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
In the Dissolution test in the USP monograph
for Divalproex Sodium Extended-Release Tablets,
it says to filter the sample solution through a
20-µm filter. Why is this filter used if the sample
for HPLC analysis needs to be filtered through a
0.45-µm filter?
A
Filtration is one of the most important steps in a dissolution test. It stops
the dissolution process by removing all
particulates in suspension, including undissolved particles
of drug substance. The filter used in dissolution is selected
in a case-by-case approach. The selection of the filter
pore size and filter material will depend on the formulation composition.
The filter must be evaluated for possible adsorption of the active ingredient
and for possible
interference of leachables, extractables, or both in the
quantitative procedure. The verification of the filter used
will demonstrate that it is adequate to produce a filtrate
that can be used in the HPLC analysis. See more information in the USPGeneral
Chapter <1092> The Dissolution
Procedure: Development and Validation.
Q
Most of the dissolution tests use 900 mL of
medium. How was this volume defined? Is there
any correlation with the volume of gastric fluid in
humans?
A
The volume of dissolution medium to be used is defined considering "sink condition."
The solubility of the
drug substance is quantitatively determined in several dissolution media within the
physiological pH range at 37 °C.
Using this value, the volume of dissolution medium necessary to obtain a saturated
solution of the highest dose of
the product to be marketed is calculated. Sink condition is
considered as at least 3 times this volume. Some companies work with 5 times or 10
times this value. There are
some instances where the dissolution test is more discriminative if sink condition
is not followed. The volume of
dissolution medium has no relationship with the volume
of gastric fluids in humans. According to information available in the literature,
a realistic volume to simulate the
total fluid available in the stomach in the fasted state is in
the range of 250-300 mL.
Q
I have been assigned to develop a dissolution
test for an extended-release capsule product for
which I need to change the medium from acid to
buffer after 4 h. My product contains granules
with different particle sizes, from about 150 to
500 µm. With the paddle apparatus after 4 h in
acid, all these granules are floating in the medium. How can I make the change
to the other
medium without losing granules?
A
USP Apparatus 3 and 4 may be good options in a case
such as this one. The appropriate screen mesh can be
used in the bottom and top of the reciprocating cylinder
in Apparatus 3, and it will retain the granules inside the
cylinder when the rack is moved from the acid medium
row to the next row of tubes containing the buffer
medium. Apparatus 4 will contain the granules inside
the cell. When the dissolution medium leaves the cell, it
passes through a filter retaining all the granules inside
the cell. If you are using USP Apparatus 2, the option is to
put a filter or mesh screen at the tip of the cannula used
to remove the medium by vacuum. After the removal
of the acid medium, the buffer medium can be added
through the same cannula washing all the granules back
to the vessel.
Q
I am working with a gastroretentive drug delivery system for a fixed combination
product. Drug
A has absorbance in 0.1 N HCl while drug B does
not. Can I use two separate media for the fixed
combination product, 0.1 N HCl for drug A and
water for drug B?
A
The selection of the dissolution medium is based on
the solubility of the drug substance and on the release
mechanism of the dosage form. The dissolution medium
should be biorelevant, which means that it should have
a composition or pH similar to the in vivo region that the
dosage form will encounter during in vivo dissolution and
that absorption of the drug substance will occur. Gastroretentive dosage
forms have longer gastric residence
times than other solid oral dosage forms. This approach is
used to increase the time for dissolution of the drug in the
stomach. Therefore, the composition of the medium for
this type of dosage form should have a pH close to the pH
of the stomach, and this is not the case with water. Water
would only be used if it is a more discriminative medium.
There is no standard procedure for dissolution tests for combination products. The same conditions can be applied to all drug substances present in the dosage form, some of the conditions can be different, or only the acceptance criterion is different. At the extreme, you can have completely different dissolution tests for each drug substance in the fixed combination product. The selection of the conditions is done in a case-by-case approach.
Q
We are developing a gastroretentive dosage
form for a combination of antidiabetic drugs containing metformin. It is reported
that metformin
has absorbance in 0.1 N HCl, but we do not see
any peaks in the absorbance spectrum. Can we
consider phosphate buffer as dissolution medium
for both drug substances? Should we use different dissolution media for both drugs?
A
See previous question.
Q
We are developing a floating tablet, and it
remains floating in the dissolution vessel during
the entire test. Is it mandatory that the tablet
should remain on the bottom of the dissolution
vessel?
A
Your tablet needs to have good contact with the dissolution medium. You can use
USP Apparatus 1 (basket),
USP Apparatus 2 (paddle) with sinkers, USP Apparatus
3 (reciprocating cylinder), or USP Apparatus 4 (flow-through cell). Apparatus 3
may be a good option in this
case because of its higher turbulence when compared
with Apparatus 1 and 2. The selection should be done in
a case-by-case approach. You need to select the dissolution conditions that are
the most discriminating for each
product.
Q
I am preparing a dissolution medium, and
when I mix the buffer with a 2% sodium lauryl
sulfate solution, I get a cloudy solution. Is this
because of temperature? What could be done?
A
The phenomenon you are facing has nothing to do
with temperature. Probably you are using the potassium
salt of the reagent in the preparation of the buffer. Sodium lauryl sulfate is
not compatible with potassium salts.
Try using the sodium salt of the reagent.
Q
We are developing a 200-mg tablet containing
cefpodoxime. Our product is bioequivalent to the
reference product, but it fails the dissolution test
in three media (pH 1.2, pH 4.6, and pH 6.8), and
the results for f2dissolution profile comparison
are less than 50. What can we do for the biowaiver request for cefpodoxime
100-mg tablet?
A
Before you start developing a dissolution test, you need
two very important pieces of information:
(1) Solubility of the drug substance at 37 °C in various dissolution media within the physiological pH range. The solubility needs to be determined with the actual drug substance that will be used in manufacturing the dosage form. This information will help in selecting the dissolution medium and defining the biopharmaceutics classification (BCS) of the drug substance. Also, it is important to verify any information available in the literature about a possible BCS classification for the drug. According to some papers, cefpodoxime proxetil is a BCS Class 4, which means low solubility and low permeability.
(2) Composition and release mechanism of the dosage form. This information will also help in defining the dissolution conditions. Cefpodoxime has very low solubility in aqueous media. Each company may formulate the product in a different way to overcome or minimize this problem. Consequently, the in vitro performance will be formulation dependent. The objective is a dissolution test that is discriminative for the formulation. In the case of a low solubility drug substance, the pH range for the various dissolution profiles will be defined around the pKaor pKb of the drug substance. A dissolution medium with a pH value outside of the physiological range requires proper justification.
Biowaivers for lower doses of a product that contains a low solubility drug substance may be possible only if the formulation is proportional to the higher doses and the release mechanism and manufacturing processes are the same.
Q
I am working on a project to enhance the
solubility of a drug that is insoluble in water. I am
uncertain on how to develop the dissolution test;
I would like to use phosphate buffer as dissolution medium, but the drug is not
soluble in this
buffer.
A
For the drug to be absorbed, it must be in solution.
If the drug is insoluble in water, some formulation
strategies should be used to increase its solubility in
aqueous solvents. Some of these strategies exploit
amorphous solid dispersions, micronize the drug, use
surfactants or buffering agents in the formulation, use
excipients such as cyclodextrins that create a micro-environment where the drug has
higher solubility, use
selfemulsifying systems, and so forth. Each formulation will require a different
dissolution test depending on the strategy used. If the formulation contains
surfactants, the dissolution test will probably be performed using simple buffers
or acid solutions. Whatever dissolution conditions are chosen, they should be
discriminative for the critical quality attributes such as
particle size of the drug substance.
Q
Is a dissolution test needed for the active substance as a single component in a
capsule dosage
form, or would a disintegration test be adequate?
A
If the drug substance is a solid, it will still need to dissolve once the capsule
shell opens. Disintegration will
show that the capsule shell has disintegrated but not that
the drug substance has gone into solution. You will first
need to develop a suitable dissolution test. Then, depending on the characteristics
of your product (if it is BCS Class
1 or 3) and if it can be shown that disintegration correlates
with dissolution, you can replace the dissolution test with
a discriminative disintegration test. Keep in mind that all
the decisions in dissolution/disintegration method development should be justified
with data.
Q
When transferring a dissolution method to another lab, should we run the
dissolution test with
6 or 12 units? Can we use f2as the acceptance
criterion for this method transfer?
A
There are no official rules for the number of units to
be used in dissolution method transfer. It is up to the lab
to select the appropriate number of units in each case.
There are several approaches that can be used in analytical method transfer
(see USPGeneral Chapters <1092>
The Dissolution Procedure: Development and Validationand
<1224> Transfer of Analytical Procedures). For the transfer of dissolution
methods, the recommendation is that
each lab should perform a dissolution profile at least in
duplicate and evaluate the individual values, mean, and
standard deviation at each time point in each dissolution
profile. All labs should use the same batch of product. It
is up to the labs to define the acceptance criteria for the
method transfer, and it may be product dependent.
Q
How can I define the time for the dissolution
test for ibandronate sodium tablets? Considering
the characteristics of this drug substance, is 30
min appropriate? Similar molecules such as alendronate sodium and risedronate
sodium have
times of 15 and 30 min, respectively.
A
The time is selected from the dissolution profiles obtained with all batches
tested (pilot batches, manufacturing batches, bio batch, pilot batches with
deviations in the
critical attributes, and the batches under stability studies).
You are going to select the time and tolerance (amount dissolved) so that the
dissolution method is the most discriminative for the critical attributes of a
particular product.
Q
The certificate for a particular lot of USP
Prednisone Tablets RS used in the performance
verification of dissolution apparatus stated,
"measure the absorbance at 242 nm (the approximate wavelength of maximum absorbance)."
However, I found that the maximum absorbance
in my equipment was 244 nm. The certificate for a
different lot of USP Prednisone Tablets RS stated
only, "measure the absorbance at 242 nm." What
is the appropriate procedure? Should I use the
wavelength of maximum absorbance?
A
The wavelength accuracy of spectrophotometers
depends on the conditions of each individual instrument.
That is why the wavelength of maximum absorbance for
a particular solution may differ among equipment. The
best practice is to use the absorbance maximum obtained
with the instrument that is going to be used to perform
the analysis. USP has found that for prednisone solutions
in water, the maximum will be at about 242 nm. Your
observed maximum confirms these statements. Typically,
if the observed wavelength is more than 1 nm from a standard value, the
wavelength accuracy of the instrument
should be checked. A number of standard approaches
for this evaluation are given in the USPGeneral Chapter
<851> Spectrophotometry and Light Scattering.
Q
The USP monograph for Orlistat Capsules calls
for the use of a wire coil sinker. We were not able
to find a vendor for this type of sinker. Could you
please give the specification for this sinker or
suggest a possible supplier?
A
The instructions on how to prepare this type of sinker
are given in the USPGeneral Chapter <1092> The Dissolution Procedure:
Development and Validation, under Sinkers. Additional information on the
selection of sinkers for
capsules can be found in the USPGeneral Chapter <1094>
Capsules—Dissolution Testing and Related Quality Attributes
(published in Pharmacopeial Forum39(3), available free of
charge at www.usppf.com). Sinkers play a
very important
role in dissolution, and the design and size used should be
selected in a case-by-case approach.
Q
If a USP monograph has multiple dissolution
tests, should we perform all of them on our product or can we choose one of them?
A
The dissolution tests in any USP monograph are the
tests approved by FDA for the products to be marketed
in the U.S., and they may not be appropriate for products
available in other regions. For products approved for the
U.S. market, the appropriate dissolution test should be
part of the labeling. Products approved by the FDA are
listed in the Orange Book. The Orange Book is available
free of charge at
http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm.
For products that have not been approved by the FDA, the first step in evaluating the suitability of any of the dissolution tests in USP monographs is to run a dissolution profile with the conditions stated in the monograph. A test procedure may be suitable for your formulation if it gives results that are similar to the times and tolerances stated. It is important to remember that a suitable dissolution test will have sensitivity to changes in manufacture and on stability. Once a promising procedure is identified, you need to do a complete validation, including validating the filter and deaeration procedure (see USPGeneral Chapter <1092> The Dissolution Procedure: Development and Validation). If none of the tests is suitable for your product, you need to develop a new test discriminative for your formulation.
Q
In the dissolution test of a particular USP
monograph, the standard solution is prepared at
a specific concentration in dissolution medium.
The drug substance has very low solubility in medium. How can we prepare this solution?
A
The USPGeneral Chapter <1092> The Dissolution Procedure: Development and
Validationrecommends that when
the compound has low solubility in dissolution medium, a
small amount of organic solvent, in most cases not more
than 5% of the final volume of the first dilution, may be
used to help dissolving the compound. Typically, solutions
within that concentration limit do not pose an interference to the analysis.
Interference to the analysis should be
evaluated, especially if a higher amount of organic solvent
is needed.
Q
Is it advisable to dilute the aliquot of a dissolution sample or is it better
to inject the aliquot
withdrawn directly into the instrument?
A
It depends on the linearity of the quantitative method
that is used to determine the amount of drug released.
The final concentration of the sample solution should be
within the linear range of the quantitative method. Once
the sample solution is filtered, provided the filtration step
was properly validated, it can be treated in any suitable
way to give reproducible results.
Q
Why does the USP monograph for Glimepiride Tablets have three different dissolutions
tests?
A
Glimepiride is practically insoluble in aqueous solvents.
Because the drug needs to be in solution to be absorbed,
each company is going to use a different formulation-
manufacturing process strategy to increase the solubility
of the drug substance. Therefore, the dissolution test will
be formulation dependent. Each one of the three tests is
specific for a particular product approved by FDA for the
U.S. market, and they may not be appropriate for other
formulations.
Q
I would like to know if there are any USP monographs or FDA approved products that use USP
Apparatus 4.
A
The only USP monograph that calls for the use of USP
Apparatus 4 is Rufinamide Tablets. You can find the dissolution conditions
recommended by the FDA Office of
Generic Drugs at the web site
http://www.accessdata.fda.gov/scripts/cder/dissolution/index.cfm
There you can
find the following products approved with a dissolution/
drug release test using USP Apparatus 4: betamethasone
acetate and betamethasone sodium phosphate injectable suspension, methylprednisolone acetate injectable
suspension, and rufinamide tablets.