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
There are several types of sinkers available on the
market. How can one decide which sinker design is
the best one?
A
The type of sinker used should be carefully evaluated
because it can have a big impact on the release of the drug
from a dosage form. (See Soltero et al.,J.Pharm.Sci. 1989, 78
(1),35�39.) The sinker can affect the dissolution rate by
either restricting the dissolution by forming a barrier or by
providing additional agitation in the environment of the
dosage form.The sinker can cover the capsule shell,
retarding its dissolution. This can also be the case with the
dissolution of the capsule contents,where the sinker does
not allow proper contact between the dosage form and the
medium.When comparing the dissolution rates obtained
with different sinkers, the variability of the results should be
evaluated;the lower the variability,the better,provided the
low variability is not caused by very slow and thwarted
dissolution. Another item to be evaluated is which design
gives more uniform liquid flow and better mixing. Observations
of the behavior of the system during the test will be of
use when a sinker is evaluated. If one sinker gives faster
dissolution than another,you will have to determine which
one is acceptable. Faster dissolution may be a result of
sinker interference with the hydrodynamics. Slower dissolution
may result from an inhibiting effect of the sinker. As the
goal of the dissolution test is control of the performance of
the dosage form,the ideal sinker should not interfere. Once
a sinker design is selected for a particular application,the
dimensions and drawings should be recorded to ensure
uniformity in the procedure.
Q
Is a dissolution test necessary for fixed combination
products? If so,how is such a test developed?
A
Yes,the dissolution test is necessary for fixed combination
products,and it is developed in the same way as for products
containing only one active pharmaceutical ingredient. See
the USP General Chapter <1092> The Dissolution Procedure:
Development and Validation. Sometimes the same dissolution
conditions (medium,apparatus,rotation,etc.) and tolerances
are suitable for all the drugs in the formulation.There
are some cases where,depending on the physical-chemical
characteristics of the drugs,different dissolution conditions or
tolerances will be necessary. In some regions,if provided with
adequate justification,the regulatory agencies may accept a
dissolution test developed only for the drug with the lowest
solubility in the formulation.This should be confirmed with
the appropriate regulatory agency. For multivitamin products
with or without minerals,see the USP General Chapter
<2040> Disintegration and Dissolution of Dietary Supplements.
Q
What is the difference between releasing media
and discriminating media?
A
A releasing medium is the one that promotes solubilization
of the drug substance from a pharmaceutical dosage
form without further qualification. A discriminating medium
is the one where the more subtle aspects of the pharmaceutical
dosage form can be differentiated by observing their
individual rates of dissolution. Particle size,crystal form,salt
form,presence of water of hydration,differences in the manufacturing
processes,and so forth,may all affect the dissolution
performance.The dissolution test should be sensitive to any
attribute that may affect the in vivo performance of the
product.
Q
What is the right procedure to use pepsin in dissolution
testing of gelatin-containing formulations?
A
Gelatin can develop cross-linking in the presence of
certain compounds or due to environmental conditions and
with aging becoming relatively insoluble in aqueous solvents,
which slows down the in vitro release rate. (A good review of
this issue is Singh,S.,Rao,K.V. R.,Venugopal,K.,Manikandan,R.
Alteration in dissolution characteristics of gelatin-containing
formulations.A review of the problem,test methods,and
solutions. Pharm.Technol.,April 2002,36�58.) To overcome
this problem,enzymes can be added to the dissolution
medium. Details on the types and amounts of enzymes to be
used can be found in the USP General Chapter <711> Dissolution.
Where water or a medium with a pH of less than 6.8 is
used,purified pepsin can be added to the medium in an
amount that results in an activity of 750,000 Units or less per
1000 mL. Keep in mind that purified pepsin,with high activity
per mg,should be used.The specifications for this purified
pepsin can be found in the section of USP Reagents,Indicators,
and Solutions,under Reagent Specifications.The activity
of the enzyme should be determined just before use. For
media with a pH of 6.8 or greater,pancreatin can be added to
produce not more than 1750 USP Units of protease activity
per 1000 mL.The pancreatin to be used should meet the
requirements in the USP monograph for Pancreatin.
Q
Regarding the use of pooled sampling, is the
procedure of pooled sampling applicable for
releasing the drug product? Is this procedure applicable
during the stability study? How can one decide
when pooled sampling could be used?
A
The concept of pooled sampling in dissolution was developed
several years ago to reduce the number of quantitative
analyses performed during dissolution testing.To select the
product for which this concept could be used,some requirements
were established:it must be an immediate-release
dosage form;the active ingredient should not have bioavailability
problems;the drug should not have a narrow therapeutic
index;and it should have a long history of dissolution
results. Based on these requirements,there are only 79 USP
monographs where the use of pooled sampling is allowed.
Pooled sampling cannot be used unless the USP monograph
calls for it. A few years ago,USP received several comments
regarding the applicability of pooled sampling. Several
companies commented that with the use of pooled sampling,
information regarding the variability of the product is lost,
and this information is very important to monitor the performance
of the product.These companies proposed not to
expand the pooled sampling approach to other products.The
USP Biopharmaceutical Expert Committee,responsible for
the general chapters <701> Disintegration, <711> Dissolution,
and <724> Drug Release,among others,agreed with this
proposal.At this time,pooled sampling is limited to the 79
products already in USP.
Please note that USP General Notices distinguish between compendial standards and release tests in that compendial standards define what is an acceptable article at any time from production to consumption and provide test procedures to demonstrate compliance.
Variability in dissolution performance is expected as a product ages. Pooled sampling tends to mask some of that variability.
Q
What might cause floating tablets during the
dissolution test using baskets?
A
One possible cause is the presence of an air bubble being
trapped in the center of the disk.The vent hole in the disk of
the rotating basket apparatus is located on only one side,and
trapped air does not readily escape.Another cause is the
surface interaction at the flat surface of the tablet.Occasionally,
the tablet will ride up to the top of the basket when the
apparatus is lowered and remain there for several minutes
before the tablet top surface becomes wetted,allowing it to
fall to the bottom of the basket. Floating tablets are often
associated with anomalous dissolution results.The value of
recording observations of the behavior of samples during the
test can not be stressed enough.
Q
What apparatus is used to evaluate drug release
from ointments?
A
There are several apparatus suitable for the evaluation of
drug release from topical preparations;among them are (1)
USP Apparatus 4,flow-through cell with a special cell developed
specially for this type of dosage form;(2) vertical diffusion
cell,also known as Franz cell;and (3) modified semisolid
holding cell systems (e.g.,�enhancer�cell). See Ueda,C. et al.
Performance test for topical and transdermal dosage forms.
Pharm.Forum 2006,32 (5),1586�1589.More papers on this
subject can be found at www.NCBI.NLM.NIH.GOV (access free
of charge).
Q
What can cause dissolution results to be higher
than the assay results for the same batch of a particular
product?
A
Considering that the appropriate filter was selected and
validated and that the interference from any excipients was
evaluated and discarded,dissolution results higher than the
assay results can be found because of the variability associated
with the uniformity of dose. In general,the acceptance
criterion for uniformity of dose is 85�115% of the label claim.
This means that a small percentage of dosage form units with
content higher than 100% can be found if the manufacturing
process is under control giving higher results than those
obtained in the assay test.The assay test is performed on a
composite sample,usually of 20 units,to minimize the variability
due to the uniformity of dose.Thus,an acceptable
sample might have a lower assay value but also some higher
dissolution values. If dissolution values are consistently higher
than the assay,it may be an indication of problems with
elements of the dissolution method validation.