One-Step Aqueous Enteric Coating Systems - Pharmaceutical ...

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.
PVAP System
Acrylic System
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 PVAP System Acrylic System
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.
PVAP System
Acrylic System
% 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.
PVAP System
Acrylic System
% 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

ased 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
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MN), 27 (2000).
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(3), 64–70 (2000).
7. “Acryl-Eze Preparation and Use Guidelines,” technical information,
Colorcon Limited, West Point, PA.
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Characteristics of Enteric Film Coating Systems,” contributed
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Circle/eINFO 35
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