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
Why can differences be observed between
dissolution profiles obtained with water and pH 6.8
phosphate buffer if the pH of both media is almost
the same?
A
It is advisable to measure the pH of the water
immediately before using it. Do not assume that the pH is
always going to be around 6.8. The pH of water can vary
according to the purification process, when it was
obtained, if it was degassed or not, the length of time it
was stored, and so forth. Also keep in mind that water has
negligible buffering capacity. During the dissolution
process, depending on the characteristics of the drug
substance and the formulation, the pH of the medium can
reach a value where the drug substance is poorly soluble,
and this is going to decrease the release rate or even stop
it. Water is not generally considered a biorelevant medium.
For the reasons stated, the use of water as a dissolution
medium is discouraged.
Q
It was observed during a development project
that the dissolution profile was dependent on the
ionic strength of the medium. Is there any preferred
ionic strength enforced by regulatory agencies such
as FDA or EMEA?
A
No, you are going to use the dissolution medium with
the ionic strength that is the most discriminative for
your formulation and that does not interfere with the
release mechanism or with the quantitative step of the
dissolution test. It is advisable to work with ionic strengths
as close as to the biological ones as possible to have more
biorelevant media.
Q
Is there any suitable sinker to use when doing
disintegration testing of hard gelatin capsules to
avoid the flotation of these dosage forms?
A
Please refer to the USP General Chapter <701>
Disintegration, under Procedure, Hard Gelatin Capsules.
In this situation, a removable wire cloth that has a plain
square weave with 1.8- to 2.2-mm mesh apertures and
with a wire diameter of 0.60�0.655 mm can be attached to
the surface of the upper plate of the basket-rack assembly.
The wire mesh will prevent the capsule from floating out
of its tube. Furthermore, the General Chapter has been
revised to state that at no time should the top of the
basket rack assembly become submerged thus preventing
escape of capsules during testing. Although their use is
not favored, disks can be used to limit the tendency of a
capsule to float.
Q
For the preparation of simulated gastric
fluid according to the USP, can one rely on the
information stated on the label of the pepsin to
be used?
A
The description of Simulated Gastric Fluid TS in the
Reagents section of USP says to use 3.2 g of purified
pepsin that has specific qualities. Those qualities are that it
is derived from porcine stomach mucosa and that it has an
activity of 800�2500 units per mg as determined by the
test in the Food Chemical Codex (FCC). The FCC test uses
the reduction in volume of egg albumin with time and
compares the sample with the USP Reference Standard.
Enzymatic activity depends on several conditions such as
pH, temperature, substrate, and so forth. Therefore,
enzymatic activity determined using differing substrates
and conditions cannot be easily compared. The activity of
the pepsin should be determined according to the USP
requirements to demonstrate its acceptability for use in
preparing the Test solution. The claim on the label of the
reagent may not reflect this. The enzymatic activity of
pepsin should be determined just before use. Any
degradation it may have undergone should also be
considered.
Q
When the quantitative step of the dissolution
test is by UV absorption, should the use of pepsin in
the preparation of simulated gastric fluid be
avoided because pepsin might introduce a high UV
background? Can this problem be avoided by using
HPLC with a UV detector?
A
Pepsin contains aromatic amino acid residues that
contribute to the background absorbance of dissolution
samples. While this will tend to decrease the absorbance
range available, the absorbance due to the enzyme in the
sample and in the blank will be equal, allowing the
absorbance of the analyte to be measured. Therefore, the
UV analysis may still be practicable. It is not clear that this
type of sample would be better analyzed using HPLC with
UV detection, but because of the separation mechanism
involved, the possible interference due to the enzyme
could be reduced or eliminated.
Q
Can the f1 and f2 equations employed to
compare dissolution profiles be used to compare
intrinsic dissolution rates?
A
Typically, an intrinsic dissolution measurement is made
on a pure drug substance. The usual methods involve
evaluating the dissolution rate from a sample provided
that a constant surface area is maintained. For those
methods, the intrinsic dissolution rate is calculated from
the slope of the curve concentration versus time, but only
while this relationship is linear. The comparison between
two such curves can be as simple as the ratio of the slopes
of their linear portions. More information on the use of
intrinsic dissolution to classify drugs can be obtained in
the paper: Yu, L. X.; Carlin, A. S.; Amidon, G. L.; Hussain, A. S.
Feasibility studies of utilizing disk intrinsic dissolution rate
to classify drugs. Int. J. Pharm. 2004, 270 (1�2), 221�227.
Q
When using dissolution medium containing
large amounts of surfactant, how can foaming be
avoided?
A
To reduce or avoid the foaming, an antifoaming agent
could be used. Its concentration should be as low as
possible, and any interference in the quantitative step of
the dissolution should be investigated. An example of a
possible antifoaming agent is one or two drops of
n-octanol in 10 L of dissolution medium. Any added
component in the dissolution medium should be
recorded and ultimately must be described in standard
procedures.