C H A P T E R

3
Aqueous polymeric coatings: New
opportunities in drug delivery systems
Abid Riaz Ahmeda, Joana Portugal Motab,c, Ahmad Abdul-Wahhab
Shahbad, Muhammad Irfane
a
Merck Healthcare KGaA, Darmstadt, Germany
b
Lecifarma—Laboratório Farmac^eutico, Lda, Várzea do Andrade—Cabeço de Montachique,
Lousa, Portugal
c
CBIOS-Research Center for Biosciences and Health Technologies, Lusófona University,
Lisbon, Portugal
d
Kayyali Chair for Pharmaceutical Industries, Department of Pharmaceutics, College of Pharmacy,
King Saud University, Riyadh, Saudi Arabia
e
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, GC University Faisalabad,
Faisalabad, Pakistan

1 Introduction polymer dispersions can be prepared by emul-

sion polymerization of a monomer (latex) or by
Aqueous film coatings have been extensively emulsification of a polymer (pseudolatex) [12];
applied to solid substrates as tablets, pellets, physical properties and method of preparation
granules, and capsules, for several purposes. of pure aqueous dispersion are summarized in
They include odor and taste masking, improve- Table 3.2. The formation of a thin and transparent
ment of dosage form appearance, protection of film from aqueous latex or pseudolatex disper-
the drug from environmental conditions (light, sion takes place in parallel with evaporation of
oxygen, and water vapor), isolation of incompat- water. Film formation is illustrated in Fig. 3.1.
ible materials, easy identification of drug During spraying of the aqueous dispersion
products for both patients and healthcare profes- onto a substrate, water evaporates at a constant
sionals and to modify drug release (Table 3.1) rate and the particles form a closed and ordered
[5–7]. Aqueous-based coatings are an attractive packing. Deformation and fusion of the colloidal
alternative to organic-based coatings, due to particles lead to a film with water-filled cavities.
environmental reasons and reduced processing Finally, particle coalescence occurs when the
time (high polymer content) [8–11]. The aqueous capillarity forces are strong enough [13–15].

Drug Delivery Aspects 33 # 2020 Elsevier Inc. All rights reserved.

https://doi.org/10.1016/B978-0-12-821222-6.00003-8
34 3. Aqueous polymeric coatings: New opportunities in drug delivery systems

TABLE 3.1 Examples of aqueous based polymers used for immediate and modified release coatings.
Immediate release Polymers (Trade name) Ref.

Taste and odor masking • Hydroxy ethylcellulose (Natrosol), hydroxy proylcellulose (Klucel), hydroxy [1–3]
propylmethylcellulose (Methocel)
Moisture protective
• Polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat IR)
Easy identification • Polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol
(Kollicoat Protect)
Improving ingestion • Aminoalkyl methacrylate copolymer (Eudragit E 100)
and swallowing
Isolation of
incompatible materials

Improving appearance
Modified release
Sustained release • Ethylcellulose (Aquacoat ECD and Surelease) [2, 4]
• Ammonio methacrylate (Eudragit RS 30 D, Eudragit RS 30 D and combination of them)
• Ethylacrylate methylmethacrylate (2:1) (Eudragit NE 30 D and Eudragit NM 30 D)
• Polyvinyl acetate (Kollicoat SR 30 D)
Enteric/colonic release • Cellulose acetate phthalate (Aquacoat CPD)
• Hydroxypropyl methylcellulose acetate succinate (AQOAT)
• Methacrylic acid copolymer (Eudragit L 30 D 55)
• Polymethylacrylate-co-methyl methacrylate-co-methacrylic acid (Eudragit FS 30 D)

TABLE 3.2 Physical properties and method of preparation of pure aqueous dispersions.
Aqueous
dispersion Polymer Additives (%) Method of preparation Tg (°C) MFT (°C) Ref

Aquacoat Ethylcellulose Sodium dodecyl Emulsification of 90 81 [30, 31]

ECD sulfate (0.9–1.7) polymer (pseudolatex)
Cetyl alcohol
(1.7–3.3)
Surelease Ethylcellulose Oleic acid (1.9) Inverse emulsification 50 32 [32, 33]
Dibutyl sebacate (pseudolatex)
(3.5)
Aquacoat Cellulose acetate Poloxamer (7) Emulsification of 40 Information [16, 34]
CPD phthalate polymer (pseudolatex) not found
AquaSolve Hydroxypropyl Oleic acid (1.9) Redispersion of a Depends on N/A [35]
methylcellulose Dibutyl sebacate polymeric powder substitution
acetate succinate (3.5) degree
Eudragit Ammonio Sorbic acid (0.25) emulsification of 55 45 [1, 36]
RS 30 D methacrylate type B NaOH (0.1) polymer (pseudolatex)
Eudragit Ammonio — N/A 50 40
RL 30 D methacrylate type A
 1 Introduction 35

TABLE 3.2 Physical properties and method of preparation of pure aqueous dispersions—cont’d
Aqueous
dispersion Polymer Additives (%) Method of preparation Tg (°C) MFT (°C) Ref

Eudragit Ethylacrylate Nonoxynol 100* Emulsification 8 5 [1, 37]

NE 30 D methylmethacrylate (1.5) polymerization (latex)
(2:1)

Eudragit N/A PEG stearyl ether N/A N/A N/A [1, 38]
NM 30 D (0.7)

Eudragit Methacrylic acid Sodium lauryl N/A >100 25 [1, 39]

L 30 D 55 copolymer sulfate (0.7)
Polysorbate
80 (2.3)
Kollicoat Polyvinyl acetate Polyvinyl N/A 46 18 [40, 41]
SR 30 D pyrrolidone (2.9)
Sodium dodecyl
sulfate (0.1)

N/A, not applicable.

polymeric dispersion. The MFT depends on

the elastic modulus (resistance to particle defor-
I mation). Another important characteristic is the
Aqueous dispersion deposited on glass transition temperature (Tg) of the polymer
surface [18] (Fig. 3.2). Below the Tg, the polymer exists in
Water evaporation and
a rigid and glassy state with extremely limited
particles packing
polymer segment mobility. Above the Tg, the
polymer is in a soft and rubbery state, and the
II
polymer chains present a significant movement.
Closely packed spheres with water filled Where the Tg of a polymer is higher than the
voids Water evaporation and desired operating coating temperatures, a plas-
polymer deformation ticizer should be added to obtain good film for-
mation. Generally, plasticizers reduce the
III
cohesive forces along with polymer chains, lead-
Apparently continuous polymer ing to an increase in flexibility, reduction in ten-
film Water diffusion and sile strength, and reduction of Tg and MFT,
polymer interdiffusion facilitating the polymer particle coalescence
[19–22]. A plasticizer should be compatible (mis-
cible) with the polymer and show no (or little)
FIG. 3.1 Film formation of thin films from polymeric tendency to migrate [23]. Plasticizers are high
lattices. boiling point organic compounds, with low
vapor pressures and different water solubility
In order to obtain a good-quality film (free of (Table 3.3) [12].
cracks), the coating temperature is usually The water-soluble plasticizers dissolve in the
10–20°C above the minimum film formation polymer aqueous dispersion, whereas the water
temperature (MFT) [5, 16, 17] of the aqueous insoluble plasticizers are emulsified in the
36 3. Aqueous polymeric coatings: New opportunities in drug delivery systems

aqueous phase of the dispersion. The most widely dispersions may occur [51]. Recently, polyvinyl
used plasticizers are: triethyl citrate (TEC) and tria- pyrrolidone, polyvinyl alcohol-polyethylene gly-
cetin (TA) as water-soluble plasticizers and acetyl- col graft copolymer, and carrageenan have been
triethyl citrate (ATEC), acetyltributyl citrate successfully used to modify drug release from
(ATBC), dibutyl sebacate (DBS), diethyl phthalate aqueous-based coatings [52–54] as Aquacoat
(DEP), and tributyl citrate (TBC) as water- ECD-coated dosage forms without destabilizing
insoluble plasticizers. The decrease of the MFT the aqueous dispersion.
and thus the effectiveness of the plasticizer depend After completion of the coating process, a
on the plasticizer amount and its effectiveness for curing step (short thermal treatment) is regularly
each aqueous polymeric dispersion. The effects performed to improve polymer particle coales-
of type and concentration of plasticizers on MFT cence. This curing step is of utmost importance
of aqueous polymeric dispersions are shown in to promote complete film formation from a poly-
Table 3.4. In addition, the type and amount of mer aqueous dispersion [55, 56]. The curing can be
plasticizer can also change the diffusivity of the performed in the coating equipment or in an oven.
coating and thus the drug release rate [42–45]. A curing temperature 10–20°C above the MFT of
In the case of polymers with low Tg or where the the aqueous dispersion is recommended to pro-
plasticizer strongly decrease the Tg and MFT, gli- mote the “further gradual coalescence” (micro-
dants and antitacking agents are used to avoid scopic coalescence). The specific temperature,
tackiness or agglomeration during coating, dry- time, and presence of humidity on the curing step
ing, curing, and storage. Talc, magnesium stea- is dependent on each formulation as aqueous
rate, kaolin, and glycerol monostearate are polymeric dispersion properties, plasticizer type,
frequently used. The content of the antitacking presence/absence of talc, and coating conditions,
agent depends on its nature—for example, talc to name a few. Tackiness and agglomeration can
is used in the range of 25%–100% (w/w, based occur during the curing process, and to circum-
on dry polymer), while 5%–20% (w/w, based on vent these problems, a thin HPMC overcoat can
dry polymer) of glycerol monostearate is highly be used [46, 57] or talc can be blended with coated
effective [5, 46]. Pigments are generally added to dosage forms before placing them in the oven [16].
polymeric dispersions to enable easy product During the curing step, drug migration through
identification and to improve the elegance of the coating can occur, especially if the drug has
pharmaceutical dosage form. In addition, tita- a low melting point and affinity for the polymeric
nium dioxide has been incorporated into film coating [56, 58]. In this case, a subcoating can avoid
coating formulations as an opacifying agent drug migration during the curing step [58].
to improve the stability of light-sensitive drugs After the curing step, coated dosage forms are
[47, 48]. The concentration of pigments should stored under high temperature and humidity
not exceed critical pigment volume concentration conditions (the International Committee on
(CPVP) and the CPVP is characteristic of each Harmonization recommends 25°C/60% RH and
polymer-filler combination [49]. Surfactants such 40°C/75% RH) for a defined time. Often, drug
as sodium lauryl sulfate, poly vinylpyrrolidone, release rate decreases after these storage condi-
and polysorbates are used to stabilize the aqueous tions due to the well-known physical aging.
polymeric dispersion [1]. Pore formers can also be Physical aging or enthalpy relaxation is observed
incorporated in the coating to modify the drug with all amorphous polymers. Amorphous mate-
release. Polyethylene glycol, polyvinylpyrroli- rials are not in thermodynamic equilibrium when
done, hydroxypropyl cellulose, and in particular they are cooled below their Tg [59]. Since this is an
hydroxypropyl methylcellulose (HPMC) [24, 50] energetically unfavorable state, the polymer
have been used to increase permeability of the chains in a glassy film will reorient to achieve
coatings. However, destabilization of the aqueous the equilibrium over time [60].
 1 Introduction 37

Specific volume
Truly glassy Aging range
state

Equilibrium line

Tβ Tg

Temperature
FIG. 3.2 Origin of physical aging. Tg is the glass transition temperature of the polymer and Tβ is the temperature of the
highest secondary transition. Adapted from Guo J-H. Aging processes in pharmaceutical polymers. Pharm Sci Technol Today
1999;2(12):478–483.

TABLE 3.3 Physical properties of plasticizers commonly added to aqueous polymeric dispersions.
Water Solubility Boiling Vapor pressure Vapor density
Plasticizer solubility (%) parameter (J/cm3)1/2 point (°C) (mmHg) (air 5 1) Ref.

TEC 6.5–6.9 20.4–21.1 294 1 at107°C 9.7 [12, 24–28]

Triacetin 7.0–7.1 18.5 258 1 at 100°C 7.52 [12, 26–28]

ATBC < 0.01 17.7 326 0.8 at 170°C 14.1 [12, 26–28]
ATEC 0.72 18.3 294 – – [26–28]
DBS 0.01 18.8 344–394 10 at 200°C 10.8 [12, 24, 28, 29]
DEP 0.15 19.1 295 100 at 220°C 7.66 [12, 24, 27, 28]
TBC < 0.01 19.5 322 1 at 170°C 12.4 [12, 25–28]

TABLE 3.4 Effect of plasticizer type and content on MFT from different aqueous
dispersions.
Aqueous dispersion Plasticizer (%) MFT (°C) Ref.

Aquacoat ECD TEC 25 30 [79]

30 <23

DBS 25 28
30 27
Aquacoat CPD TEC 25 36
35 35
45 34

Continued
38 3. Aqueous polymeric coatings: New opportunities in drug delivery systems

TABLE 3.4 Effect of plasticizer type and content on MFT from different aqueous
dispersions—cont’d
Aqueous dispersion Plasticizer (%) MFT (°C) Ref.

DEP 25 40

35 38
45 36
Aquot AS-LF TEC 20 <20 [35]
Aquot AS-MF 28 0
Aquot AS-HF 35 35
Eudragit RS 30 D TEC 10 20–22 [1]

20 5
DBS 10 20–22
20 15–17
Eudragit RL 30 D TEC 10 10
20 <0

DBS 10 7–8
20 <0
Eudragit L 30 D 55 TEC 10 0 [80]
ATEC 10 10
Kollicoat SR 30 D TEC 5 8 [40]
10 1

PG 5 16
10 14

PG, propylene glycol.

The difference between the Tg of the polymer drug release also decreases. With polymeric
and the temperature of the storage conditions films resulting from aqueous polymer disper-
will determine the rate at which the reorienta- sions, the physical aging is related with further
tion of the polymer chain occurs. The molecular polymer particle coalescence with continued
mobility will be greater when the storage tem- interdiffusion of latex particles [15]. Moreover,
perature is near or greater than the Tg of the mechanical changes such as decrease in elonga-
polymer. Physical aging results in a denser film tion [62] and creep compliance [63], in addition
[61] with reduced porosity and tortuosity. Con- to increase in elastic modulus [62] and tensile
sequently, film permeability decreases, and strength [15], may occur during storage.
 2 Coating types and polymers used 39

2 Coating types and polymers used Aquacoat ECD is 81°C [31] and plasticizer
addition is required prior to coating process, to
2.1 Aqueous-based coatings for sustained reduce MFT below the coating temperature
drug release (cellulosic type) (Table 3.4). The manufacturer (FMC Biopolymer)
recommends the use of DBS, Myvacet, ATEC
2.1.1 Ethylcellulose (water insoluble), triacetin, and TEC (water
Ethylcellulose is the most commonly used soluble) as plasticizers for Aquacoat ECD [30].
polymer for sustained release (Fig. 3.3), but is Plasticization time (the time from plasticizer
also used for moisture protection and taste addition to the polymer dispersion and the
masking. It is insoluble, but permeable in water spraying process) was shown to have a strong
and guarantees a pH independent drug release. influence on film formation [31, 64, 65] and con-
Aquacoat ECD and Surelease are two pseudola- sequently on drug release [66]. In general, with
tex dispersions of ethylcellulose available on the water-soluble plasticizers, the plasticization
market. Aquacoat ECD is prepared by a direct time does not affect the drug release because of
emulsion solvent evaporation method [30]. its rapid uptake by the colloidal polymer parti-
This aqueous ethylcellulose dispersion (30% cles. With water-insoluble plasticizers, plastici-
solids) is stabilized with sodium lauryl sulfate zation time strongly influences film formation.
(SLS) and cetyl alcohol. Although ethylcellulose Increasing plasticization time improves film
assures pH-independent sustained release formation due to a more complete uptake of plas-
profiles, the drug release rate from Aquacoat ticizer in the polymer particles, resulting in a bet-
ECD coatings was demonstrated to be slower ter film formation and slower drug release rates
in acidic media due to the presence of SLS in [66]. However, a thermal treatment at elevated
the dispersion [8, 43]. The MFT of unplasticized temperatures (curing step) after coating may

OR OR
RO O
O O O
O
RO OR
OR n

Polymer Substituent groups (R)

Ethylcellulose
—H —CH2CH3

Cellulose acetate phthalate

(CAP) O O
—H
CH3C— O
OH

Hydroxypropyl
methylcellulose acetate O O
—CH2CHCH3
(HPMCAS) OH
—H CH3C— O
OH
—CH2CHCH3 —CH2CHCH3
CH3
OCOCH3 OCOCH3COO

FIG. 3.3 Molecular structure of cellulosic polymers used to modify drug release.
40 3. Aqueous polymeric coatings: New opportunities in drug delivery systems

reduce or eliminate the effect of plasticization guarantee complete polymer particle coalescence
time with water-insoluble plasticizers [66]. The and no further changes in drug release profiles.
curing step at elevated temperatures is per- The ratio of curing temperature and time need
formed to promote further gradual coalescence. to be adjusted for each formulation. For example,
At temperatures above the Tg of the polymer, it was shown that at least 1 h was necessary to
chain mobility increases, and thereby coales- complete film formation when curing at 60°C
cence is accelerated. [43, 55]. In contrast, in another study it was
The curing time and temperature were found shown that at least 8 h was necessary to complete
to decrease with increasing plasticizer amount film formation from Aquacoat ECD coatings [66].
[50, 56]. Increasing the plasticizer concentration, Discrepancy in the required curing time could
polymer particle coalescence is improved at the be attributed to variation of plasticizer type,
end of the coating process and complete film for- amount, and coating temperature within the
mation is achievable at lower curing tempera- two studies. Both curing time and temperature
tures or shorter curing times. In addition, the have an impact on the completeness of the film
curing temperature that is necessary to reach a formation; however, it was demonstrated that
constant drug release was dependent on the curing temperature had a more dramatic impact
water solubility of the plasticizer [50]. For a in film formation than curing time [43, 68]. Film
water-insoluble plasticizer (DBS), lower curing formation was better at higher curing tempera-
temperatures were necessary to complete film tures and lower curing times than at lower curing
formation in comparison with a water-soluble temperatures and longer curing times.
plasticizer (TEC). The type of plasticizer in com- Besides time and temperature, humidity can
bination with coating level strongly affected the be introduced in the curing step to improve film
curing effect on drug release [67]. When using a formation. Under thermal humidity curing, heat
water-soluble plasticizer (TEC), increasing the increases the mobility of polymer chains, and
harshness of the conditions (time, temperature, the water vapor is adsorbed by the film and
and relative humidity) caused the drug release the capillarity forces can deform the polymer
rate to decrease, for all coating levels. On particles. Moreover, water acts as a plasticizer
increasing the temperature, time, and humidity, for ethylcellulose [16]. Consequently, a denser
better film formation was achieved, and drug film is formed, and coating permeability
release decreased. When using DBS and Myva- decreases, as does drug release [52, 67, 69]. After
cet (water-insoluble plasticizers), the former the curing step, long-term stability study of the
relationship was just observed for a 5% coating coated dosage is usually carried out. When
level. At intermediate coating levels (7.5%), the using 20% TEC as a plasticizer, drug release
curing conditions had no effect on drug release, from Aquacoat ECD-coated pellets was
and at high coating levels (10%), the release unchanged under ambient storage conditions
rate initially increased and then decreased with but decreased under stress test conditions (40°
increasing harshness of the curing conditions. C/75% RH), suggesting continuous film forma-
These opposite behaviors were attributed to tion. With 20% DBS, no storage effect was
two competing phenomena: improved film for- observed at both conditions, indicating that
mation and drug migration into the polymeric with this plasticizer, complete film formation
membrane. Increased drug release profiles after was achieved during curing [50]. In another
thermal curing were also related with loss of study, it was shown that theophylline release
plasticizer [68]. from Aquacoat-coated pellets was almost
The curing temperature in combination with unchanged upon 18 months’ storage at room
curing time are important parameters to temperature [66].
 2 Coating types and polymers used 41
Physical instabilities can lead to cracking and profiles were obtained from Surelease-coated
chipping of the film coating. This was observed drug layered sugar cores, whereas increased
with Aquacoat ECD coatings under storage at drug release rates were observed from sphero-
high relative humidity. The increase in water nized drug and microcrystalline cellulose cores.
content in the films was the reason for the aging Upon storage in humid conditions, the sphero-
effect [70]. Microruptures were also observed in nized MCC cores swelled (due to moisture
uncured Aquacoat-coated pellets stored at room uptake), creating a high internal stress in the
temperature. The ruptures lead to an increase coating, which in turn led to cracks in the coating
in drug release with time [66]. Surelease, a and increasing drug release [77].
product from Colorcon, is an ethylcellulose dis-
persion with 25% solids. It is an aqueous disper- 2.2 Aqueous-based coatings for enteric
sion produced by a phase inversion, using an drug release
in-situ emulsification technique [32]. Surelease
is preplasticized with DBS and does not require 2.2.1 Cellulose acetate phthalate
extra addition of plasticizer prior to coating. The Cellulose acetate phthalate (CAP), a cellu-
MFT of the dispersion is 32°C [71]. Thermal lose ester derivative, is widely used as an
curing showed no effect on drug release from enteric polymer coating in the pharmaceutical
pellets coated with Surelease coatings [33]; industry [78] (Fig. 3.3). It dissolves in buffered
however, thermal humidity curing showed medium at pH values >5.5. This pseudolatex is
significantly decreased drug release from available as Aquacoat CPD, by FMC, and the Tg
Surelease-coated pellets [72], due to water being of the dispersion is 40°C [34]. The addition of
extremely important for the capillarity forces, plasticizers is recommended to decrease the
and water acts as a plasticizer for ethylcellulose. Tg and the MFT of the aqueous dispersion
In another study [73], three main variables (Table 3.4). FMC recommends DEP, TEC, and
were studied for the curing step: temperature, triacetin as plasticizers for Aquacoat CPD
humidity, and time, using four model drugs [34]. Usually 25%–35% (w/w, based on dry
with different physiochemical properties. As polymer weight) is sufficient to obtain good
observed with Aquacoat ECD coatings, curing film formation [2]. Obara and McGinity [79]
temperature and humidity had a more dramatic determined the MFT of Aquateric (now Aqua-
effect on decreasing drug release than curing coat CPD) between 32°C and 42°C with the
time. Drug release from Surelease-coated pellets addition of TEC or DEP. At the same plasticizer
decreased after 60°C/24 h and increased after amount, TEC was slightly more effective than
60°C/48 h and 40°C/75% RH/1 week. It was DEP. Moreover, during the coating process,
suggested that in the first 24 h, film formation less TEC was lost than DEP [78]. Williams
was the predominant mechanism, decreasing and Liu [16] demonstrated a clear and strong
drug release, and after film cracks were the rea- relationship between coating temperature, cur-
son for the fast release [74]. Storage at 40°C/80% ing temperature, humidity, and time. The
RH slightly decreased drug release from authors showed that above the MFT of the
Surelease-coated pellets [75], whereas storage aqueous dispersion, the higher the coating tem-
at RT in sealed plastic containers had no effect perature, the worse the film formation was. It
on drug release [76]. The core type (drug- was suggested that at too-high coating temper-
layered sugar vs. spheronized drug microcrys- atures, the evaporation rate of water may have
talline cellulose cores) affected drug release overcome the diffusion of water between the
tremendously from Surelease-coated pellets polymer particles to the surface and prevented
after storage at 40°C/75% RH. Stable release the development of capillary forces required
42 3. Aqueous polymeric coatings: New opportunities in drug delivery systems

for particle deformation. In addition, thermal in the absence of heat did not improve the film
curing (60°C/12 h) only decreased drug release formation as much as elevated humidity in
from pellets coated at the lowest temperature the presence of heat. Film formation from
above the MFT. This was attributed to the fact aqueous-based cellulosic polymers is tremen-
that pellets coated at this temperature con- dously dependent on the presence of heat
tained more moisture, which was involved in (increasing polymer chain mobility) and the
the polymer particle coalescence. The presence presence of high relative humidity (capillarity
of humidity and heat during the curing step forces to deform polymer particles are depen-
strongly enhanced polymer particle coales- dent on the presence of moisture, and water is
cence, resulting in coating films with enteric a plasticizer for cellulosic polymers). On storage,
properties and higher mechanical strength. a comparison demonstrated that tablets coated
Moisture (water) in the coating film is required with aqueous HPMCAS were more stable than
for the capillary forces to deform polymer par- tablets coated with pseudolatex CAP [11] .
ticles and coalescence, and water is a plasticizer
for CAP. Moreover, it was demonstrated that
Aquacoat CPD coatings were stable at 25°C/ 2.3 Acrylate-type aqueous-based coatings
60% RH and 40°C/75% RH in a closed system
with desiccant [9]. Although humidity contrib- 2.3.1 Ammonio methacrylate copolymers
uted significantly to coalescence of CAP during Eudragit RS 30 D and Eudragit RL 30 D are
the curing process, long-term storage humidity commonly used for sustained drug release.
should be avoided to maintain the chemical They are also named ammonio methacrylate
stability of the CAP and the enteric properties copolymers Type A (Eudragit RL) and
of coated films. B (Eudragit RS) (Fig. 3.4). Eudragit RL has a
higher content of ammonio methacrylate pen-
2.2.2 Hydroxypropyl methylcellulose dant groups, and thus films produced by this
acetate aqueous dispersion are more permeable than
Hydroxypropyl methylcellulose acetate films from Eudragit RS 30 D [1, 36]. Often they
(HPMCAS) is another enteric polymer (Fig. 3.3), are mixed at any ratio to provide film coatings
commercially available as Aqoat (redispersible with the desired permeability [46]. They are
powder) [35]. There are three grades of Aqoat: pseudolatexes with an MFT of 45°C (Eudragit
AS-LF, AS-MF, and AS-HF, differing in the per- RS 30 D) and 40°C (Eudragit RL 30 D) [80].
centage of acetyl and succinoyl substitution. The TEC, DBS, ATEC, and ATBC are recommended
ratio between succinoyl and acetyl group substi- plasticizers in a concentration of 20% (w/w,
tution determine the onset of aqueous solubility based on dry polymer) [1]. Eudragit RS
of HPMCAS. The MFT of HPMCAS is depen- 30 D-coated dosage forms are known to have
dent on the substitution type of the polymer: sticking problems during coating and curing
HF > MF > LF [35]. The manufacturer recom- [81]. To circumvent these problems, talc or
mends TEC as the only compatible plasticizer glyceryl monostearate are frequently added to
for HPMCAS [35]. The MFT of HPMCAS-MF the aqueous dispersion prior to coating, and
was determined as <23°C with the addition of talc can also be blended with the coated pellets
28% TEC [79] (Table 3.4). The addition of talc prior to the curing step. Otherwise, an HPMC
is also recommended to avoid tackiness. Ther- over-coating can be performed [46].
mal humidity curing was also reported to The effect of thermal curing has been reported
improve film formation in comparison with to decrease [17, 82, 83] and increase [81, 82, 84]
only thermal curing [10]. It was also shown that drug release from Eudragit RS 30 D or Eudragit
curing in the presence of elevated humidity and RL 30 D-coated pellets. The decrease of drug
 2 Coating types and polymers used 43

R1 R3 R1 R3

C CH2 C CH2 C CH2 C CH2

C O C O C O C O

O O O O

R2 R4 R2 R4
n

R1 R2 R3 R4

Eudragit RS/RL H, CH3 CH3, C2H5 CH3 CH2CH2N(CH3)3+Cl–

Eudragit NE/NM H, CH3 CH3, C2H5 H, CH3 CH3, C2H5

Eudragit L CH3 H CH3 CH3

FIG. 3.4 Molecular structure of Eudragit polymers used to modify drug release.

release was attributed to further gradual coales- when plasticizer (TEC) concentration was
cence, leading to a denser and less permeable film. increased [17] from 10% to 20%.
This effect was mainly observed at low curing
temperatures, high curing temperatures/short 2.3.2 Ethyacrylate methylmethacrylate
curing times [82, 83], and in the presence of high Eudragit NE 30 D and Eudragit NM 30 D are
relative humidity [17]. In contrast, the increase polymethacrylate-based coating systems used
in drug release was related with loss of plasticizer for sustained release (Fig. 3.4). They are a latex
at higher curing temperatures and longer curing dispersion of a neutral polymer produced by
times [82, 84]. The loss of plasticizer created a more emulsion polymerization of ethyl acrylate and
porous film, resulting in an increase in drug methyl methacrylate. The difference between
release. In addition, due to intense sticking of Eudragit NE 30 D and Eudragit NM 30 D is in
the coated pellets, damage of the coating occurred, the content and nature of emulsifier. Eudragit
leading to an increase in drug release [81]. It was NE 30 D contains α-(4-nonylphenyl) ω-hydroxy-
proposed that Eudragit RS 30 D or Eudragit RL poly-(oxy-1, 2-ethanediyl), namely nonoxynol
30 D coatings require a thermal “optimal” curing 100 (1.5%) and Eudragit NM 30 D contains poly-
[84, 85] in which polymer particles coalescence ethylene glycol stearyl ether (0.7%) [37, 38].
occurs, leading to a decrease in film permeability Coating films resulting from both aqueous dis-
and decreased drug release. Beyond this optimal persions are insoluble in the gastrointestinal
curing, the loss of water and plasticizer can lead tract, and show very low permeability and a
to a more brittle and porous film, increasing drug pH independent swelling [2]. The MFT of
release. The addition of insufficient amounts of Eudragit NE 30 D and Eudragit NE 30 D is
plasticizer can result in polymeric films that are 5°C [80] and addition of plasticizer is not
brittle or require longer curing times for the coa- required, but addition of talc is recommended
lescence to be completed. It was reported that to avoid tackiness and agglomeration of the
the time to achieve stable drug release profiles coated pellets [86]. In spite of the low MFT of
under storage at 40°C/50% RH was 3 months these polymers, drug release significantly
44 3. Aqueous polymeric coatings: New opportunities in drug delivery systems

decreased under thermal curing [82, 87] which after curing at 40°C and 60°C, and was equili-
was attributed to further gradual coalescence. brated within 4 h. This was attributed to an
These results suggested that film formation increase of interaction between the polymer
was not completed at the end of the coating pro- and substrate resulting from a more complete
cess. Moreover, it was also reported that the cur- film formation. Upon thermal curing, the sol-
ing temperature was found to have a stronger vent evaporates and coalescence leads to an
impact on decreasing drug release compared increase of contact areas for binding sites to
to the curing time. It was suggested that to occur between the polymer and the substrate.
achieve a stable state, the polymer requires Storage of coated dosage forms at elevated tem-
energy to overcome the barriers, which cause peratures and humidity can have an impact on
the stable state to be disfavored. At lower curing adhesion of the polymer to the substrate due
temperatures, fewer polymer molecules are able to increased internal stress [20, 25]. Decreased
to overcome this energy barrier and accomplish adhesion between the Eudragit L 30 D 55 coating
a stable state, meaning that changes in drug and tablet substrate was observed, irrespective
release are expected to happen slowly over time, of the storage conditions [20]. At elevated
until the stable state is reached. In contrast, at humidity and despite the fact that water plasti-
higher temperatures more molecules reach the cizes the polymer [21], the decrease of adhesion
stable state, and this is reflected by a slower drug was a result of swelling of the film and tablet
release rate [60]. As a result, Eudragit NE and core leading to internal stress in the polymer.
Eudragit NM-coated dosage forms need a ther- In the absence of humidity, adhesion also
mal curing step in order to complete film forma- decreased due to internal stress in the coating
tion and guarantee stable drug release profiles resulting from moisture loss that causes the film
on storage [88]. Stability issues were reported to be more brittle. At high temperatures, water
with Eudragit NE 30 D due to its endogenous evaporates, leading to a decrease in elongation
excipient, nonoxynol 100. Upon storage, crystal- at adhesive failures and adhesive toughness.
lization of the surfactant may occur, due to its
high melting point (60°C), resulting in an
increase in drug release [89–92]. 2.4 Aqueous-based flexible polymer
coatings for sustained drug release
2.3.3 Methacrylic acid copolymers for
enteric drug release 2.4.1 Polyvinyl acetate
Methacrylic acid copolymers are extensively Kollicoat SR 30 D is a polymeric aqueous dis-
used for enteric coatings. Eudragit L 30 D 55 is persion based on polyvinyl acetate (PVAc), pre-
a latex dispersion of an anionic copolymer based pared by emulsion polymerization (Fig. 3.5).
on methacrylic acid and ethyl acrylate (Fig. 3.4), Since the polymer is insoluble in water, it pro-
with free carboxyl groups in a ratio of 1:1 with vides sustained release and film coatings are
the ester groups [39]. The carboxylic groups
begin to ionize in aqueous media at pH 5.5 and
CH2 CH2
above, being the polymer resistant to acidic
media but soluble in intestinal fluid. Eudragit O
L 30 D 55 has an MFT of 25°C and with the addi- C= O
tion of 10% TEC it is reduced to 0°C [80]. Curing CH3
temperature and time were found to have an
effect on adhesion of Eudragit L 30 D 55 coating FIG. 3.5 Molecular structure of polyvinyl acetate
to a tablet substrate [93]. The adhesion increased polymers.
 3 Strategies to improve storage stability 45
pH independent (no charge or ionizable Similarly to curing, when evaluating the
groups) [40]. It has an MFT of 18°C and can effect of storage on drug release from Kollicoat
be coated without the addition of plasticizers; SR 30 D-coated pellets, some misunderstanding
however, plasticization enhances film forma- may arise. Shao et al. reported that drug release
tion and improves flexibility of the films [40]. was stable under 25°C/60% RH and decreased
Recommended plasticizers and the respective under 40°C/75% RH (closed bottle, in both
concentrations are described in Tables 3.3 and cases) [94]. The authors suggested that continu-
3.4. The MFT of Kollicoat SR 30 D, plasticized ous film formation was the reason for the
with 10% TEC (w/w, based on the polymer), decrease in drug release at higher tempera-
is 1°C [58]. Due to low MFT, tackiness during tures. In contrast, Ensslin et al. showed a
coating process or storage usually occurs and decrease in drug release under 25°C/60% RH,
antitacking agents as talc are required prior to due to continuous film formation, and an
the coating process, or coated dosage forms increase after 40°C/75% RH, due to damage
should be mixed with colloidal silica (0.5%– of the coating resulting from a strong agglomer-
1% w/w) after coating [40]. Contradictory ation of the coated pellets [103]. In both studies,
results are found when reviewing the literature the plasticizer was the same and similar coating
about the curing effect on Kollicoat SR 30 D dos- levels were used. However, formulation
age forms. Dashevsky et al. reported no curing parameters (plasticizer amount, talc, and the
effect (60°C/24 h) on drug release [58] and Shao presence of a hydrophilic additive) were
et al. showed that drug release decreased at slightly different and could potentially affect
60°C/16 h, due to continuous film formation polymer particle coalescence. In the first study
[94]. Additionally, Shao et al. speculated that [94], plasticizer concentration was twice as high
the discrepancy in the results could be due to as in the second one [103], which may have con-
different types of drug and substrate used. tributed to a better film formation and no fur-
However, on close examination of these two ther changes on drug release under storage at
studies, formulation and process parameters 25°C/60%. In addition, talc content was 3.4
were also somewhat different. The plasticizer times higher in the first study, thus no agglom-
(TEC) and talc content were slightly different eration on storage at 40°C/75% RH was
in the studies. Plasticizer amount affects the observed. The decrease in drug release at this
MFT of the dispersion and the temperature at condition was attributed to further gradual
which coating process is performed. In another coalescence [94].
study, drug release from Kollicoat SR 30 D was
shown to decrease under thermal curing
(60°C/24 h) and decreased further under ther-
mal/humidity curing (60°C/75% RH/24 h) 3 Strategies to improve storage stability
[95]. The reason was attributed not to continu-
ous film formation, but rather to a decrease of As discussed above, curing and storage
adhesion between the polymer coating and conditions have a significant impact on the stabil-
the drug layer (local detachment). Moreover, ity of a polymeric film. A careful adjustment of
the authors also reported that drug release aqueous-based coating properties, coating pro-
was unchanged after curing (thermal and ther- cess, curing, and storage conditions should be
mal/humidity) when the HPMC content in the performed. However, storage stability is still one
drug layer was reduced and the talc amount in of the main obstacles associated with aqueous-
the coating film was increased (Fig. 3.5 and based coatings. Several strategies that have been
Table 3.5). used to stabilize and prevent the physical aging
TABLE 3.5 Strategies to improve stability of coated dosage form under storage.
Additive
Content Aqueous Curing Storage conditions
Strategy Type (%) dispersion conditions and time Ref.

Curing n.a. n.a. Aquacoat ECD: 80°C/24 h 40°C/75% RH/3 weeks [96]
conditions HPMC 9:1 60°C/75% (open containers)
RH/24 h
Plasticizer Ibuprofen 40a Eudragit RS 30 D 40°C/24 h 23°C/0% RH/12 months [19, 97]
type and
content Methylparaben 15, 20 Eudragit RS 30 D 40°C/48 h 23°C/0% RH/6 months [97]

High Tg Methacrylic acid 16.7b Eudragit NE 60°C (5 days) [98]

polymers copolymer 30 D (drug release profiles stabilized in 4 h)
(Eudragit L 30 D
55)
Methacrylic acid 25b Eudragit RS 30 D – 40°C (4 days) [99]
copolymer
(Eudragit L 100-
55)
Hydrophilic PVA-PEG graft 5, 10, Aquacoat ECD 60°C/24 h 40°C/75% RH/6 months [100]
excipients copolymer and 15b 60°C/48 h RT/ambient RH/
(Kollicoat IR) 60°C/75% 6 months
RH/24 h (open containers)
60°C/75%
RH/48 h

Propylene glycol 5, 10, Aquacoat ECD 60°C/24 h RT/ambient RH/

alginate and 15b 60°C/48 h 6 months
60°C/75% (open containers)
RH/24 h
60°C/75%
RH/48 h
Methacrylic acid/ 35b Aquacoat ECD 60°C/48 h 25°C/60% RH/ [101]
ethyl Acrylate 24 months
copolymers (open containers)
(Kollicoat MAE 40°C/75% RH and 25°
30 DP) C/60% RH (closed
containers)
HEC 10a Eudragit RS 30 D 40°C/24 h 25°C/60% RH [15]
(4 months)
(open containers)
Albumin 10a Eudragit RS 40°C/12 h 40°C/75% RH/3 months [102]
30 D:Eudragit 25°C/60% RH/3 months
RL 30 D (95:5) (closed containers)

Gelatin 10a 40°C/75% RH/3 months

(open and closed
containers)
High solids Talc 200a Eudragit RS 60°C/24 h 40°C/75% RH/3 months [46]
content 30 D:Eudragit (closed containers)
RL 30 D (95:5)
a
w/w, based on the dry polymer.
b
w/w, based on total weight.
 3 Strategies to improve storage stability 47
from aqueous-based coatings are summarized in pellets were cured at 40°C for 24 h and stored at
Table 3.5 and discussed here. 23°C/0% RH. Drug release profiles were
unchanged for 12 months. In another study,
3.1 Optimization of curing conditions methylparaben was also used as a plasticizer
for Eudragit RS:RL 30 D (95:5) [97]. After a
Before subjecting coated dosage forms to curing step of 40°C during 48 h, drug release
long-term stability, it is important that curing is was stable up to 6 months if stored at
performed with optimized conditions (tempera- 23°C/0% RH.
ture/time/elevated humidity) for each formula-
tion, until no further changes on drug release are
observed, at this step. For example, pellets coated 3.3 Addition of high Tg polymers
with Aquacoat ECD: HPMC showed stable One way to stabilize drug release from
release profiles at ambient conditions if cured aqueous-based coatings is the addition of misci-
(prior to storage) at 60°C/2 h or 24 h. In contrast, ble high glass transition temperature polymers.
drug release strongly decreased when stored at The stabilization mechanism is thought to occur
40°C/75% RH, due to further gradual coales- by decreasing molecular mobility of the polymer
cence. Drug release was unchanged under stress film, by increasing the Tg of the polymer blend
conditions (40°C/75% RH), only if pellets were coating. The high Tg polymer acts as a frame-
cured at 80°C/24 h or 60°C/75% RH/24 h [96]. work that resists deformation and fusion of
polymer particles, preventing further coales-
3.2 Plasticizer type and content cence of the lower Tg aqueous polymer. Conse-
quently, film coating permeability and drug
Plasticizers are added to the aqueous disper- release do not change significantly on storage
sion to decrease the Tg and MFT, and to promote [98]. Drug release from pellets coated with the
better polymer particle coalescence. They blend Eudragit NE 30 D:Eudragit L 30 D 55 [5,
decrease the polymeric intermolecular attrac- 9] was stabilized after 4 h of storage at 60C and
tions and increase molecular mobility. This was unchanged up to 5 days under storage. Fur-
molecular mobility also accelerates the inter- thermore, the presence of Eudragit L 30 D 55 also
diffusion of polymer chains of adjacent fusing produced a less tacky film coating [98]. In
latex particles and eases the final phase of parti- another study, Eudragit RL 30 D was blended
cle coalescence and complete film formation. It with Eudragit L 100-55 in a ratio 3:1 and no
was shown that increasing the plasticizer aging effects were observed under storage at
amount in the formulation increased film forma- 40°C [99].
tion during coating process, leading to almost no
changes in drug release profiles during the cur-
3.4 Addition of hydrophilic excipients
ing step [17, 56]. However, high plasticizer
amount may reduce the Tg and MFT to very Another way to stabilize drug release from
low values, causing tackiness and agglomera- aqueous-based coatings is by addition of hydro-
tion, which are undesirable. philic excipients. It was suggested that the stabi-
Loss of plasticizers during coating process lization mechanism is by improvement of film
and storage have been reported [84, 104]. To formation during the coating process and curing
overcome this issue, ibuprofen was used as a [100] and/or by a blocking mechanism of coales-
nontraditional plasticizer (and in solid state) cence [15, 100, 101]. Stable release profiles were
for Eudragit RS 30 D coatings [19]. The coated achieved from pellets coated with the blends
48 3. Aqueous polymeric coatings: New opportunities in drug delivery systems

Aquacoat ECD: PVA-PEG graft copolymer (95:5, from Eudragit RS 30 D-coated pellets decreased
90:10, and 85:15) on storage at ambient condi- on storage at 25°C/60% RH. Cast films of the
tions and stress conditions up to 6 months, irre- same formulation showed an increase in tensile
spective of the curing conditions [100, 105].The strength and a decrease in water vapor perme-
authors suggested that the addition of the ability during 1 month of storage. After addition
hydrophilic excipient to Aquacoat ECD trapped of 10% HEC, drug release was stable for
water within the polymeric system during film 4 months in storage at 25°C/60% RH, and simi-
formation. The water is extremely important larly no changes were observed with the cast
for the capillarity forces to deform the polymer films. HEC formed an incompatible phase
particles and acts as a plasticizer for ethylcellu- around Eudragit RS 30 D and prevented further
lose, increasing the molecular mobility, which coalescence of acrylic polymer particles and
in turn leads to an easier coalescence. Further- chain interdiffusion.
more, the presence of the hydrophilic excipient Proteins were also used to stabilize drug
in the coating might hinder film formation dur- release from Eudragit RS 30 D:Eudragit RL
ing long-term storage. Another hydrophilic 30 D (95:5) [102]. Drug release was unchanged
excipient, propylene glycol alginate, was also for up to 3 months in storage at 40°C/75% RH
investigated in the same study. Drug release (hermetically sealed containers with desiccant),
from Aquacoat ECD: propylene glycol alginate when 10% albumin was added to the Eudragit
90:10 coatings was unchanged under storage dispersion. Prior to addition of the albumin,
at ambient conditions but decreased after Eudragit RS 30 D:Eudragit RL 30 D (95:5) had
6 months at 40°C/75%, due to further polymer to be acidified to pH 2.5, to avoid intermolecular
particle coalescence. It was suggested that the interaction between the positively charged qua-
continuous film formation was due to a nonop- ternary ammonium groups of the polymer and
timized coating process. In another study, the the negatively charged protein. In addition,
aqueous Kollicoat MAE 30 DP dispersion 10% gelatin in Eudragit RS 30 D:Eudragit RL
(enteric polymer methacrylic acid/ethyl acry- 30 D (95:5) coating prevented aging effects in
late copolymer) was added to Aquacoat ECD open or closed containers at 40°C/75% RH for
in order to stabilize drug release from coated 3 months.
pellets. Drug release from Aquacoat ECD: Kolli-
coat MAE 30 DP (65:35)-coated pellets was sta-
3.5 High solids content
ble for up to 24 months in storage at ambient
conditions. The results were attributed to inhibi- Increasing the amount of talc was another
tion of film formation during storage at this strategy to improve storage stability from
condition. However, drug release profiles con- Eudragit RS 30 D: Eudragit RL 30 D (95:5)-coated
tinuously decreased under storage at 40°C/ pellets. Talc is often used as an antitacking agent
75% RH. When coated pellets were stored in to avoid agglomeration during the coating pro-
closed containers at the same storage conditions, cess and storage. However, high concentration
drug release profiles did not change for (200%) of talc was also shown to prevent aging
24 months [101]. It was reported that humidity of the coated pellets during curing and storage
was the main driver for the further coalescence [46]. It was reported that pellets coated with
on storage. the acrylic dispersion containing 200% talc and
Hydroxyethylcellulose (HEC) has been 10% or 20% TEC showed good mechanical
shown to stabilize drug release from pellets strength and stable drug release profiles during
coated with Eudragit RS 30 D [15]. Drug release storage at 40°C/75% RH.
 4 Solidification of self-nanoemulsifying drug delivery systems by fluid bed coating 49

4 Solidification of self-nanoemulsifying SNEDDS solidification into SL-SNEP could not

drug delivery systems by fluid bed coating stop CN degradation within the system, and sig-
nificant drug degradation was observed in both
Self-nanoemulsifying drug delivery systems accelerated and long-term storage conditions
(SNEDDS) represent one of the most promising [114]. This was attributed to the following rea-
techniques in terms of improving the in vivo sons: (1) in CN SL-SNEP, the drug was still in
performance of orally administered poorly direct contact with the solidified SNEDDS (Fig.
water-soluble drugs. However, liquid SNEDDS 3.6) and (2) chemical reactions (including drug
experience several limitations such as possibility degradation) would also occur in solid state,
of drug precipitation, incompatibility with but at slower rates [115]. Therefore, to eradicate
capsule shell, risk of formulation leakage, and the problem, the drug has to be isolated from
rancidity [106–109]. Furthermore, some drug SNEDDS excipients during and after
moieties may chemically degrade in the pres- manufacturing. To fulfill such requirements,
ence of SNEDDS excipients such as lipids and an innovative design was implemented to pre-
related excipients [109]. Recently, solid SNEDDS pare the multilayer self-nanoemulsifying pellets
have been explored as more effective alterna- (ML-SNEP; see Fig. 3.7) [116]. The ML-SNEP
tives to the conventional liquid SNEDDS [110]. invention was recently patented based on its
Solid SNEDDS could retain all the benefits of unique design that involved multiple coating
liquid SNEDDS (such as enhanced aqueous sol- layers where the drug layer was completely iso-
ubility and bioavailability) along with those of lated from the SNEDDS layer using a protective
solid dosage forms (such as better patient com- layer [117]. Furthermore, moisture sealing and
pliance and higher chemical and physical stabil- anti-adhesion layers were applied to protect
ity) [111]. Among various solid SNEDDS forms, against drug hydrolysis and pellet adherence
self-nanoemulsifying pellets offer numerous upon storage, respectively.
desirable advantages such as reduction of This invention is the first of its kind in the
intra- and inter-subject variability, improvement field of self-emulsifying formulations because
of drug efficacy, and safety and flexibility in it involves preparation of drug-free SNEDDS
dose dividing [107, 112]. which is being completely isolated from the
Recently, single-layer self-nanoemulsifying drug-layer to enhance drug stability and mini-
pellets (SL-SNEP) of cinnarizine (CN), a poorly mize chemical degradation during storage. On
water-soluble drug with diminished chemical the other hand, upon oral administration and
stability in both aqueous- and lipid-based sys- pellet exposure to aqueous media (Fig. 3.7),
tems, were efficiently prepared using fluid bed the following six main steps were hypothesized
coating [113]. The process involved spraying to take place as follows:
the aqueous dispersion of drug-loaded liquid
SNEDDS (with other coating excipients) over (1) water penetration into the anti-adhesion
nonpareil sugar spheres (Fig. 3.6). Upon oral layer;
administration, SL-SNEP would quickly self- (2) disintegration of the moisture sealing layer;
emulsify to produce numerous drug-loaded (3) disintegration of the drug layer and release
nanoemulsion droplets (Fig. 3.6). The produced of the active pharmaceutical ingredient;
SL-SNEP retained the superior dissolution (4) disintegration of the protective layer;
enhancement of liquid SNEDDS and maintained (5) self-emulsification of the drug-free SNEDDS
>85% CN in solution, even at pH 6.8. However, layer leading to the formation of drug-free
a follow-up stability study revealed that nanoemulsion; and simultaneously
FIG. 3.6 Schematic diagram and mechanism of action of single-layer self-nanoemulsifying pellets (SL-SNEP), upon oral
administration. SNEDDS: self-nanoemulsifying drug delivery systems. Adapted with modification from Shahba AA, Alanazi
FK, Abdel-Rahman SI. Stabilization benefits of single and multi-layer self-nanoemulsifying pellets: a poorly-water soluble model drug
with hydrolytic susceptibility. PLoS One 2018;13(7):e0198469.

FIG. 3.7 Schematic diagram and mechanism of action of multi-layer self-nanoemulsifying pellets (ML-SNEP), upon oral
administration. SNEDDS: self-nanoemulsifying drug delivery systems. Adapted with modification from Shahba A, Alanazi F,
Ahmed A, Multi-layer self-nanoemulsifying pellets for dual enhancement of drug solubility and stability. Saudi patent no# 6357. Kingdom
of Saudi Arabia; 2019.
 5 Conclusion 51
(6) the active pharmaceutical ingredient would incorporate a wide range of drugs with various
partition inside the formed nanoemulsion solubilization and stabilization requirements.
droplets, leading to enhanced drug
dissolution and bioavailability [117].
5 Conclusion
To validate the hypothesis, a proof-of-concept
study was conducted to investigate the ability of The advantages and success of aqueous-
CN to migrate spontaneously into nanoemul- based coatings are well documented in the liter-
sion droplets produced from the isolated drug- ature. One of the major challenges is the storage
free SNEDDS [116]. The study proved that the stability of the aqueous-based coated dosage
isolation between CN and self-nanoemulsifying forms. Decreased drug release profiles due to
layer did not adversely affect drug dissolution. continuous film formation are often reported.
CN was able to partition spontaneously into The continuous film formation or physical
the nanoemulsion droplets produced from aging of aqueous-based coatings is highly
drug-free SNEDDS. ML-SNEP showed superior dependent on coating formulation, coating con-
dissolution compared to the marketed tablet ditions, and curing conditions. It is a sequential
Stugeron® at pH 1.2 and 6.8. Particularly, on and interconnected process that must be evalu-
shifting to pH 6.8, ML-SNEP maintained >84% ated carefully. Despite the fact that there are
CN in solution while Stugeron® showed signif- standard and recommended procedures, each
icant CN precipitation, leaving only 7% CN in application of aqueous polymeric dispersion is
solution. On the stability prospect, the somehow unequaled. For instance, after any
moisture-sealed ML-SNEP showed significant modification in the coating formulation, the
enhancement of CN chemical stability com- coating and curing conditions need to be
pared to liquid SNEDDS and SL-SNEP. In par- adjusted to reduce the aging effects as much as
ticular, ML-SNEP coated with Kollicoat possible. If this adjustment is not performed,
Smartseal 30D showed robust stability and misinterpretation of the results can lead to con-
maintained 95% within all the storage condi- fusing outcomes. In addition, the curing condi-
tions. The observed stability enhancement is tions must guarantee completeness of film
attributed to the complete isolation between formation (no further change in dissolution pro-
CN and SNEDDS layer as well as the effective files) prior to long-term storage.
moisture protection provided by Kollicoat Another problem faced by the formulator sci-
Smartseal 30D. Hence the degradation problem entist is the long time of the storage stability
could be eradicated. In addition, the incorpora- tests. Consequently, it is crucial to identify pos-
tion of silicon dioxide, as an anti-adherent, had sible aging effects and determine the underlying
an important role in the inhibition of pellet mechanism as early as possible. To understand
agglomeration upon storage. better these complex mechanisms and possible
Accordingly, ML-SNEP played a vital role in interactions, coupled techniques are required
the stabilization of CN within lipid-based for- to investigate the physical changes in the
mulations and upon exposure to humidity. This aqueous-based coatings. Besides drug release
innovative design offers several advantages studies, thermal analysis, mechanical proper-
such as enhancement of drug dissolution by ties, film permeability, and free volume mea-
SNEDDS technology, dual protection of unsta- surements may help to characterize the
ble drugs against lipid-based excipients and physical aging further.
atmospheric moisture, enhancing the product Recently, several methods have been success-
physical stability along with flexibility to fully carried out to prevent aging, and stable
52 3. Aqueous polymeric coatings: New opportunities in drug delivery systems

drug release profiles were achieved during stor- [10] Siepmann F, Siepmann J, Walther M, MacRae R,
age at different conditions. Moreover, it is Bodmeier R. Aqueous HPMCAS coatings: effects of for-
mulation and processing parameters on drug release
important to consider the correct or appropriate and mass transport mechanisms. Eur J Pharm Biopharm
packaging for the coated dosage form during 2006;63(3):262–9.
storage. [11] Thoma K, Bechtold K. Influence of aqueous coatings on
Fluid bed coating was recently introduced as the stability of enteric coated pellets and tablets. Eur
an innovative application of aqueous-based J Pharm Biopharm 1999;47(1):39–50.
[12] Carlin B, Li J-X, Felton LA. Pseudolatex dispersions for
coating to solidify SNEDDS into free-flowing controlled drug delivery. In: James W, McGinity LAF,
pellets. This technique showed great potential editors. Aqueous polymeric coatings for pharmaceuti-
to achieve enhanced solubilization and stabiliza- cal dosage forms. 3rd ed. New York: Informa Health-
tion of poorly soluble drugs. care; 2008. p. 1–46.
[13] Lin F, Meier DJ. A study of latex film formation by
atomic force microscopy. 1. A comparison of wet and
dry conditions. Langmuir 1995;11(7):2726–33.
[14] Keddie JL. Film formation of latex. Mater Sci Eng R: Rep
References 1997;21(3):101–70.
[1] Skalsky B, Petereit H-U. Chemistry and application [15] Zheng W, Sauer D, McGinity JW. Influence of hydro-
properties of polymethacrylate systems. In: - xyethylcellulose on the drug release properties of the-
McGinity JW, Felton LA, editors. Aqueous polymeric ophylline pellets coated with Eudragit® RS 30 D. Eur
coatings for pharmaceutical dosage forms. 3rd ed. J Pharm Biopharm 2005;59(1):147–54.
New York: Informa Healthcare; 2008. p. 237–77. [16] Williams Iii RO, Liu J. Influence of processing and cur-
[2] Miller DA, McGinity JW. Aqueous polymeric film coat- ing conditions on beads coated with an aqueous disper-
ing. In: Augsburger LL, Hoag SW, editors. Pharmaceu- sion of cellulose acetate phthalate. Eur J Pharm
tical dosage forms: tablets. New York: Informa Biopharm 2000;49(3):243–52.
Healthcare; 2008. p. 399–438. [17] Amighi K, Moes A. Influence of plasticizer concentra-
[3] Kollicoat® protect technical information. Limburgerhof: tion and storage conditions on the drug release rate
BASF; 2010. from Eudragit RS 30D film-coated sustained-release
[4] Gupta VK, Beckert TE, Deusch NJ, Hariharan M, theophylline pellets. Eur J Pharm Biopharm 1996;42
Price JC. Investigation of potential ionic interactions (1):29–35.
between anionic and cationic polymethacrylates of mul- [18] Okhamafe AO, York P. Studies of interaction phenom-
tiple coatings of novel colonic delivery system. Drug ena in aqueous-based film coatings containing soluble
Dev Ind Pharm 2002;28(2):207–15. additives using thermal analysis techniques. J Pharm
[5] Petereit H-U, Weisbrod W. Formulation and process Sci 1988;77(5):438–43.
considerations affecting the stability of solid dosage [19] Wu C, McGinity JW. Influence of ibuprofen as a solid-
forms formulated with methacrylate copolymers. Eur state plasticizer in Eudragit RS 30 D on the physico-
J Pharm Biopharm 1999;47(1):15–25. chemical properties of coated beads. AAPS PharmSci-
[6] Lecomte F, Siepmann J, Walther M, MacRae RJ, Tech 2001;2(4):24.
Bodmeier R. Polymer blends used for the aqueous coat- [20] Felton LA, McGinity JW. Influence of plasticizers on the
ing of solid dosage forms: importance of the type of adhesive properties of an acrylic resin copolymer to
plasticizer. J Control Release 2004;99(1):1–13. hydrophilic and hydrophobic tablet compacts. Int
[7] Bruce LD, Petereit H-U, Beckert T, McGinity JW. Prop- J Pharm 1997;154(2):167–78.
erties of enteric coated sodium valproate pellets. Int [21] Gutierrez-rocca JC, McGinity JW. Influence of aging on
J Pharm 2003;264(1–2):85–96. the physical-mechanical properties of acrylic resin films
[8] Wesseling M, Bodmeier R. Drug release from beads cast from aqueous dispersions and organic solutions.
coated with an aqueous colloidal ethylcellulose disper- Drug Dev Ind Pharm 1993;19(3):315–32.
sion, Aquacoat®, or an organic ethylcellulose solution. [22] Banker GS. Film coating theory and practice. J Pharm
Eur J Pharm Biopharm 1999;47(1):33–8. Sci 1966;55(1):81–9.
[9] Liu J, Williams RO. Long-term stability of heat- [23] Pearnchob N. Evaluation of new film coating pro-
humidity cured cellulose acetate phthalate coated cesses and materials. Berlin: Freie Universitaet Berlin;
beads. Eur J Pharm Biopharm 2002;53(2):167–73. 2002.
 References 53
[24] Frohoff-H€ ulsmann MA, Lippold BC, McGinity JW. [41] Wei H, Li-Fang F, Bai X, Chun-Lei L, Qing D, Yong-
Aqueous ethyl cellulose dispersion containing plasti- Zhen C, et al. An investigation into the characteristics
cizers of different water solubility and hydroxypropyl of chitosan/Kollicoat SR30D free films for colonic drug
methyl-cellulose as coating material for diffusion pel- delivery. Eur J Pharm Biopharm 2009;72(1):266–74.
lets. II. Properties of sprayed films. Eur J Pharm Bio- [42] Crawford RR, Esmerian OK. Effect of plasticizers on
pharm 1999;48(1):67–75. some physical properties of cellulose acetate phthalate
[25] Felton LA, Shah NH, Zhang G, Infeld MH, Malick AW, films. J Pharm Sci 1971;60(2):312–4.
McGinity JW. Physical-mechanical properties of film- [43] Bodmeier R, Paeratakul O. Process and formulation var-
coated soft gelatin capsules. Int J Pharm 1996;127 iables affecting the drug release from chlorpheniramine
(2):203–11. maleate-loaded beads coated with commercial and self-
[26] Gutierrez-Rocca J, McGinity JW. Influence of water sol- prepared aqueous ethyl cellulose pseudolatexes. Int
uble and insoluble plasticizers on the physical and J Pharm 1991;70(1–2):59–68.
mechanical properties of acrylic resin copolymers. Int [44] Johnson K, Hathaway R, Leung P, Franz R. Effect of tria-
J Pharm 1994;103(3):293–301. cetin and polyethylene glycol 400 on some physical
[27] Wang C-C, Zhang G, Shah NH, Infeld MH, Waseem properties of hydroxypropyl methylcellulose free films.
Malick A, JW MG. Influence of plasticizers on the Int J Pharm 1991;73(3):197–208.
mechanical properties of pellets containing Eudragit® [45] Rohera B, Parikh N. Influence of plasticizer type and
RS 30 D. Int J Pharm 1997;152(2):153–63. coat level on Surelease® film properties. Pharm Dev
[28] Rowe RC, Sheskey PJ, Quinn ME. Handbook of phar- Technol 2002;7(4):407.
maceutical excipients. 6th ed. Pharmaceutical Press [46] Maejima T, McGinity J. Influence of film additives on
and American Pharmacists Association; 2009. stabilizing drug release rates from pellets coated with
[29] Mark JE, Zeng W, Du Y, Xue Y, Frisch H. Solubility acrylic polymers. Pharm Dev Technol 2001;6(2):211.
parameters. In: Physical properties of polymers hand- [47] Bechard SR, Quraishi O, Kwong E. Film coating: effect
book. Springer New York; 2007. p. 289–303. of titanium dioxide concentration and film thickness
[30] Aquacoat ECD product brochure. Philadelphia: FMC on the photostability of nifedipine. Int J Pharm
BioPolymer; 1996. 1992;87(1–3):133–9.
[31] Lippold BC, Lippold BH, Sutter BK, Gunder W. Proper- [48] Rowe RC. Modulus enhancement in pigmented tablet
ties of aqueous, plastic Izer-containing ethyl cellulose film coating formulations. Int J Pharm 1983;14(2–3):355–9.
dispersions and prepared films in respect to the produc- [49] Felton LA, McGinity JW. Influence of insoluble excipi-
tion of oral extended release formulations. Drug Dev ents on film coating systems. Drug Dev Ind Pharm
Ind Pharm 1990;16(11):1725–47. 2002;28(3):225–43.
[32] Surelease product information. West Point: Colorcon; [50] Frohoff-H€ ulsmann MA, Schmitz A, Lippold BC.
2006. Aqueous ethyl cellulose dispersions containing plasti-
[33] Porter SC. Controlled-release film coatings based on cizers of different water solubility and hydroxypropyl
ethylcellulose. Drug Dev Ind Pharm 1989;15 methylcellulose as coating material for diffusion pellets.
(10):1495–521. I. Drug release rates from coated pellets. Int J Pharm
[34] Aquacoat CPD product brochure. Philadelphia: FMC 1999;177(1):69–82.
BioPolymer; 1996. [51] Wong D, Bodmeier R. The impact of the use of floccu-
[35] AQOAT product brochure. Shin-Etsu: Tokyo; 2005. lated colloidal dispersions on the drug release from
[36] Specifications and test methods for EUDRAGIT® RL drug-containing films and coated tablets. Pharm Res
30 D and EUDRAGIT® RS 30 D. Darmstadt: EVONIK 1994;11:s-185.
R€ohm GmbH; 2007. [52] Siepmann F, Muschert S, Zach S, Leclercq B, Carlin B,
[37] Specifications and test methods for EUDRAGIT® NE Siepmann J. Carrageenan as an efficient drug release
30 D. Darmstadt: Evonik R€ ohm GmbH; 2007. modifier for ethylcellulose-coated pharmaceutical dos-
[38] Specifications and test methods for EUDRAGIT® NM age forms. Biomacromolecules 2007;8(12):3984–91.
30 D. Darmstadt: EVONIK R€ ohm GmbH; 2007. [53] Dashevsky A, Ahmed AR, Mota J, Irfan M, Kolter K,
[39] Specifications and test methods for EUDRAGIT® Bodmeier RA. Effect of water-soluble polymers on the
L 30 D-55. Darmstadt: EVONIK R€ ohm GmbH; 2007. physical stability of aqueous polymeric dispersions
[40] Kossena G, Charman W, Boyd B, Porter C. A novel cubic and their implications on the drug release from coated
phase of medium chain lipid origin for the delivery of pellets. Drug Dev Ind Pharm 2010;36(2):152–60.
poorly water soluble drugs. J Control Release 2004;99 [54] Siepmann F, Hoffmann A, Leclercq B, Carlin B,
(2):217–29. Siepmann J. How to adjust desired drug release patterns
54 3. Aqueous polymeric coatings: New opportunities in drug delivery systems

from ethylcellulose-coated dosage forms. J Control [68] Hutchings D, Kuzmak B, Sakr A. Processing consider-
Release 2007;119(2):182–9. ations for an EC latex coating system: influence of cur-
[55] Gilligan CA, Li Wan Po A. Factors affecting drug release ing time and temperature. Pharm Res 1994;11
from a pellet system coated with an aqueous colloidal (10):1474–8.
dispersion. Int J Pharm 1991;73(1):51–68. [69] Hutchings D, Clarson S, Sakr A. Studies of the mechan-
[56] Bodmeier R, Paeratakul O. The effect of curing on drug ical properties of free films prepared using an ethylcel-
release and morphological properties of ethylcellulose lulose pseudolatex coating system. Int J Pharm 1994;104
Pseudolatex-coated beads. Drug Dev Ind Pharm (3):203–13.
1994;20(9):1517–33. [70] Chowhan ZT, Amaro AA, Chi L-H. Comparative eval-
[57] Harris M, Ghebre-Sellassie I, Nesbitt R. Water based uations of aqueous film coated tablet formulations by
coating process for sustained release. Pharm Technol high humidity aging. Drug Dev Ind Pharm 1982;8
1986;10(9):102–7. (5):713–37.
[58] Dashevsky A, Wagner K, Kolter K, Bodmeier R. Physi- [71] McConnell E, Tutas J, Mohamed M, Banning D, Basit A.
cochemical and release properties of pellets coated with Colonic drug delivery using amylose films: the role of
Kollicoat® SR 30 D, a new aqueous polyvinyl acetate aqueous ethylcellulose dispersions in controlling drug
dispersion for extended release. Int J Pharm 2005;290 release. Cellulose 2007;14(1):25–34.
(1–2):15–23. [72] Lorck CA, Grunenberg PC, J€ unger H, Laicher A. Influ-
[59] Guo J-H. Aging processes in pharmaceutical polymers. ence of process parameters on sustained-release the-
Pharm Sci Technol Today 1999;2(12):478–83. ophylline pellets coated with aqueous polymer
[60] Kucera SA, Felton LA, McGinity JW. Physical aging of dispersions and organic solvent-based polymer solu-
polymers and its effect on the stability of solid oral dos- tions. Eur J Pharm Biopharm 1997;43(2):149–57.
age forms. In: Felton LA, McGinity JW, editors. Aque- [73] Surelease. The influence of post coating thermal treat-
ous polymeric coatings for pharmaceutical dosage ment on film properties and drug release from ethylcel-
forms. 3rd ed. New York: Informa Healthcare; 2008. lulose barrier membrane coating systems. Colorcon;
p. 445–74. 2009.
[61] Greiner R, Schwarzl FR. Volume relaxation and physi- [74] Missaghi S, Fegely KA, Rajabi-Siahboomi AR. Investiga-
cal aging of amorphous polymers. I. Theory of volume tion of venlafaxine HCl release from extruded and
relaxation after single temperature jumps. Colloid spheronized beads coated with ethylcellulose using
Polym Sci 1989;267(1):39–47. organic or aqueous coating systems. In: Controlled
[62] Priestley RD, Ellison CJ, Broadbelt LJ, Torkelson JM. release society annual meeting; 2008.
Structural relaxation of polymer glasses at surfaces, [75] Sheen P-C, Sabol PJ, Alcorn GJ, Feld KM. Aquesons
interfaces, and in between. Science 2005;309 films coating stuied of sustabined release niciotine acid
(5733):456–9. fellets: an in-vitro evaluation. Drug Dev Ind Pharm
[63] Guo J-H, Robertson RE, Amidon GL. Influence of phys- 1992;18(8):851–60.
ical aging on mechanical properties of polymer free [76] Rekhi GS, Porter SC, Jambhekar SS. Factors affecting the
films: the prediction of long-term aging effects on the release of propranolol hydrochloride from beads coated
water permeability and dissolution rate of polymer with aqueous polymeric dispersions. Drug Dev Ind
film-coated tablets. Pharm Res 1991;8(12):1500–4. Pharm 1995;21(6):709–29.
[64] Bodmeier R, Paeratakul O. Plasticizer uptake by aque- [77] Duerig T, Harcom WW, Kinsey BR, Tewari D,
ous colloidal polymer dispersions used for the coating Lewis RK. Fundamental studies on modified release
of solid dosage forms. Int J Pharm 1997;152(1):17–26. pellets coated with ethylcellulose. Aqualon: Wilming-
[65] Siepmann J, Paeratakul O, Bodmeier R. Modeling plas- ton; 2005.
ticizer uptake in aqueous polymer dispersions. Int [78] Williams RO, Liu J. The influence of plasticizer on heat-
J Pharm 1998;165(2):191–200. humidity curing of cellulose acetate phthalate coated
[66] Wesseling M, Bodmeier R. Influence of plasticization beads. Pharm Dev Technol 2001;6(4):607–19.
time, curing conditions, storage time, and core proper- [79] Obara S, McGinity JW. Influence of processing variables
ties on the drug release from aquacoat-coated pellets. on the properties of free films prepared from aqueous
Pharm Dev Technol 2001;6(3):325–31. polymeric dispersions by a spray technique. Int
[67] Yang QW, Flament MP, Siepmann F, Busignies V, J Pharm 1995;126(1–2):1–10.
Leclerc B, Herry C, et al. Curing of aqueous polymeric [80] Meier C. Physico chemical properties of anionic
film coatings: importance of the coating level and EUDRAGIT® polymers and their influences on film
type of plasticizer. Eur J Pharm Biopharm 2010;74 properties. In: 4th international GI-targeting worksho-
(2):362–70. pEvonik R€ ohm GmbH: Darmstadt; 2008.
 References 55
[81] Wesseling M, Kuppler F, Bodmeier R. Tackiness of [94] Shao Z, Morales L, Diaz S, Muhammad N. Drug release
acrylic and cellulosic polymer films used in the coating from kollicoat SR 30D-coated nonpareil beads: evalua-
of solid dosage forms. Eur J Pharm Biopharm 1999;47 tion of coating level, plasticizer type, and curing condi-
(1):73–8. tion. AAPS PharmSciTech 2002;3(2):87–96.
[82] Bhattacharjya S, Wurster D. Investigation of the drug [95] Irfan M, Ahmed AR, Dashevsky A, Kolter K,
release and surface morphological properties of film- Bodmeier R. Formulation parameters affecting the
coated pellets, and physical, thermal and mechanical adhesion of Kollicoat® SR 30 D coatings to the drug
properties of free films as a function of various curing layer in coated pellets and their implications on curing
conditions. AAPS PharmSciTech 2008;9(2):449–57. phenomena. Copenhagen, Denmark: Controlled
[83] Hamed E, Sakr A. Effect of curing conditions and plas- Release Society; 2009.
ticizer level on the release of highly lipophilic drug from [96] K€ orber M, Hoffart V, Walther M, Macrae RJ,
coated multiparticulate drug delivery system. Pharm Bodmeier R. Effect of unconventional curing conditions
Dev Technol 2003;8(4):397–407. and storage on pellets coated with Aquacoat ECD. Drug
[84] Noemi CG, Kalidas K, Kenneth RM. Investigation of Dev Ind Pharm 2010;36(2):190–9.
film curing stages by dielectric analysis and physical [97] Wu C, McGinity JW. Influence of relative humidity
characterization. J Pharm Sci 1997;86(3):329–34. on the mechanical and drug release properties of
[85] Wurster DE, Bhattacharjya S, Flanagan DR. Effect of theophylline pellets coated with an acrylic polymer
curing on water diffusivities in acrylate free films as containing methylparaben as a non-traditional plasti-
measured via a sorption technique. AAPS PharmSci- cizer. Eur J Pharm Biopharm 2000;50(2):277–84.
Tech 2007;8(3). [98] Zheng W, McGinity JW. Influence of Eudragit® NE 30 D
[86] Nimkulrat S, Suchiva K, Phinyocheep P, blended with Eudragit® L 30 D-55 on the release of
Puttipipatkhachorn S. Influence of selected surfactants phenylpropanolamine hydrochloride from coated pel-
on the tackiness of acrylic polymer films. Int J Pharm lets. Drug Dev Ind Pharm 2003;29(3):357.
2004;287(1–2):27–37. [99] Wu C, McGinity J. Influence of an enteric polymer on
[87] Lin A, Muhammad N, Pope D, Augsburger L. A study drug release rates of theophylline from pellets coated
of the effects of curing and storage conditions on con- with Eudragit® RS 30D. Pharm Dev Technol 2003;8
trolled release diphenhydramine HCl pellets coated with (1):103.
Eudragit® NE30D. Pharm Dev Technol 2003;8(3):277. [100] Siepmann F, Muschert S, Leclercq B, Carlin B,
[88] Mota J. Matrix- and reservoir-type oral multiparticulate Siepmann J. How to improve the storage stability of
drug delivery systems. Berlin: Freien Universit€at Berlin; aqueous polymeric film coatings. J Control Release
2010. 2008;126(1):26–33.
[89] G€opferich A, Lee G. The influence of endogenous sur- [101] Kranz H, Gutsche S. Evaluation of the drug release pat-
factant on the structure and drug-release properties of terns and long term stability of aqueous and organic
Eudragit NE30D-matrices. J Control Release 1992;18 coated pellets by using blends of enteric and gastroin-
(2):133–44. testinal insoluble polymers. Int J Pharm 2009;380
[90] Lin AY, Muhammad NA, Pope D, Augsburger LL. (1–2):112–9.
Study of crystallization of endogenous surfactant in [102] Kucera SA, McGinity JW, Weijia Z, Shah NH,
Eudragit NE30D-free films and its influence on drug- Malick AW, Infeld MH. Use of proteins to minimize
release properties of controlled-release diphenhydra- the physical aging of EUDRAGIT® sustained release
mine HCl pellets coated with Eudragit NE30D. AAPS films. Drug Dev Ind Pharm 2007;33(7):717–26.
PharmSci 2001;3(2). [103] Ensslin S, Moll K, Haefele-Racin T, M€ader K. Safety
[91] Bajdik J, Pintye-Hódi K, Regdon G, Fazekas P, Szabó- and robustness of coated pellets: self-healing film
Revesz P, Erős I. The effect of storage on the behaviour properties and storage stability. Pharm Res 2009;26
of Eudragit NE free film. J Therm Anal Calorim 2003;73 (6):1534–43.
(2):607–13. [104] Skultety PF, Sims SM. Evaluation of the loss of propyl-
[92] Zelkó R, Orbán Á, S€ uvegh K. Tracking of the physical ene glycol during aqueous film coating. Drug Dev Ind
ageing of amorphous pharmaceutical polymeric excip- Pharm 1987;13(12):2209–19.
ients by positron annihilation spectroscopy. J Pharm [105] Muschert S, Siepmann F, Cuppok Y, Leclercq B,
Biomed Anal 2006;40(2):249–54. Carlin B, Siepmann J. Improved long term stability
[93] Felton L, Baca M. Influence of curing on the adhesive of aqueous ethylcellulose film coatings: importance
and thermomechanical properties of an applied acrylic of the type of drug and starter core. Int J Pharm
polymer. Pharm Dev Technol 2001;6(1):53. 2009;368(1–2):138–45.
56 3. Aqueous polymeric coatings: New opportunities in drug delivery systems

[106] Lei Y, Lu Y, Qi J, Nie S, Hu F, Pan W, et al. Solid self- with special emphasis on self-emulsifying systems.
nanoemulsifying cyclosporin a pellets prepared by ISRN Pharm 2013;2013:16.
fluid-bed coating: preparation, characterization and [112] Abdalla A, M€ader K. Preparation and characterization
in vitro redispersibility. Int J Nanomed 2011;6: of a self-emulsifying pellet formulation. Eur J Pharm
795–805. Biopharm 2007;66(2):220–6.
[107] Wang Z, Sun J, Wang Y, Liu X, Liu Y, Fu Q, et al. Solid [113] Shahba AA, Ahmed AR, Mohsin K, Abdel-Rahman SI,
self-emulsifying nitrendipine pellets: preparation and Alanazi FK. Solidification of cinnarizine self-
in vitro/in vivo evaluation. Int J Pharm 2010;383 nanoemulsifying drug delivery systems by fluid bed
(1–2):1–6. coating: optimization of the process and formulation
[108] Shahba AA, Alanazi FK, Mohsin K, Abdel-Hamid M. variables. Pharmazie 2017;72(3):143–51.
Stability assessment of cinnarizine in self-emulsifying [114] Shahba AA, Alanazi FK, Abdel-Rahman SI. Stabilization
drug delivery systems. Latin Am J Pharm 2012;31 benefits of single and multi-layer self-nanoemulsifying
(4):549–54. pellets: a poorly-water soluble model drug with hydro-
[109] Gumaste SG, Dalrymple DM, Serajuddin ATM. Devel- lytic susceptibility. PLoS One 2018;13(7).
opment of solid SEDDS. V. Compaction and drug [115] Byrn SR, Xu W, Newman AW. Chemical reactivity in
release properties of tablets prepared by adsorbing solid-state pharmaceuticals: formulation implications.
lipid-based formulations onto Neusilin® US2. Pharm Adv Drug Deliv Rev 2001;48(1):115–36.
Res 2013;30(12):3186–99. [116] Shahba AA-W, Ahmed AR, Alanazi FK, Mohsin K,
[110] Bansal T, Mustafa G, Khan ZI, Ahmad FJ, Khar RK, Abdel-Rahman SI. Multi-layer self-nanoemulsifying
Talegaonkar S. Solid self-nanoemulsifying delivery pellets: an innovative drug delivery system for the
systems as a platform technology for formulation of poorly water-soluble drug Cinnarizine. AAPS
poorly soluble drugs. Crit Rev Ther Drug Carrier Syst PharmSciTech 2018;
2008;25(1):63–116. [117] Shahba A, Alanazi F, Ahmed A. Multi-layer self-
[111] Gupta S, Kesarla R, Omri A. Formulation strategies to nanoemulsifying pellets for dual enhancement of
improve the bioavailability of poorly absorbed drugs drug solubility and stability. Saudi patent no# 6357.
Kingdom of Saudi Arabia. 2019.