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
We would like to know if it is acceptable to develop
dissolution test methods for gelatin capsules that
add enzyme to the dissolution media from the beginning,
before pellicles are noted.
A
To better answer this question,we contacted the Division
of Bioequivalence/Office of Generic Drugs/FDA and
we were informed that it is not acceptable to add enzyme
to the medium as a routine first test. The firm has to go to
Tier 1 testing first and only after failing to conform,can
they go to Tier 2 (with enzyme). The Tier 2 testing is
allowed only when the product’s stability is well-known.
However, an occasional retest at Tier 1 should be made to
ensure that nothing unexpected has happened and that
the original data on the product is still valid.
Q
Can a preservative be added to the water bath of
dissolution equipment?
A
Yes,you can add any algaecide to the water bath;
however,the water should still be replaced frequently. The
bath water must be clear enough to allow you to see what
is happening (bubbles,how the granules are dispersed,
how the dosage form is disintegrating, etc) inside each
dissolution vessel.
Q
Are the Calibrator tablets tested for stability at
the USP?
A
The stability of the various reference materials used in
calibration of dissolution apparatuses is evaluated. Accelerated
stability studies using elevated humidity and
temperature are conducted on the tablets in open dish
and on the packaged tablets. This helps USP Reference
Standard scientists determine the appropriate storage and
shipping procedures. In addition,at predetermined times
samples taken from inventory are evaluated for continuing
quality.
Q
How can I obtain the history of determination of
medium and apparatus for each drug? We note that
many drug products exist that do not have a monograph
in USP.
A
Much of the information that is received by USP in
support of monograph standards is considered confidential
and cannot be released. Refer to the USP Document
Disclosure Policy (Appendix E of USP 27) where the type of
document that can be made available is defined.
Please note that the USP is working to obtain approximately 800 high-priority monographs for excipients,drug substances and drug products. It is critical that these monographs come from sources with direct knowledge of the specification used to evaluate the quality of the material. Interested parties are encouraged to visit the USP website (www.usp.org) and review the Call for High Priority Monographs for Drug Substances,Drug Products,and Excipients.
Q
Is it necessary to take the weights of the tablets or
capsules we are testing for dissolution.We understand
that it is not used in computation.Can I therefore
waive the taking of the weights of the six tablets
or capsules in order to minimize a step that is not
relevant to the dissolution test? We are considering
this change to increase productivity.
A
The weight of an individual tablet subsequently used as
a sample in dissolution testing is not necessarily a
compendial requirement. However,weighing the sample
dosage form will allow an additional piece of information
relating to product quality. Please note that uniformity of
dosage unit is the separate test that gives compendial
requirements relating to the variation in product content.
Weight uniformity is one test that is sometimes applied to
demonstrate content uniformity.
Editors Note: The following Question deals with formulations issues and dissolution.We consulted with one of our Editorial Board Members, Dr. Lew Leeson, who supplied the response. His email address is blll@optonline.net.
Q
I am working with carbamazepine immediate
release tablet.My formulation with starch paste as
binding agent,croscarmellose sodium as disintegrant,
microcrystalline cellulose as bulking agent
and magnesium stearate as lubricating agent
showed poor dissolution.
I could not figure out the reason,since the disintegration
time is about 30 seconds only.
A
The fact that you found excellent disintegration, but a
poor dissolution rate, for your tablet is not unusual,especially
for carbamazepine, as well as some other poorly
soluble APIs. In working with carbamazepine,you should
be aware that there are a number of pitfalls possible when
formulating this compound. First of all,carbamazepine,
which can exist as the anhydrous crystalline form,can
convert to a trihydrate in the presence of water. These crystals
are fairly large needles which have a poor aqueous
solubility. However, this crystalline form is readily identified
by the usual physical chemical tests, such as x-ray crystallography,
moisture content measurement,DSC,DTA,and
even by melting point or microscopy. It should not be a
problem for a reliable manufacturer to supply you with the
proper form to use in your product.
Assuming that you are utilizing carbamazepine API which is anhydrous,employing an aqueous granulating agent, such as starch paste, probably results in a conversion of the anhydrous material to the trihydrate. I would look under a microscope for the presence of needle formation. However, in order to make a better product I suggest the following as possible tablet development approaches: