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
Could you provide some guidelines on how to do
validation of dissolution methods?
A
The ICH guidance Q2(R1), Validation of Analytical
Procedures: Text and Methodology (available at
www.ich.org),
does not give details on how to validate
dissolution tests. The U.S. Pharmacopeia developed a new
general chapter, <1092> The Dissolution Procedure:
Development and Validation, where more details on what
parameters should be validated and how to do this
validation are provided. The new general chapter was
preceded by a paper that contains suggestions on
acceptance criteria for the validation parameters (see 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
Can the linearity in the validation of dissolution
methods be done using volumetric glassware
instead of dissolution vessels?
A
Yes. You are going to prepare at least five standard
solutions of the drug substance, ranging in concentration
from approximately ±20% of the lowest to ±20% of the
highest concentration expected to be released in the
dissolution profile. If the solubility of the drug substance in
the dissolution medium is not complete, organic solvents
at no more than 5% (v/v) of the final volume of the first
dilution can be used to enhance the solubility of the
compound.
Q
How is the accuracy of a dissolution method
evaluated?
A
To evaluate the accuracy of dissolution procedures, it is
recommended that all the components of the formulation,
in the same proportion as found in the dosage form, are
transferred to the dissolution vessel. This step can be
done by weighing each component of the formulation
separately or by using a placebo blend. A minimum of
three concentration levels of the drug, ranging from
approximately ±20% of the lowest to ±20% of the highest
concentration expected to be released in the dissolution
profile, should be evaluated. In the case of low solubility of
the drug substance in the dissolution medium, an organic
solvent not exceeding 5% (v/v) of the first dilution can be
used. An aliquot of a stock solution of the drug substance
in organic solvent can be transferred to the vessel, or the
drug substance can be transferred to the vessel and
dissolved with organic solvent, then all the other
components of the formulation are added. In any case, the
amount of organic solvent used should not exceed 5% of
the volume in the vessel.
Q
When the USP deaeration procedure is used, the
medium ends up at 41 °C. How can the volume
specified for the test be measured for transfer to
the dissolution vessel?
A
Considering the difference in density of the medium at
41 °C from that at 25 °C, a larger volume of the heated,
deaerated medium needs to be transferred than is
specified for the test. To compensate for this difference,
the USP laboratory determines the density at 25 °C, and
then by calculating the mass equivalent to the specified
volume, the appropriate weight can be measured out into
each vessel. Please note that the USP General Chapter
states that the volume given in the test procedure refers
to measurements made between 20 and 25 °C.
Q
Can the replacement of the medium in the
dissolution vessel create turbulence?
A
Yes, when replacing the medium withdrawn during a
dissolution profile or dissolution test for delayed- or
extended-release dosages, turbulence is going to be an
issue. Therefore, this procedure needs to be carried out as
gently as possible. One possible way is to slowly deliver
the volume of medium onto the wall of the vessel using a
pipet or a syringe.
Q
Does the use of a hollow shaft for the sampling
meet the USP sampling criteria?
A
Every time a sampling procedure that deviates from
the procedure described in the USP General Chapter
<711> Dissolution is going to be used, it is necessary to
demonstrate that the alternative procedure is equivalent
to the USP procedure, and it must be validated.
Q
Can baskets with other mesh measurements be
used in dissolution testing?
A
The most used basket is 40-mesh, but baskets with
other mesh sizes can be used if properly justified. The
alternative mesh should be properly characterized in the
documentation for the procedure.
Q
What should be the specific distance between
two dissolution apparatus on the same bench?
A
A measurement of the vibration at the dissolution
equipment should be made with all the equipment on the
same bench running. Then, the positioning of the
equipments on the bench can be modified until the
lowest vibration level is found. The whole lab environment
needs to be taken into account because vibration can
come from other areas close to the lab through the floor
or walls. The vibration should be measured in several
conditions, and an attempt to minimize it should be
made. A discussion of the possible acceptable levels
of vibration at the dissolution test assembly can be
found in the Dissolution Toolkit available at the USP
website,
http://www.usp.org/USPNF/compendialTools.html
Q
Should the pH of the dissolution medium be
adjusted before heating or after heating?
A
The pH of the dissolution medium should be adjusted
at room temperature, before heating it in the dissolution
bath.
Q
Most of the dissolution methods employ
500�900 mL of dissolution medium, but the patient
usually takes a tablet or a capsule with about
250 mL of water or juice. How can these differences
be justified?
A
The volume of medium used in the dissolution test is
defined by taking into account the sink conditions of the
drug substance being analyzed. The solubility of the drug
substance in various media is determined, the saturation
concentration is calculated considering the highest dose
of the product, and the volume of medium is defined by at
least three times the volume of a saturated solution. The
dissolution test is not necessarily limited to in vivo
conditions. The volume of 250 mL of medium is considered
when classifying the solubility of drug substances
according to the Biopharmaceutics Classification System
(see FDA Guidance for Industry�Waiver of In Vivo
Bioavailability and Bioequivalence Studies for Immediate-
Release Solid Oral Dosage Forms Based on a
Biopharmaceutics Classification System, available at
www.fda.gov/cder/guidance/3618fnl.htm). According to
this guidance, a drug substance is considered highly
soluble when the highest dose strength is soluble in
250 mL or less of aqueous media over the pH range of
1.7.5. This volume of 250 mL is derived from typical
bioequivalence studies that prescribe administration of a
drug product to fasting human volunteers with a glass of
water.
Q
This is a question regarding the interpretation of
the Acceptance Table 2 for extended-release
products. If the specification is 15�25% for one of
the time points, and the table says that �none is
more than 10% of labeled content,� how do we
calculate the wider range allowed?
A
The USP General Chapter <711> Dissolution gives
acceptance criteria that may be applied where the
monograph does not have a more specific acceptance
table. At the L2 level of the test (12 units tested), the
criteria refer to the number of results that may fall outside
of limits defined by 10% of labeled content. The text
explaining the table states that those limits �are expressed
in terms of the percentage of labeled amount.� This means
that for a monograph specification of 15�25% at a
sampling time, the expanded range would be 5�35% (i.e.,
[15 � 10]% to [25 + 10]%) for samples taken at that time.