pharma tech europe june 2011
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Pjarmaceutical Technology Europe June 2011TRANSCRIPT
Advancing process solutions
E U R O P E D I G I TA L June 2011
LATEST ISSUES AND INSIGHTS
3 The rising uptake of immediate release and ODT formulations
5 The influence of superdisintegrants
7 Tablet testing techniques
9 Film coatings and immediate release
WHAT IS DRIVING NEW DEVELOPMENTS IN IMMEDIATE-RELEASE DRUG DELIVERY?
2 Patient compliance, patent renewal and drug efficacy.
Immediate release
Hand sketch: Stock Foundry/Getty Images
Are pharma’s formulators pushing the right buttons?
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CONTENTS ODT FORMULATIONS
TABLET TESTING
SUPERDISINTEGRANTS
FILM COATINGS
In April, we spoke with experts
to find out more about the
latest trends and challenges in the
tabletting industry (www.PharmTech.
com/ptedigital0411 if you missed
out!) and now, for this issue, we’ll
be taking a closer look at a related
area: immediate release tablets. The
formulation of immediate-release
dosage forms has become a popular
Immediate release formulationpractice for pharma manufacturers
— mainly because of the need for
patent renewal, and improvements in
drug efficacy and patient compliance.
According to a survey conducted on
our website www.PharmTech.com,
all of these drivers are more or less
of equal importance when it comes
to influencing new developments in
immediate release.
In this month’s special feature, PTE
spoke to a selection of experts to
find out more about the growing
popularity of immediate-release drug
delivery, with a particular emphasis
on orally dispersible tablets, which
have become extremely popular with
patients. Experts also examine tablet
testing techniques and the use of
superdisintegrants. PTE
32%Patient compliance
38%Drug efficacy
30%Patent renewal
What is driving new
developments in immediate-
release drug delivery?
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CONTENTS ODT FORMULATIONS
TABLET TESTING
SUPERDISINTEGRANTS
FILM COATINGS
How do immediate-release
formulations boost drug
efficacy and aid patient compliance?
In general, immediate release
formulations are applied both to
classical solid oral dosage forms like
tablets, which release the drug in the
stomach, and new dosage forms such
as orally disintegrating tablets (ODTs)
that dissolve in the patient’s mouth.
With classical tablets, coatings are
usually applied to increase patient
compliance by creating a smooth,
glossy finish that enables easier
swallowing compared with uncoated
cores. Coatings can also be applied
to make tablets different colours,
which help patients to differentiate
between tablets when taking
multiple medications — a factor that
is becoming increasingly important
with the ageing population across
the globe. In addition, coatings fulfil
The rising uptake of immediate release and ODT formulations
the fundamental need for mechanical
protection of a tablet.
ODT formulations have significant
potential for enhancing both drug
efficacy and patient compliance. An
ODT dissolves directly in the saliva,
without the need for additional
water, which makes them easy
to administer and renders the
swallowing of unpleasant tablets
obsolete. At the same time, the
immediate dissolution in the saliva
releases the API, which can be directly
absorbed by the mucosa.
How has the demand for
excipients that enable
immediate release changed in
recent years?
Because of the benefits, demand
for immediate release excipients
continues to grow. In the future,
such excipients will become
even more crucial. As well as
the already-mentioned ageing
population, the benefits relating
to improved patient convenience
(and hence the greater likelihood
of compliance) will drive more
pharmaceutical formulators to
utilise immediate release excipients
for new developments to keep up
with competition on the market.
Additionally, such excipients can also
be used for drug products already
available on the market as ODT
dosage forms offering new ways of
prolonging a product’s lifecycle.
Immediate release excipients
typically do not negatively impact
other tablet properties — they are
specifically designed to not interact
with active ingredients and to not
adversely affect the release profile.
In fact, their character targets to
improve key properties such as
mechanical stability
and protection from environmental
influences. For example, a coloured
film coated with a polymer can
protect a sensitive active from
degradation through light or
oxidation.
What have been the latest
innovations in immediate-
release excipients, and what are
excipient manufacturers working
towards in terms of future
innovations?
Jan Bebber
Q
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CONTENTS ODT FORMULATIONS
TABLET TESTING
SUPERDISINTEGRANTS
FILM COATINGS
The industry has seen quite an
evolution over the past decades when
it comes to immediate release coating
excipients. The first-generation
coating polymer is Hydroxy Propyl
Methyl Cellulose (HPMC), but this
showed high viscosity and required
a plasticiser for formulation. The
second generation, Poly Vinyl Alcohol
(PVA), brought an improvement in
lower viscosity, but still needed a
plasticiser.
Recently, a third generation of
coating polymers has become
available: grafted copolymers with
low viscosity and which do not
require a plasticiser. The plasticiser
function is already built into the
grafted copolymer and the low
viscosity enables the coating to be
made with high amounts of solid
content, which leads to a faster and
more efficient process.
For ODTs, suppliers have started to
offer co-processed excipients that
provide desirable properties for the
patient, such as fast dissolution and a
good mouthfeel.
This trend is expected to be one
of the future innovation drivers
for excipients suppliers because it
provides products that are easier
to use and more convenient to
handle for formulators, providing
valuable improvement in production
process robustness and efficiency.
Consequently, in the future we will
see more co-processed materials and
products where certain characteristics
are systematically modified. PTE
27-28 September 2011, The Ashling Hotel, Dublin
+44 (0)1939 250383
Hear the latest developments and best practice in generating test results and
data to support successful regulatory submission to the FDA and EMEA
Organised by:
For more information and to register online, visit:
Register before
22 July and save
€300
Media Sponsor:
Jan Bebber
is responsible for global marketing
of new products, pharma
ingredients and services at BASF SE
in Ludwigshafen (Germany).
www.basf.com
An extended version of this
interview is available at:
www.PharmTech.com/Bebber
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CONTENTS ODT FORMULATIONS
TABLET TESTING
SUPERDISINTEGRANTS
FILM COATINGS
When it comes to
immediate-release tablet
formulations, the choice of
disintegrant can have a significant
effect on the rate and extent of
drug dissolution. Once a tablet
disintegrates, the characteristics
of the API, either alone or assisted
by other formulation ingredients,
determine the dissolution rate and
extent of the API. Thus, the choice
of superdisintegrant is important,
especially with poorly soluble APIs.
Not all superdisintegrants are the
same
The three most common classes
of superdisintegrants are:
crospovidone, croscarmellose
sodium and sodium starch glycolate.
In general, all of these provide rapid
disintegration at low use levels
in both wet and dry granulations
The influence of superdisintegrants on immediate release
and direct compression tablet
processes; however, the classes of
disintegrants differ in chemistry and
particle morphology. Crospovidone
possesses unique pyrrolidone
chemistry and a highly porous
particle morphology that results
in high surface area. The high
surface area combined with unique
chemistry results in high-interfacial
activity that serves to enhance the
dissolution of poorly soluble drugs
in a way that is not possible with
other disintegrant technologies.
Indeed, studies have shown that
tablets containing a poorly soluble
API and crospovidone, Type B, have
significantly faster dissolution rates
compared with tablets formulated
with other superdisintegrants (1).
It has been widely reported
that more than 60% of drugs in
development and over 40% of
recently launched drugs have issues
related to poor solubility, leading
to long development times or
cancellations. Before evaluating
advanced techniques, such as
amorphous solid dispersions, more
traditional approaches such as the
influence of superdisintegrants
on dissolution are now being
considered. The selection of a
superdisintegrant and the use level
plays a key role in determining
the drug release of finished
formulations
Choosing an optimal
superdisintegrant
It is important to consider the
impact of the superdisintegrant
with respect to the performance
of the final dosage form. As
drug dissolution is essential
for absorption by the
body, formulators no
longer select disintegrants based
on the lowest disintegration
time because it is important
to also consider the effect
of the superdsintegrant on
dissolution. Additionally, the
ionic nature of both the API
and the superdisintegrants must
also be considered. Anionic
superdisintegrants, such as
croscarmellose sodium and sodium
starch glycolate, can interact with
John Fitzgerald
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CONTENTS ODT FORMULATIONS
TABLET TESTING
SUPERDISINTEGRANTS
FILM COATINGS
cationic APIs and retard dissolution.
Thus, nonionic superdistegrants
are preferred when working
with cationic APIs. Formulators
also consider the impact of the
superdisintegrant on physical
tablet characteristics, such as tablet
breaking force and friability. In
today’s high-speed tablet presses,
superdisintegrants that provide
tablets with high breaking force
and low friability, while maintaining
fast disintegration, are particularly
important.
Oral disintegrating tablets (ODTs)
There are a growing number of
oral disintegrating tablets (ODTs)
and chewable tablets available on
the market. These products have
increased in popularity because
consumers—old and young—find
them convenient and easy to use. In
addition, pharmaceutical companies
have found an opportunity to
extend product lifecycles or
differentiate their products by
offering these new dosage forms.
To achieve rapid disintegration in
the mouth in a direct compression
ODT formulation, the selection of
superdisintegrant and optimisation
of use level is an important
consideration. In a recent internal
ISP survey of commercially
marketed ODT products, it was
found that more than 60% of
the products surveyed used a
superdisintegrant. The most
common superdisintegrant listed in
the ingredients was crospovidone.
New innovation
One recent innovation from ISP
is the introduction of two new
Grades of crospovidone that have
lower specifications for peroxides
compared with other commercially
available crospovidone products.
These low peroxide levels are
achieved by manufacturing, drying,
packaging and sealing the product
under inert conditions to limit
peroxide formation.
It is likely that the proliferation of
blended/co-processed systems will
continue, but the major innovations
will be at the polymer chemistry
level. With a better understanding
of the physico-chemical properties
achievable via advanced polymer
science, improvements such as
optimised particle morphology,
cross-link density and purity will
lead to new formulation and
processing approaches. PTE
References
1. J. Balasubramaniam and T. Bee,
Pharmaceutical Technology, Excipient
suppl. s24–s14 (2009).
John Fitzpatrick
is Global Director, Plasdone and
Polyplasdone at ISP.
www.isppharmaceuticals.com
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CONTENTS ODT FORMULATIONS
TABLET TESTING
SUPERDISINTEGRANTS
FILM COATINGS
The rising popularity of fast
dissolving, immediate-release
dosage forms can be attributed
to their convenience and ease
of administration. Although
particularly applicable to the
paediatric and geriatric markets,
fast-melting tablets (FMTs) are
suitable for consumers of all ages.
To ensure reliable and consistent
drug release, however, formulators
must conduct a thorough
disintegration analysis, as the
tablet has to be resilient enough
to endure manufacturing and
shipping, but must also disintegrate
sufficiently to provide an optimum
dissolution rate.
The traditional and most
commonplace method employed
by researchers to assess dissolution
properties involves submerging
a tablet, which is attached with
tape to the bottom of a cylinder
probe, and then testing the time
Tablet testing techniquesrequired for the tablet to dissolve.
However, because the tablet
is ‘trapped’ between the tape
and the vessel base, its exposure
to the medium is restricted. To
more accurately examine water
absorption and the disintegration of
associated particles into individual
components, it is important to
replicate the conditions of the
human mouth as closely as possible
in vivo.
Innovation
One innovative solution is to use
a tablet disintegration rig, which
enables the disintegration medium
to access the tablet from all areas.
The dry tablet sample is secured to
a probe by a thin strip of double-
sided adhesive tape along its
diameter. The probe’s surface has a
channelled design that enables the
fluid to flow freely all round the
tablet, while ensuring that contact
is maintained with the probe. Once
the probe is lowered into the
medium, the tablet is positioned
on a perforated platform and
a constant force is applied to it.
The perforated surface enables
free ingress of fluid beneath the
sample and subsequent dispersion
of the disintegrant. The rig allows
the FMT particles to detach easily
during the disintegration process,
imitating the realistic conditions of
drug administration and providing
more accurate analysis regarding
performance and efficiency.
When designing fast melting
tablets, the use of tablet film
coatings has become a popular
practice because such films fulfil
multiple roles, from aesthetics
and taste or odour masking, to
eased ingestion and prolonged
product shelf life. Problematically,
on the other hand, aqueous film
coatings also tend to act as local
stress concentrators that promote
cracking, edge splitting and peeling.
A technique called texture analysis
(see sidebar) is commonly used to
investigate the response of a tablet
in situations that mimic its actual
usage. Such analysis can measure
the adhesiveness, rupture, burst
strength, resilience and relaxation
properties of pharmaceutical film
Jo Smewing
“Recently, bi-layer dosage
forms have witnessed a
boom in popularity...”
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CONTENTS ODT FORMULATIONS
TABLET TESTING
SUPERDISINTEGRANTS
FILM COATINGS
coatings. The results of texture
analysis will help manufacturers
to optimise their formulations and
manufacturing processes to avoid
potential issues.
Jo Smewing
is Applications Manager at Stable
Micro Systems Ltd.
www.stablemicrosystems.com
Rapid release
drugs have become
increasingly popular
in the context of
chronic ailments
including heart disease
and cancer, as well
as for immediate
relief from a simple
headache. In order
to deliver consistent
performance, the
physical properties
responsible for the
manipulation of
biological barriers
or the regulation of
diffusion rates have
to undergo stringent
quality control during
manufacturing. Texture
analysis is essentially
the measurement
of the physical and
mechanical properties
of a substance.
Access to texture
analysis studies allows
pharmaceutical
manufacturers to
monitor and control
predefined quality
standards in the
physical characteristics
of the formulated
tablets.
The availability
of accurate quality
control tests allows
manufacturers to
develop formulations
that combine optimal
therapeutic efficacy
with convenient
administration, thereby
encouraging greater
patient compliance.
Texture analysis is an
invaluable tool at each
stage of development,
formulation and
production quality
control.
Texture analysis
Bi-layer tablet boom
Recently, bi-layer dosage forms have
witnessed a boom in popularity,
which can be attributed to the
added efficacy over time that they
offer. Because of their unique
characteristic, bi-layer tablets are
often used to provide a combination
of immediate-release dose for
fast-acting relief and a dose of
controlled-release to maintain the
therapeutic effect.
Not surprisingly, these tablets
are also prone to a number of
qualitative issues such as layer
separation, insufficient hardness,
inaccurate individual layer weight
control and cross-contamination
between the layers. To avoid these
pitfalls, manufacturers have to
assess the physical characteristics
of high-load APIs, which usually
require bespoke manufacturing
formulations to overcome barriers,
such as low melting points or poor
compressibility. Innovative texture
analysis methodologies mean these
quality issues can be accurately
evaluated by analysing physical
properties in conditions that closely
resemble in vivo conditions
Separation of the two individual
layers in a bi-layer tablet is a
common problem and one that
significantly impacts the quality and
efficacy of the medication. It is the
consequence of insufficient bonding
between the two layers during final
compression of the tablet. However,
this issue can be mitigated using
systems and technologies that
assess the force required to separate
the layers of a bi-layer tablet. This
allows manufacturers to identify
exactly why tablets are failing, and
to subsequently take corrective
action quickly and effectively. PTE
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CONTENTS ODT FORMULATIONS
TABLET TESTING
SUPERDISINTEGRANTS
FILM COATINGS
When film coating
immediate release dosage
forms, what are the main
challenges that arise?
When film coating immediate release
dosage forms, the main challenges
are selecting the most appropriate
coating for the dosage form and the
coating process conditions that will
be used. The coating formulation
should be selected based on the
desired functionality (e.g., moisture
barrier, oxygen barrier and taste
masking) and aesthetics required
for a particular application. In
addition, the components of
the coating formulation should
be assessed for any potential
incompatibilities with the API or
excipients in the core. An overriding
consideration is productivity. Ideally,
a film coating should provide the
requisite aesthetic and functional
characteristics, while allowing simple
application in a minimum amount of
time.
How can new techniques/
technologies overcome
these challenges?
Film coating suppliers are
developing coating formulations
based on a variety of chemistries
so that the formulator can select
the best coating to minimise
potential compatibility issues and
meet functional requirements.
Equipment manufacturers have
also optimised coating equipment
to enable fast throughput either in
batch or continuous operations.
What are the benefits
and challenges associated
with incorporating moisture
barrier protection into
immediate-release formulations?
Using film coatings, it is possible
to incorporate moisture barrier
protection. This is important
because such a barrier can
improve the physical and chemical
stability of the active components.
This potentially allows drug
manufacturer to significantly
extend the shelf life of a dosage
form.
One significant challenge in this
area is coating a moisture-sensitive
core with an aqueous coating
dispersion, which typically contains
up to 80% water. However, this can
be overcome by properly selecting
coating process conditions; for
example, by carefully balancing
process temperatures and air flow,
the moisture content of a dosage
form can be maintained, even
during an aqueous coating process.
How can new
developments in film
coatings positively impact future
immediate release formulations?
In the future, new coating
formulations will be introduced that
have improved barrier properties
and that enable high-coating
productivity. Film coating suppliers
are
constantly
screening
new
product
candidates for functionality
using a variety of considerations,
including moisture uptake,
moisture and oxygen transmission
rate through free films and “on
tablet” stability studies with
model drugs. Ultimately, an “on
tablet” assessment of physical
and chemical stability of a model
drug formulation is the most
convincing demonstration of barrier
performance of a given coating. PTE
Thomas P. Farrell
is director, product development,
at Colorcon. Thomas was also the
chair of the 2010 AAPS Excipients
Focus Group
www.colorcon.com
Q Q
Thomas Farrell
Film coatings and immediate release
Kevin Altria
GlaxoSmithKline R&D
Reinhard Baumfalk
Sartorius AG
Rafael Beerbohm
Ben Venue Laboratories
Gabriele Betz
University of Basel, Switzerland
Rory Budihandojo
Boehringer-Ingelheim
Shanghai Pharmaceuticals
Guido Dietrich
GlaxoSmithKline Biologicals
Ryan F. Donnelly
Queens University Belfast
Sven Frøkjær
The Danish University of
Pharmaceutical Sciences
Filipe Gaspar
Hovione
Sharon Grimster
Antisoma
Anne Marie Healy
University of Dublin, Ireland
Alexander Hüber
Novartis
Deirdre Hurley
Helsinn Birex
Pharmaceuticals Ltd.
David James
Invensys Systems
Makarand Jawadekar
Pfi zer
Henrik Johanning
QAtor A/S
Sebastian Kaerger
Aeropharm-Sandoz
Faiz Kermani
Consultant
Stephan Krause
MedImmune
Marina Levina
Colorcon
Roberto Margarita
Bristol-Myers Squibb
Jerry Martin
PALL Life Sciences
Luigi G. Martini
GlaxoSmithKline
Thomas Menzel
Menzel Fluid Solutions AG
Jim Miller
PharmSource Information
Services
Colin M. Minchom
Patheon
Cliff Mintz
BioInsights Inc.
Ian Pearson
Lend Lease Projects
Tim Peterson
3M
Fridrun Podczeck
UCL London
John Pritchard
Philips
Thomas Rades
University of Otago,
New Zealand
David Radspinner
Thermo Fisher
Anurag Rathore
Indian Institute of Technology
Jean Paul Remon
Ghent University, Belgium
Rodolfo Romañach
University of Puerto Rico,
Puerto Rico
Beatriz San Martin
Field Fisher Waterhouse LLP
Siegfried Schmitt
PAREXEL
Aline Seilly
Millipore Corporation
Clare Strachan
University of Otago,
New Zealand
Philip Dan Skou
Actelion
Stane Srcic
University of Ljubljana,
Slovenia
Griet Van Vaerenbergh
GEA Pharma Systems nv
Benoît Verjans
Aseptic Technologies
Jan Vogeleer
Courtoy, GEA Pharma Systems
Andreas Weiler
SAFC
Tony Wright
Exelsius
Editorial Director
Michelle Hoffman
Editor
Rich Whitworth
Tel. +44 1244 629 308
Senior Managing Editor
Angie Drakulich
Managing Editor
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Senior Editor
Patricia Van Arnum
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Amy Ritter
Associate Editors
Erik Greb, Stephanie Sutton
[email protected], [email protected]
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Andrew Davies
Tel. +44 1244 629 304
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CONTENTS ODT FORMULATIONS
TABLET TESTING
SUPERDISINTEGRANTS
FILM COATINGS
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CONTENTS ODT FORMULATIONS
TABLET TESTING
SUPERDISINTEGRANTS
FILM COATINGS