MEETING REPORT:
Dissolution
Testing of Special Dosage Forms
A workshop on the "Dissolution Testing
of Special Dosage Forms" was held in London, on September
2 and 3, under the co-sponsorship of the Royal Pharmaceutical
Society's Pharmaceutical Sciences Group and the FIP Working Group
on Dissolution Testing. The workshop featured presentations on
the scientific principles and current applications of dissolution
and drug release characteristics to non-conventional dosage forms.
The value of dissolution tests for conventional and modified release
solid oral dosage forms is well documented in the literature,
and has resulted in the development of FIP and FDA dissolution
guidances. For conventional oral dosage forms, dissolution testing
has emerged as a very important product quality assessment tool,
especially in regard to post approval changes and to surrogate
testing for bioequivalence. The overall goal of this workshop
was to evaluate the methodologies for dissolution and drug release
testing of non-conventional dosage forms.The workshop was divided
into two sessions. The first session focussed on non- conventional
oral dosage forms such as chewable tablets, chewing gum, powders,
granules, and suspensions. The second session focussed on non-oral
dosage forms such as suppositories, creams, ointments, transdermal
products, iontophoretic products, implants and microparticles.
Dr. Vinod Shah (FDA, USA) and Dr. Helga Möller (Zentrallaboratorium
Deutscher Apotheker, Germany) co-chaired the workshop.
Dr. Joseph Robinson (University of Wisconsin, USA) opened the
first session with a general overview of dissolution testing.
Dr. Robinson emphasized that the first dissolution tests were
designed as physiologically based systems. Currently, the need
for physiologically based dissolution tests is a highly debated
topic. Dr. Robinson stated that a non-physiologically based system
is acceptable as long as the system is capable of predicting the
in vivo performance of the product. Dr. Robinson stated that the
standards for dissolution testing of conventional solid oral dosage
forms have been significantly refined and harmonized over the
past 25 years. The methodologies for dissolution testing of non-conventional
dosage forms are still in the very early stages of development
and evaluation.
Dr. Ewart Cole (Capsugel Division of Warner Lambert, Switzerland)
presented on the in vitro-in vivo behavior of gelatin capsule
products. It has been reported that certain conditions, especially
the existence of trace amounts of aldehydes in the capsule fill
material or hot and humid storage, can render gelatin partially
insoluble in water or buffer due to a cross-linking reaction.
To investigate the in vivo relevance of gelatin cross-linking
in more detail, a gelatin capsule working group comprised of FDA
and industry representatives was formed. Over the past four years,
the working group has evaluated the effect of cross-linking on
both in vitro dissolution and bioavailability using a model drug
product. Based on well-controlled research studies, a two tier
testing is proposed. Gelatin products are initially tested according
to the USP or NDA/ANDA dissolution test using dissolution medium
without enzymes. If the gelatin product fails the USP or NDA/ANDA
dissolution test (due to the cross-linking of the gelatin), the
product should be tested in the same dissolution medium with the
addition of a specified amount of enzymes (Pharmacopeial Forum,
Volume 24, Number 5, September-October, 1998). If the gelatin
product passes the dissolution test in the enzyme-containing medium,
the product's performance is considered to be acceptable.
Dr. Johannes Kraemer (Laboratory and Quality Services, Germany)
discussed dissolution testing methodologies for chewable tablets
and gums. Dr. Kraemer stated that the oscillatory movement of
the reciprocating cylinder apparatus (USP Apparatus 3) was found
to be acceptable in discriminating dissolution properties of some
chewable tablets. Dr. Kraemer discussed the unique challenges
involved in dissolution testing of chewing gums where the intensity
and frequency of shearing forces (i.e., chewing action) have a
large influence on the drug release rate. The results of studies
on the drug release of dimenhydrinate from a medicated chewing
gum formulation were presented. An apparatus described in the
European Pharmacopoeia that is designed for the testing of chewing
gum products was utilized and found to be acceptable for this
study.
Dr. Berndt Müller (Kiel University, Germany) described the
dissolution behavior of powders, granules and solid solutions
and dispersions. The effects of wettability, surface area and
particle size on dissolution were presented. In summary, Dr. Müller
stated that it is impossible to characterize powders, granules
and solid solutions and dispersions based solely on their dissolution
properties and more extensive physicochemical tests are required.
Dr. Saeed Qureshi (Health Protection Branch, Canada) provided
the rationale for dissolution testing of suspensions, and the
testing techniques generally employed. In general, USP Apparatus
2 (Rotating Paddle) was found to be acceptable for the dissolution
testing of suspensions. A cone formation of the suspension at
the bottom of the dissolution vessel was sited as a potential
variable when USP Apparatus 2 is utilized for dissolution testing
of suspensions.
Dr. Vinod Shah opened the second session with a brief overview
of dissolution testing of non-oral dosage forms. Dr. Shah emphasized
that dissolution and release rate testing on non-oral dosage forms
can be utilized as a quality control tool for assessing batch-to-batch
consistency. Each topical product should have dissolution specifications
established as a quality control measurement. Dr. Shah provided
an overview of the FDA guidance on dissolution testing of semi-solid
products (SUPAC-SS) and the FDA's laboratory experiences in regard
to the testing of transdermal products. He indicated that a simple
paddle over disc method provides the same in vitro release profile
as other complicated procedures.
Dr. Jean Marc Aiache (Université d'Auvergne, France) described
the most classical scheme of drug release from a suppository.
The dissolution and diffusion methods can be divided into two
main groups: with and without membranes. In the methods without
membranes, the suppository is directly in contact with the dissolution
medium in which the drug can diffuse and dissolve after release.
The methods without membranes commonly have problems with reproducibility
Dr. Aiache sited the choice of membrane (natural or artificial)
as the common problem with this methodology. The flow-through
cell for suppositories was recently registered in the European
Pharmacopoeia.
Dr. Petra Loos (Hoechst Marion Roussel AG, Germany) discussed
the applications of the general concepts and requirements for
in vitro dissolution testing to creams and ointments. She described
test methods which utilized diffusion cells, such as the Franz
cell and the Enhancer cell. Data generated using the Franz cell
and an artificial membrane were compared to data generated using
ATR-FTIR and skin as a biological membrane. The data generated
using the ATR-FTIR methodology showed large fluctuations due to
the use of skin, a biological material with inherent uniformity
problems. Dr. Loos concluded that the Franz cell and the Enhancer
cell are the models of choice for routine batch-to-batch quality
assessment and evaluation of scale-up and post approval changes.
Dr. Ruzica Djerki (Novartis Pharma, Switzerland) presented
an overview of the release rate methods that are currently utilized
for quality control of the batch-to-batch uniformity of transdermal
therapeutic systems (TTS). The different forms of TTS that are
currently approved for marketing and methodologies utilized to
monitor the release rate of TTS such as USP Apparatus 5 (paddle
over disk), USP Apparatus 6 (rotating cylinder) and USP Apparatus
7 (reciprocating disk) were described. Dr. Djerki sited the dissolution
apparatus design, medium selection and sample preparation as critical
parameters influencing the release rate of TTS. The need for simplification
and harmonization of TTS release rate methodologies was emphasized.
Dr. Richard Guy (Centre Interuniversitaire de Recherche,
France) discussed the principles regarding the utilization of
iontophoresis in the transdermal delivery of drugs. Iontophoresis
was defined as the facilitation of (ionizable) drug delivery across
the skin by an applied electrical potential. Dr. Guy concluded
that controlling the key electrophysical parameters of iontophoresis
products such as drug content, pH of the hydrogel, electrical
conductivity of the hydrogel, magnitude and duration of current,
would sufficiently guarantee the reproducible performance of these
electrically-driven devices.
Dr. Helga Möller concluded the second session with a presentation
on the dissolution testing of parenteral implants and microparticles.
Dr. Möller stated that for tested microparticles to be effective,
it is essential that the minimum therapeutic dose of the active
pharmaceutical ingredient is released over a period of time that
corresponds to the dosing regimen. A dissolution test procedure
for microparticles using the Flow-Through Apparatus was developed
based on the comparison of in vivo and in vitro release and is
currently used as a routine test for batch analysis and stability.
Dr. Möller highlighted the evaluation of key method parameters
such as apparatus selection, composition of the dissolution medium,
agitation (flow rate) and temperature.
Each session was concluded with a panel discussion which allowed
for lively interaction between the workshop attendees and the
panel members (session speakers and FIP working group representatives).
Definitely, all workshop participants developed a better understanding
of the issues and the approaches currently being taken in regard
to the dissolution testing of special dosage forms.