Development, Optimization, and Scale-Up of Process Parameters: Pan Coating

C H A P T E R
34
Development, Optimization, and Scale-Up
of Process Parameters: Pan Coating
S. Porter1, G. Sackett2 and L. Liu3
1
Ashland Inc., Wilmington, DE, United States 2Freund-Vector Corporation, Cedar Rapids, IA, United States
3
Pfizer Inc., Morris Plains, NJ, United States
34.1 INTRODUCTION 34.1.2 Evolution of pharmaceutical-coating

technology development
In today’s pharmaceutical industry, film coating is
generally referred to as a process by which a thin, Application of coatings to medicinal products can
continuous, solid polymer layer is applied to the be traced back to the middle ages. However, a uniform
surface of a dosage form (typically tablets, capsules, and consistent film-coating process that meets the
and multiparticulates). The purpose of film coating minimum requirements imposed by today’s regulatory
includes esthetic enhancement, increased shelf life, requirements has only been available for the past few
taste masking, moderating the release profile of active decades.
pharmaceutical ingredient (API), trade-marking, and The earliest process, sugar coating, is performed in
protection of intellectual property. a solid wall, smooth bowl-shaped container, employs
The thickness of the film is generally less than an external heat source, and is a multistage process
100 µm. The composition of the film may include a that can take several days to complete. Film coating
mixture of excipients (polymers, plasticizers, colorants) emerged as an alternative to the sugar-coating process
as well as an API. to reduce process time.
The evolution in design of coating process equip-
ment has progressed from an open system to one
that is completely enclosed and self-contained. Liquid
34.1.1 The basis of film coating delivery and air-handling systems have also improved
as demand for precision and accuracy became more of
Film coatings can be applied by different methods,
a regulatory requirement.
such as spraying a liquid, dipping into a liquid, precip-
The efficiency of heat exchange in film-coating
itating from supercritical fluids, or depositing a powder
processes has been dramatically improved with the
using an electrostatic technique1.
introduction of side-vented (perforated) coating pans
Spraying a liquid is the most widely used process for
that allow the process air to pass completely through
film coating and typically includes three basic steps:
the tablet bed, while use of various types of sensors
1. Spraying an atomized liquid on the target surface facilitates the monitoring of key process parameters
that is in continuous movement (KPP).
2. Maintaining a controlled balance between spray By the end of the 20th century, film coating had
application and evaporation rates by applying evolved to such a degree that it was unrecognizable
heated process air onto the target surface from processes carried out just 50 years earlier.
3. Continuing the process until the desired amount of Other key developments involve the implementation
coating is applied2 of process analytical technology, whereby the continual
Developing Solid Oral Dosage Forms

DOI: http://dx.doi.org/10.1016/B978-0-12-802447-8.00034-0 953 © 2017 Elsevier Inc. All rights reserved.
954 34. DEVELOPMENT, OPTIMIZATION, AND SCALE-UP OF PROCESS PARAMETERS: PAN COATING
assessment of critical process parameters (CPP) that 34.2 FILM-COATING FORMULATIONS

impact critical product quality attributes allows the
process to be controlled within a well-defined design 34.2.1 Overview of types of film-coating
space, often obviating the need for routine finished formulations
product testing.
Finally, continued process improvements have led Film-coating systems are usually defined by the
to the introduction of innovative coating processes, way the coating materials are formulated into a liquid
most notably those involving continuous processing. coating system, and typically take the form of:
• Polymers applied as organic-solvent-based solutions
(typically reserved for modified-release applications
34.1.3 Coating equipment introduction today)3
• Polymers applied as aqueous solutions (most
Based on a variety of pan designs, coating pans can commonly used for immediate-release film
typically be classified as solid-wall pans (Fig. 34.1), and coatings)
fully- or partially-perforated pans (Figs. 34.2 and 34.3). • Polymers applied as aqueous dispersions (mainly
Based on the type of process, the coating pan used for modified-release applications)
can be classified as batch process-coating pan, • Various materials applied as hot melts (typically
continuous-coating pan, or off-press continuous coat- used for modified-release and taste-masking
ing pan (Fig. 34.4). While early continuous coating applications)
pans were designed to coat large batches of tablets
(5002000 kg/hour) where the desire is for large The transition to aqueous processes has been
volume throughput at low manufacturing costs, driven by a genuine desire to avoid the hazards asso-
recent designs have focused on slower throughput ciated with using both flammable and potentially
rates (approximately 50 kg/hour) to match up with toxic solvents, and the added costs of dealing with
the output of a typical production speed tablet press. environmental issues.
Water is not, however, a panacea, and use of
aqueous-coating formulations is often associated with
challenges that need to be addressed, such as:
• The possibility that processing times will be
increased; this issue can, however, be minimized by
using high solids aqueous-coating systems4,5.
• The potentially negative impact on drug stability if
water is not effectively removed during processing;
however, modern processing techniques coupled
with use of higher-solids-coating systems now
effectively eliminates this issue.
• The increased likelihood that the harsher process
conditions used may affect drug dissolution
characteristics; this problem is now minimized
by the use of specialized coating formulations
that allow processing temperatures to be
minimized.
Aqueous-coating formulations can take two forms,
namely, aqueous solutions of polymers, which are
typically reserved for immediate-release coating appli-
cations, and aqueous dispersions (latexes) of polymers,
which are frequently used in modified-release coating
applications.
When it comes to forming coatings from polymer
solutions, the process involves the conversion of
a viscous liquid into a visco-elastic solid through a
FIGURE 34.1 A solid coating pan fitted with immersion sword process of continual solvent evaporation, through
air-flow enhancement. several stages: (1) Rapid evaporation of solvent
III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

34.2 FILM-COATING FORMULATIONS 955
FIGURE 34.2 Schematic of a fully-perforated coating pan. Source: Courtesy of Vector.
FIGURE 34.3 Schematic of a partially-perforated coating pan. Source: Courtesy of Vector6.
from finely-atomized droplets of solution, which

are deposited onto the surface of the substrate
to begin the process of build-up of coating material;
(2) Continued solvent evaporation (now at a slower
rate) from the coating that is forming on the
substrate surface; (3) Immobilization of polymer
molecules (at the so-called “solidification point”),
such that continued solvent loss now leads to
the development of shrinkage stresses within the
coating; and (4) Continuation of solvent loss (usually
throughout the life of the product) at extremely slow
rates.
In contrast, the formation of coatings from aqueous
polymer dispersions (Fig. 34.5), while still involving a
process of evaporation, is radically different.
FIGURE 34.4 Example of a continuous coating pan. Source: Polymer dispersions must undergo a process of
Courtesy of O’Hara Inc. “coalescence,” where the dispersed polymer particles

When designing coating formulations, there are sev-

Evaporation of water eral important issues to consider. These generally
Polymer dispersion involve the need to optimize:
deposited on surface
of substrate • The visual characteristics of the final product
Closely packed latex • The functional characteristics of the coating
particles with water • The “processibility” of the coating system (eg, issues
filling voids relating to preparation and application of the
coating liquid, as well as those associated with
Further evaporation of
Latex particles coalesced water; polymer viscous flow processing time and costs)
into a coherent film Film coatings are applied to pharmaceutical solid
FIGURE 34.5 Schematic of film formation from aqueous polymer
oral dosage forms for a number of purposes, often
dispersions. leading to coatings being categorized on the basis of
their intent with regard to influencing drug release,
namely immediate-release coatings, which although
often used for esthetic purposes, may also be used
must flow together. For this process to occur, pressure to improve product stability, facilitate product identi-
develops within the film structure, while the particles fication, and achieve an improvement in product
of polymer soften under the influence of process organoleptic characteristics (such as taste and odor).
heat; as a result, the polymer particles tend to flow Modified-release coatings, which can be subdivided
together. Pressure development results from evapo- into two sub-categories, namely delayed-release
ration of water; as the porosity of the membrane (enteric) coatings, and extended-release (sustained- or
is reduced during the evaporative process, a capillary controlled-release) coatings.
network is formed within the structure of the coating,
resulting in the development of capillary forces that
squeeze the particles together. The ability of the 34.2.2 Overview of types of materials used
polymer particles to soften sufficiently is dependent in film-coating formulations
on these factors:
34.2.2.1 Polymers
• Heat provided by the coating process
Polymers are the essential building block of coating
• The glass transition temperature of the coating
formulations, providing the main characteristics for the
system (dictated by the properties of the polymer,
final coating formulation7,8, and are usually character-
and the properties and concentration of the
ized in terms of:
plasticizer, where needed), which determines the
minimum film-forming temperature (MFFT) of the • Chemistry, which will mainly influence:
system. The product temperature within the coating • Solubility of coating system,
pan must exceed the MFFT for film coalescence to • Rheology of coating liquid,
occur. • Mechanical properties of coating, and
• Permeability characteristics of coating.
While it is common for many coating formulations
• Molecular weight (or molecular weight
to contain a plasticizer (see later discussion), polymer
distribution), which is likely to influence:
dispersions may require the presence of a plasticizer to
• Mechanical properties of coating and
facilitate film formation. Generally, it is necessary
• Rheology of coating liquid.
to use plasticizers with polymer dispersions either
when the polymer on which the dispersion is based Unlike that of inorganic materials, the molecular
has a high glass transition temperature (such as ethyl weight of a polymer is much more difficult to define
cellulose), so that the MFFT of the system exceeds the because a sample of polymer will consist of a broad
product temperatures experienced in the process, or if distribution of molecular weights.
the flexibility of the resultant film coating needs to In order to characterize the molecular weight of a
be improved. polymer, we usually measure this molecular weight
Unnecessary, or excessive, use of plasticizers should distribution (using techniques such as “gel permeation
always be avoided, otherwise excessive tackiness will chromatography”), and then express the molecular
be experienced. weight in terms of one of two statistically defined
Common ingredients used in many film-coating for- averages (as shown in Fig. 34.6), namely, weight
mulations are: (1) polymer, (2) plasticizer, (3) colorants, average molecular weight, Mw, and number average
and (4) solvent/vehicle. molecular weight, Mn.

Solution viscosity (mPa s)

Mn
Amount of polymer
Mw
2% 12–15%
Molecular weight Polymer concentration
FIGURE 34.6 Typical molecular weight profile for a polymer. FIGURE 34.8 Effect of polymer concentration on the viscosity of
aqueous polymer solutions.
For more pragmatic reasons, we often prefer to use

the term nominal viscosity, where:
Molecular weight 5 kðnominal viscosityÞn
Mechanical property
High molecular Nominal viscosity is usually measured, in water at

weight polymers
25 C, using a solution containing 2% w/w polymer.
Low molecular weight
Not only does polymer molecular weight influence
polymers (often called oligomers) solution viscosity, but so does polymer concentration,
as illustrated in Fig. 34.8. As stated previously, nominal
viscosity is measured for dilute solutions of polymer.
No particular batch of polymer will conform exactly to
the nominal viscosity value for that grade. Thus, the
Molecular weight
manufacturers (and usually the compendia as well) will
set a specification range. As seen in Fig. 34.8, at the 2%
FIGURE 34.7 Effect of molecular weight on the mechanical prop- solids concentration (usually used for setting the nomi-
erties of polymers. nal viscosity specification), the batch-wise variation
in solution viscosity is usually quite small (often
only 6 2 cP, or m Pa s). However, as we increase the
A derived parameter that is often useful is the solids content of the solution, not only does the viscos-
polydispersity function, which is defined as: ity increase exponentially, but the difference in solution
viscosity from batch-to-batch can increase dramatically,
Polydispersity 5 Mw =Mn so that the batch-wise variation in coating solution
The influence of molecular weight on the mechanical viscosity (depending on the solids contents of our
properties of polymers is shown in Fig. 34.7, where coating solutions) may be as much as 100200 cP.
generally as molecular weight increases, tensile strength
and elastic modulus also increase, and adhesion 34.2.2.2 Plasticizers
decreases. Plasticizers are another common ingredient added
Polymer molecular weight can, as stated previously, to coating formulations. They are typically used to
affect coating solution viscosity. In absolute terms, the reduce the glass transition temperature, Tg (see Fig. 34.9),
relationship between polymer molecular weight and and increase coating flexibility.
solution viscosity is governed by the MarkHouwink Most polymers that we use in film coating are
equation: essentially amorphous materials, and as such, exhibit
a reasonably well-defined glass transition temperature
½μ 5 k Mα
(a fundamental characteristic of polymers that has a
Where [μ] is the intrinsic viscosity of the polymer, M is profound effect on polymer properties that can also
its molecular weight, and k and α are constants influence film formation, especially when using
relating to the solvent system used and the solution aqueous polymer dispersions). This transition does not
temperature. represent a change in state (as we see with melting

200
180 Propylene glycol

1. No plasticizer
PEG 200
160
Glass transition temperature (°C)
2. Medium level
Glycerol
140 of plasticizer
3. High level
Stress
120
of plasticizer
100
80
60
40
20
Strain
0
0 10 20 30 40 50 60 FIGURE 34.10 Effects of plasticizers on the mechanical properties
Quantity of plasticizer added (% w/w) of film coatings.
FIGURE 34.9 Effects of plasticizers on the glass transition tem-

perature of HPMC.
7
Quantity of plasticizer retained (%)

6
TABLE 34.1 Examples of Common Plasticizers Used in Film
Coating Formulations 5
Class Examples 4
Polyhydric Alcohols Propylene glycol.
3
Glycerol.
Polyethylene glycols.
2
Acetate Esters Glyceryl triacetate (Triacetin).
Triethyl citrate. 1
Acetyl triethyl citrate.
0
Phthalate Esters Diethyl phthalate 0 10 20 30 40 50 60
Glycerides Acetylated monoglycerides. Quantity of plasticizer added (%)
Oils Castor oil. FIGURE 34.11 Lack of plasticizer permanence (for propylene
Mineral oil. glycol in HPMC films).
are: efficiency, which defines how much plasticizer

point), but rather is indicative of a point where there is must be added to produce the desired effect; compati-
a dramatic increase in molecular mobility. At this point, bility, which indicates how effectively the plasticizer
the polymer changes from a tough, rigid, inflexible, interacts with the polymer, and the level up to which
and brittle material into one that is softer and more that interaction occurs; and permanence, which relates
pliable. These latter properties are of great value in to both plasticizer-polymer compatibility and plasti-
film coating, and thus it is beneficial to match the glass cizer volatility (see Fig. 34.11 for an example of poor
transition temperature of the final coating system to the plasticizer permanence).
coating conditions that will be used. The common general effects of plasticizers used in
For most coating systems, it is desirable that the glass film-coating formulations are shown in Table 34.2.
transition temperature of that system be optimized
for the coating process conditions used. For aqueous
polymer dispersions (or latexes), it is critical that 34.2.2.3 Colorants
such optimization is achieved, otherwise appropriate See Table 34.3 for common types of colorant used in
coalescence of the coating will not occur. film-coating formulations.
A list of common plasticizers used in coating formula- Colorants are generally used in film-coating formula-
tions is shown in Table 34.1, and their comment effects on tions to improve product appearance, aid in product
film mechanical properties are shown in Fig. 34.10. identification, and potentially improve product stability.
When it comes to selecting a suitable plasticizer While it is possible to use either water-soluble color-
for a coating formulation, some key issues to consider ants (dyes) or water-insoluble colorants (pigments),

TABLE 34.2 Summary of Common Effects of Plasticizers TABLE 34.4 Contrast Ratio Values for Coatings Colored With
Selected Pigments
Effect of increased plasticizer
Property concentration Pigment Contrast ratio
Tensile strength Reduced None 33.3
Elastic modulus Reduced Titanium dioxide 91.6

Film adhesion Variable, but increased under optimal-use Red iron oxide 99.5
conditions
Yellow iron oxide 98.4
Viscosity of coating Usually increased, with effect being
liquid greater as plasticizer molecular weight is Indigo carmine lake 99.5
increased Tartrazine lake 66.7
Film permeability Variable, depending on physicochemical
properties of plasticizer
Glass transition Reduced, with magnitude of effect being
temperature (Tg) of film influenced by compatibility with polymer
140
Quantity of light reflected (×10–3)

120
TABLE 34.3 Common Types of Colorant Used in Film-Coating
Formulations
100
Type Examples
80
Water-soluble dyes • FD&C Yellow #5
• FD&C Blue #2
60
FD&C lakes • FD&C Yellow #5 Lake
• FD&C Blue #2 Lake 40
D&C lakes • D&C Yellow #10 Lake

20
• D&C red #30 Lake
Inorganic pigments • Titanium dioxide 0

• Iron oxides 1.5 2 2.5 3 3.5
“Natural” colorants • Riboflavin Pigment refractive index
• Beta-carotene
• Carmine lake FIGURE 34.12 Hiding power and influence of pigment refractive
index.
(or contrast ratio) of the coating. The consequences of

as shown in Table 34.3, the use of pigments has several
poor hiding power include the fact that higher coating
advantages because they:
levels will have to be employed to achieve uniform
• Replace some of the polymer, thus allowing the appearance from tablet to tablet, and from batch to
solids content of film-coating liquid to be increased batch, and if the tablets are intagliated (ie, have a
while still maintaining a sprayable viscosity; logo), higher levels of coating can cause increased risk
• Act as a solid inclusion in the final dried coating, of logo bridging.
often improving the moisture barrier properties of The contrast ratios of film coatings colored with
the coating; selected pigments are shown in Table 34.4.
• Exhibit better light stability than water-soluble Generally, the main factors that can influence the
colorants; hiding power of a particular film coating are:
• Are less prone to color migration as the coatings
• The quantity of light reflected at the polymer
dry; and
pigment interface (which, in turn, is influenced by the
• Exhibit light excluding behavior, thus improving the
refractive index of the colorant, see Fig. 34.12)
stability of photo-labile drug substances
• The wave length of light absorbed by the colorant
In order to exert these properties effectively, it is • The amount of light absorbed
desirable that the colored film coating is able to • The concentration of the colorant in the coating
completely mask the substrate. The ability to achieve (see Fig. 34.13)
this goal is usually expressed as the hiding power • The thickness of the coating (see Fig. 34.13)

100 TABLE 34.5 General Effects of Pigments in Film Coatings

95 Effect of increased pigment
Property concentration in film
90
Tensile strength Reduced (but effect may be minimized by
85
effective pigment dispersion in film)
Contrast ratio (%)
80 9.5% w/w Titanium dioxide

Elastic modulus Increased
17.3% w/w Titanium dioxide
75 Film adhesion Generally, little effect
29.5% w/w Titanium dioxide
70 Viscosity of Increased, but usually not substantially
65 coating liquid
60 Film permeability Reduced, unless critical pigment volume

concentration (CPVC) is exceeded
55
Hiding power Increased, but effect is dependent on refractive
50 index and light absorption characteristics, of
20 40 60 80 100 120 pigment
Film thickness (µm)
FIGURE 34.13 Effects of pigment concentration and coating TABLE 34.6 Examples of Common Solvents Used in
thickness on the contrast ratios of colored film coatings.
Film-Coating Formulations
Class Examples
20 Water
18 Alcohols • Methanol
• Ethanol
Degradation rate constant (×10–3/min)
16 • Isopropanol
No pigment
14 Esters • Ethyl acetate
• Ethyl lactate
12
Ketones • Acetone
10
Chlorinated hydrocarbons • Methylene chloride
0.7% w/w TiO2
8 • 1:1:1 Trichloroethane
• Chloroform
6
4 0.7% w/w Tartrazine lake

34.2.2.4 Other additives
2 0.7 % w/w (TiO2 + While polymers, plasticizers, and colorants consti-
Tartrazine lake)
0
tute the major ingredients in film-coating formulations,
0 20 40 60 80 100 120 other materials that might be used for a variety of
Film thickness (µm) reasons include:
FIGURE 34.14 Photostabilization of nifedipine using pigmented • Antiadhesive agents, especially when the polymer is
film coatings. somewhat tacky;
• Flavoring agents (typically in nutraceutical
The ability of film coatings to improve product applications);
stability is generally related to: • Surfactants (to facilitate the wetting of insoluble
materials dispersed in the coating formulation);
• The influence of pigments on coating permeability
• Pore-forming agents (especially in extended-release
(generally, as pigment concentration is increased, up
film-coating formulations).
to a critical level called the critical pigment volume
concentration, film permeability to environmental 34.2.2.5 Solvents/vehicles
gases such as water vapor and/or oxygen are
Currently, most coating formulations that are
reduced); decreased permeability can lead to
applied to solid oral dosage forms are liquids. Thus,
improved product stability
the key additive that is used to render the coating for-
• The ability of the coating to exclude light, an important
mulation a liquid is a solvent (the term vehicle is used
issue when coating products containing photolabile
to describe the situation where an aqueous polymer
APIs (such as Nifedipine, as shown in Fig. 34.14)
formulation is preferred).
In summary, the general effects of pigments on the A list of common solvents used in coating formula-
properties of film coatings are shown in Table 34.5. tions is given in Table 34.6.

Quite clearly, in modern film-coating practices, water TABLE 34.10 Influence of Solvents on the Viscosity of HPMC-
is often the preferred solvent9. Nonetheless, water is a Based Coating Solutions
compromise solvent for these reasons: Polymer concentration Solution viscosity
Solvent (% w/w) (m Pa s) (cP)
• Water has higher latent heat of vaporization (see
Table 34.7), thus requiring more energy input to the 60:40 methylene 5.0 40
coating process to assure that effective drying takes chloridemethanol
place (thus often precluding the use of conventional 80:20 ethanolwater 5.0 70
coating equipment).
Water 10.0 450
• Aqueous coating systems have higher surface
tensions than their organic-solvent-based
counterparts (see Table 34.8), thus impacting
In some cases, use of organic solvents has continued,
wetting and adhesion (see Table 34.9) on
especially when:
many types of pharmaceutical tablets
(eg, vitamins). • The coating process will not accommodate the use
• Aqueous coating systems are more viscous than of water (ie, drying is poor);
organic solvent-based systems (see Table 34.10), • The adhesion achieved with aqueous systems is
thus having some impact on pumping and unacceptable;
atomization efficiency. • Certain critical ingredients (eg, polymer) are neither
water-soluble nor available as a latex system; and
• Exposure to an aqueous process would cause
TABLE 34.7 Latent Heats of Vaporization of Common Solvents stability problems for the product being coated.
Solvent Latent heat of vaporization (kJ/kg)
Methylene chloride 556.7

34.2.3 Film-coating formulations used for
Methanol 1967.1 immediate-release applications
Water 2260.4
34.2.3.1 Characteristics of polymers used
• Generally water soluble;
• Able to form strong, flexible films;
• Adhere strongly to tablet surfaces;
• Form elegant films;
TABLE 34.8 Surface Tension Values of Common Solvents • Facilitate ease of processing (pumping, spraying,
Solvent Surface tension (mN/m) at 20 C atomization, and lack of tackiness); and
• Permit rapid drug release from dosage form.
Acetone 23.7
A typical dissolution profile for a product coated
Chloroform 27.1
with an immediate-release film coating is shown in
Ethyl alcohol 22.8 Fig. 34.15.
Methyl alcohol 22.6
Water 72.8 34.2.3.2 Examples of types of polymers used
Common polymers used in immediate-release coat-
ing formulations are listed in Table 34.11.
TABLE 34.9 Adhesion Values of HPC Coatings Deposited From

Various Solvents
34.2.3.2.1 Cellulosic polymers
Cellulosic polymers, especially hydroxypropyl-
Solvent system Adhesion value (kPa) methylcellulose (HPMC), have long been the mainstay
Methylene chloride:methanol (9:1) 29.8 of film-coating formulations, with a popularity that
stems from their common usage from the early days of
Ethanol:water (95:5) 23.9
film coating when organic solvents were always used;
Acetone:water (9:1) 20.2 global regulatory acceptance; ready availability from a
Chloroform 14.4 number of vendors; and ability to form coatings gener-
Water 7.1
ally having acceptable properties (such as good film
strength and aqueous solubility).

100 34.2.3.2.3 Vinyl alcohol polymers

Poly (vinyl alcohol) has gained popularity recently
because of its good film properties, and the relatively
Percent drug released
low viscosity of its coating solutions. Typical character-

istics of coatings made with this polymer include the
fact that coating solutions that can be somewhat tacky,
while subsequent dry films tend to exhibit good adhe-
sion properties (to tablet surfaces) and excellent barrier
properties (to environmental gases such as oxygen and
Coating is soluble
in water
water vapor); however, applied coatings may, under
certain circumstances, slightly retard tablet dissolution
behavior.
0 To obviate some of the problems of the homopoly-
0 30 60 mer (especially tackiness), poly (vinyl alcohol)-poly
Time (min)
(ethylene glycol) is a copolymer designed with certain
FIGURE 34.15 Typical drug release profile for products coated improvements in mind.
with immediate-release coatings.
34.2.3.2.4 Acrylic polymers
The acrylic polymers that are typically used in film-
TABLE 34.11 Examples of Common Polymers Used in coating applications are:
Immediate-Release Coating Formulations
• Generally not water soluble, per se (the polymer
Polymer class Examples tends to dissolve readily at low pH);
Cellulosic • Hydroxypropylmethylcellulose • Traditionally used to create film coatings with
• Hydroxypropylcellulose improved taste-masking capabilities because the pH
• Hydroxyethylcellulose in the mouth is usually alkaline (ie, above that
Vinyl • Poly (vinyl pyrrolidone) where the coating will dissolve in water); and
• Poly (vinyl alcohol) • Usually applied as solutions in organic solvents,
• Poly (vinyl pyrrolidone)poly (vinyl although special polymer grades that allow aqueous
acetate) copolymers polymer suspensions to be prepared are now
• Poly (vinyl alcohol)poly (ethylene
available.
glycol) copolymers
Glycols • Poly (ethylene glycol) 34.2.3.3 Formulation strategies used
Acrylics • Amino alkyl methacrylate copolymers Immediate-release film coatings have traditionally
Other carbohydrates • Maltodextrin utilized relatively simple formulation strategies, typi-
• Polydextrose cally combining a single polymer in combination with
other ingredients, such as plasticizers and colorants.
The introduction of aqueous coatings created a major
challenge for formulators, especially with regard to
34.2.3.2.2 Vinyl pyrrolidone polymers managing the viscosity of the coating formulation and
The most common vinyl polymer used in the phar- achieving acceptable adhesion of the coating to the
maceutical industry today is poly (vinyl pyrrolidone). surface of the tablets being coated.
While this polymer has been primarily used as a wet Such challenges have typically been met, over the
binder in granulation processes, it has certain utility in course of time, by utilizing polymer mixtures, such as
film coatings (due to its potentially high film-adhesion blends of:
characteristics), although uses are somewhat limited
• Different molecular weight grades of the same
because it generally forms extremely tacky films
polymer (such as a mixture of HPMC 6 cP and
(both during application of the coating and on final
HPMC 3 cP),
coated product), and produces coatings that tend to be
• Similar polymers (such as HPMC 1 HPC), and
somewhat brittle.
• Cellulosic polymers with other carbohydrate
In contrast, poly (vinyl pyrrolidone)-poly (vinyl
materials (such as HPMC with maltodextrin,
acetate) copolymer potentially has greater utility because
polydextrose, or lactose).
it is less tacky than the homopolymer, produces films
that exhibit good adhesion characteristics, and generates The properties of some typical polymer blends are
coating solutions with low viscosities. shown in Table 34.12.

TABLE 34.12 Film Properties of Various Polymer Blends COOH COOH
COOH
Tensile Elastic Film
strength, modulus, σ/E value adhesion
Polymer σ (MPa) E (GPa) ( 3 1022) (kPa)
HPMC blend 31.74 2.25 1.41 250.5 COOH

COOH COOH
HPMC/HPC 17.68 0.99 1.79 253.5
blend Dissolution rate of coating is affected by:
HPMC/lactose 13.53 2.34 0.58 500.6
• pKa of polymer
blend
• pH of medium
• Ionic strength of medium
FIGURE 34.16 Structure of enteric-coating polymers.

34.2.4 Film coatings used for modified-release
applications
As described previously, film coatings used for 100
modified-release applications can be subdivided

into two main categories, namely delayed-release
(or enteric) coatings, and extended-release coatings. pH = 1 – 2 pH = 6.5 – 7.5
34.2.4.1 Delayed-release (enteric) coatings

Enteric coatings are primarily used for the purpose of:
• Maintaining the stability of APIs that are Coating has solubility in
water triggered by pH
unstable when exposed to the acidic conditions of 0
the gastric milieu. Such API’s include erythromycin, 0 2 4
Time (h)
pancreatin, and the class of proton pump inhibitors,
such as omeprazole. FIGURE 34.17 Typical drug release profile from products coated
• Minimizing the side effects (eg, nausea, and gastric with enteric coatings.
irritation and bleeding) that can occur with APIs
such aspirin and certain nonsteroidal inflammatory
compounds.
• The presence of imperfections in the coating
• Creating opportunities for “night-time dosing”
(eg, cracks, “pick marks,” etc.) that can also lead
strategies, where the intent is to allow the dosage
to reduced gastric resistance.
form to be consumed at bed-time, and permit
• The chemistry of the polymer used (especially
effective blood levels of the API to be attained just
dissolution pH and dissolution rate at a given pH).
prior to waking.
• The influence of the in-vitro test conditions used
• Facilitating colonic drug delivery.
(such as pH and ionic strength of the test medium;
The functionality of enteric coatings is, for the most as well as the agitation rate used in the test).
part, mediated by a change in pH of the environment
Enteric film-coating polymers are essentially poly-
to which the enteric-coated product is exposed. Enteric
acids (see Fig. 34.16), and typically only dissolve
polymers remain unionized (and thus, insoluble) at
in water above pH 5 5.06.0; these polymers are
low pH values, and begin to dissolve at a pH value of
selected for their ability not only to form robust coat-
approximately 5.05.5. In addition, the functionality
ings that adhere strongly to tablet surfaces, but also
of enteric coatings can be greatly affected by many
to permit rapid drug release from dosage form once
other factors, such as:
it passes from the stomach into the small intestine
• The nature of the API contained in the dosage form; (see Fig. 34.17).
this is especially true when that API is ionic in A list of commonly used enteric-coating polymers
nature. is given in Table 34.13, and these form the basis
• The quantity of coating applied; insufficient coating of enteric coating formulations used in either
can result in ineffective gastric resistance, while too organic-solvent-based or aqueous-coating formula-
much applied coating can seriously delay drug tions. A breakdown of coating systems specially
release when the dosage form passes into the small designed for aqueous-coating applications is shown
intestine. in Table 34.14.

TABLE 34.13 Examples of Common Polymers Used in Enteric by means of diffusion through an intact coating mem-
Coating Formulations brane. Polymer selection, and the general formulation
Polymer Comments strategies employed in this category will very much
depend on a number of factors, including a desire
Cellulose acetate phthalate Hydrolysis potential—higha to create a specific type of drug-release characteristic,
Cellulose acetate trimellitate Hydrolysis potential—mediuma minimize the risk of dose-dumping, utilize processing
Polyvinyl acetate phthalate Hydrolysis potential—lowa
methodologies that already exist within the company,
and prepare a unique dosage form that enables
Hydroxypropylmethylcellulose Hydrolysis potential—mediuma the manufacturer to take a proprietary position with
phthalate
respect to dosage-form presentation.
Hydroxypropylmethylcellulose Hydrolysis potential—lowa In order to meet these requirements, critical objectives
acetate succinate include the need to:
Poly (MA-EA) 1:1
• Achieve the target drug-release characteristics in a
Poly (MA-MMA) 1:1 Relatively high dissolution pH reproducible manner;
Poly (MA-MMA) 1:2 Relatively high dissolution pH • Ensure that drug-release characteristics are
a
insensitive to expected variations in raw materials
When exposed to conditions of elevated temperature and humidity.
MA, Methacrylic acid; EA, Ethyl acrylate; MMA, Methyl methacrylate. and coating-process conditions;
• Confirm that the coating formulations
(and associated coating processes) are essentially
uncomplicated, and facilitate scale-up from the
TABLE 34.14 Examples of Aqueous Enteric Coating Systems
laboratory into production; and
Product Form Polymer • Ensure that the final product is stable and does not
a
exhibit time-dependent changes in drug-release
Eudragit L30D Latex dispersion Poly (MA-EA)
characteristics.
a
Eudragit L100-55 Spray-dried latex Poly (MA-EA)
When it comes to designing extended-release pro-
HP-F Micronized dry powder HPMCP ducts, these may take a number of forms, namely
Sureteric Formulated, dry powder system PVAP tablets, prepared as film-coated tablets, film-coated
Acryl-Eze Formulated, dry powder system Poly (MA-EA)
mini-tablets, or compacted, film-coated particulates, as
well as capsules, prepared as encapsulated, film-
Aquarius Control Formulated, dry powder system Poly (MA-EA) coated particulates, or film-coated capsules.
ENA
Coated multiparticulates often form the basis for
Aquateric Spray-dried pseudo latex CAP extended-release products when an applied coating is
Aquacoat ECD Pseudo latex dispersion CAP the main mediator of drug release because of the
desire to minimize dose dumping, and facilitate more
Aquasolve Micronized, dry powder HPMCAS
consistent gastro-intestinal transit times. Such coated
CAP Dry powder CAP multiparticulates (see Fig. 34.18) can take the form of
CAT Dry powder CAT drug-loaded pellets (nonpareils), granules (irregularly
a
shaped granules or granules that have been sphero-
Competitive acrylic products now available from BASF, Eastman, & Sanyo.
MA, Methacrylic acid; EA, Ethyl acrylate. nized), drug crystals, and finally drug/ion-exchange-
resin complexes.
In terms of designing extended-release coating
While enteric-coated products have conventionally formulations, the types of polymers used are often
taken the form of tablets, recently a preference has been selected for their ability to exhibit similar robustness
shown for coating multiparticulates because of their characteristics as those described for enteric coatings,
more consistent gastrointestinal transit characteristics. but also for their permeability characteristics that
Enteric-coated capsules (especially one-piece softgels, allow the drug to be released at a controlled rate
containing garlic or fish oils used in nutraceutical that is consistent with the biological requirements
applications) have also become quite commonplace. for that API (see Fig. 34.19).
A list of common polymers used for extended-
34.2.4.2 Extended-release coatings release coating applications is shown in Table 34.15,
Extended-release coatings are typically completely while examples of aqueous-coating systems are shown
insoluble in water, and permit the release of the API in Table 34.16.

1. Spheronized granules 2. Drug-loaded “nonpareils” 3. Drug crystals
4. Regular granules 5. Drug/ion-exchange 6. “Mini” tablets

resin complexes
FIGURE 34.18 Examples of multiparticulates.
100 TABLE 34.16 Examples of Aqueous Extended-Release Coating

Systems
Polymer
Product used Comments
Surelease Ethylcellulose Plasticized aqueous polymer dispersion,

addition of lake colorants should be
avoided
Aquacoat Ethylcellulose Pseudo latex dispersion, plasticizer must
Coating is insoluble be added to facilitate film formation
in water
Eudragit Acrylic Latex dispersion; no plasticizer needed
0 NE 30Da copolymer unless it is necessary to improve film
0 6 12 flexibility
Time (h)
Eudragit Acrylic Aqueous polymer dispersion; no
RL 30Da copolymer plasticizer needed unless it is necessary
FIGURE 34.19 Typical drug release profile from products coated
to improve film flexibility
with extended-release coatings.
Eudragit Acrylic Aqueous polymer dispersion; no
RS 30Da copolymer plasticizer needed unless it is necessary
TABLE 34.15 Examples of Common Materials Used in
to improve film flexibility
Extended-Release Coating Formulations
a
Also available as Kollicoat Systems.
Coating material Membrane characteristics
Fats and waxes (beeswax; • Permeable and erodible

carnauba wax; cetyl alcohol; • Permeable and soluble (at high pH) The performance of extended-release coating formu-
cetostearyl alcohol) • Permeable and soluble (at high pH) lations is often defined by:
Shellac • Permeable and water-insoluble
Zein • Semi-permeable and water- • The nature of polymer used, especially in terms of its
Ethylcellulose insoluble chemistry (which can greatly influence coating
Cellulose esters (eg, acetate) • Permeable and water-insoluble permeability) and molecular weight (which has a
Acrylic ester copolymers
significant effect on coating robustness).

• Presence of additives, such as: 34.3 DESIGN AND DEVELOPMENT

• Plasticizers (which can greatly influence coating OF FILM-COATING PROCESSES
robustness, as well as the extent of film formation
when using aqueous polymer dispersions); 34.3.1 General introduction to coating
• Anti-adhesive agents (which are often used processes and equipment
to reduce agglomeration in the case of
multiparticulates, as well as reduce 34.3.1.1 Overview
imperfections in the coating caused by A film coating is usually applied onto tablets until
picking and sticking); they reach a targeted weight range, often expressed as
• Colorants which, although used for identification a percentage weight gain. A typical weight gain for an
purposes, can influence film permeability; and esthetic coating is 24%, whereas, for clear coatings,
• Water-soluble pore-forming agents, which are the weight gain may be as little as 0.51.0%. For
typically added to the formulation as a deliberate controlled-release applications, the quantity of the coat-
strategy to modify the permeability characteristics ing required is directly related to its thickness.
of the applied coating. A thickness of 3050 µm (this translates to 46 mg
• Coating thickness which is, in turn, influenced by polymer/cm2 of tablet surface) is usually sufficient to
the: provide a satisfactory enteric coating. It will require a
• Surface area to be covered, greater weight gain to achieve a controlled release film
• Quantity of coating applied, of a suitable thickness because a batch of smaller
• Uniformity of distribution of coating, and tablets contains a greater total tablet surface area.
• Coating process efficiency. The reasons for selecting a specific film-coating
process are essentially the same, regardless of whether
While extended-release coating formulations have
the process is performed in a perforated coating pan
typically been designed as polymer solutions in organic
or a fluid-bed coating process. In general, the major
solvents, there has been significant interest over the
criterion for deciding between either a coating pan or a
past 20 years in using aqueous-coating systems.
fluid-bed process is often related to the size and shape
Irrespective of the formulation approach used, it is
of the product to be coated. A rule of thumb is that if
critical that the formulation of the coating enables the
the product is approximately 6 mm or less in diameter,
appropriate drug-release characteristics to be achieved
then the preferred equipment for applying the coating
in a consistent manner, the membrane obtained should
is the fluid-bed coater, mainly because when attempt-
be structurally sound, the coating systems are readily
ing to coat small particles in a perforated coating pan
adaptable to existing coating-process technology, and
(where process air is drawn down through the tablet
the coating formulation and processes are sufficiently
bed under a negative pressure) the pressure drop
optimized to prevent the occurrence of time-dependent
across the product bed can drastically reduce the pro-
changes in drug-release characteristics.
cess air volume, a factor which will reduce the evapo-
Meeting these objectives can be more challenging
rative capacity of the pan. This, coupled with the close
when using aqueous polymer dispersions because it is
contact of the product in the spray zone (increasing
necessary to ensure that coalescence of the coating
the risk of agglomeration), makes the coating of small
during film formation proceeds to an endpoint where
particles in the coating pan less desirable. When
membrane porosity is eliminated, this completeness of
attempting to coat larger size products (such as tablets)
coalescence is either achieved during the coating
in a fluid-bed process, often the capacity of the fan is
process, or by means of a short curing step performed at
insufficient to fluidize such a product, and even when
the conclusion of that process, and further gradual
successful fluidization is achieved, product attrition
coalescence, over an extended period of time, is avoided.
may be excessive.
Thus the coating formulation used must be suitably
optimized in terms of its ability to achieve completeness
of film coalescence in the particular coating process to be
employed. This usually means that the MFFT (which is
34.3.2 Batch coating systems
closely related to the glass-transition temperature of the Batch coating of solid oral dosage forms requires a
polymer employed, either in its natural state, or as process where the equipment involved not only acts as
modified by the presence of a plasticizer) is matched to a container, but also provides constant motion and
the typical temperature conditions used in the process. facilitates the evaporation of the coating solvent. In a
In addition, the coating process conditions employed pan-coating process, the container will typically be
must also be optimized to ensure that they enable cylindrical and will rotate on a horizontal axis. The
the correct temperature conditions to be achieved coating formulation will be sprayed onto the surface of
(to facilitate film coalescence). the constantly moving product in a finely atomized

34.3 DESIGN AND DEVELOPMENT OF FILM-COATING PROCESSES 967
state, typically achieved using a spray gun. Droplets Exhaust Air handler
blower
from the spray gun are composed of a solution (or sus-
pension), which is a mixture of a liquid carrier and
solids. The principle of this type of coating is to apply
the solution in such a manner that a droplet from the
Compu
spray gun will land on the product and spread. The automated Hi-coater
temperature of the product will then rapidly evaporate control
system
the liquid from the suspension, leaving only the dried
solids. The coating solution/suspension viscosity must Solution
tank
be such that any evaporation that occurs between Solution
pump
emergence of droplets from the spray nozzles until the
time they impact the surface of the product being
coated, these droplets will retain sufficient fluidity to
enable them to spread into a uniform coating before
solvent evaporation is essentially completed. This will
FIGURE 34.20 Example of a coating system for batch processing.
leave a dry coating, consisting of the solids that were
in the solution, on the surface of the product.
In order to produce a uniform coating, each tablet
continually emptied from the process in the former. In
must have an equal probability of passing through the
a batch process, the tablets reside inside the coating
spray zone throughout the course of the coating
pan for the duration of the coating process (potentially
process. In order to facilitate such uniform distribution
14 hours depending on batch size), and only emerge
of the coating, coating pans typically have some type of
once the entire process is completed. Despite these
mixing baffle that not only facilitates the tumbling
differences, the coating principles, as well as process
action of the product being coated, but ensures that
thermodynamics, are essentially similar. A typical
product is moved back and across the coating pan.
batch coating process is shown in Fig. 34.20, while a
Finally, in order to promote efficient drying within
continuous process is exemplified in Fig. 34.21.
the process, the coating pan must not only facilitate the
application of process air across the surface of the tab-
let bed, but also ensure that this process air can pass
through the tablet bed to complete the drying process. 34.3.4 System components
Coating pans described in this section are typically The peripheral equipment for a coating system
considered to be closed systems, where the environ- for either the batch system or the continuous-coating
ment outside of the coating pan is completely system will be very similar. Figs. 34.20 and 34.21
separated from that within the coating pan, so that show equipment components typically used with both
material is contained within the process and drying batch- and continuous-coating systems.
efficiency is maximized.
Overall, the challenge in film coating is to ensure that
the coating is uniformly applied across the surface of 34.3.4.1 Overview
the product to be coated, and that process thermody- Process air is drawn in through an air handler
namics (which defines the balance between the rate at where it will be heated, dehumidified (or humidified,
which the coating liquid is applied and the rate at which depending upon requirements), and filtered before
the coating solvent is removed) are controlled in such a going to the coating pan. The process air enters the
manner that prevents both tablets from being over- coating pan and is exhausted via a plenum located
wetted, such that they stick together, and that overall below the tablet bed, to a dust collector and a blower.
process efficiency (the relationship between the amount Finally, the exhaust air is discharged into the environ-
of coating material delivered into the process and that ment (when organic solvent-based coating systems are
which actually ends up on the tablets) is maximized. used, the exhaust air will pass through a solvent recov-
ery unit or an incinerator before being discharged).
Some organic solvent systems may use a closed-loop
system where solvent is condensed from the air stream
34.3.3 Continuous-coating systems before being fed back into the inlet process air stream.
A continuous-coating system differs from a batch A closed-loop system has the advantage of using pro-
system in that tablets are continually fed into the cess air, which is conditioned to suit the operating
process, pass through the spray zone in a short period parameters required for the process, thus requiring
of time (typically 1520 minutes), and then are less energy input for the operation.

Supply air handler
Air in
Inlet air ducts
Main unit Change/conveyor hopper

Control panel
Dust collector
Powder application
Exhaust fan
Rotating drum
Solution
Exhaust air dust
pump
Product handling Solution tank

options
FIGURE 34.21 Example of a coating system for continuous process.
34.3.4.2 Pan units

34.3.4.2.1 Comparison of batch-type coating pans
The coating pan can be either fully or partially
perforated around the cylindrical surface of the
drum, which allows process air to be drawn through
the tablet bed, ensuring more effective drying. An
example of a partially perforated coating drum is
shown in Figs. 34.22 and 34.23, and displays an
integrated exhaust plenum on the outside of the
drum. A fully perforated coating pan is shown in
Figs. 34.24 and 34.25.
As the coating drum rotates, the product being
coated (eg, tablets) tumbles in the drum, always
remaining near the bottom of the pan (as indicated in
Figs. 34.23 and 34.25). Partially perforated coating pans
are constructed with exhaust plenums welded to the
outside of the pan. Process air enters the coating pan
through a mouth ring at the front opening of the pan,
or through the back of the pan, and is drawn out
through the exhaust plenums built onto the exterior of
the cylindrical portion of the drum, see Fig. 34.23. The
perforations in the coating pan are located over these
plenums. This arrangement forces all of the process FIGURE 34.22 Exhaust plenum on the exterior of a partially
air to pass through the tablet bed. There is greater perforated coating drum.

FIGURE 34.23 Air-flow diagram and chamber design of a partially perforated pan.
product drum so that the product can be discharged

into product trays placed under the units. Several of
the manufacturers will also supply product-loading
totes, fitted with chutes, that will allow the product to
be loaded from above the coating pan instead of
through the drum opening.
Coating pan capacities for laboratory size units
range from 0.5 to 110 L. Capacities for production-size
coating pans range from 90 to 1300 L. The laboratory
size units are used to perform feasibility studies and
for the purposes of product and process development.
An example of laboratory-size units is shown in
Fig. 34.26. In general, each manufacturer makes sizes
of coating pans that are comparable, although the
trend now is to provide lab-scale coating equipment
with multiple pan-size inserts.
Each manufacturer will provide specifications for
general operation of their coating pans. Typically, they
will recommend and/or furnish the peripheral equip-
ment required to complete a system.
FIGURE 34.24 Exterior of the fully perforated coating drum.
34.3.4.2.2 Comparison of continuous-coating

pressure drop in the path of the process air (compared equipment
with the fully perforated pan) because of the plenum An example of a continuous-coating unit is shown
system and the tablets. The path of the process air in Fig. 34.27. The product is moved through a drum
through the fully perforated pan is shown in (that represents a stretched version of a batch-coating
Fig. 34.25. pan) at a rate that allows the tablets to be completely
Coating can be performed with any of these pans if coated as they pass through the coating pan. Mixing
the auxiliary equipment (blowers, heater, filters, etc.) is baffles may be present to help move product from one
configured and specified properly for the physical end of the coating unit to the other end. The applica-
layout. Some coating-pan equipment includes auto tion of coating material within a continuous coating
discharge. The mixing baffles can be configured in pan is essentially the same as that in a batch side-
these pans such that when the pan is rotated in a vented coating pan. Continuous coating pans are avail-
reverse direction, the product will be discharged out of able from Thomas Engineering, O’Hara Technologies,
the door. Some coating pans have a trap door on the Driam, Bohle, and GEA.

FIGURE 34.25 Air-flow diagram and chamber design of a fully perforated pan.
FIGURE 34.27 Example of a continuous-coating pan.

FIGURE 34.26 An example of a laboratory-size coating pan.
34.3.4.3 Process air equipment

All coating-pan equipment, including continuous- dehumidification unit. The preheat section is placed
coating process equipment, requires conditioned- before the dehumidification unit to protect any chilled
process air to enable solvents (aqueous or organic) to water coil (or refrigeration coil) from freezing. Three
evaporate quickly. The process air generally should be methods of dehumidification are used: chilled water,
dehumidified, cleaned, and heated. An air handler is refrigeration, or a desiccant dryer. The desiccant dryer
used to perform these functions. A typical air handler is generally used to obtain the lower dew points. If
is made up of different functional sections as shown in humidification is required (ie, during winter when the
Fig. 34.28. air is very dry), this is accomplished by injecting steam
The first section will generally be composed of two into the process air stream. A heating coil is required
filters: a bird screen followed by a prefilter. The prefil- to heat the process air.
ter is typically rated for 30% efficiency. The next sec- The air handler shown in Fig. 34.28 is a face and
tion of the air handler is a preheat unit, followed by a bypass unit, which allows heated and room-temperature

Desiccant
dehumidifier ACWD Final hepa filter
Rain hood and
optional
bird screen
Inlet air
Clean steam
Chilled water humidifier
cooling coil optional
Louvered inlet damper
30% prefilter optional
85% prefilter Inlet blower
Chilled water dehumidification coil Face and bypass
Final heating coils
FIGURE 34.28 Example of an air-handling system.
air streams to be blended to achieve the required set- blower is operating and product is loaded in the pan.
point temperature, as well as to allow temperature The exhaust blower must provide a vacuum pressure
changes to be made quickly and facilitate better at the required air flow that will overcome the losses
control of temperature. A conventional (nonbypass created by the different components between the
type) air handler will require some time to cool down coating pan and the exhaust blower.
because the heater coils remain in the process air The outlet process air duct should be connected to a
stream after the heat has been stopped. In addition, dust collector to collect solids that did not adhere to
as heat (either electric or steam) is provided, there the product or dust that is generated when product is
tends to be a greater risk of oscillations in temperature loaded into the coating pan. The duct work before and
occurring. after the dust collector, and the dust collector itself,
The finished product is normally cooled before must be able to withstand the amount of vacuum that
being removed from the coating pan after spray appli- will be created by the exhaust blower. The dust collec-
cation of the coating is completed. The face and bypass tor also must be designed with an explosion vent that
unit can achieve a shorter production time because a will relieve the pressure in case of a dust explosion.
heating coil does not have to cool down before cooling When film coating is performed using an organic sol-
the product. The air handler comprises a fan (blower), vent, the entire system must be designed either to con-
which must be rated for the proper quantity of process tain an explosion, or allow the explosion to be safely
air to facilitate heat transfer to the product. The final vented. Typically, the equipment manufacturer will
stage of an air handler should be a high-efficiency par- recommend a system that will satisfy the requirements
ticulate air (HEPA) filter to provide clean air with for a specific type of solvent.
99.97% efficiency. As mentioned previously, the partially perforated
The schematic shown in Fig. 34.28 illustrates the coating pan generally creates greater pressure drop,
typical components of an air-handling system. thus requiring a high-pressure blower; whereas a fully
The duct work between the HEPA filter and the coat- perforated coating pan produces a lower pressure
ing pan should be stainless steel to preserve the integ- drop, but requires a larger quantity of process air.
rity of the clean, process air. The quantity of process Finally, the exhaust blower should be capable of gener-
air is generally recommended by the equipment manu- ating the recommended air flow for heat transfer and
facturer for the size of the equipment. It is desirable to producing a vacuum of 25100 mm of water column
use the maximum amount of process air possible inside the coating pan. In areas where the noise of the
to achieve the maximum heat transfer and drying blower cannot be tolerated, especially on the systems
efficiency. However, caution must be exercised when that require a high pressure blower, a silencer should
increasing the air flow within the system because pres- be used after the exhaust blower. Most manufacturers
sure drop increases exponentially and turbulence can of coating pans will provide the above peripheral
be generated that will affect the spray patterns inside equipment as part of a turnkey system. Some systems
the coating pan. The inlet blower should be capable will have a bypass section that allows the process air to
of providing sufficient air pressure at the desired bypass the coating pan, typically being used where the
quantity of air to bring the pressure in the coating coating pan door must be opened for several minutes,
pan to atmospheric pressure or slightly negative (up thus allowing cool air to enter the coating pan. If the
to 100 mm of water column), when the exhaust temperature probe, which is used for the control loop,

is in the exhaust duct work, the control loop will call must be provided to change from spray to recircula-
for a higher temperature. When the coating pan door tion. A flow-measuring device is not needed for a posi-
is closed, the inlet process air temperature will be con- tive displacement pump, but is desirable. A separate
siderably higher, which in turn can cause the product pump can be provided for each spray gun or a single
temperature to exceed the set limits. The bypass allows pump connected through a manifold can feed all spray
the process air temperature to remain constant. The guns. The manifold can create different pressures at
bypass also must have a pressure drop to prevent each gun due to the pressure drops in the manifold
the air flow from increasing, thus causing a temperature tubing, which in turn will cause different droplet sizes
change during bypass conditions. Utilizing the bypass and distributions at each gun; a manifold system also
will then allow the temperature control loop to hold the has the additional disadvantage of causing extra liquid
process air at a constant temperature during the time to be fed to the remaining spray guns should one or
the airflow is not passing through the coating pan. more nozzles become blocked. Many spray systems
use a multiple pump configuration to prevent the pres-
34.3.4.4 Spray systems sure drop problem.
The design and operation of the spray-application
34.3.4.4.1 Comparison of different spray guns
system is a critical element of the coating process. In
general, two types of spray systems are used, an open- Two types of spray guns are typically used for
loop system or a recirculation-loop arrangement. An coating: either pneumatic or hydraulic. A third type is
open-loop arrangement is typically used with both an ultrasonic, which has had limited success for
hydraulic spray guns (atomization is generated coating processes. For most circumstances, the use of
through a high liquid-line pressure) and pneumatic pneumatic spray guns dominates the industry today
spray guns (atomization is generated by a compressed because of the preference for using aqueous-coating
air stream that impinges on the liquid stream as it systems.
emerges from the nozzle), while a recirculation loop is
typically used only with pneumatic spray guns. 34.3.4.4.2 Pneumatic spray guns
Generally, a recirculation loop provides more flexibil- The pneumatic gun sprays liquid out through
ity, but requires more equipment and tubing to config- an orifice, which is then subjected to a stream of
ure. When the spray is off, the coating formulation is compressed air that breaks the spray into droplets.
recirculated back to the solution tank, providing mix- The size of the droplets, the distribution of droplets,
ing in the tubing to prevent precipitation of solids out and the type of pattern is determined by the quantity
of solution. A separate agitator in the solution tank of compressed air flow and the physical configuration
should be employed for coating formulations prone to of the spray gun. An illustration of a pneumatic spray
precipitation. To use the recirculation loop, a valve in gun is provided in Fig. 34.29, and shows the different
the spray gun and a valve in the recirculation loop ports for the compressed air supply and solution feed.
Mounting
bracket
Nozzle air Cylinder air

Atomization air adjustment
Spray pattern adjustment
Nozzle/ Pattern air
cylinder air
Atomization air
Solution
in/out
FIGURE 34.29 Example of a pneumatic spray gun with separate adjustments for atomization air and pattern air.

TABLE 34.17 Common Spray Gun Manufacturers pumps, such as a gear pumps, a lobe pump, or peristal-
tic pumps. These pumps are capable of supplying
Types of
Manufacturer Address Trade name spray guns pressures of 17 bar gage pressure to the spray nozzles.
Peristaltic pumps are most commonly used because of
Binks Sames Geneseo, IL 61254 Binks Guns Pneumatic the ease of cleaning and lower cost. Centrifugal pumps
Corporation
are normally not used because of pressure requirements
Freund Marion, IA 52302 Vector or Pneumatic and the need for a flow measurement service due to the
(Vector Corp.) Freund Guns characteristics of the pump.
Schlick Coburg, Schlick Guns Pneumatic The selection of the pump is determined by the
GERMANY 96540 Hydraulic type of spray guns used. The hydraulic spray guns
Spraying Wheaton, Spraying Pneumatic will require 24 bar of solution pressure at the
Systems Co. IL 60189 Systems Hydraulic desired flow rates. The pneumatic spray guns will
require 0.051.0 bar at the desired flow rate. The
ultrasonic spray guns require only pressure to supply
the solution to the spray head (typically less than
Table 34.17 provides manufacturers of spray guns. 0.7 bar). Normally, pumps that operate at lower
Solution and air orifice sizes on the spray guns may pressures create fewer problems relative to pump
need to be changed for different types of coating wear and sealing of connections to the pump and
suspensions but, in general, a single orifice size will spray guns. To ensure that proper flow and pressure
suffice for most commonly used coating suspensions. is provided to each spray gun, many of the spray sys-
tems incorporate a separate pump (or pump head
34.3.4.4.3 Hydraulic spray guns driven from a common drive system) for each spray
gun. A single pump or a single tubing distribution
A hydraulic spray gun uses pressure on the liquid
system, through a manifold to the spray guns will
feed lines to force the coating liquid through an orifice
result in different pressures and flow rates at the
where, under the influence of the pressure drop created
spray guns. When selecting a pump, the location
at the nozzle, the liquid is sheared into droplets. The
from which the coating solution is being drawn must
orifice must be changed for different types of spray
be considered. Some coating formulations may
patterns and spray distributions. Hydraulic spray guns
require additional pump pressure due to a high
have limited use in coating pans because the spray dis-
vacuum pressure on the inlet side of the pump. When
tribution is considerably wider than for pneumatic
using more than one pump, the inlet tubing must be
spray guns. The typical pressures required to maintain
sized for the total number of pumps and the vacuum
effective atomization also often result in spray rates
loss due to the size of the inlet tubing.
being too high for aqueous applications; however, this
The connections for the spray system are very
type of nozzle can be very beneficial when using
critical and must be installed with care. If there is a
organic solvent-based coating formulations.
leak in the tubing on the inlet side of the pump, air
In all types of spray guns, as the spray rate is chan-
bubbles are created in the suspension which travel
ged, the pattern, droplet size, droplet distribution, and
to the spray heads and cause distortion of the spray
droplet velocity will also change. The pneumatic gun
pattern and droplet size distribution. Any leaks in the
provides more flexibility because the atomizing air can
tubing, piping, or connections will result in dripping
be varied to obtain the desired spray droplet character-
onto the product because all spray guns are mounted
istics without changing the nozzle. Ultrasonic spray
inside the coating pan over the product; causing twin-
guns produce relatively small droplet size over the
ning (tablets stuck together) or picking (tablets stuck
wide range of spray rates, and have the advantage
together and separated).
in that the larger orifices they employ result in less
plugging of the nozzle. Both the hydraulic and pneu- 34.3.4.4.5 Delivery control
matic spray guns are subject to plugging, causing
The application of the coating liquid onto the tablets
disruption of the droplet size distribution and the
can only be consistent if the rate at which the liquid is
spray pattern. The hydraulic gun is more prone to
being delivered to each spray nozzle is also consistent.
plugging than the pneumatic gun because the orifice
For this reason, effective control of the flow of coating
openings are smaller.
suspension must be exercised. In the past, assumptions
have been made that if a positive displacement
34.3.4.4.4 Solution delivery pump pump is used, then the rotational speed of the pump
The open-loop arrangement described previously for shaft (rpm) can be used to determine the flow rate.
the spray-application system is generally used with However, variations in the spray gun outputs can

occur because of pressure changes in the system • Coating pan speed

and systems where more than one pump is used. • Spray rate of the coating solution
Therefore it is advisable that some form of measure-
All three control systems mentioned previously will
ment and control be used for the suspension flow.
require certain parameters to be measured in order to
The most common form of measurement is a mass-
make any coating system operate with consistent
flow meter. Spray systems that use a manifold for the
results. The manual system will have only instruments
spray guns can be configured to use a single pump,
that provide local readouts, which are used by the
but a mass-flow meter should be used at the outlet of
operator to adjust the controls. Both types of automa-
the pump. Spray systems that use multiple pumps
tion will require outputs that can be input into a
feeding individual guns should incorporate a mass
programmable logic controller (PLC) or computer.
flow meter in the common-source, line-feeding the
These measurements represent the minimum
pumps. There are several types of mass-flow meters
required for any of the coating systems to provide a
that have been used including vortex-flow meters,
consistent coating operation:
Coriolis mass-flow meters, and turbines. Turbines are
not typically used because they cannot be cleaned • Inlet process air temperature
properly without removing them from the coating sus- • Exhaust process air temperature from the coating
pension line. Differential pressure is not used because pan
this requires an orifice plate which generates more • Process air flow volume or flow rate in the inlet
pressure drop for the spray system, thus increasing duct to the coating pan
the work load for the pump. These flow devices • Pump speed or suspension spray rate.
will normally have to measure mass flow over a range • Coating pan rotation (RPM)
of 1001000 mL/minute. An alternative means to
These controls are required for each of the systems:
measure the application of the coating is to use a
weight-loss system, which involves putting the solu- • Power to the system
tion tank on load cells (weight measuring sensors) • Temperature controller
and then, knowing the density of the suspension, the • Air-flow control (manual or motorized dampers, or
amount of material applied can be determined as a blower motor speed control)
reduction in the tank weight. This weighing system • Solution volume or rate control (mechanical or
must be capable of having the tare weight set to zero pump motor speed control)
before starting application of the coating liquid. • Coating pan rotational speed (mechanical or pan
motor speed control)
34.3.4.4.6 System controls Each of these items for either measurement or con-
System controls may take one of several forms and trol will be analog in nature, either by an analog meter
should be chosen based on the tolerance required for or an analog signal to a PLC or computer.
the product, the operator’s technical knowledge level, Other measurements that may be included with a
and the extent of control desired. There are basically coating pan system are:
three types of systems:
• Process air temperature after the preheater
• Manual: All functions are selected and controlled by • Dew-point temperature after the dehumidification
an operator; or humidification
• Semiautomatic: These systems use a combination of • Differential pressure across the inlet filter to the air
manual and automatic systems; and handler
• Automatic: This system requires minimal operator • Differential pressure across the HEPA filters in the
input during the coating process. inlet air duct
• Differential pressure across the coating pan
Typically, the design of a coating process is based
• Static pressure in the coating pan
on the equipment used, and the process conditions
• Differential pressure across the dust collector
that are deemed critical to the overall success of that
• Static pressure after the air handler
process. Ideally, for any given process, these condi-
• Static pressure at the inlet of the exhaust blower
tions should be held constant:
• Product temperature
• Process air flow • Main compressed-air pressure
• Inlet process air temperature • Solution tank weighing system
• Average static pressure in the coating pan • Solution pressure
• Humidity (or dew-point) in the process air going • Solution mass-flow meter
into the coating pan • Compressed air flow rate to pneumatic spray guns

34.3.5 General characteristics of system will need to be adjusted so that the pressure
the pharmaceutical coating process drop between guns is the same. Most spray guns are
equipped with a needle valve-adjustment cap that
34.3.5.1 Typical process steps controls the clearance between the spray needle and
If this is the first time that a particular product has the liquid nozzle. Adjustment of the position of the
been coated, it is generally necessary to estimate the needle valve will in turn facilitate adjustment of
approximate batch size to use. Coating pans are the fluid delivery rate through a particular spray gun.
usually rated for a specific brim volume capacity. Brim After making an adjustment to the spray guns, the
volume can be defined as volume capacity, if loaded solution collection should be repeated. When uniform
to the very bottom of the pan opening. The initial pan solution delivery has been achieved, it is necessary to
load is usually somewhat less than brim volume in calibrate the nozzle air volume to the spray guns.
order to prevent product from spilling out of the pan Some spray guns have a common line for providing
opening should the product volume increase during atomization air and pattern air. For these systems, the
the coating process or if the product movement should air volume is achieved by setting the desired nozzle
change. As a starting point, the brim volume capacity air pressure. Other guns have separate controls for the
should be multiplied by 95% in order to estimate the atomization and pattern air, and a mist checker or
starting fill volume; this estimated volume can then be flow meter for display of the actual air volume. For
multiplied by the product’s bulk density (in g/mL) these systems, a needle valve (located on the spray
to determine the approximate maximum batch capac- gun body) is usually adjusted to set the atomization
ity. Product bulk density can be approximated by air volume. Once the atomization air volume has been
determining the weight of a 1-L volume of tablets. set for all of the guns, a second needle valve is
Batches of 7075% of the maximum can usually be adjusted to the desired volume for pattern air. After
coated without a problem. For smaller batch sizes, it is these air volumes have been set, it is possible to verify
necessary to examine product movement to verify the approximate dimensions of the spray pattern by
that it is adequate, and also determine that the passing a hand through the air stream. This spray
exhaust air plenums (in a fully perforated pan) are pattern should be checked at a distance that is equal
completely covered. Reduced height baffles can be to the distance between the tablet bed and the spray
used to improve product movement with smaller pan guns.
loading. In cases where the exhaust plenum is not
completely covered, it may also be necessary to use a 34.3.5.1.2 Loading/charging
restrictor plate to reduce the exhaust opening, thus After proper set-up of the pan and spray equipment
preventing air from being drawn around the tablet has been confirmed, the pan can be loaded with prod-
bed rather than through it. uct either through the front of the pan (pan mouth
For continuous coating pan systems, the throughput ring) or through a discharge door located on the flat of
is controlled by a combination of the pan drum angle, the pan (if it is so equipped). During the loading of the
pan speed (rpm), and tablet input rate. A higher pan, the exhaust air is usually turned on to eliminate
throughput is achieved by increasing one or more of or minimize exposure to irritating and potentially
these factors. Either one of these changes causes the hazardous dusts. It is a good idea to minimize the
product to flow more rapidly through the pan, thus distance that the product is allowed to drop during
increasing the potential production rate. charging because this will minimize or eliminate tablet
breakage. It is usually recommended that the pan be
34.3.5.1.1 Coating pan set-up jogged occasionally during loading to move product
The typical coating process consists of several towards the back of the pan.
different steps. The first step is to verify proper opera-
tion of the spray delivery system, which must be 34.3.5.1.3 Preheat/de-dusting
calibrated to deliver a consistent gun-to-gun delivery After loading, the next step is to preheat the product
of the coating solution, especially when manifold to the desired process temperature. While the product
systems are used. Calibration can be accomplished by is being preheated, it is also de-dusted by the process
individually collecting and weighing the solution from airflow. This is a good time to circulate coating solu-
each spray gun for a set interval of time. The calibration through the spray guns (if a recirculation system
tion procedure should determine if the overall delivery is used). Verification that the spray guns are posi-
of solution is accurate (if it matches the theoretical tioned correctly can be accomplished at this time,
rate) and also confirm that the variation in solution checking both the angle to and distance from the tablet
flow between guns is minimized. If there is an bed. During the preheat step, the product can either be
unacceptable variation (usually .6 5.0%), then the rotated continuously at a very slow speed (preferred)

or jogged intermittently. This will minimize attrition include: desired coating weight gain, coating process
while ensuring that the product is uniformly heated. efficiency, coating solution solids level, spray rate, and
For heat-sensitive products, it will be necessary to jog the size of the spray zone. The end of the spray cycle
on a more frequent basis to prevent overheating the is usually controlled by either time or the application
upper surface of the tablet bed. Tablets are generally of a set quantity of coating solution because these
preheated to a specific product or exhaust tempera- factors tend to be constant for a particular product.
ture. The product and exhaust temperatures are If the spray cycle is controlled by solution quantity,
typically not the same, though they tend be fairly close this can be accomplished through the use of either
during the coating process. Once the exhaust air a mass-flow meter or a mass balance. Either of these
or product has been heated to the desired starting methods will provide a totalization of the solution
temperature, application of the coating liquid can be applied.
initiated.
34.3.5.1.6 Gloss coat
34.3.5.1.4 Application of a seal/barrier coat After the primary coating has been completed, a
In a few rare cases, it may be necessary to apply a dilute over-coating may be applied to prevent the
barrier-coating after the application of the primary tablets from blocking or sticking (such as with some of
film coating. The need for a barrier/seal coat typically the aqueous dispersions that are thermoplastic) or to
occurs when there is an interaction between the film provide a higher film gloss. If the purpose is to
polymer and the product substrate (eg, interaction provide a higher gloss, a dilute HPMC solution may
between an enteric polymer and tablets containing an be used. The process temperatures may be reduced
alkaline drug, or interaction between an acid labile slightly to reduce the amount of spray drying that
drug and an enteric polymer, which is acidic). In such occurs.
cases, a seal coat of an inert film polymer, such as For some of the aqueous coating dispersions, it is
HPMC prior to the enteric polymer coating, may be recommended that the product be maintained at a
used. A second example occurs when there is an slightly elevated temperature to fully cure the coating
interaction between the coating solvent and the prod- and provide a stable release profile. After coating, the
uct (ie, an aqueous coating and an effervescent product should be cooled prior to the application of a
product). To remedy this type of problem, a seal powdered wax (if one is to be applied to improve
coating with an alternative solvent may be used. It is tablet flow and gloss). Cooling the product after
possible to coat, for example, some effervescent coating also minimizes potential problems due to heat
products with aqueous solutions if the spray rate instability of the active (since product temperature will
for the initial phase of the coating is reduced, process rise after the spray is turned off due to loss of the
temperatures are substantially increased, and the evaporative cooling effect. A product is typically
solids content of the coating suspension is high cooled to an exhaust or product temperature of
(approximately 20% w/w). 2530 C before discharging from the pan.
34.3.5.1.5 Application of the film coating 34.3.5.1.7 Wax addition

Prior to commencing the spray cycle, the pan After cool-down of the product, a powdered wax
should be set to the desired rotational speed. If a may be used to provide a higher tablet gloss.
frequency drive is used, it is important to allow The waxes typically used are either a carnauba wax, a
approximately 5 seconds for the pan to achieve the combination of carnauba and beeswax, or rice wax.
rpm set-point. Once the product has reached the A small quantity of wax (510 g per 100 kg of tablets)
required speed, the spray can be started. The initiation is applied to the rotating tablet bed. The tablets are
of the spray will cause the product and exhaust tem- allowed to rotate for approximately 5 minutes with no
peratures to drop slightly due to evaporative cooling. process air. After 5 minutes, the tablets are rotated for
If these temperatures drop below the desired range, an additional 5 minutes with the process air on. This
the inlet temperature will need to be increased. If the allows any excess wax to be exhausted. A canvas-lined
coating system has an inlet air handler with some type pan is not necessary for the wax application, although
of humidity control, there will be a very consistent it may provide a slightly higher gloss.
batch to batch correlation between the inlet tempera-
ture necessary to achieve the desired exhaust and/or 34.3.5.1.8 Product discharge
product temperatures. Some systems automatically At the conclusion of the cool-down period, the
control the inlet temperature to maintain the required product is ready for discharge. Depending on the type
exhaust temperature. The time required for the coating of pan used, the product will be discharged through a
cycle is determined by a number of factors that “trap-door” on the flat of the pan or through the front

pan door (either by manual scooping, or using one of 216630:24131:0153½ð70:0240:5 CÞ
the many emptying scoop devices supplied by the
20:10ð70:0240:5 CÞ
equipment vendor). In some systems, the pan may be Rate5
rotated backward or counter-clockwise to aid in dis- 577
charging the product, in which case the baffles are
528:51 kg=hour or 475 g=minute of water evaporated
designed to direct the product out the front door.
Discharge of the entire batch usually will be achieved
in 210 minutes, depending on the pan size and type For a 12% w/w solids coating liquid, this equals
of discharge method employed. For most cases, the 540 g/minute per total or B135 g/minute per gun.
coated product should not be allowed to drop more
than 6090 cm, otherwise tablet breakage may be 34.3.6.2 Process air
experienced. 34.3.6.2.1 Volume
In all coating pans, elevated temperatures are used
in conjunction with airflow to convert the solvent in
34.3.6 Understanding process thermodynamics the coating solution into a vapor and carry it away
34.3.6.1 Adequate evaporative rate from the tablets being coated. In general, the amount
of water vapor that can be removed is directly propor-
The theoretical evaporative rate for aqueous film
tional to the air volume that passes through the coating
coating can be determined using the following
pan and is limited by the saturation of the air stream.
equation:
Therefore, if maximum evaporative capacity is the rate
CMH 3CP 3 ‘ 3 ½ðTIN 2 TOUT Þ2 0:10ðTIN 2TOUT Þ limiting factor with respect to the spray rate, it would
Rate 5
LHV be advantageous to use as high an airflow as possible
without creating spray turbulence or air leakage.
where: Manufacturers of the coating pans will usually specify
Rate 5 Evaporative rate of water per hour (kg) the maximum airflow that can be used while still
CMH 5 Actual process airflow in cubic meters per maintaining an acceptable level of turbulence. As the
hour process air stream is heated, its capacity to hold water
Cp 5 Specific heat capacity of the air (kcal/kg C) vapor increases. Again, if maximum evaporative
‘ 5 Density of the air stream (kg/m3) capacity is the rate limiting factor, the inlet air temper-
TIN 5 Inlet process temperature ( C) ature should be as high as possible. However, spray
TOUT 5 Exhaust process temperature ( C) rates (per spray gun) are frequently limited not by
HL 5 Heat loss of the coating system (%) evaporative capacities, but rather by the diminishing
LHV 5 Latent heat of vaporization (kcal/kg C) quality of the spray as the spray rate is increased.
The total spray rate is usually limited by the number
This equation will determine the approximate quan- of spray guns, but more accurately, the size of the
tity of water (in kg/hour) that can be evaporated in a spray zone available. Therefore, the airflow capacity
coating-pan system. However, this may not be the opti- between pans of different sizes should be in direct
mal rate necessary to achieve a high-quality coated proportion to the spray zone. For example, if a coating
product. The quality level, as stated previously, depends process is developed in a pan with two spray guns
on many other factors. If all of these other critical factors (each gun possessing a 20-cm spray pattern) and a
are examined and optimized, this equation can be used process airflow of 1000 CMH (cubic meters per hour);
as a tool to determine the approximate spray rate. scale-up to a larger pan with four spray guns should
Example: have an airflow of approximately 2000 CMH. Using an
Assumptions: airflow in direct proportion to the spray rate will
Ambient air conditions 5 21.1 C/50% RH also allow a closer correlation between the process
Air flow 5 2166 m3/hour temperatures in different size pans.
Specific heat capacity of air 5 0.241 (kcal/kg C)
Density of the air stream 5 1.015 (kg/m3) 34.3.6.2.2 Humidity
Inlet air temperature 5 70 C (167 F) The process air used in a coating pan is either
Exhaust air temperature 5 40.5 C (105 F) conditioned or unconditioned. In either case, there are
Coating solution solids 5 12% day-to-day variations in the moisture present in the
Number of spray guns 5 4 air stream. Humidity in the inlet air stream is usually
Heat loss 5 10% determined by the dew-point temperature. Dew-point
Latent heat of vaporization 5 577 (kcal/kg) temperature provides a direct indication of humidity

in the air. Relative humidity can be used; however, process air) and conduction (due to the product tem-
the temperature of the air must also be known to perature). The desired exhaust temperature is depen-
determine the level of moisture. In the case of condi- dent on several factors, such as:
tioned air, variations are less (especially when the
1. Coating solution characteristics
process has the capability to dehumidify and rehumi-
The tackier the coating as it dries, the higher the
dify the air stream). With unconditioned air, these
exhaust or product temperatures must be to prevent
variations are great and can cause coating problems.
overwetting defects during the coating process.
If the air is unconditioned, the spray rate must be
If the film polymer is thermoplastic, the product
selected such that in the most humid condition
must be kept below the temperature at which the
that might occur, the film coating would still dry
polymer begins to soften to prevent the tablets
at a rate that would not result in overwetting or
from blocking or sticking together.
stability problems with the product. Some level of
2. Product temperature limits
spray-drying would occur since most batches would
If a product exhibits instability problems at
be coated at lower humidities. The severity of the
elevated temperatures, the product must be kept
spray-drying would be directly related to the variation
below these limits. This is most critical during
in the ambient humidity. Therefore, the growing
preheating of the tablet bed since evaporative
trend is to dehumidify the process air stream.
cooling of the bed is not occurring and the product
Dehumidification not only provides the coating
may not be uniformly heated if the pan is not
process with more consistent coating conditions,
being continuously rotated. The product
but also provides for greater evaporative capacity.
temperature will begin to rise immediately after
This allows the system to evaporate more moisture
the spray is stopped due to the loss of the
at a given airflow and temperature than an airflow
evaporative cooling effect. Therefore, it may be
of a higher humidity. With the advent of sustained
necessary to begin a cool-down cycle immediately
release coating, some companies have opted for
after the spray cycle.
a combination of dehumidification/humidification.
The inlet temperature required to achieve the
Such a system allows the process to be conducted at
desired exhaust temperature will be affected by the
a consistent inlet dew-point temperature, regardless
spray rate, the percentage of solids in the coating
of the ambient conditions. A system that conditions
solution, the heat loss across the pan, and the
the inlet air stream to a consistent dew point
condition of the drying air.
allows the coating process to operate at a reproducible
3. Pan speed
drying rate regardless of fluctuations in ambient
To effectively optimize film-coating quality, the
conditions.
tablets must be mixed such that each tablet has
the same probability of being in the spray zone for
34.3.6.2.3 Temperatures an equal duration of time. Therefore, it is essential
As stated previously, the coating process can be suc- that the product be examined to ensure that mixing
cessfully controlled by the inlet, exhaust, or product is uniform. Mixing problems that occur include:
temperatures. Process control based on inlet air tem- sliding of tablets (usually seen with large capsules
perature control is most common. Control based on or oval-shaped tablets), “dead-spots” or sluggish
exhaust or product temperatures will often react product movement (this can be an extremely serious
slower because of the heat sink effect of the tablet bed problem if it occurs while the tablets are in the
(such control will also require fluctuations in inlet tem- spray zone), or product thrown into the spray zone
perature, spray rate, and process air volume to occur, by the mixing baffles.
with spray rate fluctuations being the least desirable). If product movement is not uniform, the first
With inlet temperature control, the exhaust tempera- course of action should be to evaluate the product
ture will drop slightly after the spray is started. This flow at different pan speeds. The pan speed selected
temperature drop is due to evaporative cooling. This should be the lowest speed that produces a rapid
will not occur with exhaust temperature control and continuous product flow through the spray
because the inlet temperature will be controlled to zone. This will allow for the uniform application
maintain the desired set-point. In any event, control of a film coating while subjecting the tablets to a
via any of these methods will yield the same approxi- minimal amount of attrition. In general, if tablet
mate temperatures. All of these temperatures are friability is less than 0.1%, tablet attrition will not be
equally important because the moisture from the spray a problem. A smaller tablet can be slightly softer
droplets is dried by both convection (due to the since these tablets produce a less abusive tumbling

action. Product flow can be evaluated either be applied to a tablet per pass through the coating
subjectively or through mixing studies using tablets zone before the tablet begins to exhibit coating
of various colors. Tablets of different colors can be defects. Therefore, the wider the spray pattern
placed in different zones (eg, front, middle, and width (without overlapping adjacent spray
back) of the pan. Tablet samples are taken at set patterns), the greater the spray rate per gun.
time intervals to determine the length of time • Product movement—The more consistent and fast
required to achieve a homogeneous mixture. the product flow through the spray zone, the
A more sophisticated means of evaluation includes higher the spray rate that can be delivered and
the use of radioactively marked tablets and a still achieve an acceptable level of film-coating
counter mounted on the spray bar to record the uniformity. Product movement is often dictated
number of passes through the spray zone per unit by the pan speed, baffle design, tablet size and
time. The product speed is generally assumed to be shape, and tablet robustness (particularly
traveling at the same linear velocity as the inside friability).
circumference of the coating pan.
In a continuous-coating pan system the product
flow is from the charge port to the discharge port. 34.3.7.2 Droplet size distribution
Depending on the coating level, the product may One of the most critical aspects of coating concerns is
pass through multiple drums (these drums may the manner in which solution is applied onto the tablet.
be located end-to-end or stacked horizontally). The spray droplets can be almost any size if the size dis-
One continuous-coating pan system currently tribution is sufficiently narrow. If the system is set up to
available contains five spray guns for a 1.5 m operate such that smaller droplets dry properly, then
coating-drum length. larger droplets will stay wet and picking or twinning will
occur. If the system is set up to dry larger droplets prop-
erly, small droplets will be dry and not spread properly
34.3.7 Understanding spray dynamics on the tablet, thus causing “orange-peeling” and a dull,
rough film appearance will result. Most spray guns used
34.3.7.1 Spray rate in the industry today have a limited range over which
The selection of the proper spray rate is dependent the spray can be varied and still retain a uniform distribu-
on more than just the thermodynamic considerations. If tion. Examples of some typical droplet size distributions
this were not so, the ultimate coating system would are shown in Fig. 34.30. These droplet size distributions
offer unlimited airflow and temperature. The spray were produced using a coating solution with a viscosity
rate (per spray gun) is also dependent on the ability of of 130 cP. Ideally, a spray gun that produces a narrow
each spray gun to produce a consistent droplet size dis- droplet size distribution should be used. This distribution
tribution. It has been shown that the droplet size will can vary with changes in solution viscosity, spray rate, or
increase as the spray rate is increased (unless a com- a change in solution solids; therefore, the manufacturers
pensating change is made in the atomizing air). Other of the spray guns will generally not provide information
factors that must be considered when determining the concerning these parameters. A simple method of exam-
spray rate are: ining this distribution can be performed by quickly pass-
ing a sheet of paper through the spray and subjectively
• Solution viscosity—As solution viscosity is
increased, the spray gun’s ability to produce an
acceptable droplet size distribution is diminished.
Particle size distribution
Therefore, viscosity will limit the maximum spray using various spray rates
rate that can be used and still produce 8
acceptable film quality.
6
• Spray pattern width—If the spray pattern width is
50cc/min
set-up properly, the spray pattern will essentially be 4
the same as the spray gun spacing. The typical gun- 100cc/min
2
to-gun spacing is 1220 cm. At spacing greater than
20 cm, the uniformity of the spray across the pattern 0
0.0 50.0 100.0 150.0 200.0 250.0
begins to deteriorate. Spacing of less than 12 cm is
Diameter (micron)
an ineffective use of spray guns and tends to add
more expense for added spray guns, solution lines, FIGURE 34.30 Examples of droplet size distributions obtained at
and pumps. There is a limit to how much spray can different spray application rates.

analyzing the droplet size. A typical droplet distribution is increased, the spray pattern widens. An increase in
usually ranges from 5 to 250 µm. In general, if droplets the atomization air will cause a reduction in the pattern
vary in size from 5 to 1600 µm, it will be difficult to width. This is logical because the increased volume of
optimize the film-coating quality. atomization air would make it more difficult to flatten
or widen the pattern. Lastly, as the spray rate is
34.3.7.3 Coating zone/pattern increased, the spray pattern is widened. Therefore, if the
As mentioned previously, the larger the spray zone atomization air volume or spray rates are adjusted, it
per spray gun, the higher the maximum spray rate then is important to reexamine the spray pattern width
that can be used per spray gun. Therefore, if the gun to ensure that the spray zone is effectively utilized.
spacing or the spray pattern is reduced, the spray Balancing the atomizing and pattern air correctly is
rate should be reduced proportionally. Applying more critical to maximizing the size of the spray zone while
spray per unit area of the tablet bed beyond a certain avoiding undesirable effects, such as creating a
point will change the film-coating appearance. If the dumbbell-shaped spray pattern.
spray rate is increased above this maximum, either
overwetting or spray drying will occur, depending on 34.3.7.4 Coating analysis
whether the process is run dry or wet. These are some characteristics of a typical film
A recent trend in coating is to achieve greater coating process:
production through the use of elongated or “stretch”
coating pans. Lengthening the coating pan not only
increases its capacity but, more importantly, the spray Product specification: Tablet 8.0 mm
zone. This allows more spray guns to be used thereby diameter
increasing the overall spray rate. An increase in pan Weight 250.0 mg/tablet
volume achieved by increasing bed depth with Density 0.73 g/mL
no increase in spray zone does nothing to allow an
increase in overall spray rate. Therefore, one means of Coating solution Solids 12% w/w
specifications:
scaling up the process time for coating can be achieved Density 1.0 g/mL
by using the following calculations: Quantity 62.5 kg
Spray time ðlarge panÞ 5 Spray time ðsmall panÞ Equipment Pan diameter 170 cm
Batch size ðlarge panÞ specifications:
Pan volume 550 L
3
Batch size ðsmall panÞ
Pan speed 5 RPM
Spray zone ðsmall panÞ
3 Four spray guns
Spray zone ðlarge panÞ
Coating conditions: Spray tate 125 g/min per
These calculations assume that the coating zones for gun
each of the pans are used efficiently. Total spray rate 500 g/min
A number of factors have an effect on the spray pat-
tern width. As the pattern air volume for the spray gun Spray time 125 min
• Assumptions:
• Spray zone:
Per spray gun 5 Spray width 3 Spray pattern length 5 7:5 cm 3 20:0 cm 5 150 cm2
Total spray zone 5 Number of spray guns 3 Spray zone per gun 5 4 3 150 cm2 5 600 cm2
Tablets per coating zone 5 Total spray zone 3 Number of tablets=cm2
Assume 3:5 tablets=cm2 in spray zone 5 600 cm2 3 3:5 tablets=cm2 5 2100 tablets=coating zone
Total spray length 5 Spray pattern width 3 Number of spray guns 5 20 cm 3 4 5 80 cm
Tablet bed velocity ðsame as the peripheral pan velocityÞ 5 Pan circumference 3 Pan speed
5 3:14 3 170 cm 3 5:0 RPM 5 2669 cm=minute

• Tablets per minute in the spray zone:
Coating zone=minute 5 Tablet bed velocity 3 Total spray length
5 2669 cm=minute 3 80 cm 5 213; 520 cm=minute
Tablets=minute in the spray zone 5 coating zone=minute 3 Number of tablets=in2
5 213; 520 cm=minute 3 3:5 tablets=cm2
5 747; 320 tablets=minute
• Coating solution per pass through the spray zone:

Total spray rate
Coating per pass through the spray zone 5
Tablets per minute=spray zone
500 g=minute
Coating per pass through the spray zone 5
747; 320 tablets=minute
5 0:669 mg=tablet ð0:080 mg solidsÞ
• Passes through the spray zone:

Tablets per minute=spray zone
Total passes through the spray zone 5 3 Spray time
Total number of tablets
747; 320 tablets=minute
Total passes through the spray zone 5 3 125 minutes 5 55:0 passes
1; 700; 000 total tablets
• Weight gain:
Weight gain=tablet 5 Coating per pass through the spray zone 3 Number of passes
Weight gain=tablet 5 0:080 mg solids=pass 3 55:0 passes 5 4:40 mg
Weight gain=tablet
Total weight gain
Tablet weight
4:40 mg
Total weight gain 2:0%
225 mg=tablet
In this analysis, each tablet would be within the application, uniformity of product movement, and
spray zone approximately 55 times over the course of achieving an adequate evaporative rate. These factors
a 125-minute coating trial. In actuality, many of these must all be examined and optimized in order to
tablets would be in the spray zone either more or less optimize the coating process.
frequently, depending on the uniformity of the prod-
uct movement. In addition, failure to optimize the 34.3.8.1 Uniformity of the spray application
gun-to-gun delivery or spray distribution will have an 34.3.8.1.1 Spray gun design
adverse effect on the coating uniformity. Therefore, There are a variety of spray gun manufacturers.
this factor should be examined to ensure a consistently Some of the more common suppliers include Binks,
high-quality film coating. Freund, Schlick, and Spraying Systems. The most com-
mon type of gun used is air atomizing or pneumatic.
This type of gun allows for the use of variable spray
34.3.8 Controlling coating processes—critical
rates. In the past, hydraulic gun systems were used;
factors however, they did not allow flexibility in spray rates.
Once all formulation requirements have been ful- The solution nozzle orifice must be sized to match
filled, these factors can be examined to optimize the the desired spray rate. In order to change the spray
coating quality and system performance, and can gen- rate, a change in the fluid nozzle may be necessary.
erally be grouped into three areas: uniformity of spray In addition, the use of smaller nozzle orifices can

increase susceptibility to plugging of the gun tip. guns. Calibration is also recommended when using
With some types of spray guns, the air cap and spray- peristaltic pumps because the tubing is subject to
nozzle configuration produce a predetermined ratio of fatigue. Calibration is usually accomplished by adjust-
atomization to pattern air at a given supply pressure. ing a knob that controls the restriction of the spray
In other guns there are separate controls for adjusting nozzle by the spray needle.
the volumes of the atomization and pattern air. This
allows the separate adjustment of either atomization 34.3.8.1.4 Atomization air volume/droplet size
or pattern without having to change the air cap
and/or the solution nozzle. For example, the width As stated previously, the atomization air volume
of the spray pattern can be changed without changing can be adjusted to control the mean droplet size of the
the spray droplet size. The atomization air breaks the spray. An increase in the atomization air volume can
reduce the mean or average droplet size. An increase
solution stream into a fine droplet size while the pat-
in either spray rate or solution viscosity will cause an
tern air serves to flatten the spray into a fan-shaped
increase in not only the droplet size distribution, but
pattern. The volume of atomization controls the mean
also the mean droplet size. Therefore, the droplet size
droplet size of the spray. The pattern air volume
controls the overall width of the spray. should be evaluated at the exact spray rate that will be
used for the coating trial. The quality of the spray
34.3.8.1.2 Number of spray guns in terms of droplet size and distribution should be
evaluated at several different settings.
The number of spray guns needs to be adequate to
provide uniform coverage of the entire product bed.
To maximize the uniformity and application of the 34.3.8.1.5 Spray gun angle
coating, the spray zone should cover from the front Ideally, the spray gun should be directed at the
edge to the back edge of the tablet bed. Adding more middle (midway between the leading and trailing
spray guns will not automatically guarantee that the edges of the tablet bed) and at a 90 degree angle to the
overall spray rate can be increased. The use of addi- moving tablet bed. If the spray guns are directed
tional guns is only justified if the existing number higher toward the leading edge of the tablet bed, it is
of guns is insufficient to cover the tablet bed from possible that spray could be applied to the pan or onto
the front to back of the pan. The objective is to pro- mixing baffles as they begin to emerge from the tablet
duce a uniform “curtain” of spray that the tablets bed. Conversely, if the spray guns are directed too low
pass through. Spray guns are usually capable of on the tablet bed, spray applied to the tablets may not
developing pattern widths of 1220 cm without have sufficient time to dry. This could result in the
adversely affecting the spray droplet distribution. At transfer of film from the tablets to the pan surface.
greater pattern widths, the volume of pattern air If the spray guns are not directed at a 90 degree angle
needed to fan out the spray can lead to a distortion of to the tablet bed then, the spray as it exits the solution
the droplet size distribution due to recombination nozzle has a tendency to build up on the wings of the
of spray droplets. The spray guns should be set up air cap.
such that adjacent spray patterns are as wide as
possible without overlapping. Overlapping of spray
34.3.8.2 Uniformity of product movement
patterns can lead to localized overwetting of the
tablet bed. 34.3.8.2.1 Pan speed
This area was covered in an earlier section (see
34.3.8.1.3 Uniform gun-to-gun solution delivery Process Parameters-Pan Speed). Product movement
It would seem obvious that to achieve uniformity of must be uniform if a uniform application of the coating
solution application, all spray guns must be set up to solution is to be achieved and the minimum pan speed
deliver the same quantity of coating solution. A recent necessary to achieve this objective is recommended.
trend in coating systems is the use of a single-pump Once the pan speed has been determined, it can be
manifold for multiple spray guns. For these types of scaled up by duplicating the peripheral edge speed.
systems, it is mandatory that calibration be performed This is done by taking the ratio of the small pan to large
on a regular basis to ensure that all spray guns are pan diameter multiplied by the small pan speed.
delivering the same quantity of solution. Furthermore, One final note is that the product movement should
the calibration must be performed with the coating be continually evaluated and adjusted as necessary
solution to be used. Calibration with water will not be during the coating cycle. Frequently, the product
satisfactory because its viscosity is much lower than movement will change as a coating is applied to the
that of the coating liquid and it will not be as sensitive tablet surface and the degree of slip of the tablets
to differences in pressure drop between the spray increases.

34.3.8.2.2 Tablet size and shape By using only 95% instead of 100% of the rated
Different tablet sizes and shapes will exhibit very volume, one can eliminate the spillage from the pan
different flow characteristics. In general, smaller tablets mouth ring during coating. Occasionally, what appears
will flow better than larger tablets. Longer, less round to be an acceptable pan load initially may turn out to
shapes, such as capsule and oval shaped tablets will be excessive for those products that exhibit a change
tend to slide and flow more poorly (more sliding) than in product movement as a film is applied or with
other shapes. If the tablet shape or size is changed, the coatings of an extremely high weight gain. A problem
product flow properties must be reexamined. In addi- in working with smaller batches (B50%) in a perfo-
tion, if the size is too small, it will require a fine mesh rated coating pan is that, unless part of the exhaust
to cover the perforations in the pan to prevent the plenum is blocked off, the process air will preferen-
exhaust of product. One other consideration is that tially pass around the tablet bed due to less restriction
if the product is fine (B1 mm or less) and the airflow or pressure drop. Batches of this size potentially can
is exhausted down through the product bed, then be coated successfully, however, the drying efficiency
there will be a considerable pressure drop across the will be reduced.
bed. This pressure drop will cause a reduction in
the process airflow. 34.3.8.3 Adequate evaporative capacity
34.3.8.3.1 Process air volume
34.3.8.2.3 Baffle type/size/number The process air stream should be adjusted to the
The primary function of the mixing baffles is to maximum volume that yields a laminar, nonturbulent
transfer the product between the front and back of the air flow. A turbulent airflow will distort the spray pat-
coating pan. A variety of different baffle shapes and terns and lead to lower coating efficiency due to spray
sizes exist. Coating pans are usually equipped with a drying of the coating. It is important to periodically
standard baffle design that works well for the majority inspect the coating pan to ensure that all process air
of different products. However, it may be necessary to passes through the tablet bed. Any air that passes
use a different baffle design for unusual shapes and around the product will result in a reduced evapora-
sizes. Coating pans can also be fitted with anti-slide tive efficiency. The inlet air volume is more important
bars. These bars are positioned on the flat of the than the exhaust air volume as an indicator of the
coating pan and perpendicular to the product flow. evaporative capacity because it is this air that passes
They are used to prevent tablets with large flat through the tablet bed and vaporizes the water from
surfaces from sliding inside the pan. With most coat- the coating and then conveys it away from the tablets.
ing pans, it is necessary to use a reduced baffle size The exhaust air volume will typically be slightly
when working with smaller batch sizes. greater than that of the inlet due to the addition of
Standard-size baffles used with a small batch will atomizing air from the spray guns, also due to slight
result in sluggish product movement and/or excessive leakage that may exist, and by the addition of water
variation in the spray gun-to-product distance. As the vapor to the exhaust air stream. If there is a large
baffle passes through the product, it will temporarily difference between the inlet and exhaust air volumes
carry a portion of the tablets up out of the tablet bed, due to leakage, this can be a problem, because this air
thus causing a brief increase in the gun-to-bed can artificially depress the exhaust temperature.
distance. As these tablets cascade off the baffle, the
tablet bed height rises and the gun-to-bed distance 34.3.8.3.2 Spray rate
decreases. A minimum variation in the gun-to-bed The initial spray rate that is selected may be based
distance is desired so that the spray always travels a on previous coating trials that have yielded successful
consistent distance and spray droplets striking the results. This is an acceptable approach if the coating
tablets have a constant moisture level. The typical solution and product being coated are very similar.
variation in gun-to-bed distance is from 2.5 to 5.0 cm. However, it is important to remember that changes in
A reduced or small-batch baffle is generally recom- these factors can drastically affect the spray rate and
mended whenever the batch size is less than 75% of other parameters selected. Another method for deter-
the rated pan brim volume. mining an initial spray rate is to evaluate the quality of
the droplet size distribution. Spray rates for aqueous
34.3.8.2.4 Batch size film coating vary from 6 to 30 g/minute for a small
As previously mentioned, the batch size/baffle com- 2.0 L pan to 80250 g/minute per gun in a large
binations are critical to obtain an acceptable product production-scale pan. The key factors that limit the
movement. An acceptable batch size range for film maximum spray rate per gun are the viscosity of
coating is usually 5095% of the rated brim volume. the coating solution, the type of spray gun used,

and ultimately the level of film quality that a (ie, sustained release coatings), the tighter the range.
Pharmaceutical company deems acceptable. High dew-point temperatures can be reduced through
the use of a dehumidification system employing
34.3.8.3.3 Spray gun-to-tablet-bed distance either chilled water coils or desiccant dehumidifica-
For small-scale coating systems, the gun-to-bed tion. Chilled water systems are usually specified to
distance can be as little as 2.55.0 cm. The typical control the dew point at 1012 C (5053 F) or an
gun-to-bed distance is 2025 cm for a production- absolute moisture content of 7.58.5 g/kg of air.
sized coating pan. This distance usually provides an With a desiccant dehumidification system, the dew
economical tradeoff between the cost of the number point can routinely be controlled to a temperature as
of guns needed to adequately cover the spray zone low as 26 C (21 F). Low dew-point temperatures
and the desired quality of spray. If the gun-to-bed can be adjusted by humidifying the air via the
distance is less than 20 cm, then either the spray injection of clean steam into the process air. If no
rate must be reduced or the inlet temperature and attempt is made to limit the variation of the inlet
product temperature increased to compensate for the dew point, then fluctuations in ambient air conditions
shortened evaporation time. If this distance is greater can lead to reduced coating efficiency (spray drying),
than 20 cm, the inlet process temperature should longer processing times, or film defects due to
be reduced otherwise more spray drying is likely overwetting.
to occur.
34.3.8.3.4 Product/exhaust temperature

34.3.9 Scale-up
Typically, aqueous film-coating processes are set
up to achieve an exhaust temperature of 3844 C. 34.3.9.1 Batch size
Based on the desired spray rate, an inlet temperature The most accurate method of determining batch size
is determined that allows an exhaust temperature is to load the coating pan to within 2.55.0 cm of the
in the target range to be maintained. Coatings that pan opening and then rotate the pan at the desired
develop greater tackiness will require exhaust tem- rpm to ensure that the pan is not overfilled. However,
peratures to be adjusted to prevent overwetting there are two different methods for approximating the
defects, or excessive heat when working with thermo- batch size. The first method is to multiply the rated
plastic coatings that become tacky when getting too brim volume times 95%, and then multiply the resul-
hot (for these coatings, a typical exhaust temperature tant volume by the bulk density of the product. A sec-
range might be 3038 C). ond method for determining the pan load size is to
The exhaust temperature is slightly lower (B15 C) multiply a known ratio of batch size to pan volume for
than that of the product bed due to heat loss between a small-scale pan times the volume of the pan being
the measurement points. Usually, the greater the dis- scaled to. For example:
tance between the exhaust and product temperature
Small pan batch size
probes, the greater the differential. The only time
when these temperatures will vary more is during Large pan batch size Small pan volume
preheating and cool-down. A product temperature 3 Large pan volume
probe will display an average of the entire tablet bed.
The product temperature can be determined through 65:0 kg
Large pan batch size 3 550:0 L 397:0 kg
the use of either a probe that extends into the tablet 90:0 L
bed or through the use of an infrared temperature
probe directed at the zone just above the spray zone. However, on the production scale, pan fill weights
Tablets in the spray zone are at a slightly lower are often determined by compression batch weight
temperature due to evaporative cooling and are not rather than desired pan fill capacity, so coating on this
representative of the average product temperature. scale may use pan loadings that are less than ideal.
34.3.8.3.5 Dew-point temperature
The dew-point temperature is directly related to 34.3.9.2 Pan speed (angular pan velocity)
the moisture contained in the process airstream. Dew- When scaling up a coating process, it is critical that
point temperatures can be measured using either a the tablet speed through the spray zone in the larger
capacitance or a chilled mirror-type dew-point sensor. pan is comparable to that used in the smaller pan.
To accurately reproduce the drying rate from trial to In other words, the pan angular velocity must be the
trial, it is recommended to maintain the dew point same for both coating pans. Pan velocity can be dupli-
within a controlled range. The more critical the coating cated by multiplying a ratio of the small pan diameter

to large pan diameter times the pan speed used for the the total or the per gun sprays. Increasing the total
smaller coating pan. For example: number of spray guns will only be of value if the
existing spray zone is inadequately covered with
Small pan diameter
fewer spray guns. If the spray pattern width used in the
Pan speed for large pan 5 Large pan diameter larger coating pan is narrower than that used
3 Pan speed for small pan in the small pan then the spray rate per gun should be
reduced in proportion to the reduction of the spray
100 cm pan zone width. This will allow the same density of film
Pan speed for large pan 5 170 cm pan coating to be applied per unit area of the tablet bed
3 9 rpm 5 5:3 rpm surface. Otherwise, the quantity of coating applied on
the tablets per pass through the spray zone would
This equation will yield a close estimate of the pan increase. This would most likely change the quality
speed. However, subtle differences in the baffle design of the coating and could lead to overwetting or logo
between coating pans may require a slight adjustment bridging defects. Here is an example of scale-up using a
from this calculated pan speed. ratio of total spray zone utilized:
34.3.9.3 Available coating zone Pan #1 Pan #2
To scale up the coating process with any degree of Pan volumes 90.0 L 850.0 L
confidence, the spray rate must be determined using Batch size 60.0 kg 566.0 kg
the same gun-to-bed distance used in the larger coating
pan. Any change in the gun-to-bed distance will change Coating solution 2 kg 113 kg
the drying time for the spray droplets and thus alter the Number of spray guns 2 10
quality of the coating. The same spray rate used in the Spray pattern width (per gun) 20 cm 15 cm
small-scale pan can also be used in the production-scale
pan, assuming that the same spray gun spacing and Spray rate (per gun) 150 g/min To be determined
spray pattern widths are used. Typically, the use of Spray rate (total) 300 g/min To be determined
more spray guns without increasing the size of the Spray time 40 min To be determined
overall spray zone will not allow an increase in either
Pattern width for pan #2

Spray rate for large pan 5 3 Spray rate ðper gunÞ for pan #1
Pattern width for pan #1
15 cm spray pattern
Spray rate for large pan 5 3 150 g=minute per gun 5 113 g=minute per gun
20 cm spray pattern
Total spray rate for pan #2 5 per gun spray rate ðpan #2Þ 3 number of spray guns ðpan #2Þ
Total spray rate for pan #2 5 113 g=minute per gun 3 10 spray guns 5 1; 130 g=minute=total
Quantity of solution to apply

Spray time
Total spray rate
113 kg
Spray time 85 minute
1:33 kg=minute
34.3.9.4 Spray-rate-to-pan-speed ratio withstand a greater application per pass through the
One factor that is quite commonly overlooked is spray zone without any adverse effects on film
the ratio of the spray rate to the pan speed. The ratio quality or the uniformity of the coating. Whenever
of spray rate to pan speed has serious implications in the spray rate and pan speed are both increased, the
both the amount of film coating applied onto the indi- tablets should be evaluated for signs of overwetting
vidual tablets per pass through the spray zone and on or increased tablet attrition. One problem that may
the overall uniformity of the film coating itself. result if the pan speed and spray rates are too high
Therefore, with any increase in the spray rate, one relative to the evaporative rate is that wet film coating
should evaluate the need for an increase in the pan from the tablets may be transferred to the pan
speed. In some instances, the tablets may be able to surface.

34.3.9.5 Airflow-to-spray ratio design (QbD) program, as mandated by regulatory

When scaling-up the film coating process, it is agencies, should essentially help eliminate problems in
recommended that the airflow used in the larger coat- film-coating processes, with the possible exception of
ing pan be proportional to the increase in the spray those due to equipment failure.
rate. If the airflow is increased in the same ratio as the Identifying appearance-related problems is relatively
increase in spray rate and if the spray rate per unit easy because visual feedback is immediate. The magni-
area of the bed surface is the same, the same inlet and tude of the problem is also often immediate. Identifying
exhaust temperatures can be maintained. The inlet nonappearance related problems (such as those associ-
temperature must be increased to maintain the same ated with chemical stability or drug release) is more
evaporative rate if the airflow is not increased in the difficult because:
same proportion as the spray rate. If the spray rate per • The existence of the problem is often not readily
gun and the gun-to-bed distance are the same for both apparent,
pans, the airflow can be scaled up in direct proportion • Determination is often on the basis of some
to the increase in spray guns. For example: analytical procedure that evaluates only a small
sample (relative to the batch size in question) of
Pan #1 Pan #2 tablets, and
Spray rate (per gun) 125 g/min 125 g/min • Sampling, and the relevance of the samples selected
to the characteristics of the whole batch, becomes a
Number of spray guns 2 4
critical issue.
Total spray rate 250 g/min 500 g/min
Inlet airflow 1000 CMH To be determined
34.4.2 Up-front approaches to avoid
troubleshooting issues
Total spray rate for pan #2
The best solution to “fixing problems” is to avoid
Airflow for pan #2 5 Total spray rate for pan #1 them in the first place. One way in which many
3 Airflow for pan #1 coating problems can be avoided is through the proper
formulation of the product substrate and the film-
500 g=minute coating solution. Before the coating process can be
Airflow for pan #2 5 250 g=minute developed or scaled-up, the product must be evaluated
to ensure that it meets the formulation requirements
3 1000 CMH 5 2000 CMH
for film coating. Often, problems arise because the
tablet core formulation is not sufficiently robust to
withstand the rigors of film coating.
The core must be formulated such that minimal
34.4 TROUBLESHOOTING attrition occurs during the film-coating process. The
deeper the product bed, the more abuse the tablets
34.4.1 Introduction to troubleshooting must withstand. For smaller tablets (less than 100 mg),
56 kp tablet-breaking force (hardness) may be suffi-
Troubleshooting is basically a “reactive” process
cient. For medium-sized tablets, 1216 kp may be
because it deals with something that has already gone
sufficient. For larger capsule-shaped tablet, such as a
wrong. A coating problem will usually manifest in one
1 g capsule-shape, a hardness of more than 20 kp may
or more of these ways:
be necessary. A better measure of a product’s suitabil-
• Those affecting visual coated-product quality, ity for coating is friability. In general, a product with a
• Those affecting coated-product functionality, friability of 0.1% or lower should be sufficient to avoid
• Those affecting coated-product stability, and attritional problems during the coating process. Other
• Those affecting processing efficiencies and costs. core formulation issues that should be addressed prior
to developing the coating process include:
When dealing with an existing, marketed product,
the troubleshooting process is constrained by many • Product stability: All core ingredients must be
regulatory issues. These problems are the most trou- stable at the temperatures required for the
blesome in that the proper corrective action may evaporative process (typically 4045 C for
require refiling with the FDA. Therefore, other less aqueous-based coatings)
suitable remedies may be taken, which may lessen the • Product shape: The use of large flat product
symptoms rather than correct the actual cause of the surfaces must be avoided to prevent the tendency
problem. Of course, application of a suitable quality by for “twinning” of product cores

34.5 CONSIDERATION OF PRODUCT SUBSTRATE 987
• Logo design: The core logo should be designed such pan may not be sufficient for a larger pan. A tablet
that attrition and bridging of the logo do not occur hardness tester is used to determine the edge-to-edge
• Resistance to dimensional changes (avoiding (diametral) tablet hardness. Typical hardness measure-
ingredients that undergo thermal expansion, ment units include: kiloponds (kp), Strong Cobb Units
or expand through excessive moisture absorption) (SCU), and Newtons (N). The kilopond is defined as the
• Film adhesion: The core should be sufficiently force exerted by a kilogram mass upon its support in
porous to allow the film to adhere properly to a gravitational field of g 5 9.80665 m/second2. One kilo-
the surface pond is equal to 9.807 N units or 1.4 SCU. Tablet hard-
• Chemical/functional robustness: ness has traditionally been the measure of a tablet’s
• Role of amorphous, hydrophilic materials suitability for coating. However, in many cases, the tab-
• Low melting-point ingredients let may be of substantial hardness but still exhibit
• Mixing potential: Small, more round products will unacceptable capping tendencies or show excessive
tend to flow well. Large or longer tablet shapes will wear on the tablet edges or logo. Therefore, a better
tend to exhibit “sluggish” movement. means of determining a tablet’s ability to withstand tum-
bling is friability. This is usually determined by tumbling
Another issue that must be addressed before the
a certain number or weight of tablets for a set number of
coating process can be developed is the film-coating
rotations (usually 100 revolutions) inside a cylinder.
formulation, which must be extensively evaluated to
The tablets are weighed before and after tumbling and
ensure that it meets the requirements for intended
weight loss is expressed as the percent friability. A recent
coating process. Some of the issues that must be
innovation to the friability test is to line the inside of
addressed include providing:
the friability cylinder with a mesh screen. This has
• Sufficient film mechanical strength to prevent been shown to provide a better correlation between the
cracking or edge wear; friability test and actual suitability for subjecting to a
• Sufficient plasticizer to prevent the formation of coating process.
a brittle film;
• Sufficient pigment to mask the color of the tablet
core;
• Appropriate solids level that allows a coating to be
34.5.2 Weight variation
applied quickly to protect the core from attritional Tablet cores are usually produced to a particular
effects; weight range specification. However, sometimes these
• Sufficient adhesion between the coating and the ranges are not sufficiently narrow. This usually occurs
core surface; when the tablet granulation exhibits flow problems.
• A solution viscosity that is low enough to allow A wide tablet weight variation will make it difficult or
the production of a uniformly atomized spray; and impossible to accurately determine the actual tablet
• Sufficient coating suspension stability, including weight gain due to the application of the film coating,
absence of growth of microorganisms and since the weight variation in the uncoated cores can be
prevention of sedimentation of suspended coating greater than the weight of the film to be applied.
solids. In addition, wide variations in tablet weight can be
accompanied by variations in tablet hardness.
34.5 CONSIDERATION OF PRODUCT

SUBSTRATE 34.5.3 Stability
The tablets must be stable under the conditions
To effectively develop the coating process, the
required for coating. The product must be able to with-
product must be evaluated to ensure that it meets
stand the temperature and humidity of the process
the necessary criteria for a substrate.
airflow. Product temperature is significantly less than
that of the inlet air during the coating process due to
evaporative cooling. However, during the preheat
34.5.1 Hardness/friability phase, the product temperature may approach that of
The tablet core must be capable of withstanding the inlet air if the tablets are not jogged frequently
the rigors of tumbling in the coating pan. In a larger enough. Tablets should be able to handle the usual
diameter coating pan, the bed depth will be greater and product temperature of 3550 C. As mentioned previ-
therefore, subject the tablets to greater stress. So, an ously, it may be necessary to use drier conditions
acceptable tablet hardness or friability for a small coating during the initial phase of the coating process to

prevent stability problems with moisture-sensitive a change in dissolution after film coating is often
products, such as effervescent tablets. caused by exposure of the tablet core to the coating
process conditions (such as heat) rather than as a result
of a direct effect of the applied film coating.
34.5.4 Compatibility
The compatibility of the tablet core with the
excipients in the film-coating solution must be verified. 34.6 COATING FORMULATION
In some instances, certain actives have exhibited an
interaction with the plasticizer in the coating solution. 34.6.1 Film mechanical strength
The film-coating formulation must be optimized
34.5.5 Shape such that the resultant film has adequate mechanical
strength. The reasons for this are twofold; first, the
If possible, certain tablet shapes should be avoided film must be strong enough to protect the tablet from
for film coating. Tablets with sharp edges may exhibit excessive attrition while tumbling during the coating
a greater tendency for edge wear. Cores with large, flat process and, second, the applied coating must be
tablet faces may result in poor product movement due sufficiently durable to resist the erosion of the film
to sliding. Tablets with large flat surfaces (such as itself. A weak film will usually exhibit wear or erosion
deep walled capsule shaped tablets) will also show a at the tablet edges, or may crack as a result of being
much greater tendency to exhibit twinning during subjected to mechanical stress (tumbling) or excessive
coating. Adding a slight concavity (0.10.2 mm) to the heat. The addition of too many nonfilm-forming exci-
tablet faces or tablet edges reduces the likelihood of pients (such as pigments and detackifying agents
agglomeration or twinning. like talc) will decrease the strength of the film.
Such reduced film strength may also occur if a drug is
added to the coating solution.
34.5.6 Logo design
Sharp corners or small islands on the tablet logo can
lead to logo attrition problems. If the logo is too fine or 34.6.2 Plasticizer level
contains too much detail, the film coating may bridge The function of a plasticizer is to reduce the glass
or cover the logo. A draft angle of 35 degree is recom- transition temperature (Tg) of the film or, in other
mended for film-coated tablets. Tooling manufacturers words, to produce a film that is not brittle under
are usually aware of the tool design specifications normal process and storage conditions. If the film is
for tablets to be film coated. Finally, placement of a inadequately plasticized, the film will be too brittle and
logo on the crown of a tablet may lead to more crown more prone to cracking. If a film-coating formulation
erosion. has an excessive level of plasticizer, the mechanical
strength of the film will be reduced, and excessive
tackiness may be observed.
34.5.7 Core porosity
The tablet core must be formulated so that there is
good adhesion between the film coating and the tablet
34.6.3 Pigment level
surface. If the core porosity is low, poor adhesion If the coating solution contains insufficient pigment,
will result, and picking and/or peeling of the film will it will be impossible to develop the desired color
occur. Core porosity can be a problem with wax matrix intensity. In addition, low pigment levels can make it
tablets due to poor adhesion between the tablet surface difficult to minimize color variation due to poor opacity
and film-coating droplets. To remedy this, more of the applied coating. On the other hand, excessively
adhesive film polymers (ie, hydroxypropylcellulose, high pigment levels can, as stated previously, reduce
copovidone, or polyvinyl alcohol) may be used. the mechanical strength of the coating.
34.5.8 Disintegration/dissolution 34.6.4 Film solution solids

The disintegration of the tablet core must be A low solids level in the coating solution can not
sufficiently rapid when tested prior to the addition of only needlessly increase the process time, but can also
the film coating. If the core does not dissolve quickly increase the time required to provide a protective film
prior to coating, the addition of film coating may only coating, thus resulting in increased tablet attrition.
provide a further delay. However, in most instances, High solution-solids levels coupled with a low

34.6 COATING FORMULATION 989
addition level can make it difficult to achieve was an interaction between the plasticizer and the
acceptable film-coating uniformity. High solids levels active ingredient used in the tablet core. It was neces-
can also be a problem if they result in a high solution sary to reformulate the coating solution using an
viscosity. If a high solids level does not create an alternative plasticizer. Finally, when applying ionic
excessively viscous solution, it provides an excellent coatings, such as enteric coatings, interaction with
opportunity to reduce the amount of coating solution ionic materials in the core must be considered, as does
required and, thus, the coating time. Aqueous polymer potential interaction with core ingredients that are acid
dispersions available on the market provide high unstable (such as proton pump inhibitor APIs like
solids solution at an extremely low viscosity. omeprazole, lansoprazole, etc.)
34.6.5 Solution viscosity 34.6.8 Processing issues as they relate to

troubleshooting
Solution viscosity, as stated previously, is closely
tied to the solution solids level. As solution viscosity 34.6.8.1 Equipment maintenance issues
is increased (above B200250 cP) the droplet size Many coating problems can occur as a result
distribution produced by the spray guns becomes of poor equipment maintenance, and these can
increasingly wider due to an increase in larger be avoided through implementation of a routine
droplets. Slight increases in viscosity can be compen- equipment maintenance program. This program must
sated for by increasing the volume of atomization air. involve the periodic calibration of all analog and
However, at higher viscosities (greater than B350 cP) digital instrumentation. Poor maintenance of process-
it is difficult to eliminate all of the larger droplets. monitoring equipment results in decisions being made
To compensate for the presence of larger droplets, on the basis of inaccurate information. The mainte-
the operator will usually increase the inlet temperature nance program should also involve the inspection of
to prevent the larger droplets from overwetting the all wear items. The equipment manufacturer should
product. This will result in an increase in the amount be able to provide a listing of these parts with a
of spray drying due to premature evaporation of water recommendation for the frequency of inspection.
from the finer droplets. The net result is a lower
coating efficiency and a rougher film surface. 34.6.8.2 Process adjustment as a troubleshooting
initiative
The dynamics associated with the spray application
34.6.6 Stability of the coating liquid represent perhaps one of the most
The coating solution must be stable for the duration underappreciated areas of the whole film-coating
of the coating time. This includes both chemical and process.
physical stability. The most typical instability problem Key issues to be aware of include:
encountered is settling-out of solution solids. This • Fluid flow rate through the nozzle, interaction with
occurs with solutions that contain an excessive per- the driving forces for effective atomization, and the
centage of solids or when the coating has insufficient ultimate size of droplets formed
suspending capacity (due to low polymer content • Droplet velocity
and/or low viscosity). Settling of solids can lead to • The interaction of atomized droplets with the
blockage of the solution lines or the spray guns. For surrounding drying environment, and the relative
coating liquids where settling of insoluble components state of the droplets as they arrive at the tablet
(such as pigments) is a problem, use of a recirculating surface
spray system and/or using a suitable tank mixer
can help. While the importance of many operating para-
meters (air flows, temperatures, spray rates, etc.) is
relatively well understood, the ultimate impact of
34.6.7 Compatibility other parameters on the issue of troubleshooting is
often overlooked, such as:
This refers not only to the compatibility of the
coating materials, but also to the compatibility between • Mixing effectiveness in the pan, and the impact of,
the film coating and the tablet core. For example, the for example, baffle design;
addition of color concentrates that contain ethanol • Pan loading, and its impact on process efficiencies
has led to precipitation of some of the polymer used and product quality; and
in aqueous dispersions. As a remedy, a propylene • The potential change in tablet roll dynamics as
glycol-based color was used. In another product there coating is applied.

Another approach to troubleshooting involves It is important that the objectives be examined

the systematic evaluation of the film-coating process. in the order listed to effectively troubleshoot the
Film-coating processing issues can be classified into film-coating process. One should first deal with
these categories, namely achieving: issues affecting uniformity of spray application,
then issues that affect product movement, and lastly,
1. Good uniformity of the spray droplet size and
issues dealing with the evaporative rate of the
application,
coating process.
2. Effective uniformity of product movement through
For example, let’s assume that the product is exhi-
the spray zone, and
biting signs of picking, which is an over-wetting
3. Proper solvent evaporation rates for the coating
defect. Let’s also assume the root cause of this defect is
process.
due to poor product movement, which causes the
There are a number of issues that must be product to stop in the spray zone. Now it might be
addressed with regard to each of these objectives. possible to eliminate this problem by increasing
This is a partial listing of some of the factors to be the process temperatures (evaporative rate factor).
considered: However, the product movement through the spray
Issues that affect the uniformity of spray droplet zone would still be poor and coating uniformity would
size and application: be less than optimal. A better remedy would be a
corrective action that results in improved product
• Can an acceptable spray droplet size distribution be
movement (2nd Objective).
produced at the desired spray rate?
A second example might assume the same defect
• Can an acceptable spray droplet size
(picking), however in this case, the cause of the
distribution be produced using the coating
defect is due to nonuniformity of the solution deliv-
solution viscosity?
ery through the spray guns. One of the spray guns
• Is there adequate compressed air volume for the
is delivering significantly more solution than the
atomization of the coating liquid?
others. One could probably reduce the spray rate to
• Are the number and type of spray guns suitable to
eliminate the over-wetting problem; however this
provide uniform coverage of the product bed?
would not be the appropriate remedy. If this were
• Are the spray guns located at the proper spacing?
done, then the coating uniformity would still be
• Is the spray pattern width sufficient to maximize the
less than optimal and the corrective action would
size of the spray zone without overlap adjacent
have lengthened the necessary coating-process time.
spray patterns?
A more appropriate remedy would be a corrective
• Is the spray-gun-to-product-bed distance correct?
action which results in an improved spray application
• Is the solution delivery rate the same for all spray
(1st Objective).
guns?
Issues that affect the uniformity of product
movement:
34.6.9 Troubleshooting: summary
• Is the batch volume sufficient for the pan being
Overall, problems often have more than one cause,
used?
and problem resolution is likely to be complex.
• Is the correct pan speed being used?
Problem resolution may encompass minor changes
• Does the pan contain the proper baffle type and are
that have little regulatory impact, or they may require
they in the correct position?
intervention by making significant (from the regula-
• Are tablets being “thrown” into the spray zone by
tory standpoint) changes to either formulations or
baffles or baffle mounts?
• Is the product size and/or shape conducive to good processes.
The simplest approach to problem resolution is
product movement?
problem avoidance.
Issues that affect the solvent evaporation rate of the
coating process:
• Is the proper process air volume being used?
34.6.10 Film-coating defects/
• Is the incoming air stream controlled to a consistent
troubleshooting—summary
dew point?
• Are the inlet, exhaust, and product temperatures The information shown in Table 34.18 contains a
correct for the tablets being coated? brief definition of common tablet-coating defects
• Is the proper spray rate being used? together with typical causes and suggested remedies.

TABLE 34.18 Tablet Coating Defects and Suggested Corrective Actions
1. Overwetting/picking: This condition occurs when part of the film coating is pulled off one tablet and is deposited on another. If detected
early in the process, it can be covered. If detected late in the process the coating will likely be unacceptable.
Possible cause Remedies
Insufficient drying rate Increase the inlet and exhaust temperatures
Increase the process air volume
Decrease the spray rate
Inadequate atomization Increase the nozzle air pressure or the atomization air volume
Decrease film coating viscosity
Poor product movement Increase pan speed
Switch to an alternative baffle design
Adjust batch size (volume)
Poor distribution of spray Check the uniformity of solution delivery through the spray guns (calibration)
Insufficient drying rate Increase the inlet, exhaust, and product temperatures
Increase process air volume
Reduce the spray rate
Excessive variation in Process Air Dehumidify and/or humidify process air to maintain a constant inlet air dew point
Humidity
2. Twinning: Twinning is a form of overwetting whereby two or more of the tablet cores are stuck together.
May be due to any of the possible causes for overwetting
Poor tablet core design Change tablet design to eliminate large flat surfaces
3. Orange peel: Appears as a roughened film due to spray drying. This condition relates to the level of evaporation that occurs as the spray
droplets travel from the gun to the tablet bed. If there is excessive evaporation, the droplets do not have the ability to spread and form a
smooth coating. A narrow droplet size distribution is important to ensure that the majority of droplets dry at the same rate.
Excessive evaporative rate Reduce the inlet and exhaust air temperatures
Reduce the gun-to-bed distance
Excessive atomization of the spray Reduce the nozzle air pressure or atomization air volume
Large droplet size variation Reduce the solution viscosity
Reduce the spray rate
4. Bridging: Bridging is a condition in which the film coating lifts up out of the tablet logo10.
Poor film adhesion Reformulate the film coating solution to improve adhesion
Reformulate the core formulation to increase porosity
Poor logo design Redesign logo to incorporate shallower angles
5. Cracking: May occur due to internal stresses in the film10.
Brittle film coating Increase the addition level of the plasticizer
Use a different plasticizer
Use a polymer with a greater mechanical strength
Poor film adhesion Dilute the film-coating solution
Reduce the quantity of insoluble film coating additives
(Continued)
TABLE 34.18 (Continued)
6. Poor coating uniformity: Poor coating uniformity can manifest itself in either a visible variation in color from tablet to tablet, or in the form
of an unacceptable release profile for tablets.
Insufficient coating Apply a coating of 1.53.0% (for clear coating as little as 0.5%) weight gain to attain uniformity, requires higher
levels if the color of the tablets and the film are of very different colors
Poor color masking Reformulate the film coating to a darker color and/or increase the quantity of opacifier
Poor uniformity of solution Increase the pan speed

application
Reduce the spray rate/increase the coating time
Increase the spray pattern width
Increase the number of spray guns
Check the uniformity of solution delivery through the spray guns (calibration)
7. Tablet attrition/erosion: Attrition is exhibited when some portion of the product substrate exhibits a high level of friability. This typically occurs
at the tablet edge or face. Often signs of attrition will be minimal or nonexistent in smaller diameter coating pans. However, when the coating
process is scaled-up to a production-sized pan, this problem can become more severe due to the increased batch weight and bed friction11.
Insufficient tablet friability Reformulate the tablet core to a friability of no more than 0.1% friability
Poor film-coating formulation Reformulate to provide coating with greater mechanical strength
Excessive pan speed Reduce the pan speed to the minimum required to achieve a smooth and continuous bed movement
Insufficient spray rate Increase the spray rate to provide a protective film coating in a shorter time, this may require an adjustment in the
inlet air temperature
8. Core erosion: Core erosion is another type of attrition due specifically to overwetting of the tablet core. With this type of defect, excessive
overwetting may cause a partial disintegration of the core surface.
Surface overwetting Reduce the spray rate
Increase the inlet and exhaust air temperatures
Reduce the spray droplet size/increase the atomization air volume
Reformulate the core with less water sensitive excipients
Improve tablet bed movement
Increase the bed to gun distance
9. Peeling: Peeling occurs when large pieces or flakes of the film coating fall off the tablet core.
Poor adhesion Reduce the amount of insoluble additives in the coating solution
Increase the level of film former in the coating solution
Reformulate to incorporate a film polymer with greater adhesion
Reformulate the tablet core to increase porosity
Brittle film coating Increase and/or switch to an alternative plasticizer
10. Loss of logo definition: This defect occurs when the tablet logo is no longer clearly legible. It may be due to one or more of the defects
previously covered: core erosion, tablet attrition, or bridging. Loss of definition can also occur when the logo is filled in with spray dried film.
Core erosion Reduce the spray rate
Increase the inlet and exhaust air temperatures
Reduce the spray droplet size/increase the atomization air volume
Reformulate the core with less water-sensitive excipients
Improve tablet bed movement
(Continued)
34.7 APPLICATION OF SYSTEMATIC AND STATISTICAL TOOLS FOR TROUBLE SHOOTING AND PROCESS OPTIMIZATION 993
TABLE 34.18 (Continued)
Excessive film-coating level Reduce the film-coating weight gain
Improve the uniformity of the coating distribution
Tablet attrition Reformulate the tablet core to a friability of no more than 0.1%
Reduce the pan speed to the minimum required to achieve a smooth and continuous bed movement
Increase the spray rate to provide a protective film coating in a shorter time; this may require an adjustment in the
inlet air temperature
Bridging Reformulate the coating solution to improve the film adhesion
Reformulate the core formulation to increase porosity
Redesign logo to incorporate shallower angles
Excessive drying rate Reduce the inlet and exhaust air temperatures
Reduce the gun-to-bed distance
Reduce the nozzle air pressure or atomization air volume
11. Core stability issues: These problems may manifest as discoloration of the core or degradation of the core active.
Moisture sensitivity Explore the remedies for overwetting defects
Reformulate the core with less water-sensitive excipients
Heat sensitivity Decrease the inlet and/or product temperature
Tablet component incompatibility Investigate the compatibility of the tablet core with the coating formulation
Determine the compatibility of the core ingredients
12. Tablet marking: Usually evident as the presence of black marking on the face of the tablets.
Abrasion of oxide from the coating Change to a tablet shape that tumbles rather than slides (ie, round rather than oval/capsule)
pan surface
Reduce the level of titanium oxide in the coating
Add baffles to reduce the sliding of tablets
Coat the pan with coating solution to act as a barrier
Increase the spray rate or reduce the pan speed
34.7 APPLICATION OF SYSTEMATIC ICH Q8 (development)

AND STATISTICAL TOOLS FOR TROUBLE ICH Q9 (risk management)
SHOOTING AND PROCESS ICH Q10 (quality system)
OPTIMIZATION KPP/CPP
Key quality attribute/critical quality attribute
As we move firmly into the 21st century, the QbD, To meet these challenges, many systematic and sta-
physician quality reporting initiative (PQRI), and risk tistical tools are being used in a sequential manner to
management are introduced to allow the manufacturer
and the regulator to better design, monitor, and control • Identify root cause(s);
the quality of the product in United States, Europe, • Understand the KPP/CPP and knowledge space/
Japan, and other countries. control space;
These are some key initiatives: • Optimize the process; and
• Establish the control plan, which should be one for
Concept of design space continuous improvement.
QbD
Risk assessment Many pharmaceutical companies employ a variety
DOE of systematic and statistical tools and define the
Knowledge space/control space procedures of their approach. These tools include

six-sigma/DMAIC, DOE, Kepner Tregoe analysis (KT), Case Study: Using Systematic and Statistical Tools
Brightest, Pareto Analysis, Gauge RR, Lean sigma, risk by Right-First-Time Approach to Address Film Coating
assessment, and other tools. Issues.

References 6. Liu L, Smith TJ, Sackett G, Poire E, Sheskey P. Comparison of

film coating process using fully perforated and partially
1. Porter S, Bruno CH, Jackson GJ. Pan coating of tablets and perforated coating pans. In: 2004 AAPS annual meeting 2004.
granules. Pharmaceutical dosage forms: tablets, vol. 3. New York, 7. Bauer K, Lehman K, Osterwald H, Rothgang G. Coated
NY: Marcel Dekker; 1982. pharmaceutical dosage form fundamentals, manufacturing techni-
2. Liu L. The coating efficiency of a film-coating process. In: Invited ques, biopharmaceutical aspects, test methods and raw materials.
speaker, Pharmaceutical excipients conference, June 2527, CRC Press Boca Raton, FL; 1998.
Philadelphia (PA). 8. Wade A, Weller PJ. Handbook of pharmaceutical excipients. 2nd ed.
3. Liu L, McCall T, Tendolkar A, Shlyankevich A, Giambalvo D, Washington, DC: A.Ph.A; 1994.
Baumgamer C, et al. The scale-up and process optimization of a 9. McGinity JW. Aqueous polymeric coatings for pharmaceutical
ethylcellulosebased functional coating and its impact on dosage form. 2nd edition. New York, NY: Marcel Dekker, Inc.;
in-vitro/in-vivo release of a novel controlled release system. 1997.
In: The 27th international symposium on controlled release of bioactive 10. Rowe RC, Force SF. The effect of Process Conditions on
materials. Paris (France); July 713, 2000. the Incidence of Bridging of the Intagliations and Edge
4. Liu L, Giambalvo D, McCall T, Labudzinski S, Baichwal A. Splitting and Peeling on Film Coated tablets. Acta Pharm Tech
The effect of process variables on coating efficiency of an 1982;28:20710.
HPMC-based film coating using a perforated coating pan. 11. Russo EJ. Typical scale-up problem and experiences. Pharm
In: AAPS 1998 annual meeting. San Francisco (CA); 1998. Technol 1984;8(1):4656.
5. Freers S, Jensen B, Shipley C, Foltz D. Clear coated tablets with
high-solids aqueous starch coating and minimal tablet weight gain.
Vector Corporation.

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C H A P T E R

34.1 INTRODUCTION 34.1.2 Evolution of pharmaceutical-coating

Developing Solid Oral Dosage Forms

assessment of critical process parameters (CPP) that 34.2 FILM-COATING FORMULATIONS

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

FIGURE 34.2 Schematic of a fully-perforated coating pan. Source: Courtesy of Vector.

FIGURE 34.3 Schematic of a partially-perforated coating pan. Source: Courtesy of Vector6.

from finely-atomized droplets of solution, which

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

When designing coating formulations, there are sev-

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

Solution viscosity (mPa s)

For more pragmatic reasons, we often prefer to use

High molecular Nominal viscosity is usually measured, in water at

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

180 Propylene glycol

FIGURE 34.9 Effects of plasticizers on the glass transition tem-

Quantity of plasticizer retained (%)

are: efficiency, which defines how much plasticizer

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

Tensile strength Reduced None 33.3

Elastic modulus Reduced Titanium dioxide 91.6

Quantity of light reflected (×10–3)

D&C lakes • D&C Yellow #10 Lake

Inorganic pigments • Titanium dioxide 0

(or contrast ratio) of the coating. The consequences of

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

100 TABLE 34.5 General Effects of Pigments in Film Coatings

80 9.5% w/w Titanium dioxide

60 Film permeability Reduced, unless critical pigment volume

4 0.7% w/w Tartrazine lake

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

Methylene chloride 556.7

TABLE 34.9 Adhesion Values of HPC Coatings Deposited From

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

100 34.2.3.2.3 Vinyl alcohol polymers

low viscosity of its coating solutions. Typical character-

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

HPMC blend 31.74 2.25 1.41 250.5 COOH

FIGURE 34.16 Structure of enteric-coating polymers.

Percent drug released

34.2.4.1 Delayed-release (enteric) coatings

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

1. Spheronized granules 2. Drug-loaded “nonpareils” 3. Drug crystals

4. Regular granules 5. Drug/ion-exchange 6. “Mini” tablets

FIGURE 34.18 Examples of multiparticulates.

100 TABLE 34.16 Examples of Aqueous Extended-Release Coating

Surelease Ethylcellulose Plasticized aqueous polymer dispersion,

Fats and waxes (beeswax; • Permeable and erodible

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

• Presence of additives, such as: 34.3 DESIGN AND DEVELOPMENT

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

III. DESIGN, DEVELOPMENT AND SCALE-UP OF FORMULATION AND MANUFACTURING PROCESS

Supply air handler

Inlet air ducts

Main unit Change/conveyor hopper

Product handling Solution tank

FIGURE 34.21 Example of a coating system for continuous process.