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
When the dissolution medium is being transferred
to the vessels, should the medium be at room
temperature, or should it be at 37 °C?
A
Regardless of the temperature of the medium, after
transferring it to the dissolution vessels, you will need to
wait for its temperature to equilibrate with the temperature
of the water bath. Room temperature medium will
require a longer equilibration time. If the medium is
delivered at 37 °C, some method will be needed to ensure
that it is equivalent to the specified volume if measured at
25 °C. You can only start the dissolution test after the
dissolution medium in all vessels has been equilibrated to
37 � 0.5 °C. See the USP General Chapter <711>
Dissolution, under Procedure, Apparatus 1 and 2,
Immediate-Release Dosage forms, page 282 of USP 30.
Remember that temperature and timing are important
variables that impact the deaerated status of dissolution
media if that is a particular concern.
Q
Could you suggest formulations of dissolution
media that simulate fed and fasted states?
A
You can find some suggestions of formulation and
how to prepare dissolution medium simulating fast and
fed states in the paper “Dissolution media simulating
fasted and fed states,” Dissolution Technol. 2004, 11 (2), 16,
available at www.dissolutiontech.com. You can find more
information on this topic in the web site www.NCBI.NLM.
NIH.GOV (access free of charge).
Q
Can the dosage form unit be introduced in the
dissolution vessel with the paddle in movement?
A
If the dosage form is introduced with the paddle in
movement, there is a chance that the dosage form is
going to hit the paddle and possibly change the disintegration
time or damage the coating. If that happens, you
need to start the test all over again. The recommended
procedure is to introduce the dosage form with the
paddle not in movement, and as soon as the dosage form
hits the bottom of the dissolution vessel, immediately
operate the apparatus at the specified rate given in the
individual method or monograph. See the USP General
Chapter <711> Dissolution, under Procedure, Apparatus 1
and 2, Immediate-Release Dosage forms, page 282 of USP
30. For deaerated media, the rate of re-equilibration is
increased in a moving medium. Thus, for the Performance
Verification Test, USP recommends that the medium
not be stirred before the start of the test to achieve
temperature equilibration. An additional consideration is
that the motion of the medium is a critical factor
contributing to the observed dissolution rate. Different
observed dissolution rates may be observed for the same
sample in media that is initially still and media in motion.
Q
When running dissolution tests in multiple
stages, such as acid and buffer stage, how can the
dosage form be transferred from one stage to the
other?
A
We suggest you have a look at the USP General
Chapter <711> Dissolution, under Procedure, Delayed-
Release Dosage Forms, method A and B, page 282 of USP
30. There are basically two ways you can do the transfer of
the dosage form from one stage to the other: 1) you can
use 750 mL of acid medium and, after the appropriate
time and with the acid-stage sample withdrawn, add 250
mL of an appropriate buffer to increase the pH to 6.8 and
2) you can drain the acid medium and replace it with the
buffer medium. There are other alternatives you can use,
depending on your dosage form. You can remove the
dosage form from the vessel containing the acid medium
using an appropriate device and transfer it to the vessel
containing the medium for the next stage. There are some
automated dissolution systems that change the medium
with the dosage form inside the vessel.
Q
The ICH guidance Q2(R1) is not very clear on
how to validate dissolution tests. Is there any other
guidance or document with more details?
A
The U.S. Pharmacopeia developed a new general
chapter that gives more details on how to validate a
dissolution method. It is the general chapter <1092> The
Dissolution Procedure: Development and Validation, pages
579�584 of USP 30. This general chapter was preceded by a
paper published in Pharmacopeial Forum: Gray, V. A.;
Brown, C. K.; Dressman, J. B.; Leeson, L. J. A New General
Information Chapter On Dissolution. Pharm. Forum 2001,
27 (6), 3432�3439.
Q
Are there any industry practices that address
tablet calibrations on USP Apparatus 1 when two
different mesh baskets are used? For example, USP
states that a 40-mesh basket should be used unless
otherwise stated in the individual monograph.
I have a procedure that will be using a 10-mesh
basket. Should separate tablet calibrations be
performed on a single system with both 40- and
10-mesh baskets?
A
The procedure for verification of the suitability of the
dissolution apparatus has been recently reviewed, and the
new version can be found in Pharmacopeial Forum 33 (4),
page 626. USP does not specify the operational qualification
for basket screen sizes other than the nominal 40
mesh. The performance verification of USP Apparatus 1
uses the 40-mesh basket. If the equipment meets the
acceptance criteria for the particular reference standard
tablet (found at
www.usp.org/referenceStandards/useAndStorage/calibrators.html), the equipment is
considered to be acceptable.
Q
Do sample acquisition and analysis for the
dissolution apparatus performance verification
test (calibration) have to be done manually or can
they be done using an automated system?
A
The recommended procedure (that can be found at
www.usp.org/referenceStandards/useAndStorage/calibrators.html
) uses a manual procedure for sample
acquisition and UV spectrophotometry for quantification.
You can use validated automated procedures. Remember
that the automated system, while providing decreased
opportunity for variability due to operator and more
efficient use of human resources, may introduce other
sources of uncertainty not encountered with manual
methods.