Bi-layer Tablets: A Flexible Technology for Oral Drug Delivery– An Updated Review

 

Sangeetha R*, M Krishna Pillai, Y. Haribabu

Department of Pharmaceutics, Grace College of Pharmacy, Palakkad, Kerala – 678004.

*Corresponding Author E-mail: sangeethaaramakrishnan@gmail.com

 

ABSTRACT:

Bi-layer tablet is one of the new technologies for the successful development of controlled release formulations along with various features. Bi-layer tablet is suitable for sequential release of two different drugs in combination, separate the two incompatible substances and also suitable for the sustained release tablet in which one layer will be immediate release which serves as initial dose and second layer is maintenance dose. Nowadays the use of this bi-layered tablet technology has been enlarged. Bi-layer tablet is useful for gradual release of two active ingredients in combination. Two different incompatible drugs can also be formulated into a bi-layer tablet by adding an inert intermediate layer. Bi-layer tablets serves as one of the principle option to avoid chemical incompatibilities between the API’s which is mainly achieved by physical separation, and also helps to enable the progress of different drug release profiles (immediate release with extended release). In spite of their advantages, the mechanical structures of this drug delivery system have become quite difficult, requiring complicated tablet architectures due to the use of different materials and also the complex geometric boundaries. Bi-layer tablets provide specific advantages when compared to the conventional release formulation of the same drug. A number of pharmaceutical companies are now currently developing bi-layer tablets.

 

KEYWORDS: Bi-layer tablets, Formulation, Controlled release, immediate release.

 

 


INTRODUCTION:

In most recent decade, more attention in developing a combination of two or more Active Pharmaceutical Ingredients (API) in a single dosage form has been improved in the pharmaceutical industries, thereby promoting the patient compliance. Bi-layer tablets can be the primary choice to avoid the chemical incompatibilities between the APIS and also to improve the release profiles (immediate release with extended release). This is achieved by physical separation of two different API.[1]

 

Bi-layer tablets are always suitable for sequential release of two drugs in combination and it also has the ability to separate two incompatible substances. Bi-layer tablets consists of two different layers in which one layer is immediate release layer for initial loading dose and sustained release layer for maintenance dose.

 

The immediate release layer are added with some super disintegrants like sodium starch glycolate, croscarmellose sodium etc., which promotes the drug release rate and also helps to attain the onset of action rapidly (loading dose) whereas, sustained release layer releases the drug in sustained manner for prolonged period of time (maintenance dose).[2]

 

    

Conventional tablet                  Bilayer Tablet

 

Need for Bi-layer tablets

·       To control the rate of drug delivery either of single or two different API’s.

·       To spate the incompatible API from each other and also to control the release of API from one layer by using the functional property of the next layer such as, osmotic property.

·       To fabricate novel drug delivery systems such as chewing device, mucoadhesibve delivery systems, and floating tablets for gastro-retensive drug delivery.

·       To administer fixed dose combinations of different APIs and also to prolong the life cycle.

·       To modify the total surface area available for API layer either by sand witching with one or two inactive layers in order to achieve swellable/ erodible barriers for controlled release.[3]

 

Advantages of the Bilayer Tablet[1,4]

·       Greatest chemical and microbial stability compared to other oral dosage forms.

·       Cost effective when compared to other dosage forms.

·       Bi-layer tablet is suitable for preventing direct contact of two drugs and thus to maximize the efficacy of combination of two drugs.

·       Offer greatest precision and the least content uniformity.

·       Easy to swallow.

·       Bi-layer execution with optional single layer conversion kit.

·       Bi-layer tablets can be designed in such a manner as to modify the release as either of the layers can be kept as extended and the other as immediate release.

·       Flexible concept.

·       The  weight  of  each  layer  can  be  accurately

·       controlled, in the contrast to putting one drug

·       of a combination product in a sugar coating.

·       The  weight  of  each  layer  can  be  accurately

·       controlled, in the contrast to putting one drug

·       of a combination product in a sugar coating.

·       The  weight  of  each  layer  can  be  accurately

·       controlled, in the contrast to putting one drug

·       of a combination product in a sugar coating.

·       The weight of each layer can be accurately controlled.

 

Disadvantages of the Bilayer Tablet:

·       Some drugs resist compression into dense compacts, owing to amorphous nature, low density character.

·       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 enough or full drug bioavailability.

·       Adds complexity and bi-layer rotary presses are expensive.

·       Insufficient hardness, layer separation, reduced yield.

·        Imprecise individual layer weight control.

·       Cross contamination between the layers.

·       Drugs with an objectionable odor, bitter taste or drugs that are susceptible to oxygen may require encapsulation or coating.

General properties of bilayer tablet dosage form[5]:

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

ii.    The bilayer tablet should release the drug in an expectable and reproducible manner.

iii.  It should have physical and chemical stability.

iv.   It should have a chemical stability shelf life.

v.     It should have attractive product identity free of defects like chips, cracks, discoloration, and contamination.

 

Various techniques for bi-layer tablet:

OROS® push pull technology:

This system mainly consists of 2 or 3 layers in which one or more layer is essential for the incorporation of the drug or API and the other layer consist of the push layer (Fig.2). The drug layer usually consists of the drug or the API along with two or more different agents. So this drug layer is in poorly soluble form.

 

Further the suspending agent and osmotic agent are also added. A semi permeable membrane environs the tablet core.[6]

 

Figure 2: OROS® push pull technology

 

L-OROSTM technology:

This system is mainly used for the solubility issue. Alza introduced the L-OROS system which is a lipid soft gel product containing the drug present in a dissolved state is initially being manufactured and then it is coated with a barrier membrane, then with osmotic push layer and with a thin semi permeable membrane, finally drilled with an exit orifice.[7]

 

Figure 3: L-OROSTM technology

DUROS Technology:

The system consists of an outer cylindrical titanium alloy reservoir. This reservoir has high impact strength and also protects the drug molecules from enzymes. The DUROS technology is one of the miniature drugs dispensing system which opposes like a miniature syringe and release minute amount of drug in a concentrated, continuous and consistent from over months or year.[8]

 

Figure 4: DUROS technology

 

EN SO TROL Technology:

Shire laboratory use an integrated approach to drug delivery for the improvement of an order of magnitude or to create optimized dosage form that mainly focus on the identification and incorporation of the identified enhancer into controlled release technologies. [9]

 

Figure 5: EN SO TROL technology

 

DUREDAS™ Technology:

Elan drug technology is a dual release drug delivery system. DUREDAS™ Technology is a bi-layer tablet that provides immediate or sustained release of two drugs with different release rates of the same or different drugs in one dosage form. This method 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 mixture of hydrophilic polymers. [10]

 

Various Types of Bilayer Tablet Press:

·       Single sided tablet press

·       Double sided tablet press

·       Bi-layer Tablet Presses With Displacement Monitoring

 

Single sided tablet press:

This is a simplest design consisting of single-sided press with both chambers of the double feeder separated from each other. The chambers having different powders are gravity-or forced-fed and thus produces the two individual layers of the tablet. The die passes under the feeder, which initially compressed the first-layer powder and then the second layer powder is being compressed. Finally the whole tablet is compressed in one or two steps (two = pre- and main-compression). Both the layers in the die mix considerably at their interface and bond sufficiently so that no layer-separation occurs when the tablet is produced. This is one of the easiest ways of producing a bi-layer tablet.

 

Limitations of the single sided press:

·       No weight monitoring/ control of the individual layers.

·       No distinct visual separation between the two layers.

·       Very short first layer dwell time due to small compression roller, possibly ensuring 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.[11]

 

Double sided tablet press:

A double-sided press consists of an individual fill station, pre – compression and main compression for each layer. The bi-layer tablet will go through four compression stages before it gets ejected from the press. Most of the double-sided tablet presses with automated production control use compression force to monitor and manage tablet weight. The peak compression force which is exerted on each individual tablet or layer is measured by the control system at main compression of the layer. This calculated peak compression force is the indication used by the control system to refuse out of tolerance tablet and correct the die fill depth when mandatory.

 

Advantages:

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

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

·       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 two layers.

·       A clear visual separation between two layers.

 

 

Limitations:

·       The first layer is compressed at a low compression force to obtain correct bonding, 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.[12]

 

Bilayer tablet presses with displacement monitoring:

This tablet press worked on principle displacement tablet weight control, which is different from the principle of compression force. As based on standard sensitivity of control system does not depend on the tablet weight but depends on applied pre compression force. In this case the risk of capping and separation increases at higher production speed increases but can be reduced by sufficient dwell time at all four compressions.

 

Advantages:

·       Principle useful for accurate independent weight control of the individual layers. 

·       Appropriate bonding is possible as there is use of low compression force applied on the first layer avoids capping and separation of the two individual layers. 

·       Maximum production yield and clear visual separation between layers in tablet. 

·       Avoid cross contamination between the layers.

·       Ability to build adequate hardness to tablet at maximum turret speed by increased dwell time at pre-compression of both first and second layer. 

·       There is no any effect of stiffness on bilayer tablet. [13]

 

Evaluation of Bilayer Tablets:

1.     General Appearance:

The general appearance of a tablet, its visual uniqueness and overall “elegance” is essential for consumer acceptance. It mainly includes tablet’s size, color, shape, presence or absence of an odor, taste, physical flaws, surface structures, consistency and legibility of any identifying marking.

 

2.     Size and Shape:

Dimensionally, the size and shape of the tablet can be described, monitored and controlled.

 

3.     Tablet thickness:

Tablet thickness is one of the important characteristic in reproducing appearance. Some of the filling equipment makes use of uniform thickness of the tablets as a counting mechanism. Ten tablets were taken and their thickness was recorded using micrometer.[14]

 

4.     Weight variation:

 Standard procedures are followed as described in the official books.

5.     Friability:

Friction and shock are the forces that most common cause for the tablets to chip, break or cap. The friability test is related to tablet hardness and is considered to evaluate the ability of the tablet to resist abrasion during packaging, handling and shipping. It is usually calculated by using the Roche friabilator. A fixed number of tablets are weighed and placed in the apparatus where they fall at a height of 6 inches in each turn within the apparatus. After four minutes or 100 revolutions, the tablets are again weighed and this weight is then compared with the initial weight. The loss of weight due to abrasion is calculated as a measure of the tablet friability. The value is expressed in percentage. A maximum value of not more than 1% is considered generally acceptable and any broken or smashed tablets are not taken. The loss in the weight of tablet is calculated as the measure of friability and is usually expressed in percentage as:

 

% Friability = 1‐ (loss in weight/Initial weight) X 100[15]

 

6.     Stability Study (Temperature dependent):

The bi-layer tablets are packed in suitable packaging and should be stored under the following conditions for a period as prescribed by ICH guidelines for accelerated studies.

 

Study

Storage condition

Minimum time period covered by data at submission

Long – term

25°C ±2°C/40% RH ± 5% RH or

30°C ±2°C/35% RH ± 5% RH

12 months

Intermediate

30°C ±2°C/65% RH ± 5% RH

6 months

Accelerated

40°C ±2°C/not more than (NMT) 25% RH

6 months

 

After a period of 15 days, the tablets were withdrawn and analyzed for physical characterization (Visual defects, Hardness, Friability and Dissolution etc.) and also for 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.[15]

 

7.     Uniformity of Weight:

Average weight of twenty tablets which was selected at randomly was calculated. Weight Variation of these tablets was calculated and was compared with I. P. standards.

 

8.     Tablet Hardness:

The hardness of a tablet influences the resistance to shipping or breakage under conditions of storage, transportation and handling before usage. Monsanto hardness tester is used to measure the hardness of each tablet. The hardness was measured in kg/cm. [16]

 

 

CONCLUSION:

Bi-layer tablet technology is one of the excellent techniques for providing the combined release pattern of drug involving both immediate release and sustained release. Bi-layer tablet technology is one of the important design approaches in which different drugs with different indications, incompatible drugs and same drug with different release rate (e.g. IR and ER) can be designed in a single unit. Bi-layer tablet is enhanced beneficial technology to overcome the limitation of the single layered tablet. Bi-layer tablet is suitable for the gradual or sequential release of two different drugs in combination, also suitable for separating two incompatible substances and also for sustained release tablet in which one layer is for loading or initial dose and second layer is for the maintenance dose. The formulation of tablets in the form of multi layers is used to offer systems for the administration of drugs, which are incompatible and to provide controlled release tablet preparations by providing surrounding or multiple swelling layers. A complete mechanistic understanding must be developed to develop a dynamic bi-layer tablet through the application of scientific and quality risk management tools.

 

REFERENCES:

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2.      Neha P. Singh et al. Bilayer Tablet: A Review. World Journal of Pharmacy and Pharmaceutical Sciences. 2015; 4(11): 703-717.

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10.   Dr. Dinesh Kaushik et al. Bilayer Tablet Technology: A Concise Review. European Journal of Pharmaceutical And Medical Research. 2019; 6(7): 573-582.

11.   Sowmya C et al. An Overview on Bi-layer Tablets. International Journal of Pharmacy and Technology. 2012; 4(2): 2143-2156.

12.   Sonali N. Jadhav et al. Bilayer tablet technology: An overview. International Journal of Chem Tech Research. 2017; 10(5): 595-603.

13.   Bhosale M D et al. Bilayer Tablet- A Comprehensive Review. European Journal Of Pharmaceutical And Medical Research. 2017; 4(9): 241-251.

14.   Hemanth Kumar A et al. Novel Approach Of Bilayer Tablet Technology –A Review. International Journal Of Pharmaceutical, Chemical And Biological Sciences. 2103; 3(3): 887-893.

15.   Rohan D. Deshpande et al. Bi-Layer Tablets- An Emerging Trend: A Review. International Journal of Pharmaceutical Sciences and Research. 2011; 2(10): 2534-2544.

16.   Mehraj Ud Din et al. An Overview on Bilayered Tablet Technology. American-Eurasian Journal of Scientific Research. 2014; 9(1): 06-15.

 

 

 

 

 

Received on 11.01.2020           Modified on 18.03.2020

Accepted on 03.05.2020         © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(1):547-551.

DOI: 10.5958/0974-360X.2021.00099.8