sample (e.g., the six units tested) when the
sample is divided between two actual runs as in the
question, where one lot is represented with all six tested at
the same time while the second lot would only have two
units in that run with the remaining four tested in the
following run. Whatever course is decided, standard
procedures should be in place as a guide.
Q
Can nitrogen gas be introduced in the
dissolution vessel during the test in order to degas
the medium?
A
If nitrogen is introduced to the medium during testing,
it will need to be brought in through a tube. The presence
of a tube in the dissolution test during testing will change
the hydrodynamics of the test. Additionally, if the nitrogen
exits the medium as a stream of bubbles, additional
unwanted agitation will result.
As a separate issue, if the dissolved gas content of the medium is controlled using nitrogen, the use of a dissolved oxygen meter to confirm the dissolved gas content is not recommended. The nitrogen will itself saturate the medium while preferentially removing dissolved oxygen.
Q
During the validation of dissolution methods,
should the items specificity, accuracy, and precision
be carried out in dissolution vessels or in volumetric
flasks?
A
It is advisable to run the specificity, accuracy, and
precision evaluations according to the dissolution
procedure, which means in the dissolution vessel. You
need to replicate the conditions of agitation and
temperature to which the product will be submitted.
Regarding precision, you will evaluate repeatability and
intermediate precision, and in both cases, it means
running the test in the conditions specified in the
dissolution method to evaluate the variability associated
with the test and with the laboratory procedures and
conditions.
Q
How many dosage forms units should be used to
evaluate the intermediate precision of a dissolution
procedure?
A
At least six units should be used. Typically, laboratories
are doing the evaluation of intermediate precision in
duplicate, with 12 units.
Q
In the USP General Chapter <1225> Validation
of Compendial Procedures and in the ICH guidance
Q2(R1), it is recommended to evaluate only
precision in the case of dissolution procedures.
Is this enough?
A
Both documents have a footnote stating that other
items may be required, depending on the nature of the
test. Because there were no official guidances on how to
select which parameters should be validated and how to
do it, USP developed a new general chapter, <1092> The
Dissolution Procedure: Development and Validation. This
general chapter gives some recommendations on which
characteristics should be evaluated in the validation of
dissolution procedures.