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 The new lot of USP Chlorpheniramine
Maleate Extended-Release Tablets has become available and
I noticed that along with the changes in the acceptance criteria
for the dissolution rates, there were also a couple of changes
in the procedure itself from the previous lot. I would like to
know why the testing procedure itself was changed as well as the
acceptance criteria for the dissolution rates.
A The acceptance criteria for each
lot of USP calibrator tablets are set separately via the analysis
of the data generated by a collaborative study in which multiple
laboratories representing industry, regulators and USP participate.
Slight variations in performance are to be expected from lot-to-lot
with a manufactured product. The normal variation is accommodated
by setting appropriate manufacturing criteria. While USP imposes
manufacturing controls on its calibrators, the acceptance criteria
should not be confused with these controls. The suitability of
a dissolution apparatus is demonstrated by whether the results
obtained using a standard procedure are within the acceptance
criteria determined. Thus, it is essential that USP determine
the acceptance criteria appropriate to the specific lot in distribution.
The dissolution medium in this test is water. For Lot F, a small volume of 6N hydrochloric acid was added to the filtered sample aliquot as part of the procedure. No benefit either with respect to stability of the sample or quality of the absorbance spectrum around the analytical wavelength was obtained. As a further consideration, the addition of a volume of acid to the test solutions introduced a small error in the calculated drug release. The decision therefore was made to eliminate the addition of 6N HCl.
Q Do dissolution media, once degassed,
have time frames within which they must be used before they need
to be degassed again?
A
The simple answer
is that the dissolved gas concentration achieved by "degassing"
will not remain constant and will immediately start to approach
equilibrium values limited by the solubility at the medium temperature
and atmospheric pressure. Depending on your application, working
with a medium saturated with atmospheric gases may or may not
pose a problem. In our hands, the results of the 10-mg USP Prednisone
Tablets RS generally will become higher and more scattered as
the dissolved air content of the medium departs from the freshly
degassed state.
Q What is the minimum test time
required for the release of around 80% of the label claim in a
dissolution test for an immediate-release tablet?
A In general, when evaluating immediate-release
tablets that contain a highly soluble drug, you will find a Q
value of 80% of the label claim released in 30 to 45 minutes.
However, the release time and the amount released vary according
to the formulation and the drug product characteristics. In general,
the test time and tolerance should be selected so the test is
discriminating against product that has changed through manufacture,
storage, or age.
Q Should I stop the stirring when
sampling the dissolution media at the time specified in the monograph?
A - You should not stop stirring in order
to sample the solution. You are expected to take each sample from
a moving system at a standardized location.
Q What are the recommended concentrations
of surfactant in the dissolution media?
A The use of surfactants in the dissolution
medium should be a last resort because it must be justified with
data supporting the choice of type and concentration of surfactant
chosen. The concentration of surfactant will depend on your formulation
and on your drug product. A good source of information about how
to select the most appropriate surfactant and its concentration
is the paper "Steps For Development of a Dissolution Test
For Sparingly Water-Soluble Drug Products" by Noory, C.,
Tran, N., Ouderkirk, L., Shah, V. published in Dissolution Technologies,
February 2000. Also, keep in mind that sodium lauryl sulfate is
not the only available surfactant. Depending on the characteristics
of your drug product, you may need a cationic surfactant, like
cetyltriammonium bromide, or a non-ionic surfactant, such as polysorbate
(Tween).
Q Is it necessary to calibrate
the dissolution apparatus with the prednisone and salicylic calibrator
tablets, even if I have already checked all the other parameters
like speed, wobbling, depth of the paddle, temperature, etc?
A You should evaluate the mechanically
measured aspects of the system along with the demonstration of
the performance of the system by using the calibrator tablets.
In our opinion, neither mechanical calibration nor calibrator
tablets is sufficient in itself to demonstrate a suitable system.
Q In the last issue of Dissolution
Technologies you said that the dosage form should be placed inside
the vessel with the medium still and the paddle or basket motionless,
and then the agitation is started. With my dissolution equipment
I can do this only for the first vessel, and then all paddles
and baskets are moving. What should I do?
A The best way to solve this problem
is to contact the manufacturer of your dissolution equipment.
They can explain which modifications/adjustments you can make
in your equipment to stagger the stirrers.
Q In our recent calibration of
a dissolution apparatus as part of the operational qualification
procedure we obtained a high result for the USP Salicylic Acid
calibrator tablet. Can you suggest the reasons for the high results
in case of Salicylic Acid calibrator tablets?
A Salicylic Acid Calibrator Tablets
are made only of salicylic acid, there are no excipients. No
disintegration of the tablets takes place during the dissolution
process for this calibrator. We expect higher dissolution rates
when the system provides greater agitation at the dissolving surface
than is found in a well-controlled system.
One cause of high results with
paddles is the dissolved air content of the medium. We have seen
bubbles form on the tablet surface from poorly deaerated medium.
The buoyancy of the tablets is increased allowing the tablets
to "dance" under the impulse of the 100-rpm paddle stirring
rate. Typically, the tablets should be still during the 100-rpm
run. If you are carefully observing the test system, and you
see vessels where the tablets are rocking or otherwise moving
you will likely find that for those vessels you will get higher
results. We attribute the higher values to increased agitation
at the tablet surface as well as increased surface exposure in
the case where the bottom of the tablet is exposed to the medium
when it would otherwise be isolated by contact with the vessel
wall.
With baskets, your observations
may confirm that higher although not necessarily out of range
results might be obtained from a tablet that does not lie flat
on the bottom of the basket.
In general, careful inspection and control of the basket and paddle condition, alignment of the shafts and baseplate, and vibration sources will reduce the opportunity for failing results.