Bilayered Tablet Technology with Recent Advancement - A Review

 

Ratnaparkhi. Mukesh P.*, Vyas Ram Ganesh

Department of Pharmaceutics , MMM’s College of Pharmacy, Theragaon (Kalewadi), Pune-411033

 

ABSTRACT:

Bi-layer tablet is a new era for successful development of controlled release formulation along with various features to provide successful drug delivery.Bi-layer tablet is suitable for sequential release of two drugs in combination and also for sustained release of tablet in which one layer is for immediate release as loading dose and second layer is maintenance dose. Bilayer tablet is best option for drug  which have low bioavailablity and short plasma half life for formulating as a sustain release layer. Bi-layer tablets can be primary option to avoid chemical incompatibilities between APIs by physical separation and to enable the development of different drug release profiles.Several pharmaceutical companies are currently developing bi-layer tablets, for a variety of reasons: patent extension, therapeutic, marketing to name a few. So use of bi-layer tablets is a very different aspect for anti-hypertensive, diabetic, anti-inflammatory and analgesic drugs

 

where combination therapy is often used.the present article provides an introduction to bi-layer tablet technology, need and general properties of bi-layer tablet dosage form, various techniques for bilayer tablets , bi-layer compression basics, manufacturing process of bilayer tablet, and recent developments in the field of bi-layer technology and finally evaluation of bilayer tablets.

 

 

INTRODUCTION:

Bi-layer tablets are novel drug delivery systems which have been gaining importance in the recent years to treat various forms of disease or to obtain different therapeutic actions. These are systems wherein two or more drugs are compressed on top of each other to form a single unit. The two layers are generally made of different colours to distinguish between them. When two or more incompatible actives are to be delivered, formulating a bilayer tablet is the best option. [1-3]

 

Several pharmaceutical companies are currently developing bi-layer tablets, for a variety of reasons: patent extension, therapeutic, marketing to name a few. The method of preparation includes compressing granules on to previously partially compressed granules.

 

Each layer is fed from different hopper into the feed frame with individual weight control. Dust extraction is essential to avoid cross contamination. The layer with more weight is filled in first into the die through one hopper. It undergoes a pre-compression stage to avoid intermixing of granules due to mechanical vibration followed by filling of the next granules and compression.

 

Fig 1: Image of Bilayer tablet

 

Definition:

The word ‘Bilayer Tablet’ indicates that it is a solid oral dosage form, usually round, spherical, oval or biconcave in shape and consists of one or more than one medicament designed in a two layers system which can be suitable for combination therapy and biphasic release therapy. In case of combination therapy the two layers of this tablet is consist of two different medicaments and in case of bi-phasic release bilayer tablet both the layers content same drugs but the drug from one layer is immediately release and the drug release from the second layer is released for an extended period of time to maintained the therapeutic concentration of drug within therapeutic window. [4-6]

 

History:

The history for bilayer tablets is quite older from over 50 years and one of the early scientific evaluations of layered tablets was published by Stephenson. Gunsel et al. designs the method during 1970 and it made possible to check the weight of individual layers by sampling without stopping the machine, providing in process control facilities to ensure correct dosing. However, despite this, a considerable amount of expertise is still required to formulate these tablets and to ensure consistent manufacture to satisfy regulatory requirements.The formulations used for each individual layer should be compressible and compactable on their own i.e. they should show satisfactory reduction in volume and form mechanically strong, coherent solid bodies. Under this assumption the interface between the layers should weld together during compaction and strong adhesion forces should hold the layers together after tablet ejection.confirmed observations first made by Karehill et al., i.e. that the compaction pressure used to form the first tablet layer should be kept at a minimum to provide sufficient surface roughness for nesting and particle interlocking between layers to occur. Due to the increase in surface roughness there is a larger contact area between the layers, which enhances interlayer it is also necessary to devise an experimental method that can be used on bilayer tablets to detect lamination tendencies that are not already obvious after tablet ejection, but only manifest themselves after storage and handling of the compacts. [7, 8]

 

Multi-layer tablet dosage forms are designed for variety of reasons:

1      To separate incompatible Active pharmaceutical ingredient (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).

2      To control the delivery rate of either single 8 or two different active pharmaceutical ingredient(s) [9, 10]

3      To modify the total surface area available for API layer either by sandwiching with one or two inactive layers in order to achieve swellable/ erodible barriers for modified release. [7, 8]

4      To administer fixed dose combinations of different APIs ,prolong the drug product life cycle, fabricate novel drug delivery systems.[13-16]

 

Advantages of the bi-layer tablet dosage form are: [17,18]:

1)    These are unit dosage form having the greatest capabilities of all oral dosage form for the dose precision.

2)    Maximum prevention of cross-contamination between the two layers.

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

4)    Easiest and cheapest to package and strip.

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

6)    Cost is lower compared to all other oral dosage form.

7)    Lighter and compact.

8)    Easy to swallowing with least tendency for hang-up.

9)    Clear visual separation between the two layers and maximized yield.

10)  Product identification is easy and rapid requiring no additional when employing an embossed and/or monogrammed punch face.

11)  Suitable for large scale production.

 

Disadvantages of bilayer tablet dosage form:

1      Some drugs resist compression into dense compacts, owing to amorphous nature, lowdensity character.

2      Bitter tasting drugs, drugs with an objectionable odour or drugs that are sensitive to oxygen may require encapsulation or coating.

3      Difficult to swallow in case of children and unconscious patients.

4      Drugs with poor wetting, slow dissolution properties, optimum absorption high in GIT may be difficult to formulate or manufacture as a tablet that will still provide adequate or full drug bioavailability.

5      Capping

6      Hardness problem

 

General properties of bi-layer tablet dosage forms: [19]:

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

2        Should have the physical and chemical stability to maintain its physical attributes over time.

3        The bi-layer tablet must be able to release the medicinal agents in a predictable and reproducible manner.

4        It should have sufficient strength to withstand mechanical shock during its production packaging, shipping and dispensing.

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

 

Need of bilayer tablets:  [18, 20, 21]:

·      Controlling the delivery rate of either single or two different active pharmaceutical ingredient(s)

·      To separate incompatible Active pharmaceutical ingredient (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).

·      For the administration of fixed dose combinations of different APIs, prolong the drug product life cycle, buccal/ mucoadhesive delivery systems; fabricate novel drug delivery systems  such as chewing device and floating tablets for gastro-retentive drug delivery.

·      To modify the total surface area available for API layer either by sandwiching with one or two in active layers in order to achieve swellable/ erodible barriers for modified release.

 

Various techniques for bilayer tablets: [22-25]:

A. Duredas (Dual release drug absorption system): [22,23]:

Duredas utilizes a bilayer-tableting technology which has been designed to provide two different release rates or dual release of drug from single dosage form. The tablets are prepared by two separate granulations – an immediate release granulate (for rapid action) and a controlled-release hydrophilic matrix within one tablet. The controlled release matrix remains intact and slowly absorbs fluid from GI tract, making the hydrophililc matrix porous and viscous gel that serves as a barrier between drug and surrounding fluid.

Advantages offered by DUREDAS technology

1      Bilayer tabletting technology

2      Tailored release rates of two drugs

3      Capability of immediate release and modified release components in one tablet

 

B. Geomatrix technologies [23]:

It is a multilayer tablet constituting of a matrix core surrounded by one or more layers (barriers) applied during the tabletting process. The function of these barriers is to delay the interaction of the core with the dissolution medium.

 

C. OROS push pull technology:

This consists of one or more layers constituting the drug and the other consisting of the push layer. There is further addition of suspending agent and osmotic agent.. OROS is the main osmotic system owned by Alza Corporation. They designed a push-pull delivery system which is a two compartment system in the dosage form separated by an impermeable membrane. One compartment contains the drug and orifice while the other compartment contains the polymer matrix. Water can diffuse into both compartments, but when the polymer matrix swells, it pushes up against the impermeable membrane and the osmotic pressure causes drug particles to be released through the orifice. They also designed a tri-layer delivery system which contains multiple drug layers and one polymer matrix layer. The drug layers have different release kinetics that allows sustained release and constant drug blood levels.

 

Fig.2 :OROS Push Pull technology

 

D. L-OROS Technology [24]:

This system was initially developed by Alza Corporation. It constitutes of a lipid soft gelatin containing the drug in dissolved state. It is surrounded by a barrier membrane followed by a osmotic push layer, a semi permeable membrane with an exit orifice. The L-OROS has a liquid drug formulation covered by a soft gelatin capsule and a barrier inner membrane on the inside. The outside is covered by a rate-controlling membrane over an osmotic push layer. L-OROS soft capsule system can be used to enhance compliance and therapeutic effect.

 

Fig.3:  L–OROS Technology

 

E. Geminex[25]:

Geminex is a dual drug delivery technology that can deliver one or more drugs at different times. This technology controls the release rate of two drugs to maximize their individual therapeutic effect and minimize side effects. The ultimate benefit of this dosage form is that two different actives or the same active can be delivered at different rates in a single tablet.

 

Bi-layer compression basics:

A)   Initial layer die filling and compaction.

B)    Initial layer compaction showing the predominant stress transmission profile.

C)    Density profile of initial layer before die filling of the final layer.

D)   Final layer die filling and compaction.

E)    Final layer compaction showing the predominant stress transmission profile.

F)    Density profile of bilayer tablet before ejection.

G)   Ejection of a bilayer tablet.

 

Fig.4 Schematic diagram showing the manufacture of single and bilayered tablets utilising uniaxial compaction.

 

Dashed arrows show the postulated radial expansion due to energy dissipation. Black areas correspond to regions of localized high density. Arrows show the direction of the applied stress26

A     Die filling

B     Compression

C     Decompression

D     Lower punch removal and reapplication of load to the upper punch

E     Tablet fully ejected.

 

Manufacturing process of bilayer tablet 27:

Manufacturing processes such as wet granulation/roller compaction and addition of binders increases the level of complexity in understanding the critical factors governing compression and tablet breaking force. Thus, the tablet breaking force and the tablet’s propensity for delamination/capping either during manufacturing or during storage need to be carefully observed. Apart from the critical material attributes of individual components and final blend, the tablet press has large influence on the manufacture of multilayer tablets.

 

1. Skipping first layer compression:

the number of compressions in manufacturing of multi-layer tablets is equal to the number of layers in the multi-layer tablet. If the first layer is not compressed before addition of second layer, there is a possibility of uncontrolled mixing of granules of first layer into second layer at the interface.

 

2. Tablet breaking force:

According to the current USP, tablet breaking force is the force required to cause the tablets to break in a specific plane. The tablets are generally placed between two platens, one of which moves to apply sufficient force to the tablet to cause fracture.

 

 

Tensile strength is calculated by the following [19].

 

Tensile strength = 2F/πDh

Where, F is the load required breaking the tablet diametrically (as opposed to de-laminating or capping), “D” and “h” are tablet diameter and thickness, respectively. 

 

Another measure for mechanical strength is the crushing strength-friability ratio (CSFR).

 

3. Effect of lubrication:

The interfacial interactions between the first layer and the second layer may be impacted by the level of lubricant. The tablet surface smoothness increases as the level of lubricant, such as magnesium stearate is increased in order to achieve a better interfacial interaction between the layers, relatively low lubricant concentration (practically possible) and low compression forces are required for first layer tableting. Thus, adding lubricant to the dies and punches, instead of adding directly to the granules, has been investigated to understand the impact of lubricant on the critical quality attributes of the tablet.

 

4. Coating:

Often multi-layered tablets are coated to improve elegance, to protect the cores from ambient conditions or to control the release profile.

 

To avoid layer-separation during the coating process it is important to know the coefficients of thermal expansion of the tablet layers and the impact of this difference on the tablet integrity

 

Though cracking is reported for bi-layer tablets that undergo coating, it is possible that the cracking and/or separation of layers could also occur upon extended storage of the drug product

 

5. Stability:

The use of a combination of two APIs or the same API with different release rate to optimize therapy and to improve patient compliance has increased steadily over the years 27.

To achieve this objective it is imperative that the quality and the performance of the bi-layer tablets be maintained over the expiration period. The stability studies must be performed under conditions as per ICH guidelines and the supportive stability data generated during the product development phase and on the exhibit (clinical and/or BA/BE) batches to demonstrate the product quality and performance must be included in the filing.

The bilayer tablets are packed in suitable packaging and stored under the following conditions for a period as prescribed by ICH guidelines for stability studies.

 

Table 1: ICH guidelines for stability studies.

Study	Storage condition	Minimum time period
Long term	250C ±20C / 60% RH ±5 %RH	12 Months
Intermediate	300C± 20C /65 % RH± 5% RH	6 Months
Accelerated	400C± 20C /75 % RH± 5% RH	6 Months

 

Bi-layer tablets quality and GMP-requirements:

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

1        Preventing capping and separation of the two individual layers that constitute the bi-layer tablet.17

2        Producing a clear visual separation between the two layers.

3        Preventing cross-contamination between the two layers

4        Providing sufficient tablet hardness

5        High yield.

6        Accurate and individual weight control of the two layers. These requirements seem obvious but are not as easily accomplished as this article aims to demonstrate.

 

Latest advancement in the field of bilayer tableting technology:

R292f Bilayer tablet press: [19]

Double –sided rotary tablet press for single and double layer tablets having the following advantages:

·      Automatic double layer rotary press for single layer tablet production

·      Medium volume production as double layer/single output

·      Unique air compensator system at pre-compression for extended dwell time

·      High volume production as single layer/double output

·      Hard chromium plated die table

·      Replaceable punch guide bushings

 

Evaluation of bilayer tablets:

1. General Appearance:

The general appearance of a tablet, includes tablet’s size, shape, colour, presence or absence of an odour, taste, surface texture, physical flaws and consistency and legibility of any identifying marking.

 

2. Size and Shape:

The size and shape of the tablet can be dimensionally described, monitored and controlled and its vary from product.

 

3. Tablet thickness:

Tablet thickness is an important characteristic in reproducing appearance and also in counting by using filling equipment. Vernier caliper also used for measurement of bilayer tablet thickness ten tablets were taken and their thickness was recorded using vernier caliper or micrometer.

 

4. Weight variation:

Standard procedures are followed as described in the official books.

 

5. Uniformity of weight:

Twenty randomly selected tablets were weighed individually. Their average was calculated. % weight variation was calculated from average weight of tablet. Accepted percent deviation on average weight of tablet is according to the following table

 

6. Friability:

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. Randomly picked tablets weighing approximately 6.5 g were taken (X). The friability tester was kept at an angle for rotation. The tablets were loaded and set to rotations at 25 rpm. After 100 and 300 rpm, tablets were carefully removed and observed physically for any changes in appearance i.e lamination, capping, chipping. The tested tablets were de-dusted and weighed again (Y). USP limit for friability is 0.5 % to 1%.

 

% Friability was then calculated using the following formula-

%F = W₀-W/W₀ x 100

Where,

% F = Friability in percentage ,

W₀ = initial weight of tablets

W = weight of tablets after Revolutions

 

 

 

Table-2: Various Advancements in the Field of Bilayer Tablets

DRUG(S)	DOSAGE FORM	FORM RATIONAL	REF.NO.
Metformin HC1, Glimipiride	Bilayer tablets	Synergistic effect  in diabetes	28
CefiximeTrihydrateDicloxacilline Sodium.	Bilayer tablets	Synergistic effect in bacterial infections	29
Amlodipine Besilate, Metoprolol Succinate	Bilayer tablets	Synergistic effect in hypertension	30, 31
Diclofenac Sodium, Paracetamol	Bilayer tablets	Synergistic effect in pain	32
Montelukast, Levocetrizine	Bilayer tablets	To improve the stability of drugs in combination	33
Salbutamol, Theophylline	Bilayer tablets	Synergistic effect of drugs in asthma	34
Rifampicin, Isoniazid	Capsule and tablet in Capsule	To avoid interaction b/w incompatible drugs	35
Misorostol, Diclofenac	Bilayer tablets	To minimize contact b/w drugs	36
Cefuroxime axetil	Bilayer floating tablets	Bimodal drug release	37
Ranitidine Aspirin	Single layer coated Tablets	To minimize the contact of two incompatible drugs	38
Furosemide	Bilayer floating tablets	To enhance bioavailability	39

 

 

 

Table3 : Percent deviation on average weight of tablets

 

7. Hardness (Crushing strength):

The resistance of tablets to capping, abrasion or breakage under conditions of storage, transportation and handling before usage depends on its hardness. The Strong-Cobb Pfizer and Schleuniger apparatus commonly used to measure the hardness of 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. 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.[19]

 

Bi-layer tablets: 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:

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

·      Providing sufficient tablet hardness

·      Preventing cross-contamination between the two layers

·      Producing a clear visual separation between the two layers.

 

CONCLUSION:

Bi-layer tablet is improved beneficial technology to overcome the limitation of the single layered tablet. Bi-layer 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. Bilayer tablet quality and GMP-requirements can vary widely. This explains why many different types of pressesare being used to produce bi-layer tablets, ranging from simple single-sided presses to highly sophisticated machines. Whenever high quality bi-layer 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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Received on 28.07.2014                Modified on 15.08.2014

Accepted on 19.08.2014                © RJPT All right reserved