Dry Powder Coating of Pharmaceuticals

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IJP-13155; No. of Pages 15
International Journal of Pharmaceutics xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm
Review
Dry powder coating of pharmaceuticals: A review

Dorothea Sauer a , Matteo Cerea b , James DiNunzio c , James McGinity d,∗
a
Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, United States
b
Università degli Studi di Milano, Dipartimento di Scienze Farmaceutiche, Sezione di Tecnologia e Legislazione Farmaceutiche “M.E. Sangalli”,
via G. Colombo 71, 20133 Milano, Italy
c
Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110-1199, United States
d
College of Pharmacy, The University of Texas at Austin, 1 University Station A1900, Austin, TX 78712, United States
a r t i c l e i n f o a b s t r a c t
Article history: Over the last half century, film coating technology has evolved significantly in terms of compositions
Available online xxx and manufacturing processes, allowing for greater functionality, flexibility and efficiency. Driven by a
combination of cost considerations and functionality, a range of dry powder coating technologies have
Keywords: been developed in both academic and industrial settings. These technologies can be generally classi-
Dry powder coating fied into three major types based on the layer formation process: liquid assisted, thermal adhesion and
Film coating
electrostatic. In addition to specific manufacturing processes that must be implemented to achieve the
Curing
desired product attributes, many of these techniques also require the use of novel excipients and specific
Rotor granulation
Fluid bed
formulations to provide acceptable manufacturability. This review summarizes the current dry powder
Melt extrusion coating technologies and highlights their industrial applicability with publicly disclosed case studies.
Polymer Commentary on the future directions of dry powder coating is also provided.
Plasticizer © 2013 Elsevier B.V. All rights reserved.
Adhesion
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Film formation mechanisms in dry powder coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Liquid assisted coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1. Processing equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2. Formulation case studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Thermal adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1. Processing equipment considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2. Formulation case studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Electrostatic coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1. Process equipment considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.2. Formulation considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Current trends and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Introduction because of the dissolved nature of the polymer, the use of aque-
ous systems remains the preferred manufacturing approach due
Conventional technologies for the application of film coatings to the absence of solvent toxicity, increased process safety and
onto pharmaceutical dosage forms involve the atomization of poly- lower manufacturing costs. Even in light of the benefits of aque-
meric systems dispersed as solution or suspension in volatile ous systems, there are several cases where aqueous systems are
organic solvent(s) and/or aqueous vehicles. While the use of organic inappropriate and organic solvent coatings may be necessary. This
solvents is generally faster with simplified film formation processes is particularly true when the pharmaceutical ingredient is sensi-
tive to water, and organic solvents are used to prevent this issue.
In addition to degradation of the active ingredient, migration of
∗ Corresponding author. Tel.: +1 512 471 4843; fax: +1 512 471 2746. water with aqueous systems may occur during the coating process
E-mail address: mcginity.jw@austin.utexas.edu (J. McGinity). or during storage thus compromising the quality of the finished
0378-5173/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ijpharm.2013.02.032
Please cite this article in press as: Sauer, D., et al., Dry powder coating of pharmaceuticals: A review. Int J Pharmaceut (2013),
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2 D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx
product. The need to avoid aqueous and organic solvents may be scales, the adoption into commercial production of drug products
particularly critical if the drug product is formulated as an amor- has been slow. This review highlights the principles of dry powder
phous solid dispersion. From a process standpoint aqueous coatings coating and presents recent examples where the technology has
require both a substantial amount of water, as well as energy to been applied.
evaporate the water during manufacturing. While thermal energies
to drive evaporation of solvents may be lower, the need for environ- 2. Film formation mechanisms in dry powder coating
mentally friendly and safe solvent recovery significantly increases
costs around solvent operations (Bose and Bogner, 2007). Overall, From a mechanistic perspective, dry powder coating processes
this leads to longer processing times and greater overhead costs for consist of the same sequence of steps that are employed with con-
conventional film coating operations. These issues, associated with ventional solvent based coatings. In all cases the process begins
both aqueous and organic coatings, have led to the adoption of dry with the pretreatment of coating material. This is followed by the
powder coating techniques in a number of other industries. application of coating material to the substrate, relying on the
Within the pharmaceutical industry, several alternative tech- adhesive nature of the formulation to maintain uniformity of coat-
nologies have been recently proposed in order to reduce the use ing during the film formation process. Film formation occurs by a
of water or organic solvents during the coating process. Among process of evaporation, coalescence and sintering which are influ-
these are technologies which range from the atomization of molten enced by process and formulation considerations. As the amount of
materials, commonly known as melt coating, to softened pow- volatile solvent used approaches zero the evaporation process may
der layering and electrostatic adhesion (Cerea et al., 2008a). The be neglected, as is the case for many dry powder applications.
melt coating process requires the application of low melting point Pre-treatment of the coating material varies greatly based on
materials maintained at temperatures of about 40–60 ◦ C above the type of coating process utilized. For dry powder coating applica-
the melting point of the wax or polymeric component. When tions, careful consideration of material particle size will be essential
fatty-acids of glycerol esters or low melting polymers such as to ensure appropriate uniformity for the coating. It is generally rec-
polyethylene glycols are applied, the melt coating is performed in ommended that coating material diameter be less than 1% the size
a fluid bed coater with the aid of heating systems for atomized of the coating substrate. This allows for acceptable uniformity of
air to provide a molten spray plume. Unlike conventional fluid bed the material on the substrate surface, improving adhesion, appear-
coating which uses heated gas to remove solvent, inlet air will enter ance and processing times. During the dry powder coating process,
the system for melt coating at a reduced temperature to solidify the the substrates are often heated above the glass transition temper-
molten coating on the substrate. During manufacture, engineering ature of the layering materials so that the coating materials soften
controls including pipeline insulation are utilized to prevent the and adhere to the substrate. For conventional film coating, spread-
solidification of the molten material before the final cooling takes ing and adherence is well defined based on surface free energies
place on the surface of the coating cores. Recently, this technology and capillary forces where mobility is not a limiting interaction.
has also been used for particle engineering through the applica- However, powder systems may become limited by mobility, par-
tion of spray drying and melt spray congealing processes (Ilić et al., ticularly when liquid levels are reduced to the point where solid
2009; Lo et al., 2009). While melt coating is considered a solvent particle deformation becomes rate limiting. This introduces a series
free process and used in the manufacture of at least one commer- of constraints related to mechanical and thermal properties of the
cial product, it falls outside of the scope of this review which deals coating formulation. Coalescence and film formation, which are
with dry powder methodologies. highly dependent on capillary forces in conventional coating sys-
Implementing a similar strategy, liquid assisted layering strate- tems, will also be dependent on these properties. As such, glass
gies rely on interfacial capillary action of liquid formulation transition temperature and plastic deformation characteristics of
components to aid in the adhesion of the coating layer onto the the coating materials are paramount to the success of the process
substrate. In these technologies, the liquid additive can be par- and if materials are deficient in these properties then it may be
tially mixed into the feedstock or added as a separate feed stream necessary to engineer the formulations with the desired character-
into the processing zone. Based on the process similarity with con- istics.
ventional strategies, existing equipment, specifically fluid beds, Many pharmaceutical coating materials are amorphous poly-
can easily be modified to support production, although formula- mers, exhibiting a glass transition temperature related to the
tions of this type will typically require higher levels of plasticizer change from a glass to a supercooled liquid. On transition,
or tackifying agent. Longer processing times and additional post which occurs at a specific temperature, mobility of the system
processing curing steps may also be required. Process and manufac- increases significantly. The greater mobility allows for molecular
turing equipment designs will also be similar, although the choice rearrangement and alters the plastic deformation characteristics
of excipients will be governed by thermal properties of the coating of the materials. A generalized equation for prediction of the glass
materials to provide sufficient softening at moderate temperatures transition temperature of a mixture of materials is the Fox equation,
while still providing suitable mechanical properties at room tem- shown in Eq. (1):
perature. Adhesion, plastic deformation and consolidation will all
be critical points to consider during formulation design. 1 w n
i
Electrostatic modalities differ from the other forms of dry pow- = Fox equation for approximation of
Tg Tg,i
der coating both in terms of excipients as well as manufacturing i=1
equipment. For successful coating, the material must be conductive glass transition temperature (1)
to allow for charge differential formation while exhibiting desired
film forming characteristics. Electrostatic coating equipment cre- where wi is the weight fraction of individual components and Tg,I
ates specific charge fields allowing for the coating of complex is the glass transition temperature of the individual components.
designs that cannot be achieved with traditional systems. Using Based on the weight fraction of the components (wi ) and respec-
commercial scale electrostatic coaters production outputs compa- tive glass transition temperatures (Tg,i ) it is possible to estimate the
rable to conventional systems can be achieved. resulting glass transition temperature. Through the addition of low
Overall, success with many of these alternate solvent free tech- glass transition materials one can reduce the glass transition of the
niques has been demonstrated for a number of applications. While overall composition, a common approach in many dry powder coat-
many of these technologies have reached industrial manufacturing ing formulations to improve coalescence and adhesive properties.
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D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx 3
Other more detailed approaches, such as the Gordon–Taylor equa-

tion, can also be used for estimation of the resulting glass transition
temperature (Gordon and Taylor, 1952).
When processing above the glass transition temperature of a
coating material, the surface is more “liquid-like” and more suscep-
tible to plastic deformation. Depending on the difference between
glass transition temperature and processing temperature, the vis-
cosity of the coating material can be reduced sufficiently to result
in the formation of capillary forces which aid in the adherence of
the powder to the surface. Under such conditions, surface energy
differentials can aid in the spreading of the semi-molten polymer
to enhance coating efficiency.
Dry powder coating applications also rely on mechanical com-
paction that occurs naturally during the process to facilitate
adhesion and coalescence. During this process stresses on the coat-
ing layer result in consolidation of the bed and deformation driven
spreading across the interface. For elastic materials, the deforma-
tion of the material is reversible, leading to poor contact across
the surface. When coatings exhibit plastic behavior, the deforma-
tion is irreversible and the mechanical compaction leads to greater
adhesion of the surface layer due to a larger surface area for con- Fig. 1. Schematic of film formation in dry powder coating systems.
tact between substrate and coating, as well as possible mechanical
interlocking of the materials.
substrate in order to yield an acceptable film. For thermoplastic
Adhesion and spreading behavior can also be modified through
powders, this will depend on the molecular weight of the polymers
the application of a sub-coat to the substrate. This allows for a
and on the curing temperature. Unlike many solvent-based sys-
change of interfacial energy by the application of a new mate-
tems, curing of dry powder coated products is nearly ubiquitous for
rial that can facilitate adhesion of powder coat. The subcoating
both immediate release and controlled release systems to achieve
layer corresponding to 2–3% weight gain of the uncoated core has
a visually and functionally acceptable layer. The formulation must
been reported (Cerea et al., 2004). Low melting point, hydrophilic
therefore be designed to obtained the desired characteristics and
polymers (polyethylene glycol 3350) have been extensively used
be produced in the minimal amount of time while still yielding a
in the literature, however, other materials, with amphiphilic and
storage stable system.
hydrophobic properties (Pluronic 127, Cetylstearyl Alcohol) have
also been reported (Zheng et al., 2004). To further promote adhe- kR
t= time required for film coalescence in
sion with the coating layer, the subcoat can actually be intentionally
selected to be partially molten at the processing temperatures. The
dry powder coating (2)
molten priming layer promotes the adhesion of the powder coat-
ing particles by forming liquid bridges with the tablet surface. The
interfacial interactions between the tablet surface and the poly- The melt viscosity–temperature relationship can be described
mer particle are rather complex and depend on interfacial tension, by the Arrhenius equation, presented in Eq. (3), where A is a con-
wetting and adhesion (Grundke et al., 1996). Since the spreading stant, E is the activation energy for viscous flow, R is the universal
of the priming layer on the surface of the coating cores is crucial, gas constant and T is the absolute temperature. Since viscosity
the best subcoating material is selected by measuring the contact decreases when temperature increases, higher processing and cur-
angle with water of the tablet surface and those of the primer and ing temperatures can be used to produce a higher quality film, even
of the polymeric material to be layered (Sauer et al., 2007; Sauer if degradation phenomena may also be accelerated:
and McGinity, 2009a). The closer the contact angle values, the more
efficient will be the adhesion of the powder to the surface. = A eE/RT Arrhenius equation describing polymer viscosity
The mechanism of film formation of the powders layered onto as a function of temperature (3)
the solid cores can be summarized by (i) coalescence and sintering
of the particles of the polymeric materials in a process that involves
the partial fusion of the polymer; (ii) leveling of the coating mate- In order to reduce the processing temperature of the powder
rial includes densification of the layer with reduction of the empty coating and to shorten the curing phases, polymers which show
spaces and smoothing of the surface; (iii) cooling of the layer and excessively high Tg (>60 ◦ C) are combined with plasticizers able to
hardening of the coating. A schematic of this process is shown in decrease the Tg of the coating powders (Zheng et al., 2004; Sauer
Fig. 1. et al., 2007, 2009). Specific amounts of liquid or solid plasticiz-
In conventional coating applications, coalescence is driven by ers can be added to the polymeric materials via physical mixture,
the presence and subsequent removal of solvent which creates concurrent addition during production or by the preparation of a
capillary forces inside the film and lowers the glass transition tem- solid dispersion coating formulation containing plasticizer prior to
perature of the polymer. The mechanism for coalescence of dry the coating operation. The nature of plasticizer addition will ulti-
powder coated films is similar, although much more reliant on non- mately contribute to the type of coating process selected. Each of
solvent forces to achieve a uniform film. According to Eq. (2) the these approaches provides unique advantages and disadvantages,
time (t) required for two powder particles to coalesce is directly as summarized in Table 1.
related to the viscosity of the powder coating (), the radius of the Alternatively, a polymeric solution containing the plasticizer
particles (R) and the surface tension of the coating () where k is can be spray dried so that a fine pre-plasticized polymeric powder
a constant describing the process (Huang et al., 1997). From this can be obtained (Terebesi and Bodmeier, 2010). In general, powders
equation it is clear that one must maintain low polymer viscosity having a particle size below 100 ␮m (Dv 50) have been demon-
to promote distribution of the material over the surface of the solid strated to be suitable for powder coating. Further consideration of
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Table 1
Comparison of pre-processing techniques for dry powder coating.
Technology Advantage Disadvantage
Liquid assisted Use of conventional Requires co-metering

coating equipment technology for feed addition
Reduced liquid Potential for heterogeneity of
removal film components
Thermal adhesion No requirements for Requires pre-processing of

co-metering feed powders
No liquid removal Narrow temperature operation
window
Electrostatic Complex pattern Need for specialized

coating equipment
Fig. 2. Schematic illustration of dry coating with a centrifugal granulator.

the coating to substrate particle size ratio is necessary to ensure Reproduced with permission from Obara et al. (1999).
appropriate adhesion and visual appearance.
Examining the dry powder coating process as a whole, one notes
a strong dependence on coating and substrate properties, as well as
the interaction between the interfaces formed during the process.
Successful implementation of dry powder coating technologies
requires engineering of the product and process to carefully achieve
the desired material attributes of the finished product. Each of the
subsequent sections describes the application of these theoretical
principles to the achievement of successful dry powder coatings.
3. Liquid assisted coating
While conventional coating technologies rely on large volumes

of solvent to ensure adhesion and the formation of a uniform coat-
ing, liquid assisted technologies limit the amount of liquid within
the formulation. Additionally, this approach will often use a liq- Fig. 3. Schematic illustration of dry coating with a top spray fluidized bed.
uid phase excipient intended to remain in the drug product which Reproduced with permission from Obara et al. (1999).
will serve as an adhesive aid while providing some functionality

for film formation. Since this approach is mechanistically different
than conventional film coating technologies, theoretical aspects as plasticizers or emulsions of plasticizers with aqueous binder solu-
well as technological considerations must be balanced to ensure tions. The presence of the liquid film on the surface of the cores
success. increased the adhesion of the powders via capillary action while
the use of the plasticizer reduced the temperature required for the
3.1. Processing equipment softening and coalescence of the polymeric particles (Pearnchob
and Bodmeier, 2003a,b,c). The coating was achieved employing a
The first examples of dry coating processes by Obara et al. fluidized bed coater (GPCG 1, Wurster insert, Glatt® ) and loading
utilized the technology to apply enteric coatings onto pellets the powders and the liquids through separate inlets. The pellets
and tablets by layering hypromellose acetate succinate (HPMCAS, were cured in an oven at different times, temperatures and humid-
AQOAT® , Shin-Etsu) and co-spraying triethyl citrate (TEC) as the ity values, which were shown to alter the rate of release. As curing
liquid plasticizer (Obara et al., 1999). The processes were performed and coalescence were more incomplete, more rapid dissolution was
using both a centrifugal granulator or fluidized bed for coating pel- observed. Similar results were obtained more recently by Terebesi
lets and a perforated coating pan for coating tablets. Since these and Bodmeier employing a fluidized bed ball coater (Unilab 05
apparatuses are normally employed for solid oral dosage form unit ball coater, Hüttling) which exploits the presence of two different
operations, slight modifications were necessary. In addition to the nozzles by which liquid plasticizer and powder could be sprayed
liquid atomizers already in-place, these units were retro-fitted with separately inside the coating chamber (Terebesi and Bodmeier,
powder feeders to support in-line addition of the dry powder coat- 2010).
ing. The dosing rate of the powders was monitored and controlled Kablitz et al. reported on dry coating processes for obtaining
by loss-in-weight feeders, with feed streams entering directly into enteric coatings of pellets employing powder mixtures of HPMCAS
the processing chambers. Schematics of each apparatus are shown and atomizing TEC, glycerol triacetated (triacetin) and acetylated
in Figs. 2–4. During processing, differential air flows and gravita- monoglyceride (Myvacet 9-45K) mixtures as liquid plasticizers
tional forces, in combination with simultaneous addition of the during processing (Kablitz et al., 2006, 2008; Kablitz and Urbanetz,
liquid plasticizer ensured adhesion of the powder to the substrate. 2009). The processes were carried out in a rotary fluid bed unit
Elevated temperatures within the processing chamber along with (GPCG 1.1, Glatt® ) with a three way nozzle immersed in the coat-
mechanical forces resulting from product bed movement further ing bed, as shown in Fig. 5. No special modification of the apparatus
facilitated adhesion and film formation during the layering and was required since it was originally designed for the preparation of
curing processes. pellets by drug powder layering and distributed the drug as pow-
Pearnchob et al. reported on a series of experiments with dry der onto inert cores while simultaneously spraying binder solutions
powder coatings in which various polymeric powder mixtures (Vuppala et al., 1997; Gupta et al., 2001). The same equipment was
containing either ethylcellulose, Eudragit® RS or shellac were lay- used by Cerea et al. (2008a,b) for the layering of HPMCAS onto soft
ered onto drug containing pellets along with atomizing liquid gelatin capsules.
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Fig. 4. Schematic illustration of dry coating with a perforated pan tablet coating machine.
Reproduced with permission from Obara et al. (1999).
3.2. Formulation case studies coatings that contained only TEC as a plasticizer. The final TEC
level in the coating formulation was 30% based on the dry polymer
Liquid assisted dry powder coating requires the use of unique weight as shown in Table 2.
formulations in addition to the implementation of novel process During the coating process the outlet temperature was main-
designs. The compositions utilized are frequently characterized by tained at 42 ◦ C, allowing sufficient proximity to the glass transition
a higher level of plasticizer, lower glass transition temperature and temperature to supplement powder adherence achieved through
smaller particle size. Numerous examples have been published over capillary forces of the liquid plasticizer. This elevated temperature
the last two decades highlighting the design of liquid assisted dry also aided in the coalescence process. Prior to the curing process
powder coating. Several leading examples are discussed in detail at the completion of the coating process, water or an aqueous
within this section to illustrate the application of the technology. solution of hydroxypropyl methylcellulose (HPMC) was sprayed
Particle size is a critical property of dry powder coatings. As onto the coating bed to further facilitate film formation. The beads
mentioned previously, significant consideration of the coating and tablets were then cured using heated air in a fluid bed or
material size is necessary to assure both uniformity of the final tablet coater until the exhaust temperature reached 50 ◦ C. Although
film and adhesion to the substrate. In a study by Obara et al., the goal of developing an aqueous free coating process was not
HPMCAS with a particle size of less than 10 ␮m was used as the achieved since water was still required to facilitate film formation,
model polymer and coated onto drug products containing pan- the work demonstrated that solvent assisted coating was feasible
creatin as the model active pharmaceutical ingredient (API). Using while highlighting key formulation considerations for the technol-
prior experience with aqueous based HPMCAS coatings, the poly- ogy (Obara et al., 1999). As substrate geometry changed so too did
mer was pre-blended with talc prior to coating to enhance the the formulation requirements. For smaller products liquid assisted
surface smoothness of the coating and to prevent stickiness, as dry powder coating was achieved without the need for subcoating,
shown in Table 2. To increase the coating efficiency, TEC was mixed whereas larger products required the use of a HPMC subcoating.
with acetylated monoglyceride (AMG) in a 3:2 ratio. AMG demon- Although this difference in size related performance was not thor-
strated good wettability of HPMCAS as shown by a low contact oughly investigated, the authors proposed multiple reasons for this
angle with the polymer. Another advantage of the use of AMG behavior. These theories included: heterogeneous coating without
was the reduction of agglomeration that was observed for powder a subcoat, poor adhesion without subcoat, and the prevention of
surface damage during curing.
The gastric resistance of the powder coated beads and tablets
was assessed by dissolution and disintegration, respectively. As
shown in Fig. 6, higher polymer levels were required to provide
gastric resistance compared to beads and tablets that were coated
using an aqueous process. The coating efficiency for the powder
coating process was above 90% for all equipment variants used in
the study and the processing time was approximately one-third of
that for aqueous coating on the same scale. Upon storage at elevated
temperature for up to 6 months the gastric resistance of the dry
Table 2
Formulation for dry powder coating.
Type Ingredient Partsa
Powder mixture HPMCAS 100

Talc 30
Liquid mixture (Plasticizer) Triethyl citrate 30

Fig. 5. Schematic of a rotary fluid bed granulator: (1) rotor disc, (2) air slit, (3) pellet Acetylated monoglyceride 20
bed square view, (4) three way nozzle, and (5) powder feeder.
Reproduced
a
with permission from Obara et al. (1999).
Reproduced with permission from Kablitz et al. (2006). The amount of each ingredient is based on the weight of HPMCAS = 100.
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Fig. 6. Gastric resistance of enteric coated beads (A) and enteric coated tablets (B).
Reproduced with permission from Obara et al. (1999).
coated beads and tablets was comparable to ones prepared using it was possible to improve the coating process. Compared to the
an aqueous process. coating formulation proposed by Obara et al. the TEC/AMG ratio was
The HPMCAS-based powder coating process was further opti- increased. Trials confirmed that the addition of AMG reduced the
mized by Kablitz et al. for the coating of pellets (Kablitz et al., 2006; contact angle of the plasticizer dispersion on the polymer and thus
Kablitz and Urbanetz, 2009). For processing, the researchers used a improved spreading of the plasticizer on the polymer. Formulations
rotary fluid bed equipped with a three-way port nozzle to deliver containing AMG alone or TEC/AMG mixtures were characterized
polymer and plasticizer dispersion separately, but in close prox- with a higher coating efficiency and improved gastric resistance.
imity to one another, into the coating bed. The influences of talc, Since coalescence is a necessary step in the film formation process,
colloidal silicon dioxide, TEC, and AMG on processability, coating the inability of AMG to plasticize HPMCAS would drive incomplete
efficiency, drug release, and physical stability were investigated. film formation. As a result, formulations containing only AMG as
The coating formulations studied in this work are shown in Table 3. a plasticizer did not provide sufficient gastric resistance. With dry
Theophylline was used as the model API. powder coating operations, curing of the films is usually necessary
Experimental trials demonstrated that the presence of talc in the to achieve complete and uniform coalescence. Zero order release
coating formulation reduced the gastric resistance of the coated kinetics were observed for the uncured pellets in acidic media. An
pellets and decreased the coating efficiency of the process. The enteric release profile was achieved for pellets with a 25% coat-
presence of talc in the coating formulation also delayed the drug ing level that were cured at a product temperature of 53–55 ◦ C for
release in pH 6.8 buffer. However, the absence of talc in the for- 45 min.
mulation resulted in agglomeration of the pellets upon storage. The physical stability of the theophylline pellets powder coated
This behavior was attributed to the role talc played in the release with HPMCAS was evaluated in a range of conditions. The powder
and layering processes. Talc is commonly used as an anti-sticking coated pellets were stored at either 25 ◦ C/10% RH or 25 ◦ C/60% RH.
agent, lubricating surfaces to aid in flow and minimize adhesion. Formulations containing only TEC as the plasticizer were character-
This property reduced the sticking tendency of the product dur- ized with the highest agglomeration tendency at 60% RH which was
ing manufacture, however, also inhibited the adherence of the dry reflected in the loss of gastric resistance over time. The addition of
coating powder onto the substrate. The less effective coating pro- AMG and colloidal silicon dioxide or talc reduced the agglomeration
cess most likely contributed to the poor gastric resistance observed tendency of the formulations and facilitated constant gastric resis-
(Kablitz and Urbanetz, 2009). tance properties over a storage time of up to 24 months at 10% RH
As a result, colloidal silicon dioxide was used as an alternative and 60% RH. Samples stored at 40 ◦ C/75% RH agglomerated after 3
anti-tacking agent. In contrast to talc, it was not premixed with the months and were not further evaluated. While maintaining stabil-
polymer prior to coating but applied as an overcoat following the ity in moderate temperature and humidity conditions, the failure
coating process at a 1.4% level, based on the polymer weight. By of the drug product at accelerated storage conditions is a major
not only changing the material type but also the addition sequence challenge that faces many dry powder coated formulations. Due to
the need to process at reasonable temperatures and impart suffi-
cient mobility to the polymer to assure coalescence on a relevant
Table 3 time scale, it is necessary to reduce the glass transition temperature
Composition of formulations prepared with HPMCAS, talc, colloidal silicon dioxide, through formulation design. As a result, the stability performance
TEC and AMG.
under accelerated conditions can frequently become compromised.
Formulation A B C D E The role of AMG in the powder coating process was further
Powders evaluated using atomic force microscopy and DSC (Kablitz et al.,
HPMCAS (%) 45–47 75 74 75 75 2008). The adhesion force between HPMCAS and HPMCAS contain-
(%) Talc 28 – – – – ing AMG was shown to be higher compared to the force between
Colloidal silicon dioxide (%) – – 1 – – HPMCAS and TEC containing substrates. According to DSC analysis,
Liquids AMG is immiscible with HPMCAS and remained on the surface of
TEC (%) 17.5–19 17.5 17.5 25 – the polymer. As a result, AMG forms liquid bridges and exerts capil-
Acetylated monoglyceride (%) 7.5–8 7.5 7.5 – 25
lary forces between HPMCAS particles thus improving efficiency of
Total (%) 100 100 100 100 100 the process. Similar results were obtained for isopropyl myristate
Reproduced with permission from Kablitz et al. (2006) and Kablitz and Urbanetz and isopropyl palmitate as wetting agents for HPMCAS (Klar and
(2009). Urbanetz, 2009). This suggests that the design of dry powder coated
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Table 4 Table 5
Composition of formulations prepared with HPMCAS, talc, TEC and AMG. Formulations for the coating of pellets with polymer powders in a fluidized bed
coater.
Formulation A Formulation B
Formulation Composition (% w/w)
Powders
HPMCAS 50.0% 50.0% Ethylcellulose Eudragit® RS PO
Talc 30.0% 30.0%
Powders
Liquids Polymer 76.9 50.0
TEC 12.5% 20.0% Talc 23.1 50.0
AMG 7.5% –
Total 100.0 100.0
Total 100.0% 100.0%
Reproduced with permission from Cerea et al. (2008b). Liquids

Plasticizer 50.0–75.0 36.8–75.0
10% (w/w) HPMC solution 25.0–50.0 25.0–63.2
formulations must account for adhesion and film formation. It Total 100.0 100.0
further indicates that the requirements for ideal adhesive aids and Reproduced with permission from Pearnchob and Bodmeier (2003a).
film forming additives will be different. Miscibility, an essential
component for plasticization, may not be present for adhesive addi-
tives which provide better liquid bridging by forming immiscible However, dissolution performance was comparable for both for-
liquids on the surface of the dry powders. Given this, careful con- mulations and all capsules maintained their physical-technological
sideration must be made in selecting formulation components for and gastric resistance properties upon storage.
dry powder coating applications. Other adaptations of the liquid assisted powder coating pro-
Curing temperatures and times, in addition to formulation con- cess have been utilized for coating with Eudragit® RS PO and
siderations, influence the quality of film formed. The influence of ethylcellulose (Pearnchob and Bodmeier, 2003a,b,c). Studies using
these conditions on film formation was studied using scanning propranolol HCl as the model drug utilized a fluid bed for the
electron microscopy and dissolution studies. Viscous flow, parti- powder coating process. Coating powder and plasticizer were deliv-
cle deformation, and the resulting dry sintering of the polymer ered separately into the bed, with product temperatures ranging
particles are the main driving forces for film formation of powder from 34 ◦ C to 36 ◦ C for Eudragit® RS PO and from 45 to 47 ◦ C for
coatings. The powder coated pellets were prepared using HPMCAS ethylcellulose during the process. Following coating, the pellets
as model polymer and TEC/AMG mixtures as plasticizer and wetting were fluidized for 10 min and then cured in temperature controlled
agents. Following coating, the pellets were cured in a temperature ovens. Different curing temperatures (40 ◦ C and 80 ◦ C) and dura-
controlled oven at temperatures ranging from 25 ◦ C to 95 ◦ C for up tions (2–24 h) were evaluated for both polymers.
to 24 h. The glass transition temperature of the polymer/plasticizer Prior to coating Eudragit® RS PO was micronized to obtain a
mixture was identified as a critical parameter to optimize the cur- mean particle size of 9.4 ␮m. The average particle size of ethylcel-
ing conditions of a powder coated product. For a glass transition lulose and talc were 6.1 ␮m and 17.4 ␮m, respectively. Talc was
temperature of 51.7 ± 3.3 ◦ C, curing at 55 ◦ C for 45 min was deter- used as anti-tacking agent and glidant to facilitate polymer pow-
mined to be the optimum curing conditions to obtain an enteric der flow into the coating bed. The studied formulations are listed
release profile. The results were based on visual observations using in Table 5.
scanning electron microscopy and drug release studies, where poor Different plasticizers including TEC, acetyl tributyl citrate (ATC),
quality was characterized by more rapid release and greater hetero- and AMG were evaluated for the coating of pellets with Eudragit®
geneity of the layer (Kablitz and Urbanetz, 2007). Results showed RS PO and ethylcellulose. For each plasticizer three different levels
that lower curing temperatures required longer curing times, while based on the polymer weight (20%, 30%, and 40%) were investi-
higher temperatures resulted in agglomeration of the pellets. gated. Since spraying pure plasticizer resulted in agglomeration of
The HPMCAS based powder coating process was also adapted by the pellets, the plasticizers were diluted with a 10% aqueous HPMC
Cerea et al. (2008b) for the coating of soft gelatin capsules. Under solution. The level of plasticizer in the mixture ranged from 36.8 to
this approach, HPMCAS was pre-blended with talc prior to coating. 75.0% (w/w). The presence of more hydrophilic plasticizers such as
TEC and a mixture of TEC and AMG were evaluated as plasticizing TEC increased the drug release rate for both Eudragit® RS PO and
liquids and sprayed concurrently with the coating powder feed ethylcellulose based coating formulations as shown in Fig. 7 for
into the coating bed. The evaluated formulations are presented Eudragit® RS PO. Fig. 7 also demonstrates that the drug release rate
in Table 4. A rotary fluid bed with a three-way port nozzle was decreased with increasing plasticizer level, which can be attributed
used for the powder coating of the capsules. The bed tempera- to greater coalescence and enhanced film formation of the more
ture was maintained at 40 ◦ C during the coating process. In order mobile formulations.
to overcome sticking during the early stages of the coating pro- The drug release rate from pellets powder coated with Eudragit®
cess, increased levels of talc and reduced liquid quantities were RS PO and ethylcellulose was dependent on the curing conditions
utilized. To maintain a similar TEC/polymer ratio, the TEC level was and decreased with increasing temperature and curing time as
increased in the plasticizer mixture. During the initial phase of the shown in Fig. 8 for pellets coated with ethylcellulose.
coating process, only the plasticizer mixture was sprayed into the Curing of the pellets that were powder coated with Eudragit®
coating bed to prime the capsules surfaces and limit the loss of pow- RS PO was necessary to improve the physical stability of the pellets
der at the beginning of the process. Following the priming phase, upon storage. The drug release rate from Eudragit® RS PO coated
the plasticizer mixture and polymer blend were delivered in par- pellets (40% AMG based on polymer weight) did not change upon
allel to the coating bed at a rate of 5 and 1.25 g/min, respectively. storage for 3 years when the coated pellets were cured at 60 ◦ C
The coated capsules were then cured in the fluid bed at 38 ◦ C for for 2 h. In contrast, the drug release rate from uncured pellets was
60 min. Coating levels of 22 mg/cm2 were shown to provide ade- shown to significantly decrease over 3 years of storage at room tem-
quate gastric resistance. The coating efficiency of the process was perature. This behavior was attributed to better distribution of the
93% when TEC was pre-mixed with AMG and 87% for TEC alone as plasticizer and further coalescence of the polymer particles, result-
a plasticizer. As previously described by Obara et al., the improved ing in the formation of denser films causing slower drug release
process yield was attributed to the wetting of HMPCAS by AMG. rates. The physical stability of the ethylcellulose dry powder coated
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Fig. 7. Effect of plasticizer concentration on the propranolol HCl release from Eudragit® RS-coated pellets (curing at 60 ◦ C for 2 h, coating Levels 7.7–10.1%): (A) AMG, (B)
acetyltributyl citrate, and (C) TEC.
Reproduced with permission from Pearnchob and Bodmeier (2003b).
pellets was independent of curing conditions at room tempera- into the coating bed prior to the powder feed using a 1% (w/w) ratio
ture over a 3-year period indicating no further coalescence of the based on the polymer weight. Eudragit® RS was micronized and
polymer particles upon storage. preblended with talc in a 1:1 ratio prior to coating, while ethyl-
It was also noted that powder coating processes generally cellulose was used without size reduction. Size reduction of the
require higher amounts for plasticizer compared to liquid- coating material provided benefits for adhesion as well as film
based coating applications to facilitate adequate film-formation. formation during processing. Talc was included to reduce the stick-
Although dry coating processes often require higher coating lev- ing tendency. Different plasticizers were evaluated in the study
els to obtain similar release profiles, the coating times were shown including AMG and tributyl citrate. Prior to curing, colloidal silicon
to be shorter compared to liquid-based processes as presented in dioxide was applied to the pellet surface as an anti-sticking agent.
Table 6.
This brings about an important series of considerations around
Table 6
metrics used to justify manufacturing performance. Clearly, Coating time for the film coating of pellets with dry polymer powders or solvent
enhancements in processing time may provide significant improve- based coatings.
ments, which can factor into cost of goods analysis for drug product
Coating formulation Coating level (%) Coating time (min)
manufacturing. However, the added cost associated with greater
®
quantities of material required for dry powder coating may prevent Eudragit RS
Dry powder coating 15 31
a realization of economic enhancements generally associated with
20 41
the technology. As a result, careful consideration must be given
to designing formulations that improve film formation and better Aqueous-based coating 15 128
20 171
match liquid coating based counterparts.
In response to the need for greater formulation and process Ethylcellulose
enhancement, further optimized coating processes have been pro- Dry powder coating 20 30
posed for pellets using ethylcellulose and Eudragit® RS. Using a fluid Aqueous-based coating 5 44
bed design with a liquid assisted concept, pellets were coated and Organic-based coating 5 111
cured for up to 24 h. The undiluted liquid plasticizer was sprayed Reproduced with permission from Pearnchob and Bodmeier (2003a).
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Fig. 8. Effect of plasticizer concentration on the propranolol HCl release from ethylcellulose powder-coated pellets: (A) 40% AMG (coating level 30.3%), (B) 40% acetyltributyl
citrate (coating level 18.1%), and (C) TEC (coating level 18.9%).
Reproduced with permission from Pearnchob and Bodmeier (2003c).
HPMC E5 was included in the formulation and evaluated as a pore

forming agent. Theophylline and chlorpheniramine maleate served
as model drugs in the study. Higher coating levels of ethylcellulose
were required for chlorpheniramine maleate pellets to control the
drug release rate compared to the theophylline containing pellets.
Tributyl citrate was shown to more effectively promote film for-
mation than AMG for ethylcellulose. The incorporation of HPMC in
the coating formulation increased the drug release rate.
Smikalla et al. (2011) recommended the use of isopropyl myris-
tate as a wetting and plasticizing agent for ethylcellulose powder
coating applications. A fluid bed with rotor insert was used in the
study. Coating powder and liquid plasticizer were separately fed
into the coating bed. Following coating powder and plasticizer
application, the pellets were mixed with colloidal silicon dioxide
and cured in a temperature controlled oven at 80 ◦ C for up to 3
days. The study involved an extensive screening of organic cosol- Fig. 9. Contact angles (n = 4) as a function of coating efficiency (n = 3).
vents, plasticizers, surfactants, and lipids to optimize the coating Reproduced with permission from Smikalla et al. (2011).
efficiency for ethylcellulose. The contact angle of the plasticizer
with the polymer was shown to be directly correlated with the
coating efficiency (Fig. 9), which could be used as predictive tool 4. Thermal adhesion
for efficiency of the powder coating process.
The application of liquid assisted coating technologies is a useful Operating in the extreme of liquid assisted processes, where the
modality for quickly applying film coats. While time effective, addi- adhesive liquid level is minimized, one generally observes a greater
tional formulation and process development is required to make dependence on the thermal characteristics of the coating powder.
the process more efficient from a material usage and performance In fact, it becomes possible to remove the liquid aid altogether to
perspective. rely solely on thermal adhesion of the coating powder. Due to the
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complex nature of the thermal adhesion mechanism in combina- The temperature control was the most critical parameter during
tion with the requirements for manufacturability and drug product the powder coating. Due to the small scale of the equipment and
stability, these formulations must be engineered to a greater degree to the low amount of cores involved, coating trials that employed
than the liquid assisted systems. The following section describes forced hot air as the heating source were unsuccessful. With this
the process equipment considerations and formulation aspects that technique poor quality coatings having reduced yields resulted.
are essential for designing dry powder coating systems based on Curing of the powdered tablets was performed in either the
thermal adhesion. spheronizer or in a static oven on Teflon® plates. This application
is of critical importance because most of the formulations used
4.1. Processing equipment considerations will not have sufficient time to coalesce. Engineering of powder
physico-mechanical properties is often necessary to achieve nec-
When compared to liquid assisted dry powder coating, ther- essary performance. In this particular study, the tablets were cured
mal adhesion methods have received less attention, although they in a static oven after powder layering at 80 ◦ C for 12 h to complete
too have traditionally relied on adaptation of existing manufactur- film formation.
ing equipment to support production. Several of the most common SEM analysis of cross-sectioned coated tablets before and after
adaptations have largely been centered around spheronizers and curing illustrated the efficiency of the curing conditions (Fig. 11).
rotary fluid beds. For these processes, the substrate is maintained In particular, photomicrographs of the uncured coated tablets
at a temperature that facilitates softening and spreading of the coat- revealed a thick, porous layer, with polymer particles visible along
ing powder. This is further aided by mechanical forces of the process the entire cross-section of the coating. Moreover, the thickness of
which work to compact powders on the surface of the substrate. It the layer is appreciably different depending on position, with a
is also critical that the temperature is maintained below the crit- thinner coating on the edge of the tablets. On the contrary, sam-
ical threshold for agglomeration of the powder and drug product. ples cured for 12 h at 80 ◦ C produced more homogeneous coatings
Given the narrow operating window for processing, it is imperative with compact and continuous film layers. The polymer particles
to maintain a high accuracy of process control during manufacture. melted into uniform films of constant thickness on the surface of
One technique extensively reported in the literature has been the tablet.
the adaptation of a spheronizer to the production of dry powder Small-scale simulation of the curing process can be achieved
coated drug product (Cerea et al., 2004; Zheng et al., 2004; Sauer using adaptations of film casting methodologies. For these stud-
et al., 2007). This process involved only solid materials using a labo- ies, powder is layered onto substrate sheets and heated to
ratory scale spheronizer (Model 120, G.B. Caleva; Dorset, UK) with a simulate the process (Cerea et al., 2004). It is also theoreti-
smooth stainless steel disc. Represented in Fig. 10, the edges of the cally possible to incorporate pressure cycles to the powder to
disk were tilted at a 45◦ angle to facilitate the tumbling movement mimic the effects of mechanical agitation in the bed. In this
of the tablets and to prevent the loss of the coating powders. study, powder cast Eudragit® E PO films were used to opti-
A batch size of 50 g of tablets was employed for each process. The mize the curing conditions. Criteria for adequate film formation
heat necessary to perform the powder coating was generated by an were film transparency, film thickness, and morphology. Coat-
infrared lamp positioned 3 cm above the top of the spheronization ing levels of 7 mg/cm2 , 10 mg/cm2 , and 14 mg/cm2 of Eudragit®
chamber (250 W Infrared Red Heat Bulb, General Electric, USA). The E PO/talc mixtures successfully delayed the drug release in pH
temperature of the coating chamber was controlled by adjusting 5.5 and pH 6.8 buffers, as required for taste masking applications.
the power of the lamp with a variable transformer (TYPE PF1010, Using this approach an immediate release of theophylline was
Staco, Inc., Dayton, OH, USA). The temperature of the coating bed observed in pH 1.0 hydrochloric acid for all investigated coating
was constantly monitored with a digital thermoprobe. The powders levels. The coating additives PVP K-90, glycerol monostearate, and
were distributed at a constant rate on the top of the rotating tablets polyethylene glycol 3350 increased the drug release rate from the
using a single screw powder feeder. To prevent the heat loss during powder coated tablets. HPMC K4M also shortened the onset of drug
the process the spheronizer chamber was closed by a glass cover. release in pH 6.8 buffer, however, slightly increased the lag time in
pH 1.0 hydrochloric acid.
Process considerations will also need to be given for the mate-
rials themselves. Many powders will require specific sizes which
are often in the micron scale. Milling techniques will play a criti-
cal role and have already been discussed within the liquid assisted
concept. Further consideration of the nature of the powder is
also necessary. In many cases it will be necessary to combine
the polymer, plasticizer and opacifier. This mixture will still need
to maintain flowability and dispersibility while also being of a
suitable particle size. Solid dispersion technology can be used to
quickly and effectively prepare complex powder particles of the
desired size. The most commonly reported techniques for this
are spray drying and hot-melt extrusion. In a recent case study
(Terebesi and Bodmeier), two different grades of ethylcellulose
(7 cP and 10 cP) were pre-plasticized with 20% (w/w) (based on
the polymer) medium chain triglycerides (MCT) by premixing the
polymer with MCT followed by hot-melt extrusion and cryogenic
grinding. This allowed for the production of a fine dense pow-
der coating material having the necessary thermal characteristics
to support manufacturing. Alternatively, commercially available
aqueous ethylcellulose dispersions (Aquacoat® , Surelease® ) was
Fig. 10. Schematic representation of the laboratory scale spheronizer used for the
thermal coating process: (1) rotating disk; (2) infrared lamp; (3) powder feeder; (4) spray-dried. Prior to spray-drying, the Aquacoat® and MCT (20%,
temperature probe; (5) coating cores; and (6) glass cover. w/w based on the polymer) were mixed for 24 h to equilibrate the
Reproduced with permission from Cerea et al. (2004). plasticizer distribution in the mixture. Surelease® was spray-dried
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Fig. 11. Scanning electron micrographs of Eudragit® E PO powder coated tablets (14 mg/cm2 ). Cross-sections of uncured tablet (A and C) and tablet cured for 12 h at 80 ◦ C (B
and D).
Reproduced with permission from Cerea et al. (2004).
after dilution with deionized water to yield a fine powder suitable The colorants, together with opacifiers, are materials that are
for dry powder coating. Terebesi and Bodmeier noted that film- commonly used in all formulations intended for film coating for
formation was improved for the spray-dried material compared to their esthetic contribution to the final product. The colors enhance
the hot-melt extruded coating powder. The difference in film for- the image of the product making it easier for market promotion
mation was attributed to the difference in mean particle size of the and identification of the product both by the patient and during
hot-melt extrudate compared to the spray-dried material, further packaging operations. At the same time the use of dyes in the coat-
highlighting the importance of dry powder engineering and particle ing layer can help to improve the stability of the active ingredient
sizing. by protecting it from light degradation. For aqueous film coating,
water-insoluble colorants (pigments and lacquers) are preferred
4.2. Formulation case studies over soluble dyes due to the fact that during the drying step the
solvent tends to migrate to the surface bringing the soluble dye
Dry powder coating formulations are engineered to provide the molecules with it. In the dry powder coating, since no liquids are
necessary thermal characteristics. Compositionally, this is achieved involved and the process does not include a drying phase, no migra-
through the incorporation of polymer, plasticizer, opacifier, col- tion of the colorant is expected.
orant and anti-sticking agent. Unlike traditional formulations, The level of plasticizer becomes a critical aspect of successful
higher levels of plasticizers are required to ensure adhesion and formulation that strongly impacts performance. At a bed temper-
film formation. The pre-plasticization process was adapted by ature of 55–60 ◦ C successful coating of tablets with Eudragit® E
Terebesi and Bodmeier for the controlled release polymer ethyl- PO was achieved, whereas processing below the glass transition
cellulose. temperature of the polymer did not result in sufficient polymer
Anti-sticking agents are also a necessity in coating formulations adhesion (Cerea et al., 2004). In contrast, coating temperatures
to prevent adhesion during processing. Even though the amount above 70 ◦ C caused irregular polymer layering due to adherence
of anti-sticking agent inside the powder coating formulation has and physical deformation. The addition of low-melting excipients
never been extensively investigated, the presence of 10% of talc including glycerol monostearate and polyethylene glycol 3350 was
in the powder coating blends has been considered successful by shown to improve coating powder adhesion, highlighting how
researchers in the field for preventing the agglomeration of the plasticizing materials could be used to enhance performance. A
powder particles during storage and during the distribution of the modified lab-scale spheronizer was also used by Zheng et al. for
powders on the cores. Trials performed using powders without talc the powder coating of tablets with the acrylic polymers Eudragit®
resulted in excessive adhesion of the powders on the surface of the RS and RL PO with theophylline serving as the model compound.
tablets with irregular thickness of the layer (Cerea et al., 2004). The Eudragit® RS/RL PO (95:5) mixtures were pre-plasticized with
application of an additional overcoating layer of 2% of talc after TEC using a hot-melt extrusion process. Pre-plasticization of the
the curing step eliminated the tackiness of the coated tablets when polymer eliminated the need of the separate spray of a plasti-
the final coating film had a Tg value of the pre-plasticized polymer cizer solution. The extrudate was then cryogenically ground and
around 40 ◦ C (Sauer et al., 2007, 2009). blended with talc in a 10% ratio based on the weight of the
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Fig. 12. Dissolution stability testing of theophylline tablets powder-coated with Eudragit RS/RL (95:5) containing 5% TEC at 25 ◦ C/60% RH (A) and 40 ◦ C/75% RH (B), Using the
USP 27 apparatus 2 and 900 mL of 50 mM pH 7.4 phosphate buffer at 37 ◦ C and 50 rpm. : initial; : 1 month; : 3 months.
Reproduced with permission from Zheng et al. (2004).
polymer. The investigated TEC levels ranged from 5 to 15% based decrease the drug release rates both in 0.1 N hydrochloric acid and
on the polymer weight. The coating bed temperature was adjusted pH 6.8 buffer. Unlike aqueous coating, powder coating minimized
based on the plasticizer level and ranged from 55 ◦ C to 60 ◦ C for 15% partitioning of the drug into the film coating during the coating
triethyl citrate and 80 ◦ C to 85 ◦ C for 0% triethyl citrate. process. Physical stability of the powder-coated chlorpheniramine
The powder feed rate was set to 0.5 g/min. Prior to powder
coating, the tablets were primed with a low-melting excipient to
facilitate the coating powder adhesion. Polyethylene glycol, polox-
amer 407, and cetyl alcohol were evaluated as priming agents. Cetyl
alcohol was selected as the most appropriate primer for Eudragit®
RS/RL mixtures based on its hydrophobicity. Following the coat-
ing powder application, the tablets were cured in an oven at 80 ◦ C
for up to 24 h to complete the film formation process. The drug
release rate from Eudragit® RS/RL coated tablets was dependent on
the TEC level and decreased with increasing plasticizer level, which
suggested greater coalescence of the film. At the 5% TEC level a coat-
ing level of 5% Eudragit® RS/RL resulted in a lag time of about 2 h
followed by a sustained release over 10 h, demonstrating that pow-
der coating is an efficient method to control the drug release rate.
The physical stability of the powder coated tablets was also evalu-
ated using dissolution testing. The tablets were stored in induction
sealed HDPE bottles at 25 ◦ C/60%RH and 40 ◦ C/75%RH over a period
of 3 months. As shown in Fig. 12, no significant decrease in drug
release rate was observed for the investigated storage conditions
indicating excellent physical stability of the coated dosage forms.
Similar studies have also shown the application of spheroniz-
ers for the coating of tablets with Eudragit® L 100-55 (Sauer et al.,
2007; Sauer and McGinity, 2009b). Prior to coating, Eudragit® L
100-55 was pre-plasticized with up to 40% (w/w) TEC based on
the polymer weight using a similar process as proposed by Zheng
et al. Increasing TEC levels were shown to reduce the glass tran-
sition temperature, melt viscosity and spreading coefficient of the
polymer. Talc was used as anti-tack agent to prevent agglomera-
tion of the tablets during coating powder application and added in
a 10% ratio to the ground polymer powder. PEG 3350 was used as
low-melting hydrophilic wetting agent to promote coating powder
adhesion and was used both as primer and component of the coat-
ing powder. The authors demonstrated that PEG 3350 was miscible
with Eudragit® L 100-55, reducing the glass transition temperature
and the melt viscosity of the polymer (Sauer and McGinity, 2009a).
Following coating, the tablets were cured on Teflon trays at 60 ◦ C
for 24 h and overcoated with 2% (w/w) talc based on the weight of
the coated tablets.
Alternatively, coating can be achieved in the spheronizer itself,
based on the properties of the formulation. In another example,
chlorpheniramine maleate was used as a model compound within Fig. 13. Influence of TEC content and coating level on the release of chlorpheni-
tablets that were dry powder coated and cured at 60 ◦ C for 2 h ramine maleate from tablets powder-coated with pre-plasticized Eudragit® L
100-55 using USP apparatus 2. Dissolution in 900 mL 0.1 N HCl for 2 h followed by
in a spheronizer (Sauer et al., 2007). The influence of TEC con-
4 h in 900 mL, pH 6.8 buffer. , 7% polymer weight gain. , 10% polymer weight gain.
tent and coating level on the release from powder coated tablets , 15% polymer weight gain. (A) 20% TEC based on the polymer weight. (B) 30% TEC
was evaluated and the results are summarized in Fig. 13. Higher based on the polymer weight. (C) 40% based on the polymer weight.
plasticizer levels were shown to enhance film formation and to Reproduced with permission from Sauer et al. (2007).
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tablets was confirmed at 25 ◦ C/60% RH over a storage time of powder techniques, it has also been shown to be the most advanced
12 weeks. in terms of commercial application. Application of the technology
Subcoating can also be used to influence the performance of the within the pharmaceutical industry has demonstrated that more
manufacturing process and the quality of the coats (Sauer et al., intricate patterns can be formed on the coating for brand identifica-
2007, 2009). Subcoats of Eudragit® E PO and Eudragit® RL PO were tion purposes while also providing comparable production outputs
evaluated in combination with the enteric polymer Eudragit® L to larger commercial units.
100-55 for the powder coating of tablets. HPMC K4M and PEG
3350 were added to the subcoat formulations to increase water 5.1. Process equipment considerations
influx and dissolution rate in the buffer stage of the enteric test.
The pore formers were used at a 10% (w/w) ratio based on the Requiring specialized equipment, Phoqus Pharmaceuticals, Ltd.
polymer weight in the subcoat formulations. Similar to previous developed an electrostatic powder coating process for tablets
studies, Eudragit® RL PO and Eudragit® L 100-55 were both pre- (Hogan et al., 2006). In this system they utilized a custom engi-
plasticized prior to coating powder application. Talc was added at neered coating apparatus to coat both sides of the tablet cores
10% (w/w) level as anti-tack agent. The application of the Eudragit® separately. Infrared radiation was applied for a short amount of
E PO or Eudragit® RL subcoat were shown to assist with adhesion time to facilitate film formation of Eudragit® RS coatings.
of the enteric polymer Eudragit® L 100-55 and reduce the amount The technology known as LeQtracoat® exploited the electro-
of enteric polymer required for enteric protection. static attraction between oppositely charged materials to promote
Using a combination of formulation designs it is possible to alter the adhesion of the coating powders onto the surface of tablets
the adhesion, surface spreading and mobility of the coating pow- (Fig. 14). With the same principle as the ink toner deposition in
ders, leading to greater coalescence and enhanced film formation. electrophotography (photocopying) the tablets were coated indi-
While thermal adhesion methods may not currently be preferred vidually one side at a time in special manufacturing plants with
in industry, the flexibility for formulation design through solid capacity up to 250,000 units/h. With this technique, the coating
dispersion engineering and the parallel development of enhanced material was directed with such precision that 3D images could
manufacturing technologies will hopefully translate into greater be created. Final curing leading to film formation could also be
use of the technology in the future. achieved within the same apparatus, allowing for similar perfor-
mance to conventional coating operations.
Qiao et al. (2010a) developed a powder coating process that
5. Electrostatic coating combined electrostatic powder coating technology with a tradi-
tional liquid pan coating technique for the powder coating of
Electrostatic powder coatings are commonly used in the metal tablets. The pan coater was equipped with a liquid spray nozzle,
finishing industry, coating everything from metal bolts to auto- an electrostatic spray gun, and a powder feeder. Ibuprofen was
mobiles. The process involves the deposition of charged coating used a model drug for the study. The polymers Opadry® AMB
powder onto a grounded substrate (Luo et al., 2008). While this (polyvinyl alcohol based coating blend) and Eudragit® E PO were
technique has seen the lowest level of publication for any of the dry evaluated. Prior to coating, the polymer powders were ground to
Fig. 14. Schematic diagram of the electrostatic dry powder coating process.
ARTICLE IN PRESS
G Model
an average particle size of 26.6 ␮m and 10.0 ␮m for Opadry® AMB that have been gained in other industries have yet to materialize
and Eudragit® E PO, respectively. The coating process consisted for the pharmaceutical sector, leading to a much slower adoption
of the following steps: pre-heating, plasticizer spraying, feeding of the technology.
of the charged particles into the coating bed, and curing at ele- On the horizon, however, one notes several major trends which
vated temperature. Polyethylene glycol 400 and glycerol/water may help to drive the industry closer to large scale adoption of
mixtures (1:1, v/v) were used as plasticizer. In addition to lower- dry powder coating technologies for oral delivery. First, the cur-
ing the glass transition temperature, the plasticizer layer promoted rent changes in global austerity have pushed many pharmaceutical
powder adhesion by capillary forces and reduction of the electrical and biotechnology companies to seriously examine manufacturing
resistivity of the core tablets. The polymer particles were negatively costs. The lower cost associated with dry powder coating tech-
charged using an electrostatic spray gun and followed the direction nology makes it attractive for both brand and generic companies
of the electrical field between tip of the spray gun and grounded seeking to reduce operating expenses. Another major driver in the
coating pan. The repulsive forces between the polymer particles future will be the needs of advanced drug products, specifically
promoted the dispersion of the coating powder. The coating level focused in the area of counterfeit resistance and amorphous for-
was dependent on the charging voltage used to spray the coating mulation support. Counterfeit drugs are a major problem facing
powder. Film formation of the described coating process occurred global pharmaceutical companies, with steps being taken to protect
during curing at 40–60 ◦ C for 2 h based on visual observation using the supply chain and also develop visually differentiated products.
scanning electron microscopy. Dry powder coating, particularly electrostatic dry powder coating,
By achieving a charge on the powder it was possible to coat can be used to prepare novel identifying marks onto drug prod-
a drug product using this electrostatic – liquid assisted hybrid ucts in a rapid cost effective manner leading to enhanced brand
methodology. Such combinations of technologies provide benefits identification. Beyond this, the potential to eliminate the need for
for more effective film formation and may also represent the next solvents allows for more effective application of coatings to mois-
steps for applying this technology more broadly throughout the ture sensitive products. This opens up unique opportunities in the
industry. drug product design of amorphous systems and may potentially
play a role in future product designs.
Given the potential of the technology, academic research will
5.2. Formulation considerations
continue in earnest as the pharmaceutical industry continues the
adoption of the technology. Over time and driven by a number of
Compositionally, it is critical that charge can be induced into the
different factors, dry powder coating appears poised to become a
powder constituents. Similar to the other methodologies, adher-
major pharmaceutical coating technology in the future.
ence and film formation are critical aspects of formulation design.
While these are not handled in a fundamentally different way from
the previous discussion, the example below is provided to illus- References
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Dry Powder Coating of Pharmaceuticals

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ARTICLE IN PRESS

International Journal of Pharmaceutics xxx (2013) xxx–xxx

Contents lists available at SciVerse ScienceDirect

International Journal of Pharmaceutics

Dry powder coating of pharmaceuticals: A review

2 D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx 3

Other more detailed approaches, such as the Gordon–Taylor equa-

4 D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

Technology Advantage Disadvantage

Liquid assisted Use of conventional Requires co-metering

Thermal adhesion No requirements for Requires pre-processing of

Electrostatic Complex pattern Need for specialized

Fig. 2. Schematic illustration of dry coating with a centrifugal granulator.

3. Liquid assisted coating

While conventional coating technologies rely on large volumes

will serve as an adhesive aid while providing some functionality

D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx 5

Type Ingredient Partsa

Powder mixture HPMCAS 100

Liquid mixture (Plasticizer) Triethyl citrate 30

6 D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx 7

Reproduced with permission from Cerea et al. (2008b). Liquids

8 D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx 9

HPMC E5 was included in the formulation and evaluated as a pore

10 D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx 11

12 D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx 13

14 D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

D. Sauer et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx 15

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