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 International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701

___________________________________________Research Article
Bi-Layer Tablet Technology - Opening New Ways in Drug Delivery
Systems: An Overview
Swati Aggarwal1, Navneet Syan *1, Pooja Mathur2

1 Ganpati Institute of Pharmacy, Bilaspur, Yamuna Nagar, Haryana, India

2 Advance Institute of Pharmacy, Palwal, Haryana, India.
___________________________________________________________________________________________
ABSTRACT
There are many ways to deliver drugs into the body, viz oral (through swallowing), sub mucosal (through buccal
and sublingual mucosa), parenteral (through injection), transdermal (through skin), pulmonary (through inhalation)
etc. Despite disadvantages, oral drug delivery remains the preferred route of drug delivery. Novel technologies
with improved performance, patient compliance and enhanced quality have emerged in the recent past. Multi-
layer tableting is getting increasing attention from a variety of industries for a variety of reasons: patent extension,
therapeutic, marketing to name a few. To reduce capital investment, quite often existing but modified tablet
presses are used to develop and produce such tablets. While general tablet manufacturing principles remain the
same, there is much more to consider because making multi-layer tablets involves multiple-often incompatible-
products, additional equipment and many formulation and operation challenges. The present article provides a
review on the oral drug delivery system, types of tablets, and challenges in bilayer tablet manufacturing, various
tablet presses used, quality and GMP requirements for their production and recent developments in the field of
bilayer technology.

Key words: Bilayer tablets, GMP requirements, tablet press.

1. INTRODUCTION
From various current methods for treating illness and
diseases, chemotherapy (treatment with drugs) is the
most frequently used technique. It has the broad
range of applications over the greatest variety of
disease states and is frequently the preferred
treatment method 1. For many decades, treatment of
acute disease or chronic illness has been mostly
accomplished by delivery of drugs to patients using
various pharmaceutical dosage forms including
tablets, capsules, pills, suppositories, creams,
ointments, liquids, aerosols and injectables as drug
carriers 2, 3.
Despite phenomenal advances in the inhalable,
injectable, transdermal, nasal and other routes of
administration, the unavoidable truth is that oral drug
delivery remains well ahead of the pack as the
preferred route. There are of course many
applications and large markets for non-oral products
and the technologies that deliver them. However, if it
is a viable option, oral drug delivery will be chosen in
all but the most exceptional circumstances.
Moreover, if the oral route is not immediately viable,
pharmaceutical companies will often invest resources
in making it viable, rather than plumping for an
alternative delivery system 4. Oral route of drug
administration have wide acceptance up to 50-60% of
total dosage forms and is the most convenient and
preferred route for systemic effects due to its ease of
dosing administration, pain avoidance, accurate
dosage, patient compliance and flexibility in
formulation 5, 6.
The oral drug delivery market is the largest segment
of the drug delivery market and there’s no sign that it
is slowing down. With pharmaceutical companies
increasingly turning to drug delivery to extend the
revenue-earning lifetime of their biggest products,
and seeking to tap into the growing elderly
population that requires products with a level of ease-
of-use and cost benefit, it’s no surprise that the oral
delivery drug market is a $35 billion industry and
expected to grows much as ten percent per year. Oral
delivery provides the definitive break down of the
market for oral delivery drug markets 7.
Amongst drugs that are administered orally; solid
oral dosage forms i.e. tablets and capsules, represent
the preferred class of products 6, 8. Out of the two oral
solid dosage forms, the tablets are the preferred ones.
Tablets have number of advantages over other dosage
forms. Advantages as well as a few disadvantages of
the tablet dosage form are listed in table-1.1 9, 10.

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 International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701

Table-1.1: Advantages and Disadvantages of Tablets

Advantages
 Ease of accurate dosing and low content variability
 Good physical and chemical stability
 Competitive unit production costs
 High level of patient acceptability
 High convenience
 Easy to package and ship
 Simple to identify
 Convenience of self administration
Disadvantages
 Irritant effects on the gastro intestinal mucosa by some solids (e.g. aspirin)
 Possibility of bioavailability problems resulting from slow disintegration and dissolution
 Difficulty in swallowing in some patients; pediatrics and geriatrics
 Some drugs resist compression into tablets
 In emergency cases, intravenous or intramuscular injections are more effective.
Table-1.2: Various Types of Tablets

A) Oral Tablets for Ingestion

 Standard compressed tablets

 Multiple compressed tablets

a. Layered tablets
b. Compression coated tablets
c. Inlay tablets
 Modified release tablets
 Delayed action tablets
 Targeted tablets
a. Floating tablets b. Colon targeted tablets
 Chewable tablets
B) Tablets Used In the Oral Cavity
 Buccal tablets
 Sublingual tablets
 Troches and lozenges
 Dental cones
C) Tablets Administered By Other Routes
 Implantation tablets
 Vaginal tablets
D) Tablets Used To Prepare Solution
a. Effervescent tablets b. Dispersible tablets
c. Hypodermic tablets d. Tablet triturates

Fig: 1a: Single Layer Tablet Fig: 1b: Bilayer Tablet Fig: 1c: Multilayer Tablet

2. TYPES AND CLASSES OF TABLETS 11 are ingested orally. Orally ingested tablets are
Well over 90% of the tablets manufactured today designed to be swallowed intact, with the

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International Journal of Research in Pharmaceutical and Biomedical Sciences
exception of chewable tablets.
Table-1.2 summarizes the classes for the different
types of tablets.
3. LAYER TABLETS
Layer tablets are composed of two or three layers
of granulation compressed together. As the edges
of each layer are exposed, they have the
appearance of a sandwich. Fig:1a, 1b, 1c shows
various types of layered tablets. This dosage form
has the advantage of separating two incompatible
substances with an inert barrier between them.
It makes possible sustained-release preparations
with the immediate-release quantity in one layer
and the slow release portion in the second. A third
layer with an intermediate release might be added
12
. Multi-layer tablet dosage forms are designed
for variety of reasons which are as follows:
To control the delivery rate of either single or
two different active pharmaceutical
ingredient(s) 13-15.
To separate incompatible active pharmaceutical
ingredients from each other, to control the
release of active pharmaceutical ingredient
from one layer by utilizing the functional
property of the other layer (such as, different
active pharmaceutical ingredients, to prolong
the drug product life cycle 18.osmotic property).
To modify the total surface area available for
active pharmaceutical ingredients layer either
by sandwiching with one or two inactive layers
in order to achieve swellable/erodible barriers
for modified release 16, 17.
To administer fixed dose combinations of
To fabricate novel drug delivery systems such
as chewing device, buccal/mucoadhesive
delivery systems and floating tablets for gastro-
retentive drug delivery 19-21.
4. BILAYER TABLETS
Bilayer tablets are composed of two layers of
granulation compressed together. Two-layer
tablets require fewer materials than compression-
coated tablets weigh less and may be thinner.
Monograms and other distinctive markings may
be impressed in the surfaces of the multilayer
tablets. Coloring the separate layers provides
many possibilities for unique tablet identity.
Separation of the layers prior to assay may
simplify the analytical work. Since there is no
transfer to a second set of punches and dies, as
with the dry-coating machine, odd shapes (such as
triangles, squares, and ovals) present no operating
problems except for those common to keyed
tooling 12. Several pharmaceutical companies are
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ISSN: 2229-3701
currently developing bilayer tablets, for a variety
of reasons viz. patent extension, therapeutic,
marketing to name a few. Various problems are
associated with the formulation of bilayer tablets,
such as layer-separation, insufficient hardness,
inaccurate individual layer weight control, cross-
contamination between the layers, reduced yield
etc. To overcome these problems, development
and production of quality bilayer tablets need to
be carried out on purpose built tablet presses 22.
4.1 Challenges in bilayer manufacturing 23
Conceptually, bilayer tablets can be seen as two
single-layer tablets compressed into one. In
practice, there are some manufacturing
challenges.
 Delamination: Tablet falls apart when the two
halves of the tablet do not bond completely.
The two granulations should adhere when
compressed.
 Cross-contamination: When the granulation
of the first layer intermingles with the
granulation of the second layer or vice versa,
cross-contamination occurs. It may conquer the
very purpose of the bilayer tablet. Proper dust
collection goes a long way toward preventing
cross contamination.
 Production yields: To prevent cross
contamination, dust collection is required
which leads to losses. Thus, bilayer tablets
have lower yields than single-layer tablets.
 Cost: Bilayer tableting is more expensive than
single-layer tableting for several reasons. First,
the tablet press costs more. Second, the press
generally runs more slowly in bilayer mode.
Third, development of two compatible
granulations is must, which means more time
spent on formulation development, analysis
and validation.
These factors, if not well
controlled/optimized, in one way or another
will impact the bilayer compression per se and
the quality attributes of the bilayer tablets
(sufficient mechanical strength to maintain its
integrity and individual layer weight control).
Therefore, it is critical to obtain an insight into
the root causes to enable design of a robust
product and process.
4.2 Bilayer tablets: Quality and GMP
requirements 22
To produce a quality bilayer tablet, in a validated
and GMP-way, it is important that the selected
press is capable of:
 Preventing capping and separation of the two
individual layers that constitute the bilayer
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International Journal of Research in Pharmaceutical and Biomedical Sciences
tablets.
 Providing sufficient tablet hardness.
 Preventing cross-contamination between the
two layers.
 Producing a clear visual separation between
the two layers.
 High yield, accurate and individual weight
control of the two layers.
4.3 Types of bilayer tablet press 24, 25
A. Single sided tablet press
B. Double sided tablet press
C. Bilayer tablet press with displacement
monitoring.
A) Single-sided press
 The simplest design is a single-sided press
with both chambers of the double feeder
separated from each other.
 Each chamber is gravity- or forced-fed with a
different powder, thus producing the two
individual layers of the tablet.
 When the die passes under the feeder, it is at
first loaded with the first-layer powder
followed by the second-layer powder.
 Then the entire tablet is compressed in one or
two (pre and main-compression) steps.
 The two layers in the die mix slightly at their
interface and in most cases bond sufficiently
so that no layer-separation occurs when the
tablet is produced.
Limitations of single-sided press are:
 No weight monitoring/control of the individual
layers.
 No distinct visual separation between the two
layers.
 Very short first layer-dwell time due to the
small compression roller, possibly resulting in
poor de-aeration, capping and hardness
problems.
 Very difficult first-layer tablet sampling and
sample transport to a test unit for in-line
quality control and weight recalibration.
Dwell time
Dwell time is defined as the time during which
compression force is above 90% of its peak value.
Longer dwell times are a major factor in
producing a quality tablet, especially when
compressing a difficult formulation.
B) Double-sided tablet press
A double-sided press offers an individual fill
station, pre-compression and main-
compression for each layer.
 Most double-sided tablet presses with
automated production control use compression
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ISSN: 2229-3701
force to monitor and control tablet weight.
 The effective peak compression force exerted
on each individual tablet or layer is measured
by the control system at main-compression of
that layer.
 Measured peak compression force (under
constant thickness) is the signal used by the
control system to reject out-of-tolerance
tablets and correct the die fills depth when
required.
Limitations of compression force controlled
system
 A compression force-controlled system
requires a minimal compression force of
several hundreds of daN.
 However, many bilayer formulations require
less than 100 daN to compress first layer in
order to retain the ability to bond with the
second layer.
 Above 100 daN, this ability may be lost,
bonding between both layers may not be
sufficient, resulting in low hardness of the
bilayer tablet and separation of the two layers.
 At higher production speed, the risk of
separation and capping increases but can be
reduced by sufficient dwell time at
compression stages.
C) Bilayer tablet press with displacement
monitoring
The displacement tablet weight control principle
is fundamentally different from the principle
based upon compression force. When measuring
displacement, the control system sensitivity does
not depend on the tablet weight but depends on
the applied pre compression force.
This double-sided tablet press has been
specifically designed and developed for the
production of quality bilayer tablets and provides:
 ‘Displacement’ weight monitoring/control for
accurate and independent weight control of the
individual layers.
 Low compression force exerted on the first
layer to avoid capping and separation of the
two individual layers.
 Increased dwell time at pre-compression of
both first and second layer to provide
sufficient hardness at maximum turret speed.
 Maximum prevention of cross-contamination
between the two layers - a clear visual
separation between the two layers - maximized
yield.
11
International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701

4.4 Recent Developments in the Field of Bilayer
Tablets
The introduction of bilayer tablets into the
pharmaceutical industry has enabled the
development of pre-determined release profiles of
active ingredients and incorporation of
incompatible active ingredients into the single
unit dosage form. Large number of work has been
done in this field. Some of the recent findings are
explained in the preceding table-1.3.
CONCLUSION
Bilayer tablets offer an excellent opportunity for
manufacturers to separate themselves from their
competitors, improve their products’ efficacy, and
protect against impersonator products. Bilayer
tablet quality and GMP requirements can vary
widely. This explains why many different types of
Table-1.3: Various Advancements in the Field of Bilayer Tablets
presses are being used to produce bilayer tablets,
ranging from simple single-sided presses to highly
sophisticated machines. When a quality bilayer
tablet needs to be produced in conjunction with
accurate weight control of both layers,
compression force-controlled presses are clearly
limited because of their insufficient sensitivity
and hence lack of accuracy at low compression
forces required to secure interlayer bonding. Such
problems become even more apparent when the
tableting speed is high or increased. Accurate
individual layer weight monitoring/control at high
speed and in combination with reduced layer
separation risk can be achieved with the
displacement weight control system based
presses.

AUTHOR DRUG(s) DOSAGE FORM RATIONALE METHOD YEAR Ref

No.
Jamunadevi et Diclofenac Bilayer tablets Synergistic effect in Wet granulation 2011 26
al Cyclobenza-prine pain
HCl
Swamy et al Granisetron HCl Bilayer buccal To overcome Direct compression 2011 27
tablets bioavailability problem,
reducing side effects

Pattanayak et al Metformin HCl Bilayer tablets Synergistic effect in Wet granulation 2011 28
Glimipiride diabetes

Jain et al Indomethacin Bilayer floating Biphasic drug release Wet granulation 2011 29
tablets
Mohindeen et al Metformin HCl Bilayer tablets To develop polytherapy Wet granulation 2011 30
Atorvastatin for the treatment of
Calcium NIDDS &
hyperlipidemia
Kumar et al Cefixime Bilayer tablets Synergistic effect in Wet granulation 2011 31
Trihydrate bacterial infections
Dicloxacilline
Sodium

Jadhav et al Piracetam Bilayer tablets Synergistic effect in Wet granulation 2011 32

Vinpocetin Alzheimer disease

Rajendran et al Metformin HCl Bilayer tablets Synergistic effect in Wet granulation & 2011 33
Pioglitazone diabetes mellitus direct compression

Shirsand et al Atenolol Bilayer buccal To overcome Direct compression 2011 34

tablets bioavailability problem,
reducing side effects
and frequency of
administration
Parmar et al Cefuroxime Axetil Bilayer tablets Synergistic effect Dry granulation 2011 35
Potassium against microbial
Clavulanate infections and to
minimize dose
dependent side effects

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International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701

Jayaprakash et Amlodipine Bilayer tablets Synergistic effect in Direct compression 2011 36

al Besilate hypertension & wet granulation
Metoprolol
Succinate
Musle et al Diclofenac Sodium Bilayer tablets Synergistic effect in Wet granulation 2011 37
Paracetamol pain

Remya et al Ibuprofen Bilayer tablets Synergistic effect of Wet granulation 2010 38

Methocarba-mol drugs in back pain

John et al Atorvastatin Bilayer buccal To overcome Direct compression 2010 39

Calcium tablets bioavailability problem,
reducing side effects
and frequency of
administration
Gohel et al Paracetamol Bilayer tablets Synergistic effect of Wet granulation 2010 40
diclofenac drugs in pain

Hiremath et al Losartan Bilayer tablets Biphasic release profile Direct compression 2010 41

Kumar et al Metformin HCl Bilayer tablets Synergistic effect in Dry & wet 2010 42
Pioglitazone diabetes mellitus granulation

Kumar et al Guaifenesin Bilayer tablets Biphasic release profile Wet granulation 2010 43

Naeem et al Tramadol Bilayer tablets Synergistic effect of Coacervation via 2010 44

Acetamino-phen drugs in pain temp change

Kulkarni et al Atenolol Bilayer floating Synergistic effect in Direct compression 2009 45

Lovastatin tablets hypertension and
biphasic release profile
Rathod et al Montelukast Bilayer tablets To improve the stability Wet granulation 2009 46
Levocetrizine of drugs in combination

Nagaraju et al Salbutamol Bilayer tablets Synergistic effect of Wet granulation 2009 47

Theophylline drugs in asthma

Kadam et al Glipizide Bilayer tablets To avoid interaction Wet granulation 2009 48

Metformin HCl b/w incompatible drugs

Atram et al Metoprolol Bilayer tablets Synergistic effect in Wet granulation 2009 49

Succinate hypertension
Amlodipine
Besilate

Friedl et al Telmisartan Bilayer tablets To minimize contact Wet granulation 2009 50

Hydrochlor- b/w hydrochlorthiazide
thiazide & basic component of
telmisartan

Aryal et al Amlodipine Bilayer tablets To improve the stability Wet granulation 2008 51
Atenolol of drugs in combination

Bakuridze et al Ascorbic acid Double layer To avoid interaction Using suppository 2008 52
Cyano-cobalamine supposito-ries b/w incompatible base
vitamins
Gohel et al Rifampicin Capsule & tablet in To avoid interaction Wet granulation & 2007 53
Isoniazid Capsule b/w incompatible drugs compaction

Ouali et al Misorostol Bilayer tablets To minimize contact Wet granulation 2007 54

Diclofenac b/w drugs

Patra et al Propranolol HCl Bilayer tablets Bimodal drug release Wet granulation 2007 55
Godha et al Artesunate Tablet-in-tablet To minimize contact Wet granulation 2007 56
Amlodipine b/w drugs

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 International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN: 2229-3701

Kohlrausch et al Telmisartan Bilayer tablets To minimize contact Wet granulation 2006 57

Simvastatin b/n Simvastatin &
telmisartan

Dhumal et al Cefuroxime axetil Bilayer floating Bimodal drug release Granulation 2006 58
tablets

De-fang et al Metformin Bilayer tablets Synergistic effect of Wet granulation 2005 59

Glipizide drugs in diabetes

Fernandez et al Ranitidine Aspirin Single layer coated To minimize the Granulation 2003 60
tablets contact of two
incompatible drugs

Wang et al Aspirin Ranitidine Single layer tablets To minimize the Wet granulation & 2003 61
contact of two fluidization
incompatible drugs

Ullah et al Statin Aspirin Bilayer tablets To minimize interaction Dry & wet 2001 62
b/w two drugs and side granulation
effects due to aspirin

Ozdemir et al Furosemide Bilayer floating To enhance Kneading method 2000 63

tablets bioavailability

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