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Preface
1. Poly(meth)acrylate properties
5.3. Quickstarts
6. Sustained-release formulations
6.3. Quickstarts
7.3. Quickstarts
8.3. Quickstarts
9. Solubility enhancement
10. Scale-up
11. Trouble-shooting
14. Glossary
15. Literature
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We hope you enjoy working with the online version of the EUDRAGIT Application Guidelines!
Best regards,
Jonas Joh
Marketing Communications Manager
Pharma Polymers
(5) Equipment cleaning can make up a significant portion of production costs, particularly in
large-scale processes. The insoluble EUDRAGIT polymers used for sustained-release
applications set challenging conditions for the cleaner. In a recent project, we evaluated
detergents and optimized cleaning conditions in cooperation with several leading cleaning agent
suppliers. Our updated cleaning recommendations show significant improvements in terms of
time, temperature and application compared to the previous methods. Details are described in
Chapter 12.
Besides these, you will find several new application examples and updated information
throughout the entire book.
Since the launch of our versatile internet platform, the e-Lab, the Application Guidelines are also
available online now. After a quick and easy registration process, you can access the
Application Guidelines conveniently from anywhere in the world even via iPhone or iPad. To
register for the e-Lab and to benefit from the various functionalities tailor-made for EUDRAGIT
users, please go to www.eudragit.com/e-lab.
II hope the information in this new edition of the EUDRAGIT Application Guidelines supports
your development projects and helps to increase manufacturing efficiency at your site.
In line with our commitment to ongoing improvement, we look forward to receiving your
comments and suggestions for the next edition, either in the conventional way or through the
new comment feature in the online version of the Application Guidelines.
With best wishes,
Sing, Gopeshkumar
Skalsky, Brigitte, Ph.D
Weber, Frank
Weisbrod, Wolfgang
Published by
Evonik Industries AG
Kirschenallee
64293 Darmstadt
Germany
PHONE +49 6151 18-4019
FAX +49 6151 18-3520
eudragit@evonik.com
www.eudragit.com
www.eudragit.com/e-lab
www.evonik.com
Editor (responsible)
Dr. Brigitte Skalsky
Project manager
Jonas Joh
Layout
MLW KommunikationsForm GmbH Werbeagentur, Worms
Production
Dietz Druck, Heidelberg
Copyright
The editorial matter, pictures or text, may not be reproduced without the publisher's prior
permission.
This information and all further technical advice is based on our present knowledge and
experience. However, it implies no liability or other legal responsibility on our part, including with
regard to existing third party intellectual property rights, especially patent rights. In particular, no
warranty, whether expressed or implied, or guarantee of product properties in the legal sense is
intended or implied. We reserve the right to make any changes according to technological
progress or further developments. The customer is not released from the obligation to conduct
careful inspection and testing of incoming goods. Performance of the product described herein
should be verified by testing, which should be carried out only by qualified experts in the sole responsibility of a customer. Reference to trade names used by other companies is neither a
recommendation, nor does it imply that similar products could not be used.
Evonik Rhm GmbH and Evonik Industries AG are the owners of patent rights covering the use
of EUDRAGIT polymers in compositions, procedures and/or applications which may be
subject to license agreements.
= registered trademark
EUDRAGIT = reg. Trademark of Evonik Rhm GmbH, Darmstadt, Germany
Evonik Industries AG, Pharma Polymers, Darmstadt, Germany
1. Poly(meth)acrylate properties
Polymers are widely used as film formers to coat solid pharmaceutical dosage forms. Whereas
cellulose derivatives are mainly employed for unspecific film-coatings, poly(meth)acrylates
predominate in applications for functional pharmaceutical coatings. Furthermore, they are
applied as matrix formers in all common granulation techniques as well as in direct
compression.
Description and manufacture of poly(meth)acrylates
Unlike cellulose derivatives that are based on natural raw materials and may therefore vary in
terms of physicochemical properties depending on the raw material source, the methacrylic
copolymers are provided in an excellently reproducible form via free-radical polymerization. In
this, long polymer chains are formed by chain growth reactions from various acrylate or
methacrylate derivatives (see Figure 1). The functional properties of the methacrylic copolymers
and the final polymers can be adjusted by selecting from a variety of monomers. The nonfunctional co-monomers are responsible for steering the polymer properties, and the functional
co-monomers for adjusting the solubility profile. The various co-monomers are incorporated into
the polymer by static processes. The polymerization reaction can be performed in solvent, bulk,
suspension or emulsion.
apply. Viscosity measurements are easy to perform and provide viscosity-average molar
masses. The molar masses of the EUDRAGIT grades stated in the specifications are based on
measurements of this type.
Of particular interest to polymer chemists is the determination of molar mass distribution. Gel
permeation (GPC) or size exclusion chromatography (SEC) have become the predominant
methods for this purpose. They involve separation and detection of dissolved polymers
according to their hydrodynamic volume in carrier gels. Molar mass distributions are calculated
by calibrating polymers of known molar mass. In methacrylate chemistry, calibrated polymethyl
poly(meth)acrylates (PMMA) are most commonly used. Measurement of the molar masses of
EUDRAGIT polymers via gel permeation chromatography is difficult, mainly because of ionic
interactions of the functional groups. Only by using modern polyester-based gels and adding
salts to suppress this interaction it has become possible in past years to perform and publish
reproducible determinations of the molar mass distribution of EUDRAGIT grades (2) (3). The
weight-average molar masses established by these determinations are shown in the following
table.
EUDRAGIT grade
Mw [g/mole]
EUDRAGIT S 100
~ 125 000
EUDRAGIT L 100
~ 125 000
EUDRAGIT FS 30 D
~ 280 000
EUDRAGIT NM 30 D
~ 600 000
EUDRAGIT NE 30 D
~ 750 000
EUDRAGIT E 100
~ 47 000
EUDRAGIT RL 100
~ 32 000
EUDRAGIT RS 100
~ 32 000
Table 1: Weight average molar masses of EUDRAGIT grades in relation to PMMA standard
Glass transition temperature (Tg)
The glass transition temperature is an important factor for describing the physical properties of
polymers. On a macroscopic level, it describes the solidification of an anisotropic polymer melt.
At the molecular level, this is combined with the freezing-in of molecular movements. When a
polymer is heated from the glassy state, it passes beyond the viscoelastic range to a viscous
flow. Initially, this leads to molecular movement in the side chains, followed by movement in the
main chains and polymer chain sliding, which is connected with a change in specific heat. One
standard method for determining the glass transition temperature is Differential Scanning
Calorimetry (DSC), in which the difference in temperature and/or time of the test specimen is
measured as a function of the heat flow against a reference. The values in the table below were
determined as the mean value in the glass transition interval (Figure 2) according to DIN EN
ISO 11357 in the second heating cycle. In detail we, use 10 to 12 mg sample weight, heating
rates of 20 K/min and limit the temperature evaluation range for dynamic measurements, in
general, from -40C to 140C and for the flexible types (NE, NM, FS) from -100C to 100C to
prevent damaging of the functional groups during the measurement. Consequently, it is not
possible to determine values for EUDRAGIT S 100 and L 100, because of the overlapping with
the damage of the functional groups (anhydrate formation) beyond 130C.
The glass transition temperature influences, e.g. film formation, melt processing and storage of
finished pharmaceutical dosage forms. Plasticizers or solvents (including water) that act as
plasticizers usually cause a reduction in glass transition temperature which is specifically
exploited in drug formulations. The most common plasticizer for EUDRAGIT polymers is triethyl
citrate (TEC).
been formed. The minimum film-forming temperatures of the pure EUDRAGIT dispersions are
listed in Table 3.
EUDRAGIT dispersion
EUDRAGIT L 30 D-55
EUDRAGIT FS 30 D
EUDRAGIT RL 30 D
EUDRAGIT RS 30 D
EUDRAGIT NE 30 D
EUDRAGIT NM 30 D
Table 3: MFT/MFFT values of EUDRAGIT dispersions
MFT [C]
~ 25
~ 14
~ 40
~ 45
~5
~5
EUDRAGIT NE 30 D
~ 300
EUDRAGIT NM 30 D
~ 300
Film coatings of adequate flexibility are the prerequisite for the compressibility of coated
particles and also for preventing film damage when tablets are dropped. The elastic properties
can be described by various physical methods such as the modulus of elasticity. This can
readily be illustrated by the elongation at break of test specimens made from sections of fully
formed films. It allows statements to be made on the failure of polymer films under tensile
stress. Measurement is performed in line with DIN ISO 527-3 at defined temperature and
moisture. When preparing specimens for measurement, film defects that may influence the
results must be avoided.
The elasticity of polymer films can be influenced to a great extent by additives. In the final
analysis, it is once again the glass transition temperature of the polymers that determines the
basic elasticity. Plasticizers simultaneously reduce the glass transition temperature and increase
the elasticity. Another elegant way to increase elongation at break is to mix highly elastic and
compatible polymers, as shown in the example below of a mixture of EUDRAGIT L 30 D-55
and EUDRAGIT NE 30 D. Such mixtures obviate the need for large quantities of plasticizers
(see Figure 6).
(1) H.-G. Elias, Makromolekle, Vol 1: Chemische Struktur und Synthese, 6th ed., p.303ff,
Wiley-VCH, Weinheim 1999
(2) Martina Adler, Harald Pasch, Christian Meier, Raimund Senger, Hans-Gnter Koban,
Michael Augenstein, Gnter Reinhold; e-Polymers 2004, 055
(3) Martina Adler, Harald Pasch, Christian Meier, Raimund Senger, Hans-Gnter Koban,
Michael Augenstein, Gnter Reinhold, e-Polymers 2005, 057