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
What procedure should be used for the performance verification testing (PVT) and mechanical
calibration of 250-mL dissolution vessels?
A
At this time, USPprovides neither mechanical calibration nor a PVT for 250-mL vessels. Mechanical calibration
requires first an understanding of the critical dimensions
and parameters for the apparatus. Control of these dimensions and parameters is
necessary for the minimization
of variability of dissolution results as an artifact of the
apparatus. A PVT requires a probe that will confirm that
the apparatus functions acceptably as a system in its
intended purpose, specifically the production of dissolution samples that
represent the in vitro performance of
the dosage form itself. The development of a PVT is not a
trivial exercise. The maintenance of the USP Prednisone
Tablets RS and the PVT for USP Apparatus 1 and 2 consume a significant
portion of available staff, laboratory,
and volunteer resources at USP. For the present, the user
of alternative dissolution apparatus is responsible for the
demonstration of acceptable equipment performance.
Q
How is a dissolution test for an oral gel developed?
A
The development of a dissolution test for an oral gel
should follow the same steps as in the development of a
dissolution test for any dosage form. See the USPGeneral
Chapter <1092> The Dissolution Procedure: Development
and Validation. A new USPgeneral chapter was developed
for the dissolution test of semisolid dosage forms such as
gel, lotions, creams, and ointments. General Chapter <1724>
Performance Tests for Topical Drug Products, published in
Pharmacopeial Forum38(3) (www.usppf.com),
will be official
in the First Supplement of USP 36. Depending on how and
where a gel is applied, it may be necessary to use unusual
testing conditions (see USPmonograph for Minocycline
Periodontal System that uses the rotating flask apparatus).
Q
We would like to do a comparison of dissolution profiles for a particular
product that has
no compendial monograph. Can surfactants be
added to the dissolution medium? If yes, what are
the limits for the amount to be added and what is
the apparatus speed to be used?
A
The use of surfactant in the dissolution medium should
be the last resort because surfactants can mask problems in
the formulation or in the test. Before adding the surfactant,
you should explore other options such as (1) increasing
the volume of medium (with USP Apparatus 1 or 2 you can
easily use up to 2 L, or try USP Apparatus 4 that can go up
to 3 L/h); (2) increasing the agitation speed or flow rate; (3)
increasing the time to run the dissolution profile; (4) changing the
composition of the medium (ionic strength, different
counterion, different salts, etc.); or (5) using USP Apparatus
3; which has a more turbulent mixing mode than Apparatus 1 or 2. If none of these
options is appropriate, then you
can explore the use of surfactants. You need to justify the
amount and type of surfactant used. The amount to be used
should be the smallest possible. Recommendations on how
to select a surfactant and the amount to be used are given
in the paper "Steps for Development of a Dissolution Test for
Sparingly Water-Soluble Drug Products" available at
http://www.dissolutiontech.com/DTresour/200articles/200art3.html.
The list of surfactants that have already been used in
dissolution testing is available at
http://www.dissolution-tech.com/DTresour/200511Articles/DT200511_QA.html.
Q
Is it necessary to establish the discriminatory
power of the dissolution method if the test conditions (medium, apparatus,
speed, etc.) are the
same in a compendial monograph for the product
under evaluation?
A
The first step is to verify that the compendial test is suitable for your
product by running a dissolution profile. If the
drug substance present in your formulation is BCS Class 1
or 3 and if your formulation is immediate-release, there is a
good chance that the compendial test may be appropriate
for your product. If the drug substance is BCS Class 2 or 4
in an immediate-release formulation or if your product is
modified-release (delayed- or extended-release), there is a
good chance that the compendial test will not be appropriate for your
formulation because with these products, the
dissolution test is formulation/release mechanism dependent. In this case,
you need to develop an appropriate and
discriminative dissolution test for your formulation.
Q
The USPGeneral Chapter <1087> Apparent
Intrinsic Dissolution—Dissolution Testing Procedures for Rotating Disk and
Stationary Disk
recommends the use of 15 MPa in the compact
preparation. Our equipment measures pressure
as tons. How are the units converted to MPa?
A
The Pascal is an SI unit of pressure equal to 1 N/m
2
. A mega
Pascal is 10
6
Pascal. A Pascal is equivalent to 1.450377 × 10
4
psi. Therefore, a MPa is 1.450377 × 10
2
psi. From there, one
would have to know if the ton is short or long. A short ton is
2000 pounds (U.S.); a long ton is 2240 pounds (U.K.). You need
to know what is meant by the ton on your equipment.
Q
The USPGeneral Chapter <711> Dissolution
seems to suggest that only 1-L, 2-L, or 4-L vessels are allowed for dissolution,
and yet there
are monographs that use volumes less than the
typical 900 mL. I have a validated method for a
50-mg tablet using 900 mL of medium, and I want
to scale the dissolution volume down to 450 mL
so that the current validated method can be used
for the lower dose tablets. Can we scale down to
a 500-mL dissolution vessel, or should we use the
900-mL vessel with the 450-mL volume and use
extensions on the dissolution autosampler?
A
The text in the USPGeneral Chapter <711> Dissolution
specifies the nominal capacity of the vessels and not the
volume of medium to be used. The volume of medium is
defined by the sink condition. Vessels with volumes other
than the ones mentioned in <711> can only be used with
appropriated justification. The 500-mL vessel is not described in USP. Consequently,
its dimensions are not standardized, and they can vary from one supplier to another.
If you decide to use the 500-mL vessels, you need to check
the dimensions of the vessels used during method development and the ones that will be
used in routine analysis.
If you decide to use 450 mL of medium in a 1000-mL
vessel, you need to be careful when performing a dissolution profile. The volume of
medium withdrawn has to be
replaced with the same volume of a prewarmed medium.
If the volume of medium inside the vessel is less than 300
mL, it will be difficult to sample in the proper place, and
the mixing inside the vessel will be compromised.
Q
Are there any recommended procedures
regarding the investigation of extraneous peaks
observed in dissolution testing? Is there a guideline that describes at what
point an extraneous
peak should be investigated?
A
Any extraneous peak observed in dissolution testing
must be investigated at least to confirm that the active
ingredient is not degrading in the test conditions. Possible
causes for the presence of extraneous peaks are: degradation of the active ingredient;
impurities or degradation
products present in any of the components of the formulation or in any reagents used
in the test; interference
from components of the formulation; and leachables or
extractables from the filter or any other accessory including the chromatographic
column. See the USPGeneral
Chapter <1092> The Dissolution Procedure—Development and Validation. An updated
version of this chapter
will be published in Pharmacopeial Forum40(1) [Jan–Feb
2014], available free of charge at www.usppf.com.
Q
How can the acceptance criteria at different
time intervals be established for extended-release tablets?
A
The acceptance criteria are defined from the dissolution
profiles obtained from the biobatch (batches used in any
in vivo testing), the production batches, the batches with
deviations in key quality attributes, and the batches from
accelerated stability studies. The acceptance criteria for
extended-release tablets need to have at least three time
points: one at the beginning of the profile to demonstrate
that there is no dose-dumping, one in the middle, and the
last one when about 80% of the label claim has been released or when the
profile reaches a plateau. If there is an
in vivo–in vitro correlation, it can be used to better define
the acceptance criteria with even broader ranges.