INTRODUCTION:

In the last decade, interest in developing a combination of two or more Active Pharmaceutical Ingredients (API) in a single dosage form (bilayer tablet) has increased in the pharmaceutical industry, promoting patient convenience and compliance. Bilayer tablets can be a primary option to avoid chemical incompatibilities between API by physical separation, and to enable the development of different drug release profiles (immediate release with extended release). Bilayer tablets have some key advantages compared to conventional monolayer tablets. For instance, such tablets are commonly used to avoid chemical incompatibilities of formulation components by physical separation. In addition, bilayer tablets have enabled the development of controlled delivery of active pharmaceutical ingredients with pre-determined release profiles by combining layers with various release patterns, or by combining slow-release with immediate-release layers ⁽¹⁾.

However, these drug delivery devices are mechanically complicated to design/manufacture and harder to predict their long term mechanical properties due to the poor mechanical and compression characteristics of the constituent materials in the compacted adjacent layers, elastic mismatch of the layers, insufficient hardness, inaccurate individual mass control, cross contamination between the layers, reduced yield, and their tendency to delaminate at the interface between the adjacent compacted layers during and after the various stages of production downstream of the compaction process. Therefore, the major problem, that has to be overcome, is to understand in detail the sources of these problems in micro- and macro-scales and to develop remedies to solve them during solid dosage delivery design ^(2,
3).

Quality and GMP Requirements⁽⁴⁾

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

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

Ø Providing sufficient tablet hardness

Ø Preventing cross-contamination between the two layers

Ø Producing a clear visual separation between the two layers

Ø High yield

Ø Accurate and individual weight control of the two layers.

These requirements seem obvious but are not so easily accomplished.

Applications⁽⁵⁾

Ø Bi-layer tablet is suitable for sequential release of two drugs in combination.

Ø Separate Two Incompatible Substances.

Ø Sustained release tablet in which one Layer is immediate release as initial dose and second layer is maintenance dose.

Ø Promoting Patient Convenience and Compliance.

Ø Bilayer tablet is improved beneficial technology to overcome the shortcoming of the single layered tablet

Ø Bilayer tablets are used to deliver the loading dose and sustained dose of the same or different drugs.

Ø Bilayer tablets are used for bilayer floating tablets in which one layer is floating layer another one is immediate release layer of the drug.

Ø Bilayer tablets are used to deliver the two different drugs having different release profiles.

Advantages⁽^6-7)

Ø They are used as an extension of a conventional technology.

Ø Potential use of single entity feed granules.

Ø Separation of incompatible components.

Ø Patient compliance is enhanced leading to improved drug regimen efficacy.

Ø Patient convenience is improved because fewer daily doses are required compared to traditional delivery system.

Ø Maintain physical and chemical stability.

Ø _{Retain
potency and ensure dose accuracy}

Disadvantages⁽⁸⁾

Ø Adds complexity and bilayer rotary presses are expensive.

Ø Insufficient hardness, layer separation, reduced yield.

Ø Inaccurate individual layer weight control.

Ø Cross contamination between the layers.

Advantages of bilayer tablet over conventional tablets⁽⁸⁾

Ø Blood level of a drug can be held at consistent therapeutic levels for improved drug delivery, accuracy, safety and reduced side effects. Reduction of adverse effects can be accomplished by targeting the drug release to the absorption site as well as controlling the rate of release, enabling the total drug content to be reduced.

Ø Patient convenience is improved because fewer daily doses are required compared to traditional delivery systems. Patient compliance is enhanced leading to improved drug regimen efficacy.

Ø Bilayer tablets readily lend themselves to repeat action products, where in one layer on layered tablet provides the initial dose, rapidly disintegrate in the stomach. The other layers are insoluble in gastric media but are released in the intestinal environment.

Ø In bilayer tablets, where in one layer on layered tablet provides as immediate release and other layer acts as sustained release.

Ø In sustained release drug delivery system, several approaches are available to add the loading dose to the maintenance dose such as simple addition of a sustained dose of a drug to the sustained portion and placement of initial dose in a tablet coat with the _{sustaining portion in the core as in compression coated tablets.}

General properties of Bi-Layer Tablet Dosage Forms:

Ø A bi-layer tablet should have elegant product identity while free of defects like chips, cracks, discoloration, and contamination.

Ø Should have sufficient strength to withstand mechanical shock during its production packaging, shipping and dispensing.

Ø Should have the chemical and physical stability to maintain its physical attributes over time. The bi-layer tablet must be able to release the medicinal agents in a predictable and reproducible manner.

Ø Must have a chemical stability shelf-life, so as not to follow alteration of the medicinal agents.

Various techniques for bilayer tablet

Oros® push pull technology ⁽⁹⁾:

This system consists of mainly two or three layer among which the one or more layer areessential of the drug and other layer are consist of push layer. The drug layer mainly consistsof drug along with two or more different agents. So this drug layer comprises of drug whichis in poorly soluble form. There is further addition of suspending agent and osmotic agent. Asemi permeable membrane surrounds the tablet core.

Figure 1: Bilayer and trilayer OROS Push pull technology

L-oros tm technology⁽⁹⁾:

This system used 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 then a semi permeable membrane, drilled with an exit orifice.

Figure 2: L – OROS tm technology

En so trol technology⁽¹⁰⁾:

Solubility enhancement of an order of magnitude or to create optimized dosage form Shire laboratory use an integrated approach to drug delivery focusing on identification and incorporation of the identified enhancer into controlled release technologies.

Figure 3: EN SO TROL Technology

Duros technology ⁽¹⁰⁾:

The system consists from an outer cylindrical titanium alloy reservoir. This reservoir has high impact strength and protects the drug molecules from enzymes. The DUROS technology is the miniature drug dispensing system that opposes like a miniature syringe and reglious minute quantity of concentrated form in continues and consistent from over months or year.

Figure 4: The DUROS technology

Elan.drug.technologies’.dual release drug delivery system:

(DUREDAS™ Technology) is a bilayer tablet which can provide immediate or sustained release of two drugs or different release rates of the same drug in one dosage form. The tabletting process can provide an immediaterelease 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:

Ø Bilayer.tabletting.technology.

Ø Tailored.release.rate.of.two.drug.components.

Ø Capability.of.two.different.CR.formulations.combined.

Ø Capability for immediate release and modified release components in one tablet

Ø Unit.dose,tablet.presentation

The DUREDAS™ system can easily be manipulated to allow incorporation of two controlled release formulations in the bilayer. Two different release rates can be achieved from each side. In this way greater prolongation of sustained release can be achieved. Typically an immediate release granulate is first compressed followed by the addition of a controlled release element which is compressed onto .the .initial tablet. This gives.the characteristic.bilayer.effect to the final. dosage .form. A further extension of the DUREDAS™ technology is the production of controlled release combination dosage forms whereby two different drugs are incorporated into the different layers and drug release of each is controlled to maximize the therapeutic effect of the combination. Again both immediate release and controlled release combinations of the two drugs are possible. A number of combination products utilizing this technology approach have been evaluated. The DUREDAS™ technology was initially employed in the development of a number of OTC controlled release analgesics. In this case a rapid release of analgesic is necessary for a fast onset of therapeutic effect. Hence one layer of the tablets is formulated as immediate releases granulate. By contrast, the second layer of the tablet, through use of hydrophilic polymers, releases drug in a controlled manner. The controlled release is due to a combination of diffusion and erosion through the hydrophilic polymer matrix.

Various types of bilayer tablet press ^(11-12):

A. Single sided tablet press.

B. Double sided tablet press.

C. Bilayer tablet press with displacement monitoring.

A. Single sides press:

The simplest design is a single sided press with both chambers of the doublet feeder separated from each other. Each chamber is gravity or forced fed with different powers, thus producing the two individual layers of the tablets. 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 steps.

Figure 5: Single sided tablet press

a) Limitations of single sided press:

Ø No weight monitoring / control of the individual layers.

Ø No distinct visual separation between the two layers.

Ø Very short first layer dwell time due to the small compression roller, possibly resulting in poor de-aeration, capping, and hardness problems.

Ø This may be corrected by reducing the turret-rotation speed (to extend the dwell time) _{but with the consequence of
lower tablet output.}

b) Dwell time

Dwell time is defined as the time during which compression force is above 90% of its peak v a l u e. Longer dwell times are a major factor in producing a quality tablet, especially when compressing a difficult formulation.

c) Compression force

Many bilayer formulations requires a first layer compression force of less than 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, resulting in low hardness of the bilayer tablet and separation of the two layers.

B. Double sided tablet press

Most double sided tablet presses with automated production control use compression 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 the main compression of the layer. This measured peak compression force is the signal used by the control system to reject out of tolerance tablets and correct the die fill depth when required.

Figure 6: Double sided tablet press

C. Bilayer tablet press with displacement

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.

Figure 7: Bilayer tablet press with displacement

Advantages

Ø Weight monitoring / control for accurate and independent weight control of the individual layers.

Ø Low compression force exerted on the first layer to avoid capping and separation of the two individual layers.

Ø Independence from the machine stiffness

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

Ø Maximum prevention of cross-contamination between the two layers

Ø Clear visual separation between the two layers and maximized yield.

Multi-layer compression basics

Presses can be designed specifically for multi-layer compression or a standard double-sided press can be converted for multi-layers:

The multilayer tablets concept has been long utilized to develop sustained release formulation. Such a tablet has a fast releasing layer and may contain bilayer or triple layers to sustain the drug release. The pharmacokinetic advantage relies on the fact that drug release from fast releasing granules leads to a sudden rise in blood concentration. However, the blood level _{is maintained
at steady state as the drug is
released from
the
sustained granules.}

The machine concept

1) Flexible Concept

Ø Bi-Layer execution with optional single-layer

Ø conversion kit

Ø Exchangeable turret

Ø Turret sizes for product development, scale-up, and

Ø mid-range production

Ø Full production capability in a scale-up machine

Ø Self-contained, fully portable design

2) Fast and Easy Changeover

Ø Internal turret lift device for extreme simplicity in turret

Ø removal and installation

Ø Clean compression zone with quick-disconnect design

Ø Design Advantages

Ø Small-scale bi-layer capability

Ø Robust caster base permits full portability

Ø Large touch screen flush mounted

Ø Unique structural design eliminates vibration and noise

Ø Zero clearance feeder for maximum yield and optimal

Ø layer separation

Ø Retractable second layer feeder for automatic first layer

Ø Sampling

3) Full instrumentation

Ø Tamping force

Ø Pre/Main compression force

Ø Ejection force

4) Touch Screen Control

Ø Press force control and single tablet rejection capability

Ø Comprehensive data collection and analysis capability

Ø Real time display and batch data documentation

5) Containment Solution

Ø WipCon^® solution available for potent products.

Steps of compression of bi-layer tablet

Figure 8: Compression cycle of bilayer tablet

Various steps of bi-layer tablet formulation are as follow:

Ø Filling of first layer.

Ø Compression of first layer.

Ø Ejection of upper punch.

Ø Filling of second layer.

Ø Compression of both layer together.

Ø Ejection of bi-layer tablet.

Various approaches used in the Bilayer Tablets⁽¹³⁾

Floating drug delivery system

These are designed to have a low density and thus float on gastric contents after administration until the system either disintegrates or the device absorbs fluid to the point where its density is such that it loses buoyancy and can pass more easily from the stomach with a wave of motility responsible for gastric emptying. The bilayer tablet is designed in such a manner that, one layer gives the immediate dosing of the drug which gives faster onset of action while other layer is designed as a floating layer which floats in the stomach.

Disadvantages:

Ø It may not have the controlled loss of density alternatively required for it to eventually exit from the stomach.

Ø Floating tablets are not applicable to higher dose levels of highly water soluble drugs where large amount of polymer are needed to retard drug release, as in case of water soluble drugs.

Ø The performance of the floating formulation may be posture dependent.

a) Polymer bio adhesive system

These are designed to imbide fluid following administration such that the outer layer becomes a viscous, tacky material that adheres to the gastric mucosa/mucus layer. This should encourage gastric retention until the adhesive forces are weakened. These are prepared as one layer with immediate dosing and other layer with bioadhesive property.

Disadvantages:

Ø The success seen in the animal models with such system has not been translated to human subjects due to differences in mucosal amounts, consistency between animals and humans.

Ø The system adheres to mucous not mucosa.

Ø The mucosal layer in humans would appear to slough off readily, carrying any dosage form with it.

b) Swelling system

These are designed to be sufficiently small on administration on so as not to make ingestion of the dosage form difficult (e.g., less than approximately 23 mm long and less than 11 mm wide for an oval or capsule shaped tablet whereas 10-12 mm in diameter for round tablets). On ingestion they rapidly swell or disintegrate or unfold to a size that precludes passage through the pylorus until after drug release has progressed to a required degree. Gradual erosion of the system or its breakdown into smaller particles enables it to leave stomach. The simple bilayer tablet may contain an immediate release layer with the other layer as extended release or conventional release.

Characterization of bilayer tablet ^(14-15)

Ø Particle size distribution: The particle size distribution was measured using sieving method

Ø Photo-microscope study: Photo-microscope image of TGG and GG was taken (X450 magnifications) by Photomicroscope.

Ø 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 = Height

r = Radius of the powder cone.

Ø 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.

Ø 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

Ø Compressibility: The compressibility index of the disintegrate was determined by carr’s compressibility index.

C = 100 x (1-þb/þt)

Evaluation of Bilayer Tablets ^(16-17):

Ø General Appearance: The general appearance of a tablet, its visual identity and overall “elegance” is essential for consumer acceptance. Includes in are tablet’s size, shape, colour, presence or absence of an odour, taste, surface texture, physical flaws and consistency and legibility of any identifying marking.

Ø Size and Shape: The size and shape of the tablet can be dimensionally described, monitored and controlled.

Ø Tablet thickness: Tablet thickness is an important characteristic in reproducing appearance and also in counting by using filling equipment. Some filling equipment utilizes the uniform thickness of the tablets as a counting mechanism. Ten tablets were taken and their thickness was recorded using micrometer.

Ø Weight variation: Standard procedures are followed as described in the official books.

Ø Friability: Friction and shock are the forces that most often cause tablets to chip, cap or break. The friability test is closely related to tablet hardness and is designed to evaluate the ability of the tablet to withstand abrasion in packaging, handling and shipping. It is usually measured by the use of the Roche friabilator. A number of tablets are weighed and placed in the apparatus where they are exposed to rolling and repeated shocks as they fall 6 inches in each turn within the apparatus. After four minutes of this treatment or 100 revolutions, the tablets are weighed and the weight compared with the initial weight. The loss due to abrasion is a measure of the tablet friability. The value is expressed as a percentage. A maximum weight loss of not more than 1% of the weight of the tablets being tested during the friability test is considered generally acceptable and any broken or smashed tablets are not picked up. Normally, when capping occurs, friability values are not calculated. A thick tablet may have less tendency to cap whereas thin tablets of large diameter often show extensive capping, thus indicating that tablets with greater thickness have reduced internal stress the loss in the weight of tablet is the measure of friability and is expressed in percentage as:

% Friability = 1‐ (loss in weight / Initial weight) X 100

Ø Hardness (Crushing strength) 33: The resistance of tablets to capping, abrasion or breakage under conditions of storage, transportation and handling before usage depends on its hardness. The small and portable hardness tester was manufactured and introduced by Monsanto in the Mid 1930s. It is now designated as either the Monsanto or Stokes hardness tester. The instrument measures the force required to break the tablet when the force generated by a coil spring is applied diametrally to the tablet. The Strong-Cobb Pfizer and Schleuniger apparatus which were later introduced measures the diametrically applied force required to break the tablet. Hardness, which is now more appropriately called crushing strength determinations are made during tablet production and are used to determine the need for pressure adjustment on tablet machine. If the tablet is too hard, it may not disintegrate in the required period of time to meet the dissolution specifications; if it is too soft, it may not be able to withstand the handling during subsequent processing such as coating or packaging and shipping operations. The force required to break the tablet is measured in kilograms and a crushing strength of 4 Kg is usually considered to be the minimum for satisfactory tablets. Oral tablets normally have a hardness of 4 to 10 kg; however, hypodermic and chewable tablets are usually much softer (3 kg) and some sustained release tablets are much harder (10 -20 kg).Tablet hardness have been associated with other tablet properties such as density and porosity. Hardness generally increases with normal storage of tablets and depends on the shape, chemical properties, binding agent and pressure applied during compression.

Ø Stability Study (Temperature dependent) ⁽¹⁸⁾: The bilayer tablets are packed in suitable packaging and stored under the following conditions for a period as prescribed by ICH guidelines for accelerated studies. The tablets were withdrawn after a period of 15 days and analyzed for physical characterization (Visual defects, Hardness, Friability and Dissolution etc.) and drug content. The data obtained is fitted into first order equations to determine the kinetics of degradation. Accelerated stability data are plotting according Arrhenius equation to determine the shelf life at 25°C.

Table 1: Stability condition as per ICH guideline

Study	Storage Condition	Minimum time period
Long term	25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH	12 months
Intermediate	30°C ± 2°C/65% RH ± 5% RH	6 months
Accelerated	40°C ± 2°C/75% RH ± 5% RH	6 months

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 singlesided presses to highly sophisticated machines.

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Received on 07.02.2013 Accepted on 22.03.2013

Asian J. Pharm. Res. 3(2): April- June 2013; Page 49-56