Advantia Prime Coating Systems

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1 Advantia Prime Coating Systems Advancing the Science of Coatings

Table of Contents Introduction....................................................3 Development of Advantia Prime Coating Systems by Statistical Design of Experiments (D.o.E.)...........................4 Application of D.

2 Table of Contents Introduction Development of Advantia Prime Coating Systems by Statistical Design of Experiments (D.o.E.) Application of D.o.E. Results for Coating Formulation Prediction Technical Service and Support Regulatory and Safety Getting Started ISP Pharmaceuticals Advantia Coating Systems

Simply, a film coating for an immediate release tablet is comprised of polymer, plasticizer, and optionally pigment/opacifier.

3 Introduction Film coating systems are applied to immediate release dosage forms for a number of purposes including improved tablet appearance, brand identity, product and/or dose identification, taste/odor masking, elimination of dust, improved flow and improved stability. Thus, the film coating is an essential part of the final product. Simply, a film coating for an immediate release tablet is comprised of polymer, plasticizer, and optionally pigment/opacifier. ISP provides these ingredients as Advantia Prime Coating Systems, pre blended, ready to use powders that are readily dispersed in water and applied to the substrate. Advantia Prime Coating Systems are available pigmented or unpigmented and are based on existing pharmaceutically acceptable polymers, for example hydroxypropylmethyl cellulose (HPMC), hydroxyproypyl cellulose (HPC) and ethyl cellulose (EC). These polymers are used alone or in combinations to provide optimal results. The selection of ingredients and ingredient levels for a formulation is a critical factor in obtaining the target appearance and performance on the tablet core and in minimizing processing problems. Optimizing a film coating formulation requires balancing critical properties, such as film strength, film adhesion, film flexibility and opacity. ISP has utilized a scientific approach for characterizing the nature of the relationships between components and their use levels in coating formulations. As a result, each Advantia Prime Coating System is custom formulated and selected to provide the optimum performance on each substrate. ISP: A Partner for Film Coatings Experience. As a supplier of high quality excipients for solid dosage forms, including Plasdone binders and Polyplasdone super disintegrants, to the pharmaceutical, vitamin and nutritional industries for over 50 years, ISP has developed sound expertise in the formulation of tablet cores. This expertise complements our capabilities with respect to designing film coating systems. ISP has over 50 sales specialists and 40 scientists, dedicated to its pharmaceutical business, working in local offices and laboratories around the world to respond to customer needs and ensure consistent product from laboratory to commercial production. Innovative. In addition to offering film coating systems based on conventional technology, ISP is developing innovative coating systems based on its experience as a leading polymer research company. The ISP technical team has core strengths in design and development of novel functional systems based on molecular structure property relationships, to provide rapid solutions to customer needs. At ISP, our scientists are working to develop an enhanced range of film coatings designed to meet the evolving needs of the pharmaceutical industry. We are committed to advancing the science of tablet film coatings. Worldwide. With over 70 locations worldwide, serving customers in more than 90 countries, ISP can provide the global sales and service support you require from a coating supplier. Our seven pharmaceutical laboratories are staffed with scientists that have experience in the formulation of oral solid dosage forms, design of coating formulations, color matching and coating applications. ISP Pharmaceuticals Advantia Coating Systems 3

4 Development of Advantia Prime Coating Systems by Statistical Design of Experiments (D.o.E.) In order to supply a film coating that is suitable for a specific tablet core, ISP scientists have characterized the nature of the relationships between components and levels used in a film coating system. Using a statistical design of experiments (D.o.E.) approach, the polymer, plasticizer and pigment levels within the formulation, and the plasticizer type, have been varied and their effects on film performance, opacity, suspension viscosity and additional characteristics have been evaluated. Applying the data generated and the D.o.E. software, ISP can predict the performance attributes of each coating formulation. The information presented provides an overview of the data generated. Example: Impact of Plasticizers on Film Strength, Elasticity and Adhesion The purpose of this study was to understand the interactions of low molecular weight hydroxypropylmethyl cellulose (HPMC, 6cP), titanium dioxide and five commonly used plasticizers on key film properties. The plasticizers studied were: Polyethylene Glycol 400 (PEG 400) Triacetin Triethyl Citrate Propylene Glycol Glycerin A D Optimal, quadratic model design of experiments was created using Design Expert 6 software (StatEase). The model was a four factor design consisting of three mixture component factors and one categorical factor (plasticizer type). The following multi linear constraints were entered: Component Material Used Levels Polymer HPMC, 6 cp 57 75% Pigment Titanium Dioxide, USP Grade 20 35% Plasticizer Varied 3 14% The study included 35 unique formulations and 5 replicate formulations. Nineteen different responses were measured for each formulation, including film strength, elasticity, toughness, adhesion, suspension viscosity at 12% and 15% solids, and contrast ratio. A sampling of the results for three important film properties, film strength, film elasticity and film adhesion for two plasticizers are reported below. 4 ISP Pharmaceuticals Advantia Coating Systems

Film Strength and Elasticity Film strength is a measure of the force required to break the film. Elasticity is reported as percent elongation of the film prior to failure.

The results for film toughness are not reported here, since they tend to be redundant when also reporting results for film strength and elasticity.

The dried films were cut into strips and held at constant temperature and humidity for 24 hours prior to testing.

5 Film Strength and Elasticity Film strength is a measure of the force required to break the film. Elasticity is reported as percent elongation of the film prior to failure. Film toughness is a measure of the resilience of the film, and takes into account both film strength and elasticity. It is represented by the area under the stress strain curve. The results for film toughness are not reported here, since they tend to be redundant when also reporting results for film strength and elasticity. Methods: To prepare films, a 20% suspension in water of each formulation was made and a known weight of each suspension (after de aeration) was spread in a container and dried at 45 o C. The dried films were cut into strips and held at constant temperature and humidity for 24 hours prior to testing. Film thickness was measured at three points along the strip using a Mitutoyo Digimatic Micrometer. Film strength and elasticity were measured using a TA.XT Plus texture analyzer (Texture Technologies Corporation) (Figure 1). Multiple measurements were taken for each formulation. Figure 1. Texture analyzer for evaluating film strength and elasticity. ISP Pharmaceuticals Advantia Coating Systems 5

Results: Typical film strength results obtained for HPMC films with PEG 400 and propylene glycol as plasticizers are shown in Figure

5 5700 C (20) B (3) B (23) B (23) A (57) PEG 400 Propylene Glycol Figure 2.

C (40) A range of film strength values was obtained, from 3,200 to 7,000 g/mm 2.

observed impact (possibly due to plasticizer volatility).

22 16 19 14 Strain to Break 17 14 Strain to Break 13 12 11 11 A (77) C (20) B (23) B (3) A (57) C (40) PEG 400 Propylene Glycol

6 Results: Typical film strength results obtained for HPMC films with PEG 400 and propylene glycol as plasticizers are shown in Figure Film strength A (77) C (20) B (3) A (57) C (40) Film strength C (20) B (3) B (23) B (23) A (57) PEG 400 Propylene Glycol Figure 2. Film strength results obtained for HPMC films with PEG 400 and propylene glycol as plasticizers. C (40) A range of film strength values was obtained, from 3,200 to 7,000 g/mm 2. The results indicate that film strength decreased with increasing plasticizer content and, to a lesser extent, with increasing pigment content. The level of PEG 400 had the most significant impact on film strength, while that of propylene glycol had the least significant observed impact (possibly due to plasticizer volatility). Film elasticity results obtained for HPMC films with PEG 400 and propylene glycol as plasticizers are shown in Figure Strain to Break Strain to Break A (77) C (20) B (23) B (3) A (57) C (40) PEG 400 Propylene Glycol Figure 3. Film elasticity results obtained for HPMC films with PEG 400 and propylene glycol as plasticizers. A (77) C (20) B (23) B (3) A (57) These results indicate that film elasticity is impacted by both plasticizer and pigment levels. Polyethylene glycol level had the most significant impact, while the remaining plasticizers studied all showed similar results. Film elasticity values obtained ranged from 10% to 27%, as expressed by the design space. C (40) 6 ISP Pharmaceuticals Advantia Coating Systems

Adhesion Adhesion Methods: Samples for film adhesion analysis were prepared by coating 0.375 inch diameter, flat faced placebo tablets under standard conditions to a 3% weight gain.

Each coating formulation was prepared as a 12 w/w% suspension in water and applied using a 15 inch side vented coating pan.

Prior to testing, the film was carefully scored at the land of the tablet with a scalpel, and the tablet was clamped in the lower platen of the texture analyzer, with the scored edge uppermost

The probe was slowly withdrawn from the tablet surface and the force required to remove the film was measured. Multiple tests were performed for each formulation.

7 Adhesion Adhesion Methods: Samples for film adhesion analysis were prepared by coating inch diameter, flat faced placebo tablets under standard conditions to a 3% weight gain. These tablets were mixed with inch diameter normal convex tablets manufactured using the same placebo formula. Each coating formulation was prepared as a 12 w/w% suspension in water and applied using a 15 inch side vented coating pan. The flat faced tablets were separated from each batch at the conclusion of each run, and held in a constant temperature and humidity chamber for 24 hours. Prior to testing, the film was carefully scored at the land of the tablet with a scalpel, and the tablet was clamped in the lower platen of the texture analyzer, with the scored edge uppermost (Figure 4). A cylindrical probe was fitted to the upper platen of the texture analyzer and double sided foam adhesive tape used to bond to both the probe and tablet surface. The probe was slowly withdrawn from the tablet surface and the force required to remove the film was measured. Multiple tests were performed for each formulation. Typical data generated are shown in Figure 5. Figure 4. A pigmented tablet coating is tested for adhesion Adhesion C (20) A (77) 93 C (20) A (77) B (23) A (57) B (3) B (23) A (57) B (3) PEG 400 C (40) C (40) Propylene Glycol Figure 5. Adhesion results obtained for HPMC film coatings with PEG 400 and propylene glycol as plasticizers. Results: The results indicate that film adhesion increases with increasing plasticizer content. The level of polyethylene glycol had the most significant impact on adhesion. A range of film adhesion values was obtained, the range expressed by the design space being 67 to 320 g mm. ISP Pharmaceuticals Advantia Coating Systems 7

software, the responses generated from the design of experiments, weighted in terms of importance specific to each situation, can be used to design a coating formulation suitable for a particular

Example: Resolving Edge Wear on Placebo Tablets Edge wear, or chipping defects at tablet edges, is a common undesirable film coating defect, since it is aesthetically unpleasing, exposes active to

8 Application of D.o.E. Results for Coating Formulation Prediction Using the D.o.E. software, the responses generated from the design of experiments, weighted in terms of importance specific to each situation, can be used to design a coating formulation suitable for a particular tablet core, to optimize a formulation for specific performance characteristics, or to trouble shoot coating problems. Example: Resolving Edge Wear on Placebo Tablets Edge wear, or chipping defects at tablet edges, is a common undesirable film coating defect, since it is aesthetically unpleasing, exposes active to environmental factors and gives the impression of sub standard product (Figure 6). When edge wear occurs, the coating process conditions, the tablet core and the coating formulation can all be considered in the effort to eliminate the problem. Common causes of edge wear are highly friable cores; flashing at the land of the tablet; inadequate film strength; poor film elasticity; and use of inappropriate coating process conditions. Figure 6. Tablets with edge wear. In this study, the process conditions (Table 1) used in the coating of the tablets in Figure 6 were examined and found to be appropriate for a pigmented, HPMC based film coating in a 15 inch coating pan. Spray Rate Pan Speed (15 coating pan) Inlet Temperature Exhaust Temperature 18 g/min 12.5 rpm ~68 o C ~47 o C Table 1. Processing conditions were found to be within typical ranges. Next, the tablet cores were evaluated (Table 2) and the tablets were found to be suitably robust. Friability <0.1% Crushing Strength 21 kp Table 2. Tablet cores are sufficiently robust. 8 ISP Pharmaceuticals Advantia Coating Systems

After examining the film properties (Table 3), it was concluded that film strength was inadequate and that the coating should be reformulated to maximize film strength.

2% Film Adhesion 346 g mm Film Toughness 25 (kg/mm 2 ) % Table 3. Initial film coating properties. Using the D.o.E. software, the responses were weighted to improve film strength (Table 4).

Response Goal Importance* Film Strength Maximize 5 Elasticity Maximize 2 Adhesion Maximize 2 Viscosity (15% solids) Minimize 1 Contrast Ratio Maximize 3 Table 4.

9 After examining the film properties (Table 3), it was concluded that film strength was inadequate and that the coating should be reformulated to maximize film strength. In this example, changing the formulation ingredients was not an option, thus PEG 400 was retained as the plasticizer. Tensile Strength 1924 g/mm 2 Elasticity 17.2% Film Adhesion 346 g mm Film Toughness 25 (kg/mm 2 ) % Table 3. Initial film coating properties. Using the D.o.E. software, the responses were weighted to improve film strength (Table 4). The coating was then reformulated to improve film strength based on the output of the D.o.E. software. Response Goal Importance* Film Strength Maximize 5 Elasticity Maximize 2 Adhesion Maximize 2 Viscosity (15% solids) Minimize 1 Contrast Ratio Maximize 3 Table 4. The responses were weighted to improve film strength. *Scale is 1 5, 5 is most important The new coating formulation was then applied to identical tablet cores using the same process parameters and the results (Figure 7) show that the edge wear has been eliminated. Analysis of film properties (Table 5) shows that the tensile strength of the film has been significantly increased. Figure 7. The film was reformulated to eliminate edge wear. Tensile Strength 3619 g/mm 2 Elasticity 11.8% Film Adhesion 186 g mm Film Toughness 25 (kg/mm 2 ) % Table 5. Modified film coating properties. ISP Pharmaceuticals Advantia Coating Systems 9

10 ISP s Global Technical Centers Americas Wayne, NJ * Philadelphia, PA * Sao Paulo, Brazil * Mexico City, Mexico * Asia Pacific Shanghai, China * Hyderabad, India * Europe Istanbul, Turkey * = Global Research and Development * = Tech Service Center Technical Service and Support ISP is committed to providing service and support to customers globally during the development process through full scale commercial production. At ISP, we have seven technical centers dedicated to supporting our customers, and their efforts with respect to pharmaceutical oral solid dosage forms, with our excipients and film coating systems. Each laboratory location is fully equipped and staffed with pharmaceutical scientists that have experience in pharmaceutical formulation and film coating technology. As a supplier of high performance Plasdone binders and Polyplasdone super disintegrants, ISP has core capabilities in tablet formulation, including orally disintegrating tablets, and tablet process technology, involving wet granulation, direct compression, and roller compaction. We routinely evaluate tablet performance, including tablet hardness, friability, compaction profiles, and dissolution characteristics. ISP employs a compaction simulator (in our Wayne, NJ R&D laboratory) to study the fundamentals of compaction and assist customers in formulation development, excipient selection and scale up. 10 ISP Pharmaceuticals Advantia Coating Systems

To support our Advantia Coating Systems, ISP has a broad range of tools available for characterizing and assessing the properties of film coatings and film coated products, including those suitable

matching Drug release characteristics (dissolution).

11 To support our Advantia Coating Systems, ISP has a broad range of tools available for characterizing and assessing the properties of film coatings and film coated products, including those suitable for determining: Film mechanical properties (film strength and elasticity) Film adhesion Opacity (hiding power) Gloss Rheological characteristics of coating liquids Coated product stability Color matching Drug release characteristics (dissolution). Regulatory and Safety ISP recognizes the importance of providing leadership in health, safety and regulatory product oversight as a fundamental part of our business. ISP supports its products with safety testing, toxicology and risk assessments. As a leading global specialty chemical company operating in over 90 countries, ISP has experience in addressing local and global regulatory concerns. As a supplier to the pharmaceutical industry and a founding member of International Pharmaceutical Excipients Council (IPEC), ISP is experienced with regulatory reviews and filings, including Drug Master Files (DMF) and has expertise in global development of pharmacoepial monographs. Getting Started To get started, contact your local ISP sales office to discuss your requirements for film coatings for your immediate release tablet and capsule formulations or visit us at ISP also offers Advantia Performance Coating Systems for enteric release, based on acrylic polymers. Like the Advantia Prime Coating Systems, Advantia Performance Coating Systems are scientifically formulated to meet specific performance requirements. ISP Pharmaceuticals Advantia Coating Systems 11

12 GLOBAL LOCATIONS FOR SALES & CUSTOMER SERVICE INTERNATIONAL SPECIALTY PRODUCTS WORLD HEADQUARTERS INTERNATIONAL SPECIALTY PRODUCTS 1361 Alps Road, Wayne, New Jersey 07470, USA Tel: Fax: CUSTOMER SERVICE: Toll Free: 1 (800) Fax: info@ispcorp.com SAMPLE CENTER: Toll Free: 1 (800) isp@chemicalmarketing.com USA & CANADA REGIONAL SALES OFFICES PERSONAL CARE LOMBARD, ILLINOIS Toll Free: 1 (800) Tel: Fax: jdressler@ispcorp.com PHARMACEUTICALS WAYNE, NEW JERSEY Toll Free: 1 (877) Fax: emcdonald@ispcorp.com PERSONAL CARE SHERMAN OAKS, CALIFORNIA Toll Free: 1 (800) Fax: ujenkins@ispcorp.com PERFORMANCE CHEMICALS WAYNE, NEW JERSEY Tel: Fax: acalvani@ispcorp.com FOOD INGREDIENTS SAN DIEGO, CALIFORNIA Toll Free: 1 (888) Fax: foodinfo@ispcorp.com CANADA Tel: Toll Free: 1 (800) Fax: adumancic@ispcorp.com LATIN AMERICA CUSTOMER SERVICE ARGENTINA Tel: Fax: ispargentina@ispcorp.com BRAZIL Tel: Fax: ispbrasil@ispcorp.com COLOMBIA Tel: + 57 (1) Fax: + 57 (1) ldiaz@ispcorp.com MEXICO Tel: Fax: isp_mexico@ispcorp.com VENEZUELA Tel: Fax: dnelson@ispcorp.com EUROPE, MIDDLE EAST & AFRICA CUSTOMER SERVICE AFRICA Tel: +49 (0) Fax: +49 (0) info.africa@ispcorp.com AUSTRIA Tel: +43 (0) Fax: +43 (0) info.austria@ispcorp.com BELGIUM Tel: +32 (0) (0) Fax: +32 (0) info.belgium@ispcorp.com BULGARIA Tel: +359 (0) Fax: +359 (0) info.bulgaria@ispcorp.com CZECH REPUBLIC Tel: Fax: info.czech@ispcorp.com FRANCE Tel: +33 (0) (0) Fax: +33 (0) info.france@ispcorp.com GERMANY Tel: +49 (0) (0) (0) Fax: +49 (0) info.germany@ispcorp.com HUNGARY Tel: Fax: info.hungary@ispcorp.com ITALY Tel: Fax: info.italy@ispcorp.com NETHERLANDS Tel: +31 (0) Fax: +31 (0) info.netherlands@ispcorp.com NORDEN (Denmark, Estonia, Iceland, Finland, Norway, Sweden) Tel: +46 (0) Fax: +46 (0) info.norden@ispcorp.com POLAND Tel: +48 (0) Fax: +48 (0) info.poland@ispcorp.com RUSSIA Tel: Fax: info.russia@ispcorp.com SPAIN & PORTUGAL Tel: +34 (0) Fax: +34 (0) info.spain@ispcorp.com SWITZERLAND Tel: +41 (0) Fax: +41 (0) info.switzerland@ispcorp.com TURKEY & MIDDLE EAST Tel: +9 (0) Fax: +9 (0) info.turkey@ispcorp.com info.middleeast@ispcorp.com UK Tel: +44 (0) (0) Fax: +44 (0) info.uk@ispcorp.com ASIA PACIFIC CUSTOMER SERVICE N.S.W. AUSTRALIA Tel: Fax: roppy@ispcorp.com VICTORIA, AUSTRALIA Tel: Fax: roppy@ispcorp.com BEIJING, CHINA Tel: Fax: hwong@ispcorp.com CHENGDU, CHINA Tel: Fax: hwong@ispcorp.com GUANGZHOU, CHINA Tel: Fax: hwong@ispcorp.com SHANGHAI, CHINA Tel: Fax: hwong@ispcorp.com HONG KONG Tel: Fax: hwong@ispcorp.com HYDERABAD, INDIA Tel: Fax: ekalyanpur@ispcorp.com MUMBAI, INDIA Tel: Fax: ekalyanpur@ispcorp.com INDONESIA Tel: Fax: mchondrodihardjo@ispcorp.com OSAKA, JAPAN Tel: Fax: myamashita@ispcorp.com TOKYO, JAPAN Tel: Fax: myamashita@ispcorp.com KOREA Tel: Fax: ksoh@ispcorp.com MALAYSIA Tel: Fax: ffoo@ispcorp.com PHILIPPINES Tel: Fax: rcomagon@ispcorp.com SINGAPORE Tel: Fax: ffoo@ispcorp.com TAIWAN Tel: Fax: cchiang@ispcorp.com THAILAND Tel: Fax: spordi@ispcorp.com Trademark registration applied for Registered trademark of the ISP group International Specialty Products Designed & Printed in USA. Product Code: PHAR_C /2006 The information contained in this brochure and the various products described are intended for use only by persons having technical skill and at their own discretion and risk after they have performed necessary technical investigations, tests and evaluations of the products and their uses. While the information herein is believed to be reliable, we do not guarantee its accuracy and a purchaser must make its own determination of a product s suitability for purchaser s use, for the protection of the environment, and for the health and safety of its employees and the purchasers of its products. Neither ISP nor its affiliates shall be responsible for the use of this information, or of any product, method, formulation, or apparatus described in this brochure. Nothing herein waives any of ISP s or its affiliates conditions of sale, and WE MAKE NO WARRANTY, EXPRESS OR IMPLIED, OF MERCHANTABILITY OR FITNESS OF ANY PRODUCT FOR A PARTICULAR USE OR PURPOSE. We also make no warranty against infringement of any patents by reason of purchaser s use of any information, product, method or apparatus described in this brochure.

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