INTRODUCTION various coating technique. Ø Ideal for mass scale

INTRODUCTION

The
majority of the formulations available today are taken orally. It means this
route of administration is most commonly used all over the world and most of
the researchers are pulled in towards this class of formulation. The foremost
objective of the controlled drug delivery system is to minimize the dosing
recurrence. The elementary point of modified drug release formulations is to
improve a therapeutic regimen by providing prolonged and continuous action for
predetermined time period providing greater safety, efficacy and precision.
Bilayer tablet is the new age for the affluent development of modified drug
release formulation. Bilayer tablet may be better than those routine utilized
dosage forms. Bilayer tablet is great suiting for sequential arrival of two medicaments
and it is also capable of partitioning the two contrario substances. It is also
suited for sustain release tablets in which one layer is immediate release layer
and another is sustain release layer.

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                                                          Need
of Bilayer Tablet

Ø   To modulate
the delivery rate of two or more different active pharmaceutical
ingredients.

Ø  To
formulate the fixed dose combination of different APIs, increase the product
life cycle.

Ø  To
modify the total surface area available for API layer either by sandwiching
with one or more inactive layers in order to attain swellable / erodible
barriers for modified release.

                                              Advantages
of Bilayer Tablet

Ø   Less expensive previously, value concerning
illustration contrasted with different measurement structure.

Ø  Substantial
physical, chemical and microbiological steadiness as compared to other dosage
form.

Ø  Unpleasant
stench and bad taste can be conceal by using various coating technique.

Ø  Ideal
for mass scale production.

Ø  Lighter
and compact.

Ø  Versatile
and Functional concept

Ø  Recognition
of product is straightforward and rapid necessitating no auxiliary steps when
employing an embossed and/ or monogrammed punch face.

                            

 Disadvantage
of Bilayer Tablet

Ø  Drugs
having bitter taste, drugs with unpleasant stench or drugs that are oxygen
sensitive might require coating.

Ø  Children
and unconscious patient may find difficult to swallow it.

Ø  Drugs
hosting poor wettability, poor release profile are difficult to formulate.

Ø  Cross
tainting might occur between two layers.

Ø  Capping

Ø  Several
drugs refrain compression due to amorphous nature, low density character.  

                   Challenges in Bilayer Manufacturing

In spite of the aforementioned
merits of the bilayer tablets, there are several complication associated with
the mechanism and compression of bilayer tablets that have been reported in the
literature in recent years.

Ø  Cross
contamination: When the granules of one layer blend/mix with the granules of
other layer, cross contamination occurs. It may repress the purpose of the
bilayer tablet.

Ø  Delamination:
Tablet separates aside when they the two parts of the gadget do not bond with
each other.

Ø  Cost:
Bilayer tablet is more expensive as compared to the traditional dosage forms.

Ø  Production
yield: Bilayer tablet have a lesser yield than single layer tablet.

                                       VARIOUS
TECHNIQUES FOR BILAYER TABLET

a)
EN SO TROL TECHNOLOGY: To increase
solubility to a magnitude or to formulate optimized medication dosage form
Shire laboratory utilized an coordinated methodology to drug delivery focusing
on identification and incorporation of the identified enhancer into controlled
release technology.

.

b) Bilayer and trilayer OROS push pull technology:
This
system is employed for the solubility issue Alza developed the L-OROS system
where a lipid soft gel product containing drug in a dissolved state is
initially manufactured and then coated with a barrier membrane, than osmotic
push layer and than a semipermeable membrane, drilled with an exit orifice.

c)
OROS® push pull technology: This technique
comprises of two or more layers among which one or more layers are essentially
of the drug and other layers consist of push layer. The drug layer mainly consists
of drug along with two or more different agents. So this drug layer comprises
of drug which is in poorly soluble form. There is further addition of
suspending agent and osmotic agent. A semi permeable membrane surrounds the
tablet core.

d) DUREDASTM TECHNOLOGY:
(DUREDAS™
Technology) is a technology which provides immediate or sustained release of
two drugs or different release rates of the same drug in one dosage form. The tableting
process can provide an immediate release granulate and a modified-release
hydrophilic matrix complex as separate layers within the one tablet. The
modified-release properties of the dosage form are provided by a combination of
hydrophilic polymers.

Benefits
offered by the DUREDAS™ technology include

1)
Bilayer tableting technology.

2)
Tailored release rate of two medication components.

3)
Capability of two different Controlled Release Formulations combined.

4)
Ability for immediate release and modified release components in one tablet.

5)
Unit dose tablet.

e) PRODAS
or programmable oral drug absorption system

PRODAS
is a mutliparticulate drug delivery technology that is primarily based on the
encapsulation of controlled release minitablets in the size range of 1.5 to 4
mm in diameter .This technology represents a combination of multiparticulate
and hydrophilic matrix tablet technologies and thus provide the desired release
rates .These considerations may include immediate release delayed release and /
or controlled release minitablets. In addition to controlled release absorption
over a specified period .PRODAS technology also enables targeted delivery of
drug to specified sites of absorption throughout
the GI tract .Combination products also are possible by using minitablets
formulated with different ingredients.

 

 

f)
GEMINEX TECHNOLOGY

In
this drug delivery system at different times more than one drug can be
delivered. This technology basically increases the therapeutic efficacy of the
drug by decreasing its side effects. It is useful both to industry as well as patient
as in single tablet it provides delivery of drug at different rates.

g)
ERODIBLE MOLDED MULTILAYER TABLET

Egalet
erodible molded tablets in an erosion based platform. It has the benefit of

delivering
zero order or delayed release with minimum effect from the gastrointestinal

environment.
Egalet erodible molded multilayered tablets are prepared by injection moulding
egalet technology comprises of a coat and a matrix. Drug release is controlled
through the gradual erosion of the matrix part. The mode and rate of release
are designed and engineered by altering the matrix the coat and the geometry to
achieve by altering the matrix the coat, the geometry to achieve either a zero
order release or a delayed. For a zero order, a drug is dispersed through the matrix.
The coat is biodegradable but has poor water permeability to prevent its penetration.
The matrix tends to erode when in contact with available water .The erosion of
the matrix is caused by GI fluids and promote by gut movements in the GI tract
.The drug release is mediated almost wholly by erosion because the dosage form
is designed to slow

down
the water diffusion into the matrix .It is definitely more desirable for drugs
with

chemical
and physical stability issues after contacting with water .Egalet delivery

technology
is developed based on standard plastic injection molulding to ensure accuracy
,reproducibility and low production cost.

TYPES OF BILAYER TABLET PRESS

A)
Single sided tablet press.

B)
Double sided tablet press

C)
Bilayer tablet press with displacement monitoring.

D)
Multilayer compression basics

A)
Single sided press

Various
types of bilayer presses have been designed over the years .The simplest design
is a single sided press with both chambers of the double feeder separated from
each other. Each chamber in gravity fed , or force 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 of powder followed
by the second-layer powder then the entire tablet is compressed in one or two
steps ( two pre and main compression) . 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 this is the simplest way of
producing a bilayer tablet.

LIMITATIONS OF
SINGLE SIDED PRESS

? No
weight monitoring or control of the individual layers

? No
distinct visual separation between the two layers

? Dwell
time due to the small compression roller possible resulting in poor deareation
capping and hardness problems.

DWELL TIME

Dwell time is
defined as the time during which compression force is above 90% of its peak value.
Longer dwell time is the major factor in the production of quality tablets.

COMPRESSION
FORCE

Many bilayer
tablets require a first layer compression force of 100 daN in order to retain
the ability to bond with the second layer . above 100daN this ability may be
lost and bonding between both layers may not be sufficient. this results in low
hardness bilayer tablets and might cause separation of the two layers.

B)
DOUBLE SIDED TABLET PRESSES

Most
of the double sided tablet presses which are automated production control use
the compression force to monitor and control the weight of the tablet weights. The
effective compression force exerted on each individual tablet with the help of
the compression system at the main compression of the layer. This system helps
in to reject out the tolerance tablets and correct the dies fill depth when required.

 

ADVANTAGES

1.
Low compression force exerted on thefirst layer to avoid capping and separation
of the individual layer.

2.
Increased dwell time at pre compression of both first and second layer to
provide sufficient hardness at maximum turret speed.

3.
Maximum prevention of cross contamination between two layers.

4.
A clear visual separation between the two layers.

5.
Displacement weight monitoring for accurate and independent weight control of
the individual layer.

6.
Maximized yield.

LIMITATIONS

Separation
of the two individual layers is due to insufficient bonding between the two
layers during final compression of bi-layer tablet. Correct bonding is only
obtained when the first layer is compressed at a low compression force so that
this layer can still interact with the second layer during final compression.
Bonding is too restricted if first layer is compressed at a high compression
force. The low compression force required when compressing the first layer unfortunately
reduces the accuracy of the weight monitoring/control of the first layer in the
case of tablet presses with “compression force measurement”. Most of the double
sided tablet presses with automated production control use compression force.

3)
BILAYER TABLET PRESSES WITH DISPLACEMENT

The
principle of bilayer tablet press is fundamentally different from the principle
of compression force. In this case the accuracy increases with reduced
compression force .At higher production speed the risk of capping and separation
increases but can be reduced by sufficient dwell time at all four compression stages
.

ADVANTAGES

·        
Displacement weight monitoring/control
for accurate independent weight control of the individual layers.

·        
 Increased dwell time at
precompression of both first and second layer to provide sufficient hardness at
maximum turret speed

·        
 Maximum prevention of
cross contamination between the layers.

·        
 A clear visual
separation of the layers

·        
 Maximized yield .

4)
MULTILAYER COMPRESSION BASICS

Presses
can be designed specifically for multilayer compression or a standard double
press can be converted for multilayer. The multilayer tablets concept has been
long utilized to develop sustained release formulations such tablets have fast
releasing layer and may contain bilayer or triple layers to sustain drug
release from the tablet. The pharmacokinetic advantage relies on the fact that drug
release from fast releasing granules leads to sudden rise in blood
concentration however the blood level is maintained at a steady state as the
drug is released from the sustained granules.

PREPARATION
OF BILAYER TABLET

Bilayer
tablets are prepared with one layer of drug for immediate release with the
second layer designed to release drug later, either as a second dose or in an
extended release form. The bilayer tablets with two incompatible drugs can also
be prepared by compressing separate layers of each drug so as to minimize area
of contact between two layers. An additional intermediate layer of inert
material may also be included.

COMPACTION

To
produce adequate tablet formulation, certain requirements such as sufficient mechanical
strength and desired drug release profile must be met. At times, this may be difficult
task for formulator to achieve these conditions especially in bilayer tablet formulation
where double compression technique is involved, because of poor flow and
compatibility characteristic of the drug which will result in capping and/or
lamination. The compaction of a material involves both the compressibility and
consolidation.

COMPRESSION

It
is defined as reduction in bulk volume by eliminating voids and bringing
particles into

Closer
contacts.

CONSOLIDATION

It
is the property of the material in which there is increased mechanical strength
due to interparticulate interaction (bonding). The compression force on layer 1
was found to be major factor influencing tablet delamination.

 

5)
DIFFERENT TYPES OF BILAYER TABLET PRESSES

A)
PICCOLA BILAYER

This
rotary press was designed to represent two-layer tablet production
conditions at a small scale, according to the needs of new product
development.Piccola Bi-layer press meets cGMP standards and can use type D or B
tooling complying with TSM or EU standards, which allows the employment of the same
punches used in production. For an appropriate adjustment in tablet production,
there are totally independent systems for weight, height and hardness
adjustment, both for the first and second layers. A PLC system having a touch
screen and software designed for Galenic Development and Production Control
allows the integrated control of all parameters, including production rate and,
separately, the rate of each of the star forced feeder. There are varied accessories
and options for the software used; such as the possibility of weight control
during production and the use of data obtained for calculation and statistics.

B)
ROTAB BILAYER

a)
Software

It
is modular designed software to which additional functions can be added.
PCsystem with 15″touchscreens is an advanced system which provides fast graphical
evaluations with accurate results.

b)
Working

RoTab
bilayer when using is switched to production mode. Dose and compression

force
is automatically regulated by adjusting filling speed and die table. Hardness
is also regulated when required.

c)
R and D modified technique

R
and D modified RoTab Bilayer is featured with measuring points on which there
are graphical visualization and evaluation are possible. There is an additional
alarm function on which punch tightness is controlled. Anytime upgration is
possible which is R and D Plus.

d)
R and D Plus.

R
and D Plus provides improved standards in tabletting technology with all
important

functions
such as punch tightness control display of force displacement and tablet
scraper force.

C) BILAYER TABLET PRESS

The Xm bilayer tablet press features a rectangle second layer
feeder that permits automated first layer sampling at production speeds . The
first layer sampling capability also offers a hardening feature , which the main
compression station will automatically compress , the first layer tablet for
in-process measurement .The two feeders are zero clearance and are configured
with an integrated dust extraction manifold which cleans the dis table and
completely eliminates any potential of cross contamination .

wipcon® solution available for potent for layer tablet press is a
small scale press which is ideal for product development, scale up, clinical
trials and midrange production . The bilayer execution, single layer conversion
kit and exchangeable turret offers, a new standard in GMP with extreme
accessibility to the compression zone and a combination of quick disconnects
and smooth surfaces that permit fast cleaning and changeover the machine
concept:-

ADVANTAGES

Flexible concept.

Bilayer execution with optional single layer.

QUALITY AND
GMP-REQUIREMENTS

To
produce a quality bi-layer tablet, in a validated and GMP-way, it is important
that the Selected press is capable of five:

1.
Preventing capping and separation of the two individual layers that constitute
the bi-layer tablet

2.
Providing sufficient tablet hardness

3.
Preventing cross-contamination between the two layers

4.
Producing a clear visual separation between the two layers

5.
High yield Accurate and individual weight control of the two layers.

These
requirements seem obvious but are not so easily accomplished.

EVALUATION
OF BILAYER TABLET

A) PARTICLE SIZE DISTRIBUTION

The particle size distribution was measured using sieving method.

B) PHOTON MICROSCOPE STUDY

Photo-microscope image of TGG and GG was taken (X450
magnifications) by photomicroscope.

C) ANGLE OF REPOSE

The diameter of the powder cone was measured and the angle of
repose was calculated using the following equation.

Tan Ø=h/r

Where h and r are the height and radius of the powder cone.

D) MOISTURE SORPTION CAPACITY

All disintegrates have capacity to absorb moisture from atmosphere
which affects

moisture sensitive drugs. Moisture sorption capacity was performed
by taking 1 g of disintegrate uniformly distributed in Petri-dish and kept in
stability chamber at 37±1°C and 100% relative humidity for 2 days and investigated
for the amount of moisture uptake by difference between weights.

E) DENSITY

The loose bulk density (LBD) and tapped bulk density (TBD) were
determined and calculated

using the following formulas.

LBD ¼ weight of the powder=volume of the packing ð2Þ

TBD ¼ weight of the powder=tapped volume of the packing ð3Þ

F) COMPRESSIBILTY

The compressibility index of the disintegrate was determined by
Carr’s compressibility index.

C = 100 x (1-ÞB/ÞT)

(Indian Pharmacopoeia, 1996; United States Pharmacopoeia,
2000:1944).

G) HAUSNERS RATIO

It is calculated by the formula, freely settled bulk density of
the powder tapped density of the powder

 

 

7) EVALUATION OF SUSTAIN RELEASE BILAYER TABLET

A) TABLET THICKNESS AND SIZE

Thickness and diameter of tablets were important for uniformity of
tablet size.

Thickness and diameter was measured using venire caliper.

B) TABLET HARDNESS

The resistance of tablets to shipping or breakage under conditions
of storage,

transportation and handling before usage depends on its hardness.
The hardness of tablet of each formulation was measured by Monsanto hardness
tester. The hardness was measured in kg/cm2.

C) FRIABILITY

Friability is the measure of tablet strength. Electrolab EF- 2
friabilator (USP) was used for testing the friability using the following procedure.
Twenty tablets were weighed accurately and placed in the tumbling apparatus
that revolves at 25 rpm dropping the tablets through a distance of six inches
with

each revolution. After 4 min, the tablets were weighed and the
percentage loss in tablet

weight was determined.

% loss = (Initial wt. of tablets – Final wt. of tablets)/ Initial
wt. of tablets ×100.

 

D) UNIFORMITY OF WEIGHT

Twenty tablets were selected at random and the average weight was
calculated. Weight

Variation
was calculated and was compared with I. P. standards.

E)
DISSOLUTION STUDIES

Bilayer
tablets were subjected to in vitro drug release studies in simulated gastric
and

Intestinal
fluids to assess their ability in providing the desired controlled drug
delivery . Drug release studies were carried out using USP dissolution test
apparatus I at 100 rpm,

37±0.5°C,
and pH 1.2 buffer (900 ml) (i.e. 0.1N HCl) for 2 hours, since the average
gastric emptying time is about 2 hours. The dissolution medium was replaced
with pH 6.8 phosphate buffer (900ml) and experiment continued for another 10
hours. At different time intervals, 5ml of the samples were withdrawn and
replaced with 5ml of drug-free dissolution medium. The samples withdrawn were
analyzed by UV spectrophotometer using multi component mode of analysis.

CONCLUSION

Bilayer
tablet is improved beneficial technology to overcome the shortcoming of the
single layered tablet. There is various application of the bi-layer tablet it
consist of monolithic partially coated or multilayered matrices. Bilayer tablet
is suitable for sequential release of two drugs in

combination,
separate two incompatible substances and also for sustained release tablet in

which
one layer is immediate release as initial dose and second layer is maintenance
dose. The

preparation
of tablets in the form of multi layers is used to provide systems for the
administration of drugs, which are incompatible and to provide controlled
release tablet preparations by providing surrounding or multiple swelling
layers. Bilayer tablet quality and GMP-requirements can vary widely. This
explains why many different types of presses are being used to produce bi-layer
tablets, ranging from simple single sided presses to highly sophisticated
machines such as the Courtoy-R292F. Whenever high quality bilayer tablets need
to be produced at high speed, the use of an ‘air compensator’ in combination
with displacement control appears to be the best

Solution.

 

 

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