Extended release tablet with active coating

Abstract:
Oral modified-release multiparticulate dosage forms, which are also referred to as oral
multiple-unit particulate systems, are becoming increasingly popular for oral drug delivery
applications. The compaction of polymer-coated multiparticulates into tablets to produce a
sustained-release dosage form is preferred over hard gelatin capsules. Moreover,
multiparticulate tablets are a promising solution to chronic conditions, patients’ adherence,
and swallowing difficulties if incorporated into orodispersible matrices. Nonetheless, the
compaction of multiparticulates often damages the functional polymer coat, which results
in a rapid release of the drug substance and the subsequent loss of sustained-release
properties. This review brings to the forefront key formulation variables that are likely to
influence the compaction of coated multiparticulates into sustained-release tablets. It
focusses on the tabletting of coated drug-loaded pellets, microparticles, and nanoparticles
with a designated section on each. Furthermore, it explores the various approaches that are
used to evaluate the compaction behaviour of particulate systems.

Keywords: multiparticulate; pellets; nano/microparticles; compaction; polymers

1. Introduction
On the other hand, multi-dose therapy is feasible for short-term conditions such as
colds and flus, migraines, and neuralgia, in which treatment may last a few days.[1]
However, for long-term chronic conditions where treatment may be for several months or
even years, multiple daily dosing is undesirable and inconvenient for the patient, and can
result in missed doses or made-up doses. However, it is not just a financial burden; patients
who choose to ignore medical advice given to them or forget to take their medication
(which is more common with geriatric patients) risk worsening their condition or in some
cases reducing their chances of survival.[2] It is estimated that around 125,000 deaths are
caused every year as a direct result of nonadherence to medication. Martin et al. conducted a
separate study; patients suffering from hypertension were placed on a thrice daily dosing
regimen and a once-daily regimen. Patient adherence to the thrice-daily schedule was 59%
whereas for the once-daily regimen, around 84% of patients complied with the medication
schedule .
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Oral modified-release dosage forms are becoming increasingly more popular and effective
alternatives to IR solid oral dosage forms. [3].
Modified-release dosage formulations are classified into two distinct categories. They
can be administered orally in single-unit dosage forms (SUDF) or multiple-unit dosage
forms (MUDF), which are also referred to as multiparticulate dosage forms.[3]. To act as an
effective sustained-release dosage form[4].
There is now growing interest in the compaction of coated multiparticulates into
sustained-release tablets as opposed to hard gelatin capsules. Tablets are much easier and
cheaper to produce with a higher production speed. There has been an emphasis on the
development of tabletting technology as one of the most common solid oral dosage forms.
[5]. Adding multiple-unit dosage forms into an orodispersible matrix can offer far more
advantages as a sustained release oral formulation, especially to dysphagia patients[6].
Upon the oral administration of a sustained release tablet consisting of coated
multiparticulates, the rapid disintegration of the tablet matrix is expected, and this should
release the individually coated particulates, which may be pellets, microcapsules, or
nanocapsules. The small size of such multiparticulates would enable better spreading and
distribution over a large surface area along the gastrointestinal tract.[6] This prevents high
local drug concentrations and thus a reduction in potential local irritation (especially with
weak acids). [7]This system reduces the risk of adverse side effects and the toxicity that is
associated with ‘dose dumping’, Nonetheless, the compression of the particulate systems
during tablet manufacturing might be challenging. The aim of the current review is to
critically appraise the previous studies that looked at the compression of particulate systems
into multiple-unit tablets and provide an insight into future developments in this field. Three
different types of polymer-coated particulates—pellets, microparticles, and nanoparticles—
will be surveyed. Significant formulation parameters are discussed, including the type of
coating polymer used (e.g., cellulosic or acrylic), the quantity of polymer coating used, the
effect of plasticisers and excipients in addition to other process variables such as the effect
of compression force on protecting the integrity of the polymer coat. The review also briefly
summarised the various compaction theories that can be used to understand the compaction
behaviour of particulate systems.

2. Compaction Process
The compaction is affected by the physical properties of the powder (such as particle
size and morphology), powder mixture, and compaction forces, in addition to the effect of
the process condition.[8]
By applying pressure over powder granules, the powder volume and the amount of air
between the powder particles are decreased through an endothermic process .[9] During the
process, a number of bonds could be formed between the powder particles; many factors
affect the type of the bond formed, such as the amount of pressure applied and the powder
properties.

Challenges Associated with Compression of Coated Multiparticulates

This section focuses on the the compaction of reservoir-type multiparticulate drug
delivery systems (coated multiparticulates) into sustained release tablets and the subsequent
drug release behaviour of these dosage forms, which ideally should not be affected by the
UCP
compaction process. The polymeric coating surrounding each drug-loaded particulate must
retain its integrity, withstand the compaction force, and remain intact and free of cracks.
Damage to the coating can significantly alter the release/dissolution behaviour of the
drug and cause a rapid release of the drug substance, therefore resulting in the loss of the
controlled release properties.

3. Coated Pellets (Reservoir-Type Multiparticulate Drug Delivery Systems)

Each individual pellet contains the drug substance where the total drug dose is divided.
There are two main methods by which coated pellets (reservoir systems) are prepared for
compression into tablets.[10] Extrusion–spheronization, as shown in Figure1, is the process
by which the dry powder mixture (consisting of the active pharmaceutical ingredient (API)
and excipients) is agglomerated with the aid of a binding fluid. This mass is then processed
in an extruder whereby extrudates are produced. Finally, the spheronizing stage converts
these extrudates into spherical granules, i.e., pellets. These spherical drug-loaded pellets are
then coated with polymer, followed by compression into a multiple-unit pellet system
tablet.[10]

Figure 1. Diagram showing how drug-loaded pellets are prepared using an

extrusion spheronization technique.
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Figure 2. Schematic representation of tablet comprising of coated pellets.

3.1.Compression of Coated Pellets into Tablets

3.1.1. The Type of Coating Layer

The choice of polymeric coating for drug pellets is essential, as these coated pellets
undergo compression to form tablets. Therefore, it is important that the polymeric coating
can withstand the compression force by having the right combination of plasticity,
elasticity, and thickness without rupturing.[5] Damage to the coating polymer can
compromise the sustained release properties, thus resulting in the fast release of drug (dose
dumping).
The polymer coatings can be formulated as either aqueous polymeric dispersions or
organic solutions. Aqueous dispersions are preferred, as they avoid the flammability and
toxicity hazards associated with organic solutions, and they are also a cheaper alternative.

Cellulosic Polymers
The most common cellulose-based polymer used for sustained release dosage forms is
ethyl cellulose (EC).[11] However, EC is known to be a brittle polymer with inappropriate
mechanical properties. It has a low puncture strength and low elongation (<5%). Other
polymers (semisynthetic and synthetic) with different mechanical properties have been
used.

Hosseini et al. repared EC-coated propranolol hydrochloride pellets and incorporated a

cushion layer to act as a surrogate to absorb the energy of compaction to help protect the EC
polymeric coating, so that it remains intact during compression. Standard tabletting
excipients, such as microcrystalline cellulose (MCC), lactose, or sorbitol, were layered onto
the ethyl cellulose-coated pellets to form the cushion layer. Upon compression, the cushion-
layered pellets ruptured, and the integrity of the EC coating was compromised, leading to an
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uncontrolled drug release. [12]However, by incorporating a glidant, such as magnesium
stearate, to the cushion layer, the mechanical strength of the pellet was improved, and the
rupturing tendency of the polymer coat was reduced during compression.
Sawicki and Mazgalski developed a tabletting method to overcome the brittleness
of the EC film that is used to coat the pellet core. They used hot tabletting to compress
the EC-coated pellets into tablets, which use a lower compression force in comparison
to the normal tabletting process. Tramadol hydrochloride pellets were coated with
Aquacoat® ECD. These coated pellets were then compressed into tablets using the hot
tabletting method where a compression force of 1 kN was used.

Polyethylene glycol3000 was a vital component that was incorporated during the tabletting
process to provide additional protection to the tablets and ensure that the EC polymer coat
remains intact during compression. The results revealed a successful sustained release of
tramadol hydrochloride from the palletised tablets, which was attributed to the intact
polymer coat. Therefore, hot tabletting can be considered as an alternative to the traditional
tabletting procedures to manufacture tabletted pellets using EC as the sustained release film
[12].
Microcrystalline cellulose (MCC) is considered the gold standard for pellets’
preparation by extrusion spheronization, as it provides appropriate plasticity to the wet mass
[13]. Since the 1990s, MCC has been widely used in preparing multi-unit tablets. MCC also
offers superior compaction and disintegration properties. On the other hand, MCC was
found to prolong the drug release, especially for poorly water-soluble drugs, as the polymer
does not disintegrate quickly. MCC was found to be incompatible with some drugs (and
adsorb some drugs to the surface of its fibers [14]. In the study of Abbaspour et al., at least
10% MCC was used to aid the pellets’ formulations process to obtain Eudragit RS/RL
pellets with 60% drug loading [15].
Johansson and Alderborn evaluated the degree of deformation of MCC pellets during
compaction. It was concluded that the MCC pellets did not fragment under compression,
and the pellets’ porosity was the main factor affecting the structural deformation of the
pellets.[16] Another study conducted by Nicklasson et al. compared the compaction
behavior of MCC pellets and pellets made of 20% MCC and 80% dicalcium phosphate
dehydrate (DCP). DCP/MCC pellets were rigid and less prone to densification. These
pellets were extensively deformed from their surfaces and formed tablets with weak
mechanical properties. On the other hand, MCC pellets formed tablets with high tensile
strength[16]. Kallai et al. investigated the effect of pellets’ core materials on the mechanical
properties and release kinetics of their tabletted pellets. MCC, isomalt, or sugar were used
as inert cores. It was noted that the drug release profile was affected by the core material
used. MCC-tabletted pellets managed to sustain the release of diclofenac sodium, which was
attributed to the ability of MCC to swell in water. On the other hand, sugar and isomalt-
based pellets showed faster release profiles, as the core was water-soluble and dissolved
quickly. Besides, the tensile strength of MCC pellets was higher than that of sugar and
isomalt pellets.
Hydroxy propyl methyl cellulose (HPMC) is a water-soluble polymer that was used as
a binder in coated pellets. HPMC was used as a binder to load omeprazole into pellets with
a sugar core or MCC core. HPMC is also known as a pellets-hardening agent, as it is able to
generate durable pellets.[12] In a study conducted by Nguyen et al., HPMC was used as a
sealing agent, and pellets that hardened with HPMC showed superior physical strength.
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Increasing HPMC concentrations increased the ability of the prepared pellets to resist
compaction pressure. Besides, HPMC was found to delay glipizide release by creating a lag
time. HPMC was also reported as a pore-forming agent in pellets manufacturing. The
polymer was used at 7.5% w/w in studies to form pores through which water penetration
was achieved to enable the drug release.[17]

3.1.2. Characteristics of the Coating Layer

Generally, a thicker polymer coating increases the mechanical strength of the coated
pellets, helping to protect the film integrity during compaction into tablets. A thicker
coating is also believed to help improve the plastic and elastic deformation characteristics of
pellets [17]. Therefore, this prevents rupturing of the polymer coat upon compaction, and
allows for a slow and sustained release of the active pharmaceutical ingredient once the
tablet has disintegrated to release the individual drug-loaded pellets.
Sawicki and Lunio developed floating pellets containing VH (40 mg) along with other
excipients. The pellets were coated with Kollicoat® SR 30 D along with the addition of
propylene glycol as a plasticiser to enhance flexibility. Two polymer films of different
thicknesses were used: film A (35 µm in thickness) and film B (50 µm in thickness), and the
compressibility of these polymeric films was assessed. The study showed that pellets with a
film thickness of 35 µm were unable to withstand the pressure force exerted during
tabletting, and were thus deformed. [5]. The polymer coating may have also ruptured as a
result of deformation, which caused a fast drug release from the tabletted pellets, and
therefore, the sustained-release properties of the polymer coat diminished. In contrast,
coated pellets with a thickness of 50 µm resulted in a slower release of VH from the
tabletted pellets. This meant that the thicker polymeric coating was able to better withstand
the compression force of the tabletting process.[18]
Further research was performed by Sultana et al., in which sustained-release pellets
were incorporated with salbutamol sulphate as the model drug. Two different aqueous
polymeric dispersions were used to coat the pellets: Eudragit RS® 30 D and Kollicoat
SR® 30 D. The drug-containing cores were coated with different thicknesses/polymer
loads (5%, 10%, 15%, 20% and 25% w/w). The study concluded that the rate of drug
release was dependent upon the thickness of the coating polymer. Accordingly, a higher
percentage w/w of polymer led to a slower rate of drug release. Increasing the thickness
of the polymer film also decreased the porosity of the film coating, therefore retarding
drug release . It can be noticed from the obtained results that the properties of the
coating layer have impacts that should be considered during pellet preparation.

3.1.3. Role of Plasticisers

Plasticisers are additional components incorporated within the polymer coating to
enhance film-forming properties, as most polymers are brittle at room temperature, so upon
compaction, they are likely to damage or rupture, resulting in the faster release of the drug
from the tabletted s;
EC-based coatings are a prime example of such behaviour. Plasticisers are employed to
increase the elasticity of the polymer film and thus film elongation, reduce moisture
permeability, and decrease the MFT. Common plasticisers employed are triethyl citrate
propylene glycol (PPG).Abbaspour et al. developed ibuprofen pellets coated with Eudragit
RS 30 D and Eudragit RL 30 D aqueous polymeric dispersions in a 4:1 ratio. Varying
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proportions of triethyl citrate were also incorporated as a plasticiser; the amounts included
were 10%, 20%, and 30% (w/w). The plasticiser amount was varied to determine the
optimum plasticiser amount that is required to increase the elasticity, and thus the elongation
of the polymer film, so that they do not rupture upon compression. It was concluded that
20% TEC was the optimum plasticiser concentration to be incorporated within the coating
formulation. In general, as the percentage of the plasticiser incorporated within the film
coating was increased, so too was the elongation of the film coating. However, the stress at
break decreased. So, although 30% TEC had the highest percentage elongation, it had the
lowest stress at break. Meanwhile, 10% TEC had the highest stress at break, but the lowest
percentage elongation. Therefore, 20% TEC was chosen to be incorporated within the
coating formulation, as it had the right balance of elongation and stress at break. Upon
compaction of the Eudragit RS 30 D/RL 30 D (including 20% TEC) coated ibuprofen pellets,
it was concluded that the they had sufficient mechanical strength to withstand the compaction
force of the tabletting press, and so drug release was successfully sustained.[19]

3.1.4. Effect of Pellets’ Porosity on Compression Behaviour

Both intergranular (air voids between pellets) and intragranular (air voids within
pellets) porosity impact the characteristics and performance of pharmaceutical pellets.
Porosity has profound effects on the compression mechanism, and therefore the polymer
coat integrity and tensile strength of the resulting tablet formed after compression.
Generally, highly porous pellets undergo an increased degree of deformation (change in
pellet shape) during compression, which leads to slightly flattened pellets. However, they
are not fragmented, and therefore, the polymer coat does not rupture, and the resulting
tablets have high tensile strength due to the presence of strong intergranular bonds, and
drug release will be unaffected. This is also the case with the high intragranular porosity of
pellets.
Tunón et al. investigated the compression behaviour and the resulting drug release rate
of three batches of pellets with varying intragranular porosities (low, intermediate, and high
porosity). These varying porosities were achieved by using different proportions of ethanol
and water in the granulation liquid, and the pellets were coated with a thin layer of EC. The
study concluded that the more porous pellets were much less affected by the compaction
force of the tabletting process, and therefore maintained the integrity of the polymer coat,
and a sustained drug release was not impaired. Pellets with high porosity gave rise to
increased deformation and densification upon compression, and so the sustained release of
the drug was unaffected. Whereas pellets with low porosity were only slightly deformed and
densified, and so drug release was relatively high. These results come in accordance with
Johansson and Alderborn’s study that evaluated the MC granules of two types—irregular
and spherical shapes—with different original intragranular porosities (low, intermediate,
and high).

3.1.5. Coating Layer

The key purpose for surrounding drug-containing microcapsules with a polymer
coating is to embrace a time-controlled or sustained-release characteristic. However, similar
to coated pellets, the polymer film coating must be able to withstand the compressive force
applied during tabletting.
The polymer coating must be chemically compatible with the microcapsule core and
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must not react with it. It should also be non-hygroscopic, and can produce a cohesive film
surrounding the microcapsule. Moreover, the polymer coat should have the right
combination of mechanical strength, elasticity, and thickness to allow for it to remain intact
after compaction.
Alginate is one of the polymers that have an influence on tablets’ mechanical properties
. The chemical structure and the ratio of glucuronic and mannuronic acid (of salt form
alginate) are affect the compaction performance. A low ratio of guluronic acid is associated
with more elastic properties than with a low mannuronic acid ratio. Sodium alginate was
found to possess lower plastic properties than potassium alginate. Sodium alginate produced
compressed tablets with low rigidity and high elasticity .
Alternatively, Sawicki et al. used hot tabletting to compress coated microcapsules
consisting of tramadol hydrochloride (TH) into a sustained release dosage form. Four
different polymeric coating systems were explored (two aqueous dispersions and two
organic solutions). Aquacoat ECD and Eudragit® RS/Eudragit® RL mixtures were chosen
as the aqueous dispersions, and an ethanol solution of EC and acetone/isopropanol solution
of Eudragit® RS/Eudragit® RL were chosen as the organic solutions. The polymers were
coated onto the drug-loaded microcapsules by means of the fluid bed coating. All of the
polymer films could be sprayed onto the TH-containing microcapsules, except for the
aqueous dispersion of Eudragit® RS/Eudragit® RL mixture. The coated microcapsules
were compressed into tablets using the hot tabletting method, which uses a much lower
compression force (1 kN) and a temperature of 56 ◦C in comparison to traditional
tabletting. Granules consisting of melted Polyethylene glycol (PEG) 6000 were combined
with the coated TH microcapsules during compression. The addition of PEG 6000 was vital
to enable good flow properties, which would be otherwise be affected by the tackiness of
the heated tablet formulation. In vitro drug release studies carried out compared the percent
release of TH from tabletted-coated microcapsules prepared by traditional tabletting (10
kN/25 ◦C) with tabletted coated microcapsules prepared by hot tabletting (1 kN/56 ◦C)
over an eight-hour period. Overall, the tabletted microcapsules prepared by hot
tabletting sustained the release of TH better than the ones prepared by traditional tabletting.
Also, the dissolution characteristics of the hot tabletted microcapsules were similar to that of
the commercial brand: Tramadol Retard tablets.

3.1.6. Thickness/Quantity of the Coating Layer

Besides the type of polymer membrane that is used to coat drug-containing
microcapsules, the amount of polymer coating is also a very important parameter. The
thickness of the polymer can affect the deformation characteristics of these coated
microcapsules upon compaction into tablets. A thicker polymer coating improves the
plastic-elastic properties of coated microcapsules when compressed; therefore, plastic and
elastic deformation is observed when the amount of polymer is increased. Once the
sustained release tablets consisting of coated microparticles disintegrate upon oral
administration, the individually coated microparticles should slowly release the drug over a
longer period. By increasing the polymer content, the thickness of the coating layer also
increases; thus, it takes even longer for the drug to diffuse through the thick coating layer,
and the drug release rate is further decreased. Garekani et al. prepared sustained-release
theophylline microparticles coated with different amounts of polymer using the spray-
drying technique. The spray dried microparticles were prepared with drug-to-polymer (D:P)
ratios of 1:1, 1:2, and 1:3, and were then compacted into tablets. Aqueous copolymer
dispersion, Eudragit RS 30 D, was incorporated as one of the coating polymers in amounts
of 16.7 g, 33.4 g, and 50 g. Meanwhile, Eudragit RS PO was incorporated in amounts of 5
g, 10 g, and 15 g, and was dissolved in ethanol to produce an organic solution as the second
coating polymer. Dissolution studies showed that drug release from tabletted spray-dried
microparticles using organic solutions of Eudragit RS in ethanol was significantly affected
by the amount of polymer coating used. After a period of 5 h, compacted spray-dried
microparticles with a D:P ratio of 1:1 released ~25% of theophylline, microparticles with a
D:P ratio of 1:2 released ~20% of theophylline, and microparticles with a D:P ratio of 1:3
released just over 10% of theophylline It was evident that the compacted spray-dried
microparticles with the higher proportion of polymer coating exhibited a slower release of
drug and sustained the release of theophylline over the period investigated. In contrast, drug
release from tabletted spray-dried microparticles using an aqueous dispersion of Eudragit
RS was unaffected by the amount of polymer used. An increase in the amount of polymer,
and thus the thickness, failed to decrease the drug release rate; however, there was still a
sustained release of drug with the dissolution profile being similar for all three drug-to-
polymer ratios (1:1, 1:2, and 1:3). It is believed that the aqueous polymer dispersion of
Eudragit RS 30 D failed to act as a polymer coat to encapsulate the theophylline
microcapsules, and subsequently formed a micromeritic matrix system instead of a reservoir
system.
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