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 dissolution test is a two-step process; the first
step involves placing the dosage form in the dissolution
apparatus and letting the dissolution occur, and the
second step is the analysis of the aliquot taken from
the dissolution medium. According to the USPGeneral
Chapter <1225> Validation of Compendial Procedures,
dissolution testing is a Category 3 test, and the only
parameter recommended for its validation is precision.
I would like to know if this precision is evaluated only
in the first step or in the first and second steps of the
dissolution test.
A
The USP General Chapter <1225> Validation of
Compendial Procedures does not give details for validating
dissolution procedures. For more information, refer to
<1092> The Dissolution Procedure—Development and
validation. See the revised version of this chapter in the
First Supplement to USP 38. The parameters that need
to be validated for dissolution procedures are specificity,
linearity range, accuracy, and precision. The limit of
quantification is useful when you have a dosage form
with very low drug content.
Q
How much sampling volume can be withdrawn at
each sampling time without medium replacement?
A
This needs to be evaluated in a case-by-case approach.
Although maintaining constant and reproducible
hydrodynamics is an issue, the drug substance solubility
may also be a consideration. The solubility of the drug
load should not violate sink conditions with the reduced
volume.
Q
When should the pH of a dissolution medium
containing surfactant be measured, after or before the
addition of the surfactant to the buffer?
A
You need to consider the type (anionic, cationic, and
amphoteric) and the concentration of the surfactant
in the medium. These two parameters may affect the
performance of the electrode. It may be necessary to
regenerate the electrode after the measurement. It will
be advisable to check the recommendations from the
electrode manufacturer.
Q
What should be the water level in the dissolution
water bath?
A
You should always check the recommendations of the
manufacturer of the dissolution equipment. The level of
water in the water bath should always be above the level
of dissolution medium in the vessel.
Q
The USP has a monograph where the dissolution test
is done with ordinary vessels. Can we use peak vessels
in the dissolution test of this product?
A
The vessel is part of the test conditions. Furthermore,
the conditions of the test cannot be changed without
proper justification. Peak vessels are not compendial
apparatus, and their use also requires proper justification.
In most cases, the problem can be solved just by increasing
the speed of the paddle.
Q
What type of adhesives can be used to fix the
transdermal system (TDS) on the USP Apparatus 6?
A
Several options on how to fix the TDS in the USP
Apparatus 6 are described in the USP General Chapter
<724> Drug Release. They need to be selected in a caseby-
case approach and verified for possible interference
with the quantitative procedure.
Q
We are developing a dissolution test for soft gelatin
capsules and are finding a relative standard deviation
(RSD) greater than 20% after 2 h. After 3 h, the dissolution
is completed and the RSD is around 0.5%. Does the RSD
have significance in dissolution testing?
A
Yes, RSD does have significance in dissolution testing.
The variability in dissolution has two components: the
variability from the manufacturing process and the
variability of the dissolution procedure. It is difficult
to determine the contribution of each one of these
components. Variability should be evaluated along the
dissolution profile to understand the product and evaluate
the test method. In most cases, as with your results at 3
h, the variability from the dissolution procedure tends to
decrease after a certain time because the dissolution rate
is decreasing as complete drug release is approached.
For your soft gelatin capsule, the high variability after the
relatively long time of 2 h may indicate that the capsule
contents are dissolving variably due to capsule shell
opening or to the properties of the capsule contents.
Q
What is the logic behind using 6 units in the
dissolution test and 12 units for dissolution profile?
A
We recommend that you read the article “An Early Look
at Dissolution Testing, Including Equipment, Calibration,
and Acceptance Criteria” by Dr. Tim Grady published in
Dissolution Technologies (August 2014).
Q
After a mechanical calibration is performed on
a dissolution equipment setup for baskets, we are
keeping each vessel-basket-shaft combination
constant for the calibration to remain valid. In other
words, post-calibration, the baskets are not to be
used interchangeably among all the vessels. Is this
interpretation correct? If a basket was damaged during
the cleaning procedure, does the replacement basket
need to be calibrated before use? Or, can the new basket
be considered “like-for-like” and be used right away?
When switching a calibrated system from 40-mesh
baskets to 100-mesh baskets, is calibration required on
the new 100-mesh baskets?
A
There are two schools of thought on this subject.
Strictly, the apparatus is the shaft, stirring element,
vessel, and position of the test assembly. From that
point of view, any change will have to be qualified. We
recommend this more conservative approach where
the suitable performance of the system is confirmed.
Our recommendation is to demonstrate that the new
system acts as a whole system and provides acceptable
performance. Once qualified, the stirring elements and
vessels should be kept in the positions where they were
qualified. We do not have any data for baskets with finer
mesh baskets.
Q
How should peak vessels be calibrated?
A
There is no official procedure to calibrate peak
vessels. Because this type of vessel is not compendial, it
is not standardized and the dimensions may vary among
different vessel manufacturers. A full description of the
vessel should be included in the dissolution procedure.
Q
If we have one drug product in two different
strengths, can we select one of these two strengths to
validate the dissolution method?
A
Especially when differences in formulation exist, the
method needs to be validated for all strengths.
Q
USP has a monograph for Mefenamic Acid Capsules
with a dissolution test. If we want to use this dissolution
procedure for a tablet formulation, will we only need to
perform a method verification following the USP General
Chapter <1226> Compendial Method Verification?
A
No. First, you need to verify that the dissolution
procedure is suitable for your formulation by evaluating
dissolution profiles obtaining with your samples. If you
find it suitable for your product, you would need to do a
complete validation of the method.
Q
What are the mesh sizes of baskets that can be used
in dissolution?
A
See USP General Chapter <701> Dissolution. The sizes
are 40 (default), 20, and 10 mesh. Any other mesh size can
be used with appropriate justification.
Q
How should the concentration range for the
validation of linearity of a dissolution test be selected?
One document we found states that the range should
be ±20% of the Q value, and another document says
that it should be ±20% of the dissolution profile.
A
You need to select a quantitative procedure that is
linear and has the appropriate levels of accuracy and
precision for all the points in the dissolution profile.
Therefore, you need to consider the entire dissolution
profile to define the concentration range for the
evaluation of linearity. Some companies also include the
upper limit of uniformity of dose in this range.
Q
The instructions for the Performance Verification
Test (PVT) for USP Apparatus 1 and 2 call for water as
dissolution medium. Where in USP is the description of
the quality of this water?
A
The specification for water for analytical purposes can
be found in the Reagents, Indicators and Solutions section
of the USP under 4. Definitions, 4.7 Water.
Q
The deaeration procedure in USP General Chapter
<701> Dissolution instructs to heat the medium to 41 °C
and immediately filter under vacuum. The Performance
Verification Test (PVT) for USP Apparatus 1 and 2 states
that the temperature should not drop below 37 °C to
avoid raising the dissolved gas level in the medium.
Also, <701> states that the medium volume is specified
between 20 and 25 °C. At what temperature should I
transfer the medium to the vessels?
A
The USP deaeration procedure results in medium that
is above the test temperature, so you need to measure
the volume by weight using the density of water at room
temperature. You will transfer the weighed deaerated
medium to the vessel as soon as possible and let it
equilibrate by cooling to the appropriate temperature in
the water bath.
Q
In the proposed new monograph for Hard Gelatin
Capsule Shell published in Pharmacopeial Forum
41(1) (www.usppf.com), under Disintegration test,
the instructions are to fill up the capsule with an inert
excipient such as lactose and use the disks. Meanwhile,
USP General Chapter <701> Disintegration states to run
the test for hard gelatin capsules with a removable wire
cloth. Why are the instructions in these two documents
different? Should the instructions in the monograph be
the same as those in the general chapter?
A
USP general chapters contain the instructions that are
applicable in most cases. Any deviation from the general
chapter or additional instructions will be described in the
appropriate particular monograph. The information in a
USP monograph supersedes the information in any USP
general chapter.
Q
We are running the dissolution test for a delayedrelease
formulation by performing the acid stage
with 750 mL of dissolution medium and, after the
appropriate time and sampling, adding 250 mL of the
buffer dissolution medium. Should the buffer be at 37
°C?
A
Yes. Any time you add dissolution medium to the
vessel, whether in the case of delayed-release dosage
forms or when replacing the volume of any aliquot
withdrawn, the medium needs to be prewarmed to the
temperature of the test.
Q
In the USP General Chapter <701> Dissolution there
are two ways of running the dissolution test for delayedrelease
dosage forms: one option is to begin with 750
mL of the acid stage medium and later add 250 mL of
a buffer; the second option is to use 1000 mL of both
acid and buffer stage medium. How can the appropriate
option be selected when developing a dissolution test
for this kind of product? When using the second option,
how can the dosage form be transferred to another
vessel if the dosage form sticks to the bottom of the
vessel?
A
The selection of the procedure should be done
during method development and in a case-by-case
approach. The way the sample will be transferred to
the other vessel depends on the type of dosage form
(tablet, granules, capsule) and how the dosage form
behaves during the dissolution test. Depending on the
formulation, the dosage form may remain intact or can
partially disintegrate during the acid stage. If the dosage
form remains intact, you can use any instrument (spatula,
tweezer, scoop, etc.) to transfer it to the other vessel. For
granules, it may be necessary to filter the contents of
the vessel to collect all the granules. In some cases, you
will remove the dissolution medium by vacuum or any
other procedure, and the dosage form will remain in the
vessel. If the dosage form sticks to the vessel wall, it may
necessary to use an appropriate sinker.
Q
In the Question & Answer section of the February
2014 issue of Dissolution Technologies, you stated,
“instead of measuring the amount of drug substance
released into the acid stage medium of the dissolution
test for a dosage form containing this type of compound,
you can measure the amount of drug substance that still
remains in the dosage form” when the drug substance
degrades in the acid stage medium. Could you give more
details on how to run this procedure?
A
It depends on the type of dosage form. If it is a tablet
and it remains intact during the acid stage, you can use any
appropriate tool (spatula, tweezer, scoop, etc.) to remove
it from the vessel, and then you run the quantitative
procedure used in the evaluation of uniformity of dose.
If the dosage form is granules, you may need to filter the
entire contents of the vessel. You can use a cannula with a
filter attached and remove the medium by vacuum.
Q
We are developing a drug release method that uses
USP Apparatus 6 (cylinder), and we would like to know
the requirements to control the speed of the cylinder.
A
The rotation speed of the USP Apparatus 6 (cylinder)
should be controlled using the same range as for USP
Apparatus 1 (basket)—within ±4% of the rate stated in the
monograph or method.