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www.ejpmr.com │ Vol 10, Issue 12, 2023. │ ISO 9001:2015 Certified Journal │
Jahan et al. European Journal of Pharmaceutical and Medical Research
667
INFORMATIVE REVIEW OF LAYERED TECHNOLOGY OF TABLET- AN EMERGING
INNOVATION IN ORAL DRUG DELIVERY SYSTEM
Mahabub Alam and Khurshid Jahan*
Mahabub Alam, World University of Bangladesh.
Article Received on 23/10/2023 Article Revised on 13/11/2023 Article Accepted on 03/12/2023
INTRODUCTION
Oral route is the most common and preferred way to
administer medications. There are numerous formulas on
the market. They can exist as semi-solids, liquids, or
solids. When creating a formulation, one of the most
important things to take into account is its
pharmacological stability. This route is well-known for
its simplicity, self-medication, patient compliance, and
diversity in terms of readily available dosage forms.[1]
Solid dosage forms are thought to make up about 90% of
all dosage types utilized to deliver therapeutic substances
to the body systemically. Depending on the patient's
administration or presentation technique, pharmaceutical
tablet varies. There are many factors that are important
for customer acceptance of a tablet, including its general
appearance, visual identity, and overall style. Tablets can
be found in different sizes, shapes, colors, odors tastes,
surface textures, physical flaws, consistencies, and
identifying markings.[2] A layered tablet is a combination
of one or more APIs (Active Pharmaceutical Ingredients)
with auxiliaries, cast in two or more layers into a single
whole dosage form. Formulating a combination of drugs
into a single dosage form is valuable for treatment. A
notable feature is that the drug is released without
pharmacokinetic interactions with the individual issue
rates. This can greatly help minimize the frequency of
dosing and can increase the synergistic effect.[3] Layered
tablets are currently being produced by a number of
pharmaceutical companies due to the numerous
therapeutic benefits of reducing the number of doses
required. These tablets also have the added benefit of
being more production-friendly. The multilayer tablet is
a recent successful idea development of a controlled-
release formulation with several properties that provide
the opportunity for a successful drug delivery system.[4]
They consist of an active matrix core and one or more
layers applied during tableting which may act as barriers
and regulate drug release.[5] Bi-layer tablet is suitable for
the sequential release of two drugs in combination,
separate two incompatible substances, and also for
sustained-release tablets in which one layer is immediate
release as an initial dose and the second layer is the
maintenance dose.[6] The design feature provides, unique
product performance objectives otherwise not achievable
by conventional tablets, but also brings a new set of
challenges for formulation design, manufacturing
process, controls, and product life performance
requirements.[7] Challenges during development include
layer weight ratio, first layer tamping force, elastic
mismatch of the adjacent layers, and cross-contamination
SJIF Impact Factor 6.222
Review Article
ISSN 2394-3211
EJPMR
EUROPEAN JOURNAL OF PHARMACEUTICAL
AND MEDICAL RESEARCH
www.ejpmr.com
ejpmr, 2023, 10(12), 667-675
ABSTRACT
Oral route is most popular method of drug administration. Tablets are designed to deliver a precise dosage to a
particular location in the body. They can also be given sublingually, buccally, rectally, or intravaginally. In
addition to convenience, it has the benefit of improved absorption. Tablet is the most commonly utilized dosage
form because of its durability and patient acceptability. These dosage forms stand out and are preferred over other
forms due to their superior aesthetic qualities, such as color, texture, mouth feel, and flavor masking capabilities.
Layered tablets typically increase patient compliance and lower production costs in half. Drugs with release
boosters, fillers, or numerous dosages of the same drug are all examples of layered technology. This technology
usually contains two to three APIs or APIs along with functional or nonfunctional placebo layers. Layered tablets
provide more promise for improved patient outcomes and continue to be production-friendly. Comparing multi-
layer tablets to conventional immediate-release reveals many significant advantages. By streamlining dosing
regimens in combination therapy, the use of such solid oral dose forms increases patient compliance day by day.
This study reviews the primary advantages of the layer stressing its key advantages as an oral dosage form as well
as outlining its current difficulties and strides in product quality and manufacturing process improvement.
KEYWORDS: Bilayer tablet, combination drugs, incompatible, multi-layered tablet, drug release kinetic.
*Corresponding Author: Khurshid Jahan
Mahabub Alam, World University of Bangladesh.
www.ejpmr.com │ Vol 10, Issue 12, 2023. │ ISO 9001:2015 Certified Journal │
Jahan et al. European Journal of Pharmaceutical and Medical Research
668
between layers.[8] Moreover, the other challenges
associated here are delamination at the interface between
the layers caused by insufficient adhesion, the
incomplete separation of tablet portions, the relatively
low yield compared to traditional single-layer tablets,
and the challenge of achieving the desired weight of
individual layers with multilayer tableting. Furthermore,
if the compressed layers become excessively soft or too
rigid, they will not connect properly with each other,
compromising their structural strength.[9] So the purpose
of this review was to discuss all things the layered tablet
like- objectives, advantages, and limitations of the
layered tablet, types, manufacturing technology, and
challenges in layered tablet manufacturing.
Layered tablet
A layer tablet is made up of two to three layers of
compressed granulation. Each layer's borders are visible,
giving them a sandwich-like look. This particular dosage
form has the special benefit of putting an inert barrier of
separation between two incompatible APIs.[10] There may
be a decrease in the need for excipients like fillers when
two or more medications are provided in a single dosage
form. In the case of long-term care and various
pharmacological therapies, layered tablets are strongly
desired. To maintain a stable plasma concentration when
a mixed-release approach is used a rapid initial release of
the medication followed by a slow release is
necessary.[11] There are mainly two types of layered
tablets used in pharmaceutical industries.[12]
A. Bi-layer tablets
B. Tri-layer tablets.
Rationale of multi-layered tablet[13]
To regulate the delivery rate of either a single or
more different active pharmaceutical ingredients.
To provide synergistic effects.
As the layers are typically various colors, these
layered tablets also provide high product
identification, making it simple for patients to
recognize the tablets.
There may be a decrease in the need for excipients
when two or more medications are provided in a
single dose form.
The life cycle of the drug product can be extended
by layering active pharmaceutical ingredients with
one or more excipients (polymers) to create erodible
or swellable barriers for drug release modification.
Additionally, different APIs can be administered by
fixed-dose combinations.
To separate incompatible Active pharmaceutical
ingredients (APIs) from each other, to control the
release of API from one layer by utilizing the
functional property of the other layer (such as
osmotic property).
Multi-layered tablet dosage forms are also designed
for a variety of reasons: patent extension, efficient
pharmacological effect, better patient compliance,
etc.
Problems associated with conventional dosage
forms[14]
Repeated dosing
Poor bioavailability
Dose dumping
Poor bioavailability
Poor absorption
An early expulsion from the body
Fluctuation of plasma drug concentration
Ideal properties of layered tablet[15][16]
It needs to be stable enough chemically and
physically to keep its physical properties throughout
time.
The therapeutic components must be capable of
controlled, recurrent release.
Layered tablets must possess a sophisticated brand
identity and be devoid of imperfections like chips,
fractures, contamination, and color changes.
It should be strong enough to withstand mechanical
shock while being manufactured, stored, transported,
and administered.
Should have a stable chemical composition and shelf
life to avoid causing the therapeutic agents to
change.
Advantages[17],[18],[19]
They enable the integration of various release
profiles and separate APIs that are incompatible.
The great advantage is different APIs in
combination have proven advantages over single
compounds administered separately for therapeutic
effect and get a dual release profile so as to reduce
dosing frequency and thereby increase patient
compliance.
They are unit dosage forms and provide the best
properties of all oral formulations’ highest dosage
accuracy and the lowest variation of content.
A drug's blood level can be maintained at a
therapeutic level for increased drug delivery, safety,
accuracy, and side effect reduction.
Multilayer tablet enables a sustained-release
formulation with an immediate-release portion in the
first layer and a sustained-release portion in the
second layer. A third tier of intermediate releases
can be added.
Compared to other oral dose forms the cost is lower
easiest, and least expensive to strip and package.
Limitation[20]
The layers should be able to bind the formulation
together well enough. High throughput pre-
formulation and planning are necessary for this.
Long-term physical and chemical integrity
throughout the shelf life.
Other challenges during development include
establishing the order of layer sequences.
Each layer must have certain properties tested, such
as hardness and thickness.
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Jahan et al. European Journal of Pharmaceutical and Medical Research
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Layered tablets are more expensive to produce since
high work intensity and sophisticated equipment are
required.
Bilayer tablet
Bi-layer tablets are medicines that consist of two same or
different drugs combined in a single dose for effective
treatment of the disease. One of its layers is made to
ensure the instant release of the drug and aims to reach a
high serum concentration in a brief time. Its second layer
is a controlled-release hydrophilic matrix that aims at
maintaining an efficient plasma level for a long time.[21]
Fig 1: Bi Layered Tablet.
Quality and good manufacturing practice (GMP)
requirements of bi-layer tablets
Avoid capping and separating the two distinct layers
that make up the bi-layer tablet. Ensuring adequate
tablet hardness.[22]
Unique and precise weight control for the two
layers. Although they appear straightforward, these
criteria are more difficult to meet.[23]
Manufacturing bilayer tablets with no contamination
transferring among the two layers.[24]
Due to the tiny compression roller, the initial layer-
dwell time was very short, which might have an
impact on de-aeration, capping, and hardness issues.
This can be fixed by slowing the turret's spin (to
increase the dwell time), but the result will be
reduced tablet production.[25]
Classification of bi-layer tablet
The concept of bi-layered tablets refers to tablets that
include either the same (homogeneous) or various
(heterogeneous) subunits.
A. Homogeneous: Bilayer tablets are preferred when
the release patterns of the drugs vary from one
another. A layer of the drug in bilayer tablets is
meant for immediate release, while a second layer is
meant for the medication to be released later, either
as a second dosage or in an extended-release
form.[26]
B. Heterogeneous: Heterogeneous type bi-layer tablets
are fabricated for sequential release of two
incompatible drugs in combination.[27]
Fig. 2: (With Two Different Drugs- Heterogenous)
and (Same Drug with Different Release Pattern-
Homogenous).
Types of bilayer tablet press
A. Single-sided tablet press.
B. Double-sided tablet press.
C. Bilayer tablet press with displacement
A. Single-sided tablet press
A single-sided press with the two chambers of the
doublet feeder separated is the most basic type. Each
chamber is gravity or force-fed with a variable amount of
power, resulting in two distinct layers of tablets. When
the die passes beneath the feeder, the first layer of
powder is filled first, followed by the second layer of
powder. The tablet is then compacted in one or two
processes.[28]
B. Double-sided tablet press
Compression force is used for tracking and controlling
tablet weight in most double-sided tablet presses with
automated production control. The control system
measures the effective peak compression force applied
on each individual tablet or layer during major
compression of the layer. When out of tolerance, the
control system uses this measured peak compression
force to reject it and rectify the die fill depth.[29]
C. Bilayer tablet press with displacement: The
principle of bilayer tablet press differs significantly from
the principle of compression force. In this situation,
when the compression force is lowered, accuracy
improves. The danger of capping and separation rises as
production speed increases however, it can be mitigated
by allowing enough dwell time in tall four compression
stages.[30]
VARIOUS TECHNOLOGY FOR BILAYER
TABLET
Oros push-pull technology
This system primarily consists of two or three layers, of
which one or more layers are necessary for the
medication and the remaining layers are push layers. The
primary components of the drug layer are drugs and two
or more diverse agents. As a result, the medication in this
layer is in a relatively insoluble form. Osmotic and a
suspending agent have also been added. The tablet core
is surrounded by a membrane that is semi-permeable.[31]
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Jahan et al. European Journal of Pharmaceutical and Medical Research
670
Fig 3: Oros push pull technology.
L – oros Tm technology
This method was used to address the solubility difficulty.
Alza created the L-OROS system, in which a lipid soft
gel product including medicine in a dissolved condition
is first created and then coated with a barrier membrane,
an osmotic push layer, and a semi-permeable membrane
drilled with an escape hole.[32]
Fig 4: L – oros Tm technology.
En so trol technology
Shire Laboratory uses an integrated strategy for drug
delivery with an emphasis on the discovery and
implementation of the discovered booster into controlled
release technologies to increase solubility by an order
larger or to generate optimum dosage forms.[33]
Fig 5: En So Trol Technology.
Duros technology
An exterior cylindrical titanium alloy reservoir makes up
the system. High impact strength and enzyme protection
are provided by this reservoir. The DUROS technique
uses a tiny needle to deliver a continuous stream of
concentrated liquid over the course of a year or several
months.[34]
Fig. 6: The duros technology.
Geminex technology
This method significantly improves the therapeutic
efficiency of the medications while reducing their
adverse effects. It administers one or more medications
with various rates of release in a single dosage. Pen West
uses it extensively for cardiovascular illnesses, CNS
problems, diabetes, cancer, and disorders of the central
nervous system (CNS), and it is very advantageous for
both patients and the manufacturing sector.[35]
Elan drug technologies’ dual-release drug delivery
system
The DUREDASTM Technology offers both prolonged
release and immediate release of a single medicine, or a
mix of sustained release and quick release. This
composition combines many controlled-
release substances.[36]
Various approaches used in bi-layer tablets[37][38]
Floating drug delivery system
Based on a technical and manufacturing standpoint,
floating drug delivery methods are a much simpler and
more sensible choice for creating gastro-retentive dosage
forms (GRDFs).
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Fig. 7: Release pattern in a floating bilayer tablet.
Polymeric Bio Adhesive System
These are intended to absorb fluid administration such
that the outer layer transforms into a viscous, sticky
substance that sticks to the mucus layer and
gastrointestinal mucosa. While the adhesive forces are
being reduced, this should promote stomach retention.
One layer of them is designed for quick dosage, and the
other layer has a bio-adhesive feature.
Multiple unit type floating pill
These types of systems are made up of two layers around
sustained release capsules that act as "seeds."
Effervescent agents make up the inner layer while
swellable membrane layers make up the outer layer. The
system lowers instantly when submerged in dissolving
liquid at body temperature, then generates enlarged pills
that resemble balloons and float because they have a
reduced density.
Swelling System
Tablets are made to be tiny enough when administered
that swallowing the dose form won't be challenging. On
intake, they expand, break down, or unfold quickly to a
size that prevents passage through the pylorus until drug
release has reached the necessary stage. It might exit the
stomach by gradually eroding away or dissolving into
smaller pieces. A basic bilayer tablet may have an instant
release layer and a prolonged release layer or a standard
release layer between them.
Preparation of bilayer tablets
Bilayer tablets are made with a layer of medication
intended for quick release and a second layer intended
for delayed or longer release of the medication. It is also
possible to produce bilayer tablets with two incompatible
medications by compressing individual layers of each
drug to reduce the area of contact between the two
layers. There may also be a further inert layer added in
the middle. Certain conditions, including the required
mechanical strength and desirable drug release profile,
must be satisfied in order to manufacture an appropriate
tablet formulation. Due to the drug's poor flow and
compatibility characteristics, it may occasionally be
challenging for the formulator to accomplish these
parameters, especially when bilayer tablet formulation
involves a twofold compression procedure.[38]
Compaction
The method through which a powder's porosity is
reduced as a consequence of the granules being
compressed together by the force of mechanical
methods. Compressibility and consolidation are both
factors in a material's compaction.[39]
Compression
It is described as a decrease in bulk volume
accomplished by filling voids and bringing particles
closer together.[40]
Consolidation
It is a material feature characterized by enhanced
mechanical strength as a result of interparticulate contact
(bonding). The compression force on layer 1 was
discovered to be a significant element determining tablet
delamination.[41]
Various steps involved in bilayer tablet formulation
are as follows[42]
(1) Filling of the first layer
(2) Compression of first layer
(3) Ejection of upper punch
(4) Filling of second layer
5) Compression of the second layer
(6) Ejected fully bilayer tablet
Evaluation of bi-layer tablets
The manufactured bilayer tablets from each batch of
improved formulation were assessed against the official
standard evaluation parameters to ensure proper drug
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production and release rate. The following assessment
parameters were used:
Size, shape, and thickness
When a compressive load is constant, changes in the die
fill, particle size distribution, packing of the particle mix,
and tablet weight cause thickness to change, but when a
compressive load is variable, thickness changes in
response to changes in compressive load. The pill's
thickness should remain well within a +5% range of its
typical value.
Hardness
The degree of a tablet's hardness indicates how well it
can manage mechanical shocks. It is measured (kg/cm2)
using a hardness tester. An average of five duplicate
decisions will be calculated.
Friability
A tablet's friability is used to measure its strength. The
tumbling apparatus, which rotates at a speed of 25
revolutions per minute and lowers the tablets six inches
at a time, will be filled with twenty tablets that have been
carefully weighed. After 4 minutes, the tablets will be
weighed to determine the amount of weight loss.
Uniformity of Weight
The average weight of twenty tablets will be weighed
after a random selection. The weight variance will be
determined.
In vitro dissolution studies
The tablet release rate (n=3) will be evaluated using the
dissolving testing equipment II (paddle technique) of The
United States Pharmacopoeia (USP). The dissolving test
will be carried out using 900 ml of dissolution media at
37 oC and 75 rpm.
Drug release kinetic
The kinetics of drug release must be assessed since
different layers may have different release rates, which
can affect the profile. Characterizing sustained release
and immediate release patterns is crucial since each layer
may display a different rate of release.
Stability studies
The stability of every layer is investigated. There may be
varying levels of deterioration between layers. Based on
the properties of each layer, shelf life is calculated.
Morphology analysis
Visualization can be used to assess physical attributes.
Using cross-section samples, scanning electron
microscopy can be used to see the morphological
features.
Thermal analysis
The detection of drug-excipient, drug-drug, and
excipient-excipient interactions in the formulation is of
higher interest when using thermal analysis. Differential
Scanning Calorimetry can be used to determine the drug
substance's molecular dispersion in the tablet matrix
system.
Crystallinity
Drug stability, solubility, and a number of other Physico-
chemical properties are directly influenced by the
crystalline and amorphous structure of the substance.
The X-ray diffractometer (XRD) is used to assess the
crystal nature of medicinal compounds at different
levels. It is possible to research if the nature of medicine
changes from crystalline to amorphous throughout
manufacturing or storage.
Challenges in Bilayer Manufacturing[12][43][44]
Bilayer tablets can be conceptualized as a combination of
two single-layer tablets. There are various manufacturing
difficulties in real life. Such as-
Delamination
When the two tablet parts do not fully join, the tablet will
break. When crushed, the two granulations ought to stick
together.
Cross-contamination
Cross-contamination happens when the granulation of
the first layer mixes with the granulation of the second
layer or the other way around. It may defeat the bilayer
tablet's fundamental aim. Cross-contamination may be
greatly reduced with proper dust collection.
Production yields
Dust removal is necessary to prevent cross-
contamination, which results in losses. As a result,
single-layer tablets provide higher yields than bilayer
tablets.
Cost
For a number of reasons, bilayer tableting is more
expensive than single-layer tableting. The tablet press is
more expensive, to start. Second, in bilayer mode, the
press often operates more slowly. Third, creating two
compatible granulations is necessary, which requires
extra effort to create, analyze, and validate the
formulation. These variables will have an effect on the
bilayer compression in general and the quality
characteristics of the bilayer tablets (sufficient
mechanical strength to retain its integrity and individual
layer weight management) in one way or another if they
are not effectively regulated or optimized. In order to
build a solid product and process, it is crucial to get
insight into the underlying reasons.
Individual layer
Inaccurate individual layer weight control and impact of
high temperature and humidity on layer adhesion upon
storage.
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Jahan et al. European Journal of Pharmaceutical and Medical Research
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Triple layer tablet
These tablets feature three layers, the first of which
indicates an instantaneous release, the second a
continuous release, and the third a separation of the two
layers that are present in the middle.[45]
Fig 8: Triple layer tablet.
Typically, controlled-release formulations are used to
create three-layer tablets. Such tablets have a drug-filled
inner core layer sandwiched between a polymer layer
and a barrier layer. Generally, the following geometric
adjustments may be used to modulate drug release from
the triple-layer matrix system:
Gradients in drug concentration are created, and the
matrix layers are eroded differently.
Barrier layers restrict the swellable matrix's
releasing surface.
Exterior layers are inflated and differentially eroded
to maintain a consistent surface area and continual
release.
Dissolution of the differential layer for pulsatile or
quick slow-release applications.[46]
Manufacturing of tri-layer tablets
Tri-layer tablets are made in the same way as bilayer
tablets, with the addition of a third hopper used to
integrate a third active pharmacological component or a
polymer (inert) mix.[47]
Evaluation of prepared three-layered tablets
The uniformity of the tablet thickness, the thickness of
the barrier layers, and the in vitro release properties were
all assessed for all of the created three-layered tablet
formulas.[48]
CONCLUSIONS
Manufacturing of bilayer or tri-layer tablets is one of the
great inventions in pharmaceutical technology for oral
dosages and it has many advantages. A multi-layered
tablet does the same thing better than a single
formulation for rapid or long-lasting release. By creating
surrounding or multiple swelling layers, multilayer tablet
formulations may be utilized to create controlled-
release tablet preparations as well as systems for the
delivery of incompatible medications. Due to the
multilayer technology, there is no need to take multiple
tablets at the same time. It is possible to have one or two
different functions simultaneously. This technology
improves compliance and provides inexpensive capital
expenditure and efficient production. Layered tablets
continue to be preferred from the standpoints of
producers, doctors, and patients. Therefore, more
emphasis can be placed on this technology in the future
to research this dosage type further.
ACKNOWLEDGMENT
The corresponding author is thankful to the other author
who was supportive throughout the time of writing and
evaluating the quality of the article.
Disclosure of conflict of interest
The authors declare that they have no conflict of interest.
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