Advantia Prime Coating Systems - Microsoftvertassets.blob.core.windows.net/download/7ae8c7d4/... · factor in obtaining the target appearance and performance on the tablet core and

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Advantia™ Prime Coating Systems

Advancing the Science of Coatings

Table of ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3

Development of Advantia™ Prime Coating Systems by Statistical Design of Experiments (D.o.E.) . . . . . . . . . . . . . . . . . . . . . . . . . . .4

Application of D.o.E. Results for Coating Formulation Prediction . . . . . . . . . . . .8

Technical Service and Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10

Regulatory and Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11

Getting Started . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11

2 • ISP Pharmaceuticals • Advantia™ Coating Systems

IntroductionFilm coating systems are applied to immediate–release dosage forms for a numberof purposes including improved tablet appearance, brand identity, product and/ordose identification, taste/odor masking, elimination of dust, improved flow andimproved 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 arereadily dispersed in water and applied to the substrate. Advantia™ Prime CoatingSystems 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, filmflexibility 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 customformulated and selected to provide the optimum performance on each substrate.

ISP: A Partner for Film CoatingsExperience. 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 pharmaceuticalbusiness, 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 conventionaltechnology, ISP is developing innovative coating systems based on its experienceas a leading polymer research company. The ISP technical team has core strengthsin 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 coatingsdesigned 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 than90 countries, ISP can provide the global sales and service support you requirefrom a coating supplier. Our seven pharmaceutical laboratories are staffed withscientists 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

Development of Advantia™ PrimeCoating 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 levelswithin the formulation, and the plasticizer type, have been varied and their effectson film performance, opacity, suspension viscosity and additional characteristicshave 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 AdhesionThe purpose of this study was to understand the interactions of low molecularweight hydroxypropylmethyl cellulose (HPMC, 6cP), titanium dioxide and fivecommonly 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:

The study included 35 unique formulations and 5 replicate formulations. Nineteen different responses were measured for each formulation, including filmstrength, 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.


Component Material Used Levels

Polymer HPMC, 6 cP 57–75%

Pigment Titanium Dioxide, USP Grade 20–35%

Plasticizer Varied 3–14%


Film Strength and ElasticityFilm 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 ameasure of the resilience of the film, and takes into account both film strengthand 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 spreadin a container and dried at 45oC. The dried films were cut into strips and held at constant temperature and humidity for 24 hours prior to testing. Film thicknesswas 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.


Results: Typical film strength results obtained for HPMC films with PEG 400 and propylene glycol as plasticizers are shown in Figure 2.

A range of film–strength values was obtained, from 3,200 to 7,000 g/mm2. 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 propyleneglycol 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 3.

Figure 2. Film strength results obtained for HPMC films with PEG 400 and propylene glycol as plasticizers.

PEG 400

C (40)

A (57)

A (77)

5800

5150

4500

3850

3200

Film

str

engt

hC (20)

B (23)

B (3)C (20)

Propylene Glycol

C (40)A (57)

Film

str

engt

h

B (23)

B (3)

6310

6127.5

6005

5852.5

5700

Figure 3. Film elasticity results obtained for HPMC films with PEG 400 and propylene glycol as plasticizers.

PEG 400

C (40)

A (57)

A (77)

22

19

17

14

11

C (20)

B (3)

B (23) B (23)

C (40)

A (57)

A (77)

16

14

13

12

11

C (20)

B (3)

Propylene Glycol

These results indicate that film elasticity is impacted by both plasticizer and pigment levels. Polyethylene glycol level had the most significant impact, whilethe remaining plasticizers studied all showed similar results. Film elasticity valuesobtained ranged from 10% to 27%, as expressed by the design space.

Stra

in to

Bre

ak

Stra

in to

Bre

ak


AdhesionMethods: 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. These tablets were mixed with 0.375–inch diameter normalconvex 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 fromeach 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 scoredat 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 theupper platen of the texture analyzerand double–sided foam adhesive tapeused to bond to both the probe andtablet surface. The probe was slowlywithdrawn from the tablet surface and the force required to remove thefilm 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.

A (77)

B (3)

B (23)

330

268

205

143

80

Adhe

sion

A (57)

C (40)

C (20)

Adhe

sion

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.

A (77)

B (3)

B (23)

A (57)

C (40)

C (20)

170

151

132

112

93

Figure 5. Adhesion results obtained for HPMC film coatings with PEG 400 and propylene glycol as plasticizers.

PEG 400 Propylene Glycol


Application of D.o.E. Results forCoating 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 formulationfor specific performance characteristics, or to trouble–shoot coating problems.

Example: Resolving Edge Wear on Placebo TabletsEdge 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, thecoating process conditions, thetablet core and the coating for-mulation can all be consideredin the effort to eliminate theproblem. Common causes ofedge wear are highly friablecores; flashing at the land of thetablet; inadequate film strength;poor film elasticity; and use ofinappropriate coating processconditions. 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.

Next, the tablet cores were evaluated (Table 2) and the tablets were found to be suitably robust.

Spray Rate 18 g/min

Pan Speed (15” coating pan) 12.5 rpm

Inlet Temperature ~68 oC

Exhaust Temperature ~47oC

Table 1. Processing conditions were found to be within typical ranges.

Friability <0.1%

Crushing Strength 21 kp

Table 2. Tablet cores are sufficiently robust.


After examining the film properties (Table 3), it was concluded that film strengthwas inadequate and that the coating should be reformulated to maximize filmstrength. In this example, changing the formulation ingredients was not an option, thus PEG 400 was retained as the plasticizer.

Tensile Strength 1924 g/mm2

Elasticity 17.2%

Film Adhesion 346 g–mm

Film Toughness 25 (kg/mm2)–%

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.

The new coating formulationwas then applied to identicaltablet cores using the sameprocess parameters and the results (Figure 7) show that theedge wear has been eliminated.Analysis of film properties(Table 5) shows that the tensilestrength of the film has been significantly increased.

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

Figure 7. The film was reformulated to eliminate edge wear.

Tensile Strength 3619 g/mm2

Elasticity 11.8%

Film Adhesion 186 g–mm

Film Toughness 25 (kg/mm2)–%

Table 5. Modified film coating properties.


AmericasWayne, NJ √ *Philadelphia, PA *Sao Paulo, Brazil *Mexico City, Mexico *

Asia PacificShanghai, China *Hyderabad, India √ *

EuropeIstanbul, Turkey *

√ = Global Research and Development

* = Tech Service Center

Technical Service and SupportISP is committed to providing service and support to customers globally during the development process through full–scale commercial production. At ISP, wehave seven technical centers dedicated to supporting our customers, and their efforts with respect to pharmaceutical oral solid dosage forms, with our excipientsand film coating systems. Each laboratory location is fully–equipped and staffedwith pharmaceutical scientists that have experience in pharmaceutical formulationand 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.

ISP’s Global Technical Centers


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 SafetyISP 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 leadingglobal 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 StartedTo 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 www.ispcorp.com.

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.

INTERNATIONAL SPECIALTY PRODUCTS

LATIN AMERICA CUSTOMER SERVICE

EUROPE, MIDDLE EAST & AFRICA CUSTOMER SERVICE

ASIA PACIFIC CUSTOMER SERVICE

USA & CANADA REGIONAL SALES OFFICES

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 andevaluations 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 ofthe 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 thisbrochure. 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 warrantyagainst infringement of any patents by reason of purchaser’s use of any information, product, method or apparatus described in this brochure.

™ Trademark registration applied for ® Registered trademark of the ISP group © International Specialty Products. 2006 Designed & Printed in USA. Product Code: PHAR_C1001 10/2006

GLOBAL LOCATIONS FOR SALES & CUSTOMER SERVICE

WORLD HEADQUARTERSINTERNATIONAL SPECIALTY PRODUCTS 1361 Alps Road, Wayne, New Jersey 07470, USATel: +1 973 628–4000 Fax: +1 973 628–3311

www.ispcorp.com [email protected]

CUSTOMER SERVICE:Toll Free: 1 (800) 622–4423Fax: +1 973 628–4001

[email protected]

SAMPLE CENTER:Toll Free: 1 (800) 243–6788

[email protected]

PERSONAL CARELOMBARD, ILLINOISToll Free: 1 (800) 323–2272Tel: +1 630 932–4022Fax: +1 630 495–[email protected]

PHARMACEUTICALSWAYNE, NEW JERSEYToll Free: 1 (877) 389–3083Fax: +1 973 628–[email protected]

PERSONAL CARESHERMAN OAKS, CALIFORNIAToll Free: 1 (800) 505–8984Fax: +1 818–906–[email protected]

PERFORMANCE CHEMICALSWAYNE, NEW JERSEYTel: +1 973 628–3169Fax: +1 973 628–[email protected]

FOOD INGREDIENTSSAN DIEGO, CALIFORNIAToll Free: 1 (888) 472–5446Fax: +1 619 557–[email protected]

CANADATel: +1 905 607–2392Toll Free: 1 (800) 465–5094Fax: +1 905 607–[email protected]

ARGENTINATel: + 54 11 4314–8971

+ 54 11 4314–0659+ 54 11 4314–3293

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VENEZUELATel: + 58 212 991–4545

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GERMANYTel: +49 (0) 2236 9649–260

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HUNGARYTel: +36 1 209 2629Fax: +36 1 466 [email protected]

ITALYTel: +39 0275 419 642Fax: +39 0275 419 [email protected]

NETHERLANDSTel: +31 (0) 20 65 45–361Fax: +31 (0) 20 65 45–[email protected]

NORDEN(Denmark, Estonia, Iceland, Finland,Norway, Sweden)Tel: +46 (0) 8 519 920–10Fax: +46 (0) 8 519 920–[email protected]

POLANDTel: +48 (0) 22 556 25 20Fax: +48 (0) 22 556 25 [email protected]

RUSSIATel: +7 495 981 39 53Fax: +7 495 981 39 [email protected]

SPAIN & PORTUGALTel: +34 (0) 91 375–3026Fax: +34 (0) 91 375–[email protected]

SWITZERLANDTel: +41 (0) 1 439 53–66Fax: +41 (0) 1 439 53–[email protected]

TURKEY & MIDDLE EASTTel: +9 (0) 216 537 0870Fax: +9 (0) 216 537 [email protected]@ispcorp.com

UKTel: +44 (0) 207 519–5054

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Advantia Prime Coating Systems - Microsoftvertassets.blob.core.windows.net/download/7ae8c7d4/... · factor in obtaining the target appearance and performance on the tablet core and