Roles
of Dissolution Testing:
Regulatory, Industry and Academic Perspectives
Dissolution has been traditionally
used to assess product quality after manufacture and during shelf-life.
For these purposes it is crucial to know whether 100% of the dose
can be released from the dosage form or not, so for the most part
the compendial dissolution tests have been designed to ensure
sink conditions for the dissolution of the active ingredient.
A quarter of a century ago, it was
already recognized that particle size of the active could have
a great influence on the dissolution rate and also on the bioavailablity
of the compound. Efforts to establish in vitro/in vivo correlations
(IVIVC), for example with digoxin products containing different
particle size of the active ingredient, met with success. Subsequently,
IVIVC was tried for many other products, but good correlations
could mostly only be obtained on an a posteriori basis and dissolution
testing for IVIVC purposes became less popular.
With the advent of the Biopharmaceutics
Classification System (BCS) it became evident that IVIVC cannot
be expected for drugs with certain properties. At about the same
time,
dissolution test(er)s that attempt to more closely model the physiological
conditions were developed, for example the flow-through tester
and certain more biorelevant media. As a result, we now have the
tools necessary to determine when an IVIVC is reachable, and what
in vitro tests we need to do to achieve an IVIVC on an a priori
basis. To quote Prof. Henning Kristensen (University of Copenhagen,
1998), "Biopharmaceutics is Back!". To further improve
the predictive capability of dissolution testing, there needs
to be further refinement of the media used, use of appropriate
volumes, and hydrodynamic designs that can better model flow patterns
in the gut. These points will continue to be a focus of academic
research in the coming years, with the greatest challenges being
associated with the development of suitable tests for controlled
release products and the translation of the dissolution tests
used for IVIVC into workable tests for quality control purposes.
A further challenge is to establish
suitable dissolution tests for non-conventional oral dosage forms,
for example chewable tablets, swellable dosage forms and wafers
that are designed to dissolve on the tongue. The classical methods
do not provide suitable agitation conditions on the one hand,
and the volumes used are unrealistic for wafer-type dosage forms
on the other hand. Likewise, the suitability of current methods
for non-oral dosage forms continues to be an area of controversy
and research.
The evaluation of results is also an area of continued interest
for the academic as well as the regulatory community. The utility
of the recently proposed f2 factor and its benefits and disadvantages
compared to other evaluation methods (both model dependent and
independent) will need to be carefully scrutinized using a wide
variety of data sets, including drug products from each of the
BCS categories and data sets for controlled release products.
Finally, the controversy related
to calibration of dissolution testers continues. Alternatives
to the current USP calibrator tablets need to be developed, with
the most desirable approaches being those that avoid the batch
to batch reproducibility problems associated with the current
tablets, those that are efficient in terms of time and effort
required and those that can be applied in a wide variety of laboratory
settings.
In summary, dissolution testing is enjoying a resurgence of interest
on an academic as well as on industrial and regulatory levels.
Provided the groundwork continues to be focused on the development
of dissolution tests and testers that are both biorelevant and
can be adapted to routine quality control, it is likely that dissolution
testing will become an even more powerful tool for the assurance
of product quality, in its broadest sense in the years to come.