EUDRAGIT Application Guidelines (online version) Preface Preface to the online version of the EUDRAGIT Application Guidelines Preface to the 12th Edition Contributors to this edition / Imprint 1. Poly(meth)acrylate properties 2. General handling of EUDRAGIT polymers 2.1. Handling of incoming containers containing aqueous dispersions 2.2. Storage recommendations and storage stability 2.3. Handling of containers after opening 2.4. Handling of EUDRAGIT polymers in melt extrusion processes 2.5. Spray suspension preparation 2.6. Spraying process 2.7. Post coating treatment 2.8. EUDRAGIT polymer combinations 2.9. EUDRAGIT in combination with other polymers 2.10. Compatible auxiliaries 3. Drug surface calculations and determinations 4. Equipment and technologies 4.1. Fluid bed coating 4.2. Pan coating 4.3. Tablet compression 4.4. Melt extrusion 5. Enteric & GI targeting formulations 5.1. Application fields for enteric & GI targeting formulations 5.2. Formulation basics for enteric & GI targeting formulations 5.3. Quickstarts 5.4. Enteric & GI targeting formulation examples 6. Sustained-release formulations 6.1. Application fields for sustained-release formulations 6.2. Formulation basics for sustained-release formulations 6.3. Quickstarts 6.4. Sustained-release formulation examples 7. Taste masking formulations 7.1. Application fields for taste masking formulations 7.2. Formulation basics for taste masking formulations 7.3. Quickstarts 7.4. Taste masking formulation examples 8. Protective coating formulations 8.1. Application fields for protective coating formulations 8.2. Formulation basics for protective coatings 8.3. Quickstarts 8.4. Protective coating formulation examples 9. Solubility enhancement 9.1. Application fields for solubility enhancement 9.2. Formulation basics for solubility enhancement 9.3. Solubility enhancement formulation examples 10. Scale-up 10.1. General scale-up considerations 10.2. Scale-up formulations enteric coatings 10.3. Scale-up formulations protective coatings 10.4. Scale-up formulations sustained-release coatings 10.5. Scale-up formulations solubility enhancement 11. Trouble-shooting 11.1. Physical changes of latex dispersions 11.2. Spray suspension preparation 11.3. Coating process 11.4. Tablet compression 11.5. Melt extrusion process 12. Cleaning of equipment after processing EUDRAGIT 12.1. General considerations 12.2. Aqueous cleaning agents 12.3. Cleaning EUDRAGIT L 30 D-55 / L 100 / S 100/ FS 30 D 12.4. Cleaning EUDRAGIT E 12.5. Cleaning EUDRAGIT RL 30 D / RL PO / RL 100, EUDRAGIT RS 30 D / RS PO / RS 100, EUDRAGIT NE 30 D/ NE 40 D, EUDRAGIT NM 30 D 12.6. Contact information cleaning agent manufacturers 12.7. Organic solvents as cleaning agents 12.8. Dry ice blasting 12.9. Cleaning of melt extrusion equipment 12.10. Cleaning polymers for hot melt extrusion 12.11. Suppliers of further cleaning equipment and services 12.12. Cleaning procedure examples 13. Measures & units 14. Glossary 15. Literature

Preface to the online version of the EUDRAGIT Application Guidelines

Dear Ladies and Gentlemen, For more than 50 years, Pharma Polymers has been providing technical and development support to our customers through close collaboration and technical knowledge-exchange regarding the latest developments in formulation of oral modified-release dosage forms. Open channels and a direct dialog between our scientists and customer formulation scientists are key aspects in achieving the best results.Knowing that opportunities to meet face to face are not always possible, we are pleased to be able to provide an excellent written-substitute, in the form of the EUDRAGIT Application Guidelines.Welcome to the brand new 12th edition of the EUDRAGIT Application Guidelines.

We offer the Application Guidelines in two formats: as hard copyand as an online version.The advantages of the online version are: You always read the most current version incorporating all recent changes. You can comment on chapters and respond to other users' comments. You can easily find chapters dealing with the topic of your interest by using the full text search in the upper right corner of the screen. You can access the online versionfrom anywhere in the world, even with an iPhone or iPad.We hope you enjoy working with the online version of the EUDRAGIT Application Guidelines!Best regards,

Jonas JohMarketing Communications ManagerPharma Polymers

Preface to the 12th Edition

The pharmaceutical industry is requiring simpler and shorter production processes, making ever greater optimization a major goal. This striving for improvement is one of the guiding principles in present and future development projects.For the 12th Edition of the EUDRAGIT Application Guidelines we have taken this trend into consideration. Hence, we provide you with various simplified and cost-saving approaches as well as scientific background information which will support you when working with EUDRAGIT. Here are some highlights from the 12th Edition:(1) To improve the entire process concerning taste-masking and protective coatings with EUDRAGIT E PO functionality in terms of efficiency, we have launched the ready-to-use powder EUDRAGIT E PO ReadyMix. It contains all coating formulation ingredients and is provided as a customized product matching the specific requirements of our customers, including color matching. To prepare the spray suspension, you simply add EUDRAGIT E PO ReadyMix to water and stir with a conventional stirrer or with a homogenizer. Preparation takes less than one hour. Find out more about this new product and its applications in chapters 7 and 8.(2) With PlasACRYL T20, we have launched a ready-to-use GMS dispersion which matches our formulation recommendations. It can be used in enteric and sustained-release formulations and is directly stirred into the coating suspension. Since neither heating nor high shear mixing is required, it saves you significant time, energy and costs. You will find several new example formulations and the corresponding "Quickstarts" in the different application chapters.(3) Formulating solid dispersions is a solution for enhancing the solubility of poorly soluble actives, whose numbers are continuously growing. Following the traditional, empirical way of development often requires a significant number of lab trials, which take considerable time and drug consumption. With MemFis, Evonik has developed a prediction tool that ensures the best possible start in solid dispersion development using melt extrusion or spray drying, thereby allowing you to save time, costs and API. You can find an introduction to the MemFis features in Chapter 9. For applying the tool, please feel free to contact your regional Evonik representative.(4) When we introduced the in-process curing method for EUDRAGIT RL/RS in 2006, a large number of companies switched from the conventional tray drying process to the innovative post-coating treatment in the coating equipment. Now we are pleased to provide you with process recommendations for in-process curing of EUDRAGIT NE/NM formulations. You can find them in Chapter 6.(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,

Dr. Brigitte SkalskyDirector Global Marketing Services

Contributors to this edition / ImprintAlbers, Jessica, Ph.D.Annamalai, MuthaiahAssmus, ManfredAsgarzadeh, Firouz, Ph.D.Br, HansBull, Randy, Ph.D.Bttner, DennisChen, RogerDassinger, ThomasEisele, Johanna, Ph.D.Felisiak, ThomasForlizzi, IlariaFrst, Thomas, Ph.D.Gallardo, DiegoGryczke, AndreasHensel, OdetteHofmann, FelixIde, JonasIshii, TatsuyaJoh, JonasKucera, Shawn, Ph.D.Lchner, Sabine, Ph.D.Meier, Christian, Ph.D.Morita, TakayukiNiepoth, PeterNollenberger, Kathrin, Ph.D.Nyamweya, Nasser, Ph.D.Petereit, Hans-UlrichRupp, ThomasRusswurm, SylviaSchminke, SilkeShabana, SusanSiefert, MelanieSing, GopeshkumarSkalsky, Brigitte, Ph.DWeber, FrankWeisbrod, Wolfgang

Published byEvonik Industries AGKirschenallee64293 DarmstadtGermanyPHONE +49 6151 18-4019FAX +49 6151 18-3520eudragit@evonik.comwww.eudragit.comwww.eudragit.com/e-labwww.evonik.comEditor (responsible)Dr. Brigitte SkalskyProject managerJonas JohLayoutMLW KommunikationsForm GmbH Werbeagentur, WormsProductionDietz Druck, Heidelberg CopyrightThe 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 trademarkEUDRAGIT = 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)acrylatesUnlike 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 non-functional 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.

Figure 1: Free-radical polymerization started by initiator (1)

Variations in chain length are obtained via various termination and transfer reactions. The description of molar mass therefore is one of the most interesting ways to characterize polymers.Molar mass / molar mass distributionThe molar mass is usually described via mean values. Some of those may be specific to the individual method of determination and therefore difficult to compare. Moreover, there are few absolute methods of determination, such as light scattering, that are very time-consuming to 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 gradeMw [g/mole]

EUDRAGIT S 100~ 125 000

EUDRAGIT L 100~ 125 000

EUDRAGIT L 100-55/ L 30 D-55~ 320 000

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 standardGlass 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. Figure 2: Glass transition interval in a DSC diagram

EUDRAGIT gradeTg,m [C] +/- 5

EUDRAGIT E 100 / E PO45

EUDRAGIT L 100-55 / L 30 D-5596

EUDRAGIT FS 30 D43

EUDRAGIT RL 100 / RL PO63

EUDRAGIT RS 100 / RS PO58

EUDRAGIT NE 30 D6

EUDRAGIT NM 30 D 9

EUDRAGIT L 100> 130

EUDRAGIT S 100> 130

Table 2: Glass transition temperatures of EUDRAGIT grades

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).Minimum film-forming temperature (MFT/MFFT)To be able to form a film, the polymer chains must be mobile. Films are usually formed from a solution or dispersion, but may also be obtained from polymer melt by spreading out or film extrusion processes. The film-forming mechanism of a solution is fundamentally different to that of a dispersion. Film formation of a solution takes place through evaporation of the solvent, so that the polymer chains move closer and closer until they enter into contact. The plasticizing effect of the solvent is usually sufficient to obtain the required elasticity for film formation without cracking. In some cases, additional plasticizers can be added to influence the properties of the resulting film.Aqueous dispersions contain polymer latexparticles rather than individual dissolved polymer molecules. Upon evaporation of the water, only the individual particles move closer, without interpenetration. Only when the particles collide, and given adequate elasticity of the polymer spheres, do the particles coalesce due to their surface tension, giving rise to the formation of a homogenous film (see Figure 3).

Figure 3: Film formation from a dispersion

The coalescence of the particles is determined by the polymer itself, the formulation and the process parameters. The characteristics of interest in this context are the glass transition temperature and the particle size of the dispersed particles. The temperature at which film formation takes place is the minimum film-forming temperature (MFT/MFFT) that is characteristic of the dispersion. Naturally, this can be influenced by adding plasticizers. The minimum film-forming temperature (DIN ISO 2115) is determined by applying the dispersion with a doctor knife on a band heater at a defined temperature gradient. The MFT corresponds to the lowest temperature at which a crack-free film is formed and is slightly above the whitening point, the temperature at which the dispersion film is still whitish because the film has not yet fully been formed. The minimum film-forming temperatures of the pure EUDRAGIT dispersions are listed in Table 3.EUDRAGIT dispersionMFT [C]

EUDRAGIT L 30 D-55~ 25

EUDRAGIT FS 30 D~ 14

EUDRAGIT RL 30 D~ 40

EUDRAGIT RS 30 D~ 45

EUDRAGIT NE 30 D~ 5

EUDRAGIT NM 30 D~ 5

Table 3: MFT/MFFT values of EUDRAGIT dispersions

It is important to know or adjust the minimum film-forming temperature of coating formulations because this makes it possible to establish the temperatures for coating processes. As a rule, the product temperature should be at least 10, or better 20C above the minimum film-forming temperature. In practice, this often means that the MFT has to be reduced by adding plasticizers. The choice of plasticizer depends on its effectiveness and influence on the permeability of the resulting polymer films. An example for the influence of hydrophilic and hydrophobic plasticizers on the minimum film-forming temperature of EUDRAGIT L 30 D-55 can be seen in Figure 4. It shows why triethyl citrate (TEC) is recommended as an effective plasticizer for use of this EUDRAGIT type.

Figure 4: Influence of plasticizers on the MFT/ MFFT of EUDRAGIT L 30 D-55Particle size of dispersionsAs described above, the size of the dispersed particles plays an important role in the coalescence process for film formation. There are many different modern methods for determining the particle sizes of dispersions. The most common are laser scanning methods, but these deviate from each other due to different geometric setups and calculation algorithms and thus prevent direct comparison. The mean particle diameters of EUDRAGIT dispersions are around 100 nm, and can be made visible by scanning electron microscopy of dried dispersions (Figure 5).

Figure 5: Scanning electron micrograph of a dried EUDRAGIT L 30 D-55 dispersion

Residual monomer contents of polymersAt the beginning of this chapter we described the manufacture of EUDRAGIT grades by free-radical copolymerization. This process is influenced by diffusion up to the radical-bearing end of the polymer chain. Towards the end of polymerization, small quantities of monomer are always left that have been unable to react. By selecting suitable polymerization processes and process parameters, and by physical methods to remove these residual monomers, our aim is to reduce these quantities as far as possible by state of the art. The determination of the residual monomer contents of the EUDRAGIT grades is described in their monographs and specifications. Upon closer consideration, further reduction down to the detection limit can be expected when spraying the EUDRAGIT dispersions or organic solutions in coating processes.Properties for special applicationsFurther polymer properties can be decisive for special applications, beyond the basic characteristics of EUDRAGIT polymers described above, e.g. water vapor permeability, elongation at break or thermal stability.Water vapor transmission rate (WVTR)The water vapor transmission rate of polymer films may have a decisive influence on the storage stability of moisture-sensitive actives and their formulations. To achieve controlled improvement, it is very useful to determine and understand the water vapor transmission rate. A simple method for this is gravimetric determination of the weight gain of a hygroscopic material (e.g. silica gel) on a defined surface and at defined layer thickness at a specified moisture level and temperature, as stated in DIN 53122. Table 4 gives an overview of the values obtained with EUDRAGIT films using a modified sample preparation.

EUDRAGIT gradeWater vapor permeability rate [g/m2d]

EUDRAGIT E 100 (organic)~ 350

EUDRAGIT E PO (stearic acid formulation)~ 100

EUDRAGIT L 100 / S 100 (redispersed)~ 150

EUDRAGIT L 30 D-55 (10%TEC)~ 100

EUDRAGIT FS 30 D (3% TEC)~ 100

EUDRAGIT NE 30 D~ 300

EUDRAGIT NM 30 D~ 300

EUDRAGIT RS 100 (organic)~ 250

EUDRAGIT RL 100 (organic)~ 450

Table 4: Water vapor permeability rates of EUDRAGIT filmsComparison of these values with the value for hydroxypropyl methyl cellulose (HPMC) of 900 g/m2d illustrates the superiority of poly(meth)acrylates for this application field. The water vapor transmission rates can be influenced via the choice of further excipients in the film-coating formulations. The WVTR of EUDRAGIT E 100 is reduced in the stearic acid containing formulation with EUDRAGIT E PO to much lower values than in an organic application of the pure polymer (see Table 4). Elongation at break

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).

Figure 6: Elongation at break values of EUDRAGIT filmsThermal stabilityIn past years, melt extrusion has become increasingly important in the development of solid pharmaceutical dosage forms. Being poly(meth)acrylates, all EUDRAGIT grades are thermoplastic polymers and therefore in principle suitable for such applications. The thermal integrity is a factor that is just as important as the active ingredients that are to be compounded with the polymers. The thermal stability levels as a function of temperature and time can be examined via thermogravimetric determination, and can if necessary be identified by combination with mass spectroscopy. Tests such as these have shown that depolymerization reactions occur at temperatures higher than 250C. Even at lower temperatures there was damage to the functional groups on the side chains. The maximum temperatures (Tmax) in the following illustration were calculated for a time of 4.5 minutes (an average dwell time in an extrusion process) and with damage to 1% of the functional groups.

Figure 7: Thermostability Tmax of different EUDRAGIT polymers at a residence time of 4.5 minutes (< 1% to the functional groups damaged)These values also indicate that for many EUDRAGIT grades it makes sense to use plasticizers for melt applications, although the actives to be incorporated frequently provide the extrusion mixture with enough of a plasticizing effect.In summary, it has been shown that the process of radical polymerization provides many opportunities for optimizing polymers for pharmaceutical applications. The pharmaceutical functionality of EUDRAGIT polymers is determined by the chemical properties of the side chain, and the physicochemical properties are determined primarily by the main chain. Modern analytical techniques make it possible to extensively characterize the polymers both in development and for assuring steady production.

(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