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
What tolerance is allowed between results
obtained with manual and automatic sampling?
A
There are no official tolerances for the variability
associated with manual and automatic sampling. This
should be evaluated on a case-by-case basis. When results
are not highly variable, one possible approach is to use
two concurrent runs with the same sampling intervals and
six units for each, using manual and automated sampling
methods. Compare the results obtained from each with
the criteria used for intermediate precision. If the results
are highly variable (i.e., the relative standard deviation
[RSD] is above 20% in the earlier time points and about
10% in the later time points), perform the comparison by
pulling the sample from the vessel simultaneously by
manual and automated procedures for each time point.
Be warned that the hydrodynamic effects of the probe will
not be obtained with simultaneous sampling. Attention
should be paid to the volume correction in the second
case. More information can be found in the paper: 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
Are there any specific requirements stating that
the dissolution test has to be done with the whole
capsule if the product is a capsule?
A
The instruction in the USP General Chapter <711>
Dissolution, page 272, of USP 31 under Procedure,
Apparatus 1 and Apparatus 2, Immediate-Release Dosage
Forms is to place one dosage unit in the apparatus. If the
product is intended to be taken by the patient as a whole
capsule, the dissolution test should be performed with the
introduction of the whole capsule into the apparatus. If
the product labeling instructions recommend that the
patient open the capsule and disperse its contents in an
appropriate liquid or sprinkle it on some type of food, the
dissolution test should be performed in a way that is as
close as possible to what the patient is going to do with
the product.
Q
We are developing 200-mg mebendazole tablets
that are going to be marketed outside the United
States. We used the dissolution test described in the
USP monograph for this product, and we are
getting about 50% of the tablet label claim
released. Do you have any suggestions for what
may be the problem?
A
If you are going to use a USP monograph for a product
not marketed in the United States, the first step is to search
the FDA website to see the product strengths approved for
the USA. You can do this search in the Orange Book or at
Drugs@FDA available at www.fda.gov/cder.
Doing this
search for mebendazole tablets, you will see that the
product approved by FDA is a 100-mg tablet. Therefore, the
dissolution conditions stated in the USP monograph for
Mebendazole Tablets were selected for a tablet containing
100 mg of the drug substance. The USP dissolution test for
this product uses 900 mL of medium. If you are getting
about 50% of the tablet label claim dissolved with this
volume, there is a good chance that if you use a larger
volume, such as 1500 mL, 1800 mL, or even 2000 mL, the
amount of drug dissolved is going to be higher.
Q
What is the maximum upper limit for the amount
of drug dissolved in dissolution tests?
A
There are no upper limits for dissolution tests. The
highest amount of drug dissolved depends on the range
of uniformity of dose for each batch of product. In the
dissolution test, one dosage unit is introduced in each
vessel; it is not a composite sample as used in the assay
test. Content uniformity is going to depend on the
variability of the manufacturing process. You can have
units that are at the lowest limit, but you can have units
that are the highest limit of the uniformity of dose. Please
keep in mind that the dissolution test is not an assay for
the amount drug in the product, but a measure of the
amount of drug dissolved under controlled conditions.
Q
Q Can you suggest some references on the procedures
for setting dissolution acceptance criteria?
A
Here are some suggestions. More information can be
found in Chemical Abstracts and at
www.NCBI.NLM.NIH.GOV
(access free of charge).
Cholayudth, P. Using the Bergum method and MS Excel to determine the probability of passing the USP dissolution test. Pharm. Technol. 2006, 30 (1), 88�94.
Hofer, J. D.; Gray, V. A. Examination of selection of immediate-release dissolution acceptance criteria. Pharm. Forum 2003, 29 (1), 335�340.
Wojcik, R. C. Setting dissolution specifications. Dissolution Technol. 1997, 4 (3), 12�20.
Hokanson, G. C. Setting specifications for solid oral dosage forms: leveraging development experience. Am. Pharm. Rev. 2001, 4 (2).
Hauck, W. W.; Foster, T.; Sheinin, E.; Cecil, T.; Brown, W.; Marques, M.; Williams, R. L. Oral dosage form performance tests: new dissolution approaches. Pharm. Res. 2005, 22 (2), 182�187.
Dumont, M. L.; Berry, M. R.; Nickerson, B. Probability of passing dissolution acceptance criteria for an immediate release tablet. J. Pharm. Biomed. Anal. 2007, 44, 79�84.