Product Guide

Pharmaceuticals
Performance Enhancing Technology

Advantia Performance Coating Systems

for Delayed (Enteric) Drug Release

Advancing the Science of Coatings

Table of Contents
Introduction.................................................................................................. 3
ISP: A Partner for Film Coating ........................................................................................3

Development.of.Advantia.Performance.Coating.Systems.. by.Statistical.Design.of.Experiments............................................................. 4
Advantia Performance 190024HA49 .............................................................................5 Color Coating Systems .....................................................................................................5

Application.of.Advantia.Performance.Coating.Systems................................. 6
Aspirin Tablets with Advantia Performance Coating System...........................................6 Details of Coating Process Used ......................................................................................7 Overview of Results Obtained ..........................................................................................9

General.Coating.Guidelines.for.. Advantia.Performance.Coating.Systems..................................................... 12
Suspension Preparation Guidelines ...............................................................................12 General Coating Condition Guidelines ...........................................................................12 Sub-Coating Guidelines .................................................................................................13

Technical.Service.and.Support.................................................................... 14
Technical Capabilities .................................................................................................14

Regulatory.and.Safety................................................................................. 14 . Storage.and.Handling. ................................................................................ 15 Getting.Started........................................................................................... 15

2..Advantia.Performance.Coating.Systems.

Introduction
Advantia Performance Coating Systems are pre-blended, ready-to-use powders based on methacrylic acid ethyl acrylate copolymer for film coating of pharmaceutical oral solid dosage forms (tablets, multiparticulates, two-piece gelatin capsules, and softgels) to produce a delayed-release (or enteric-release) effect. Available pigmented or unpigmented, Advantia Performance Coating Systems are easy-to-use powders that can be readily dispersed in water and applied. With an Advantia Performance Coating Systems, suspension preparation is simple. The more traditional procedure for preparing enteric-coating suspensions often requires three steps. In the traditional process, the first step is to homogenize the plasticizer, detackifier and, optionally, an antifoam agent in water to form a suspension. After a suitable mixing time, this suspension is then added, with mixing, to an acrylic polymer dispersion. This combined suspension is passed through a sieve. For colored enteric-coating formulation, a colorant must be added using an additional processing step. With an Advantia Performance Coating Systems, powder is added to water (stirred in a suitable mixing tank to create a vortex) and mixed. With this process, there are fewer processing steps involved, and fewer ingredients to inventory and submit to quality control testing compared with a traditional system, thus saving time and money.

ISP:.A.Partner.for.Film.Coating
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 formulation of oral solid dosage forms. 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 our customers require from a film coating supplier. Our eight 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.Product.Guide..3 ISP.Pharma.Technologies..3

Development.of.Advantia.Performance.. Coating.Systems.by.Statistical.Design.. of.Experiments

In the development of Advantia Performance Coating Systems, ISP used a statistical design of experiments (D.o.E.) approach to understand the impact of component levels on the performance of an enteric coating system to provide consistent, reproducible enteric release profiles. Using the data generated and the predictive capabilities of the D.o.E. software, ISP can identify the optimum formulation, and its performance attributes, best suited for each customers application. For example, the data facilitate the selection of enteric film coating formulations with a broad range of potential attributes, such as: Fastest drug release in buffer, pH 6.8 Most effective gastric resistance at lowest weight gain Most suitable for enteric coating of intagliated tablets The last of these points often presents a challenge for enteric film coating since the coating deposited within the intagliation is likely to be much thinner, and possess a less suitable coating structure, so that maintaining effective gastric resistance is compromised. ISP scientists have studied enteric-coated intagliated tablets, using Terahertz analysis technology. In Figure 1, Terahertz analysis of two intagliated tablets is shown, indicating that the enteric film is significantly thinner within the intagliation and at the edges.
Figure.1..Coating thickness assessed using Terahertz technology indicates potential for compromising integrity of enteric film coating on an intagliated tablet.

Peak Intensity
-5 5 0 5 0 -5 0 -2 -4 -5

Peak Intensity 30 25 20 15
5 0 5 -5 0

10

4..Advantia.Performance.Coating.Systems.

Advantia.Performance.190024HA49.
Advantia Performance 190024HA49, a white coating formulation, has been selected as our standard concept sample and is intended to be a starting point formulation. In cases where additional performance attributes are required, ISP scientists utilize the D.o.E. software in combination with responses generated from the design of experiment, to produce a coating formulation more suitable for a given application.

Color.Coating.Systems
When a colored tablet is required, a colored Advantia Performance coating can be formulated to meet your individual color needs, limited only by specific color regulations. ISP maintains strict color control to ensure lot-to-lot consistency. Typical colored examples are shown in Figure 2. Alternatively, tablets can be enteric-coated with a white Advantia Performance Coating System and subsequently overcoated with a colored Advantia Prime Coating System (cellulosic film-coating system). For a colored product, please contact your local ISP sales office or account representative.
Figure.2..Advantia Performance Coating Systems can be pigmented to reduce the number of processing steps.

ISP.Pharmaceuticals.Product.Guide..5

Application.of.Advantia.. Performance.Coating.Systems.
Advantia Performance Coating Systems have been used for a broad range of applications requiring a delayed-release coating, including the coating of tablets, capsules (softgels) and multiparticulates. Examples of active pharmaceutical ingredients (APIs) that ISP scientists have worked on with Advantia Performance Coating Systems are shown in Table 1.
Table.1..APIs that have been the subject of coating projects with Advantia Performance Class Product.Examples Diclofenac sodium Ketoprofen Indomethacin Para-amino-salicylic acid Aspirin Omeprazole Pantoprazole Lansoprazole Rabeprazole Bisacodyl Bisacodyl + docusate sodium Sodium valproate Pancreatin

NSAIDS/Analgesics

Proton Pump Inhibitors

Laxatives Anti-epileptics Enzymes

While each coating application may have specific requirements (in terms of type of process and specific process conditions used), a project involving the enteric coating of 325-mg aspirin tablets serves as an example of the application of Advantia Performance Coating Systems.

Aspirin.Tablets.with.Advantia.Performance.Coating.System
The primary objective was to produce enteric-coated aspirin (325-mg) tablets that met all of the requirements of the U.S. Pharmacopeia (USP) in terms of enteric performance, while meeting the critical objectives imposed by accelerated stability testing, especially with respect to levels of free salicylic acid formed after such testing for three months at 40C, 75% RH.

6..Advantia.Performance.Coating.Systems.

Details.of.Coating.Process.Used
All coating trials were performed in an OHara LabCoat IIX fitted with a 19 coating pan using a Schlick ABC spray gun. Initially, 325-mg aspirin tablets were sub-coated with an Advantia Prime 199989HA09 clear coat to a 2% w/w target weight gain, then enteric-coated using Advantia Performance (9% w/w target weight gain). Process details for the application of the sub-coat and the enteric coat are shown in Table 2 and Table 3. In the case of application of the enteric coat, details are provided for two sets of process conditions (one at a lower spray rate and inlet temperature, the other at a higher spray rate and inlet temperature).
Table.2...Process conditions used for application of Advantia Prime sub-coating to 325-mg aspirin tablets Process.Parameter Quantity of tablets used (kg) Sub-coating solution Process air flow Atomizing air pressure (bar) Pattern air pressure (bar) Pan speed (rpm) Spray rate (g min-1) Inlet temperature (C) Exhaust temperature (C) Tablet bed temperature (C) Process.Setting 7.5 Advantia Prime 199989HA09 (sprayed at 10% w/w solids) 200 cfm/340 m3h-1 1.7 2.4 14.5 30 70* 51* 50*

* These temperature conditions are higher than typically recommended for application of Advantia Prime coatings, but ISPs experience has been that the stability of enteric-coated aspirin tablets can be improved when drier process conditions are used during the early phases of the coating process.

ISP.Pharmaceuticals.Product.Guide..7

Table.3..Process conditions used for application of Advantia Performance enteric coating to 325-mg aspirin tablets Process.Parameter Quantity of tablets used (kg) Enteric-coating suspension Process air flow Atomizing air pressure (bar) Pattern air pressure (bar) Pan speed (rpm) Trial.A Spray rate (g min-1) Inlet temperature (C) Exhaust temperature (C) Tablet bed temperature (C) 25 50 40 41 Process.Setting 7.5 (previously sub-coated) Advantia Performance (sprayed at 20% w/w solids) 200 cfm/340 m3h-1 1.7 2.8 15.0 Trial.B 30 60 45 45

At the conclusion of the coating trials, enteric-coated aspirin tablets were evaluated for: Gastric resistance, where 100 tablets were exposed for two hours in 0.1N HCl solution, after which the number of failures was determined (failures in this case consisted of tablets that either disintegrated or had softened and become swollen). Gastric juice uptake, where, again using 100 tablets exposed to 0.1N HCl solution for two hours, the weight of tablets was determined (after carefully drying the surface of each tablet before weighing). Drug release in gastric juice, after two hours, using the USP apparatus 2 and 0.1N HCl solution as the dissolution medium. Dissolution in phosphate buffer, pH 6.8, again using USP apparatus 2. In addition, samples of enteric-coated tablets were packaged into HDPE bottles, with desiccant packs and subsequently foil sealed, and then set up for stability testing under accelerated conditions for three months at 40C and 75 %RH. At the conclusion of the testing period, tablet samples were subjected to analysis for: Drug release in gastric juice, after two hours, using the USP apparatus 2 and 0.1N HCl solution as the dissolution medium. Dissolution in phosphate buffer, pH 6.8, again using USP apparatus 2. Free salicylic acid content.

8..Advantia.Performance.Coating.Systems.

Overview.of.Results.Obtained
The results obtained for 325-mg aspirin tablets, enteric-coated as described earlier, are shown in Table 4.
Table.4..Enteric test and stability results obtained for 325-mg aspirin tablets coated with Advantia Performance Coating System Test.Condition Initial Trial.A Acid uptake (%, mean for 100 tablets after 2 hours exposure) Gastric failures (% for 100 tablets after 2 hours exposure at 100 rpm) Dissolution in 0.1N HCl solution (% after 2 hours exposure) Dissolution in phosphate buffer, pH=6,8 (% after 90 minutes at 100 rpm) 5.5 Trial.B 3.8 Results.Obtained

5.0*

3.0*

0.61**

1.86**

100***

100***

After.3.Months.at.40C,.75.%RH Dissolution in 0.1N HCl solution (% after 2 hours exposure at 100 rpm) Dissolution in phosphate buffer, pH=6,8 (% after 90 minutes at 100 rpm) Free salicylic acid (%) 1.43** 2.64**

100*** 0.09****

100*** 0.06****

* No tablets disintegrated, and the only failures observed were tablets with a slight softening of the coating ** USP limit nmt 10% *** USP Q value > 80% **** USP limit nmt 3.0%

ISP.Pharmaceuticals.Product.Guide..9

A representative sample of the enteric-coated aspirin tablets is shown in Figure 3.

Figure.3..Enteric-coated aspirin tablets (325-mg) with Advantia Performance Coating System

As can be seen, all samples of aspirin tablets that had been enteric-coated with an Advantia Performance Coating System easily met the pre-requisites of the USP monograph for delayed-release aspirin tablets.

10..Advantia.Performance.Coating.Systems.

In terms of gastric resistance, further improvements could be obtained, if required, by adjusting the levels of enteric coating applied. Typical enteric dissolution results to be obtained by doing so are shown in Figure 4.
Figure.4.. Influence of amount of Advantia Performance Coating System applied on drug release from enteric-coated tablets
120 100 80 60 40 20 0 0 30 60 90 120 125 Time (min) 130 135 140 145 150

% Drug Released

6% Weight Gain 12% Weight Gain

8% Weight Gain 14% Weight Gain

10% Weight Gain 16% Weight Gain

Note: First two hours of test were conducted in 0.1N HCl, after which the medium was changed to buffer, pH=6.8.

ISP.Pharmaceuticals.Product.Guide..11

General.Coating.Guidelines.for.. Advantia.Performance.Coating.Systems
Suspension.Preparation.Guidelines
It is recommended to use Advantia Performance Coating Systems at 20% solids in water. The maximum solids level will depend on the particular spray gun, pump and coating equipment used. The suspension is prepared in a one-step process that involves: Adding the required quantity of water into a suitable mixing vessel and centering the propeller stirrer in the mixing vessel as close to the bottom as possible. Setting the mixer to the fastest possible speed that maintains a vortex without drawing air into the water. Adding the Advantia Performance powder to the vortex as quickly as possible, avoiding flotation of the powder and increasing the mixer speed as necessary to maintain the vortex. Maintaining mixer speed to ensure a reasonably vigorous mixing of the suspension throughout the 60-minute reconstitution period. At the end of the reconstitution period, the suspension should ideally be passed through a 60-mesh screen to remove any undispersed material. Advantia Performance Coating System suspensions should be gently mixed during the coating process in order to prevent sedimentation of suspended ingredients and thus a change in the respective ratios of critical ingredients in the coating formulation.

General.Coating.Condition.Guidelines
The suggested coating conditions for application of Advantia Performance Coating System from an aqueous coating suspension with solids content of ~20% on tablets are provided in Table 5. As the methacrylic polymers have a lower glass transition temperature (Tg) than hydroxypropylmethyl cellulose (HPMC), lower inlet, exhaust and bed temperatures are recommended compared with those conditions used for a typical cellulosic film-coating process.

12..Advantia.Performance.Coating.Systems.

Table.5. General coating conditions for application of aqueous coating suspension of Advantia Performance Coating System using a 19 fully perforated pan fitted with a Schlick ABC spray gun and loaded with 7-8kg of tablets. Parameter Inlet temperature (oC) Tablet bed temperature (oC) Exhaust temperature (oC) Spray rate (g min-1) Air Flow Atomizing air pressure (bar) Pattern air pressure (bar) Pan speed (rpm) Settings 50-60 36-42 38-44 22-32 175-225 cfm/297-382 m3 h1 2.2-2.5 2.4-2.8 12-18

Sub-Coating.Guidelines
While application of a sub-coat to the surface of the dosage form being coated is not a pre-requisite for using Advantia Performance coatings, this practice is often beneficial since it: Minimizes surface abrasion of the core prior to application of the enteric coating, thus ensuring a more reproducible result in terms of drug release. Minimizes the potential for interaction between the core and the enteric coating, especially when such interaction may compromise the functionality of the enteric coating (as is potentially the case when the core contains alkaline materials) or may affect the stability of the API should it be sensitive to the inherent acidity of the enteric-coating polymer. ISP typically recommends Advantia Prime 199989HA09 (Table 6). However, a wide range of cellulosic-based film-coating formulations can be used as a sub-coating, depending on the tablet core and local regulations. Please consult your local ISP sales office or account representative.
Table.6. Prior to application of an Advantia Performance enteric-release coating, Advantia Prime 199989HA09 should be applied as a sub-coating. Suggested. Suspension. Solids.(%) 10-12 Suggested. Weight.Gain. (%)* 1.5-3.0

Product.Name Advantia Prime 199989HA09

Color Clear

* Depending on the size, shape and surface characteristics of the core (tablets, capsules or multiparticulates).

ISP.Pharmaceuticals.Product.Guide..13

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 eight 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 is fully equipped and staffed with pharmaceutical scientists who have experience in pharmaceutical formulation and film-coating technology.

Technical.Capabilities
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 strength, friability, compaction profiles, and dissolution characteristics. We employ 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. 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 adhesion Opacity of applied coatings Film surface qualities, including gloss and coating roughness Coating uniformity, structure and density Coating permeability Rheological characteristics of coating liquids Coated product stability Color matching Dissolution characteristics

Regulatory.and.Safety
Advantia Performance 190024HA49 contains ingredients acceptable for use on pharmaceutical products sold in North America, the European Union and Japan. The polymer in Advantia Performance 190024HA49 is produced from dispersions that comply with the United States Pharmacopeia/National Formulary (USP/NF) designation for Methacrylic Acid Copolymer Dispersion and JPE monograph for Methacrylic Acid Copolymer LD. The polymer conforms to Ph.Eur 5.7 Methacrylic Acid Ethyl Acrylate Copolymer 1:1 (Type B)

14..Advantia.Performance.Coating.Systems.

Advantia Prime 199989HA09 contains ingredients acceptable for use on pharmaceutical products sold in North America, the European Union and Japan. ISP maintains Type IV Drug Master Files (DMFs) with the United States Food and Drug Administration (FDA) for Advantia Prime and Advantia Performance products (Table 8).
Table.8..To support regulatory filings of drug products with U.S. FDA, ISP supports DMFs for Advantia Coating Systems Product.Family Advantia Prime Advantia Performance Type.IV.DMF.Number 20851 21613

Please consult your local ISP sales office for information concerning the suitability for use on pharmaceutical products to be sold in other regions. ISP recognizes the importance of providing leadership in health, safety and regulatory product oversight as a fundamental part of our business. As a leading global specialty chemical company operating in over 90 countries, ISP has experience in addressing local and global regulatory concerns.

Storage.and.Handling
All Advantia Coating Systems should be stored in a cool, dry place out of direct sunlight. The containers should be tightly closed when not in use. The retest intervals for Advantia Performance Coating Systems are shown in Table 9.
Table.9..Retest intervals for Advantia Performance Coating Systems Product.Family Advantia Performance Advantia Performance Color Clear and White Color Retest.Interval 24 months 12 months

The retest interval for Advantia Prime 199989HA09 is 24 months.

Getting.Started
To get started, contact your local ISP sales office to discuss your requirements for film coatings or visit us at www.ispcorp.com.

ISP.Pharmaceuticals.Product.Guide..15

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Trademark registration applied for Registered trademark of the ISP group International Specialty Products. 2008 Designed & Printed in USA.

Product Code: PHAR_C1020 07/2008

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 products suitability for purchasers 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 ISPs 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 purchasers use of any information, product, method or apparatus described in this brochure.