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
I would like to know more about the dissolution
of orally disintegrating tablets. Can two orally
disintegrating tablets of the same drug in the same
concentration but from two different manufacturers
have different dissolution profiles in the
same medium?
The development of dissolution procedures for orally
disintegrating tablets is very similar to that for conventional
tablets, and is practically identical when the orally
disintegrating tablet does not use a taste-masking
approach. For most cases,USP apparatus 2 (paddle) is
appropriate with a paddle speed of 50 rpm,but slower
speeds may be used. The paper Dissolution Testing of Orally
Disintegrating Tablets by James Klancke, published in Dissolution
Technologies 10(2), pages 6�8, contains additional
information on this topic.
A
Two orally disintegrating tablets containing the same
drug substance in the same concentration but from two
different manufacturers can in fact have different dissolution
profiles in the same medium,mainly because of the
taste-masking procedure used to formulate each product.
Most of the drugs used in orally disintegrating tablets do
not have a pleasant taste. To overcome this problem,the
drug particles or drug-excipient granules may be coated.
This taste-masking procedure will influence the dissolution
of the dosage form. Different coating compositions,
different coating procedures,or different granulation
methods may influence the dissolution profile of orally
disintegrating tablets.
Q
Do I need to use only volumetrically calibrated
vessels in my dissolution apparatus?
A
Provided that they are not used to measure the volume
of dissolution medium, the vessels used in the dissolution
apparatus do not need to be volumetrically calibrated. The
dissolution medium should be transferred to the vessel
using a volumetric flask, a volumetric cylinder,or any other
appropriate measuring device. Alternatively, the volume
may be determined by weight in the vessel.When using
glass dissolution vessels,you need to check the smoothness
of the internal surface. Glass dissolution vessels are
manufactured in two parts, a cylinder and a round bottom,
that are fused together manually. If this procedure is not
performed properly, the connection point can be felt. The
vessels should be inspected visually and manually for
roundness and smoothness.
Q
Can I introduce more than one dosage unit into
each dissolution vessel?
A
Introducing more than one dosage unit into the dissolution
vessel is not recommended. Having more than one
dosage unit in the vessel will affect the surface
contact/interaction between dosage unit and dissolution
medium,as well as the hydrodynamics of the medium in
the vessel. To avoid placing more than one dosage unit in
each vessel,you can use 200-mL vessels with mini paddles.
However,keep in mind that this equipment is not official.
Alternatively,you can use a more sensitive analytical
procedure to quantify the drug released.
Q
How can I check for carryover in my automatic
sampler?
A
One simple way to check carryover in your automatic
sampler is to run a blank through your sampler; in most
cases the dissolution medium will serve as an appropriate
blank.You should then check that blank for the presence
of any unexpected compounds using a suitable chromatographic
or spectrophotometric procedure.
Q
How can I calibrate 2-L vessels?
A
You can use the Apparatus Suitability Test described in the
USP General Chapter <711> Dissolution,testing with the USP
Dissolution Calibrator,Disintegrating Type,and the USP
Dissolution Calibrator,Non-disintegrating Type.You can find
the acceptance criteria and procedures for both calibrator
tablets at www.usp.org/standards/calibrators.html
Q
How can I validate a dissolution method?
A
USP is developing a new general chapter,<1092> The
Dissolution Procedure:Development and Validation, that will
cover the steps involved in the development and validation
of dissolution tests. This new general chapter is
published in Pharmacopeial Forum 30(1) [Jan. � Feb. 2004]
and is now available for public comment. After reviewing
the proposed chapter,you are encouraged to make
comments and suggestions to Will Brown at web@usp.org.
Q
How can I minimize or prevent the evaporation
of dissolution medium from the vessel during very
long dissolution tests?
A
You can use the plastic cover that comes with most
dissolution equipment, or you can cover the dissolution
vessels with some material like Parafilm™. Another approach is to transfer the dissolution medium to the vessel by weight,making a mark on the outside of the
vessel at the liquid level,and periodically adding dissolution
medium to the mark.When using this technique you
need to be very careful to replace only the volatile component
of your medium (in most cases it will be water) so as
not to modify the concentration of salts or other components
of the medium. Also,you can contact the manufacturer
of your dissolution equipment to see if they offer
custom-made devices that can be used to close the vessels
more tightly.
Q
I would like some information on the effect of
the compression force on the intrinsic dissolution of
an active pharmaceutical ingredient.
A
The intrinsic dissolution rate is generally defined as the
dissolution rate of a pure drug substance under the condition
of constant surface area. The true intrinsic dissolution
rate may be better described as the rate of mass transfer
from the solid surface to the liquid phase. Intrinsic dissolution
is generally determined by measuring the dissolution
of a non-disintegrating disk made by compressing pure
powdered drug substance under high pressure using a specially constructed punch and die system. (See USP
General Chapter <1087> Intrinsic Dissolution). The test
material is compressed with a bench-top tablet press for 1
minute at the minimum compression pressure necessary
to form a non-disintegrating compacted tablet. Compression
for 1 minute at 250 MPa (~36000 pounds/in2) is sufficient
for many organic crystalline compounds but
alternative compression conditions that achieve the
desired degree of compaction may be required. Because
changes in the crystal form may occur during compression,
confirmation of the solid form should be verified by
powder X-ray diffraction or another similar technique. The
compression pressure plays an important role in the test. If
it is too low, a non-disintegrating tablet may not be
obtained, and if it is too high, it may change the crystal
form. The compression pressure should be high enough to
produce a translucent pellet with no powder or flakes on
the surface. It is important to study the effect of the
compression pressure on intrinsic dissolution rates as it
has been observed for several drug substances that the
intrinsic dissolution rate varies with changes in compression
pressure.