One-Step Aqueous Enteric Coating Systems: Scale-Up Evaluation

One-Step Aqueous Enteric Coating Systems: Scale-Up Evaluation Charles R. Cunningham* and Kurt A. Fegely Two aqueous enteric coating systems, poly(vinyl acetate) phthalate based Sureteric and acrylicbased Acryl-Eze, were evaluated for coating performance on acetylsalicylic acid 81-mg tablets. Both systems provided acceptable acid resistance at coating weight gains as low as 6%, which were achieved in as little as 1.9 h for a 130-kg batch size. Tablets coated with each system out-performed the USP requirements for dissolution and free salicylic acid levels initially and after three months storage at 40 C and 75% RH. PHOTODISC, INC. Aqueous enteric coating systems have been widely used for many years and offer substantial advantages over solvent systems, particularly with regard to environmental and toxicological concerns. Although these formulated aqueous enteric coating systems were an advancement from traditional solvent systems, they required the separate addition of plasticizers, detackifiers, pigments, and other process aids (1). Through the years, little reduction has taken place in the complexity of these systems (2). Selection of the optimal additives for each formulation adds time to the development of individual formulations (3 5). Multiple, time-consuming steps also are required in the preparation of these aqueous enteric coating dispersions (6). In addition, many of these systems are provided as liquid dispersions, which can be problematic when handling, transporting, and controlling storage conditions. Two fully formulated, aqueous enteric coating systems now are commercially available. The systems are based on two different acid-insoluble polymers. The Sureteric system is based on poly(vinyl acetate) phthalate (PVAP), and the Acryl-Eze system is based on methacrylic acid copolymer type C (Eudragit L100-55, Röhm GmbH, Darmstadt, Germany). Both systems are dry dispersible powders that do not require the use of any additional plasticizers, detackifiers, or neutralization agents. This study evaluated both systems for ease of use and acid resistance characteristics in the production-scale film coating of acetylsalicylic acid (ASA) 81-mg tablets. Charles R. Cunningham is a global technical manager in global technical support, and Kurt A. Fegely is group leader in new product development, both at Colorcon, 415 Moyer Blvd., West Point, PA 19486, tel. 215.699.7733, fax 215.661.2626. *To whom all correspondence should be addressed. Materials and equipment The tablet formulation contained ASA 40-mesh crystals (aspirin 1040, Rhodia, Cranbury, NJ), partially pregelatinized corn starch (Starch 1500, Colorcon, West Point, PA), microcrystalline cellulose (Emcocel 50M, Penwest, Patterson, NY), and stearic acid NF (purified vegetable-grade powder, Oleotec Ltd., London, UK). The tablet ingredients were dry blended in a 40-ft 3 twin-shell blender (Patterson-Kelley Co., East Stroudsburg, PA). Tablets were compressed on a 30-station rotary press (Type B4, Manesty, Liverpool, UK) using 7-mm standard concave type B tooling (Natoli Engineering Co., St. Charles, MO). Tablet hardness and weight variation were measured using a Multichek tester (Erweka, Milford, CT). 36 Pharmaceutical Technology NOVEMBER 2001 www.pharmtech.com

Table I: Composition of the coating dispersions. Component % Weight (kg) % Weight (kg) Coating solids 15.00 13.00 20.00 13.00 Deionized water 85.00 73.67 80.00 52.00 Total 100.00 86.67 100.00 65.00* * 65.0 g of antifoam emulsion was added to the water before the acrylic powder. Table II: Uncoated ASA 81-mg tablet properties. Test Average Standard Deviation Weight (mg) n 20 170.16 0.67 Breaking force (kp) n 20 10.70 0.30 Friability (%) 20 tablets 0.12 Disintegration time in water (min) n 6 3.20 0.40 Table III: Mixing time comparison (in minutes). Mixing Step Antifoam addition 0.5 Enteric powder addition 5.0 5.0 Mixing before coating 30.0 20.0 Filtration through screen 5.0 5.0 Total dispersion preparation time 40.0 30.5 Table IV: Coating process conditions. Process Parameter PVAP-Based Acrylic-Based Average inlet temperature ( C) 69.85 52.70 Average exhaust temperature ( C) 48.44 36.24 Average tablet-bed temperature ( C) 39.76 30.00 Average spray rate (g/min) 380.52 343.00 Atomizing air pressure (bar) 3.00 3.00 Fan air pressure (bar) 2.50 2.50 Pan speed (rpm) 7.00 7.00 Airflow (m 3 /h) 2600.00 2600.00 Total spray time (min) 227.76 189.50 The coating materials used were the PVAP-based white aqueous enteric coating system (Sureteric) and the methacrylic acid copolymer (acrylic) based pigmented aqueous enteric film coating system (Acryl-Eze), both manufactured by Colorcon. An antifoaming agent (30% simethicone emulsion USP, Dow Chemical Co., Midland, MI) was used in the preparation of the acrylic-based system. The PVAP-based dispersion was prepared using a model RW 28 DX mixer (IKA Labortechnik, Staufen, Germany). A model AX3 mixer (Silverson Machines Ltd., Chesham Bucks, UK) was used to prepare the acrylic-based dispersion. Early mixing guidelines for the acrylic-based product recommended the use of a high-shear mixer such as the AX3. Subsequent technical literature indicates that either high- or low-shear mixing can be used for preparing the coating dispersion (7). A side-vented 48-in. coating pan (Accelacota 150, Manesty, Liverpool, UK) was used to apply the coatings. Acid uptake testing was performed using a disintegration-testing apparatus (model ZT54, Erweka, Milford, CT). An automated dissolution test station (VK- 7010, apparatus I, VanKel, Cary, NC) with a UV spectrophotometer (Varian, Palo Alto, CA) was used for drug-release testing. An HPLC system (Alliance 2690, Waters Corp., Milford, MA) was used for free salicylic acid determinations. The packaging materials used for stability testing of the coated tablets were 85-cm 3 foil sealable HDPE bottles (Drug Plastics and Glass Co., Boyertown, PA) and desiccant packs (3964, Süd-Chemie Performance Packaging, Belen, NM). Methods Blending and tablet preparation. ASA, microcrystalline cellulose, partially pregelatinized starch, and stearic acid were blended for 20 min in the twin-shell blender. The batch size was 560 kg. The blend was compressed to a target tablet weight of 170 mg, and the compaction force was adjusted to produce tablets with a breaking force of 8 kp and 0.25% friability. Press speed was 42 rpm for a production rate of 75,600 tablets/h. Preparation of the coating dispersions. Coating dispersions were prepared by adding the dry aqueous enteric coating formulations directly into a mixing tank filled with deionized water (ambient ~20 C). Mixer speed was controlled to produce and maintain a deep center liquid vortex into which the powder was added. For the acrylic-based system, antifoam was added to the water just before the addition of the powder to reduce foam generated during the initial high-speed mixing. Immediately after the addition of the powder to the water, the mixer speeds were reduced to maintain gentle stirring. This was done for both coating polymer systems. The coating systems were dispersed at the solids concentration recommended by the manufacturer. A sufficient amount of each coating dispersion was prepared to apply a theoretical 10% weight gain of coating to the tablets (see Table I). Each of the dispersions was screened through a 250- m sieve before coating. Spray coating. Tablet coating was carried out in the 48-in. sidevented pan equipped with four spray guns. The coating dispersions were delivered to the spray guns through individual tubes fed from a peristaltic pump. The pan load of ASA 81-mg tablets was 130 kg. The coating process controls were set using the parameters recommended by the manufacturer for the enteric coating systems. Samples of tablets for performance testing were removed from the coating pan at increments from 5 10% theoretical coating weight gain. Process data were recorded throughout the trials. Acid uptake testing. A variation of the gastro-resistant tablet disintegration method (European Pharmacopoeia Third Edition 2001) was used. In this revised method, six coated tablets were weighed individually and placed in the disintegration basket tubes. We immersed the disintegration basket in 900 ml of 38 Pharmaceutical Technology NOVEMBER 2001 www.pharmtech.com

0.1 N hydrochloric acid and operated the apparatus for 2 h. The individual tablets that were still intact then were dried with a towel and reweighed. The percent of weight increase was reported as % acid uptake. Tablets that fully disintegrated during the testing were counted as having 100% acid uptake. This method has been reported to provide an accurate measure of acid resistance of the coating, and acid uptake values 5% suggest that the tablets would readily pass the acid phase of the delayed-release dissolution testing (8). Dissolution and free salicylic acid testing. The dissolution and free salicylic acid tests for the coated tablets were performed according to the USP 24 monograph for delayed-release ASA tablets. Packaging and stability. Two sets of coated tablets from each trial were packaged in high-density polyethylene (HDPE) bottles (120 tablets/bottle). One set was packaged with desiccant and the other without. All bottles were induction (foil) sealed and placed in a chamber for three months at 40 C and 75% RH. Results and discussion Uncoated aspirin tablets. Tablets used in a functional coating process must be sufficiently robust to withstand mechanical stresses and to exhibit very low potential for erosion and edge chipping. Any defects in the tablet core may result in a localized weakness of the functional film. A subcoating process may be used to strengthen friable cores before the application of the Table V: Dissolution results. % Released in t 80% in % Released in t 80% in Theoretical 0.1 N HCL Phosphate Buffer 0.1 N HCL Phosphate Buffer Weight Gain (%) after 2 h (ph 6.8) after 2 h (ph 6.8) 6 0.0 30 min 0.0 30 min 7 0.0 30 min 0.0 30 min 8 0.0 30 min 0.0 30 min 9 0.0 30 min 0.0 30 min 10 0.0 30 min 0.0 30 min Table VI: Dissolution stability. % Released in t 80% in % Released in t 80% in Theoretical 0.1 N HCL Phosphate Buffer 0.1 N HCL Phosphate Buffer Weight Gain (%) after 2 h (ph 6.8) after 2 h (ph 6.8) Packaged without Desiccant 6 25 not tested 0.0 30 min 7 0.5 30 min 1.0 30 min 8 0.5 30 min 0.0 30 min 9 5.3 30 min 0.0 30 min 10 4.9 30 min 0.0 30 min Packaged with Desiccant 6 1.6 30 min 0.0 30 min 7 0.7 30 min 0.0 30 min 8 0.7 30 min 0.0 30 min 9 0.7 30 min 0.0 30 min 10 2.1 30 min 0.0 30 min functional coat but is not desirable in terms of process time and complexity. Subcoats also may be necessary to prevent interaction between the drug substance and the coating formulation ingredients. Interactions between the ASA and either of the enteric coating systems in this study were not expected. In this study, the ASA 81-mg tablets were sufficiently robust to avoid the use of a subcoat step (See Table II). Dispersion mixing time. Because both polymer systems are fully formulated, the mixing process consisted of a simple addition of the powder formulations to the water. The total preparation time was very short for both systems (see Table III). Filtration of the material before coating was performed to ensure that no undispersed particles of polymer remained that could result in gun blockages. Coating process. The coating process for each trial was conducted using the recommended coating conditions for each coating system (9,10). The gun-to-bed distance was 24 cm, and the distance between guns was 18 cm. The spray applications were continuous from start to finish, and spray rates were held constant throughout the coating trials. The coating data are listed in Table IV. The acrylic-based system required a lower tablet-bed temperature than did the PVAP system, and the spray rate for the acrylic-based system was slightly lower. The total coating time for the acrylic-based system was shorter because of the higher solids concentration of the dispersion. The tablets were not dried further after the application of the coatings other than during a cooldown period in the pan before unloading. Coating process efficiency for both systems was 90% on the basis of the calculation of tablet-weight difference before and after coating. The coating process for both systems was free of any problems. The coated tablets had no obvious defects or signs of sticking or tackiness (see Figure 1). Acid resistance testing. Samples of the 40 Pharmaceutical Technology NOVEMBER 2001 www.pharmtech.com (a) (b) Figure 1: Photographs of coated tablets (theoretical 10% weight gain). Tablets are coated with (a) the acrylic-based system and (b) the PVAPbased system.

% Acid uptake 37.5 35.0 32.5 30.0 27.5 25.0 22.5 20.0 17.5 15.0 12.5 10.0 7.5 5.0 2.5 0.0 5 6 7 8 9 10 % Enteric coating theoretical weight gain Figure 2: Acid uptake comparison. % Acid uptake 40 35 30 25 20 15 10 5 % Free salicylic acid 3.0 2.5 2.0 1.5 1.0 0.5 0.0 % Theoretical coating level 6 7 8 9 10 PVAP-based 0.77 0.95 1.18 1.03 0.80 Acrylic-based 1.71 2.00 2.04 2.16 2.08 PVAP-based with desiccant 0.53 0.38 0.44 0.43 0.97 Acrylic-based with desiccant 0.44 0.44 0.45 0.43 0.46 Figure 4: Free salicylic acid stability. PVAP-based Acrylic-based PVAP-based Acrylic-based 0 1.5 1.8 2.0 2.3 2.5 2.8 3.0 3.3 3.5 3.8 Total coating time (h) Figure 3: Acid-resistance testing versus coating process time. tablets that were taken throughout the coating process were subjected to acid uptake testing as a measure of the necessary level of coating that would provide acceptable acid resistance. At 5% theoretical weight gain, the PVAP system exhibited less acid uptake than did the acrylic system, although both samples were well above the desired level of 5% acid uptake. Samples taken at weight gains of 6% and above all had acid uptake values of 4%. At 6% weight gain, the differences in acid uptake between the PVAP- and the acrylic-based systems did not exceed 0.63% (see Figure 2). Of concern in any coating process is the actual production time required to coat the tablets. As a batch operation, film coating is often a bottleneck in the manufacturing process. Long coating times are common for functional coatings because of the high amount of coating that must be applied as well as the need to ensure acid resistance. In the case of each enteric coating system tested in this study, the high solids concentrations and high spray rates enabled acceptable acid resistance in a relatively short time. The coating time needed to reach an acceptable level of acid resistance was 1.9 h for the acrylic-based system and 2.3 h for the PVAP-based system (see Figure 3). Dissolution testing confirmed that each system outperformed the USP requirements of 10% of ASA released in acid after 2 h and 80% released in ph 6.8 phosphate buffer within 90 min (see Table V). The USP limit for free salicylic acid in coated ASA tablets is 3.0%. It is critical to confirm that the humidity conditions and elevated temperatures in the coating process have not contributed to the degradation of the ASA. Samples taken from each trial at 6% and 10% (theoretical) weight gain had free salicylic acid levels of 0.16%. Coated-tablet stability. Dissolution and free salicylic acid content testing was conducted on the coated tablet samples after three months of storage at 40 C and 75% RH. The tablets were packaged both with and without desiccant packs as is seen in commercially available ASA products. The dissolution test results for the acrylic-coated tablet samples were virtually unchanged from the initial time point and passed USP delayedrelease requirements. The tablet samples coated with the PVAP-based system also passed the USP requirements except for the 6% weight gain sample with no desiccant in the package. The percent of ASA released in the acid phase was slightly higher overall with the PVAP system coated tablets but still well within the USP specification of 10% release (see Table VI). All tablet samples coated with either enteric coating system passed the requirements of 3% free salicylic acid. For the samples packaged without desiccant packages, the acrylic-based system had slightly higher free salicylic acid values. The addition of the desiccant packages resulted in lower free salicylic acid values (see Figure 4). Differences in the coating process conditions may explain the variation in free salicylic acid levels between the acrylic- and PVAPbased systems. Because acrylic-based systems coat at lower process temperatures, care must be taken to ensure that moisture is not absorbed by the tablet core during the coating process. Conclusion Optimum levels of enteric coating for the ASA 81-mg tablet were determined. Both fully formulated enteric coating systems, 42 Pharmaceutical Technology NOVEMBER 2001 www.pharmtech.com

based on two different polymers, were comparable in overall process and acid resistance. Although traditional aqueous enteric coating systems can require multiple component mixing steps before coating, these systems were dispersed in one step in a minimum amount of time. Each system provided acceptable acid resistance to the ASA tablets at low weight gains and high application rates. The acrylic-based system offers the additional advantage of being fully pigmented, eliminating the need for an additional color application if a colored tablet is desired. Both systems also provided good stability in adverse storage conditions in this moisture-sensitive application. Acknowledgments The authors gratefully acknowledge James Taylor and Scott McBain of Colorcon for their help in the manufacture and coating of the ASA tablets. In addition, we thank David Ferrizzi, Laura Scattergood, and Buffy Young of Colorcon for their analytical support. Circle/eINFO 34 References 1. K. Lehmann, The Application and Processing of Acrylic Coatings in the Form of Aqueous Dispersions Compared with Organic Solutions, Acta Pharm. Fenn. 91, 225 238 (1982). 2. C. Signorino, Aqueous Enteric Coating, Pharm. Technol. Tableting & Granulation Yearbook 25 26 (1999). 3. N.A. Muhammad et al., Modifying the Release Properties of Eudragit L30D, Drug Dev. Ind. Pharm. 17 (18), 2497 2509 (1991). 4. R. Bianchini, M. Resciniti, and C. Vecchio, Technological Evaluation of Aqueous Enteric Coating Systems with and without Insoluble Additives, Drug Dev. Ind. Pharm. 17 (13), 1779 1794 (1991). 5. H. Erdmann et al., Suitability of Additives to Reduce the Tack of Kollicoat Coatings, in Proceedings of International Symposium of Controlled Release Bioactive Material (Controlled Release Society, Minneapolis, MN), 27 (2000). 6. C. Dangel et al., Aqueous Enteric Coatings with Methacrylic Acid Copolymer Type C on Basic and Acidic Drugs in Tablets and Pellets, Part 1: Acetylsalicylic Acid Tablets and Crystals, Pharm. Technol. 24 (3), 64 70 (2000). 7. Acryl-Eze Preparation and Use Guidelines, technical information, Colorcon Limited, West Point, PA. 8. M.P. Jordan, J. Taylor, and P.J. Hadfield, A Comparison of the Performance Characteristics of Enteric Film Coating Systems, contributed paper presented at AAPS National Meeting, New Orleans, LA, October (1999). 9. Coating Aspirin with Sureteric in a 48-in. Accela-Cota, technical information, Colorcon, West Point, PA. 10. Acryl-Eze Coating Parameters, technical information, Colorcon, West Point, PA. PT Circle/eINFO 35 44 Pharmaceutical Technology NOVEMBER 2001 www.pharmtech.com