INTRODUCTION:

Today, many nations have developed combination therapies for conditions like cardiovascular disease and hypertension. More than 90% of today's produced formulations are taken orally. The method permits the addition of many drugs to the dose form 12.

The development of bilayer tablets utilising various polymers enables greater control over drug delivery than is possible with single or multiple drug administration methods, allowing for the possibility of targeted drug delivery in the gastrointestinal tract (GIT) using the pH development of the polymers. Many problems with the manufacturing of bilayer tablets.²⁵

The technique for extended or sustained release and immediate release formulations is the bilayer tablet. It is produced by combining two or more pharmaceutically active substances to create a single, suitable dosage form. A bilayer tablet has two layers: one for instant release (loading dose) and one for delayed release (maintenance dose). By physically separating various APIs, this method also aids in preventing chemical incompatibilities between them. This technology is being developed to achieve modified medication release. The drug concentration will fluctuate widely while using standard dose forms, which indicates undesired toxicity and poor efficacy. Typically, conventional dose forms provide a wide range of fluctuations in drug concentration in the bloodstream and tissues, resulting in undesired toxicity and low efficiency. The main goals of sustained release drug delivery are to increase patient compliance, ensure safety, and enhance treatment efficacy. To prevent chemical incompatibilities between APIS by physical separation and to enable the development of various drug release profiles (immediate release with sustained release), bilayer tablets can be a major alternative. This kind of drug delivery is mostly appropriate for diabetic, hypertensive, antihistamine, analgesic, antipyretic, anti-allergic and antibiotic drugs, the use of bi-layer tablets is significantly different, as these drugs frequently require combination therapy of drugs to be effective.^1-3

Fig 1: Bi-layer Tablet

Need of Bi-layer Tablet:

· To develop novel drug delivery methods such as chewing devices, mucoadhesive delivery systems, and floating tablets for gastro-retentive drug delivery systems.³

· To increase the overall surface area available for the API layer by sand witching with one or two inactive layers to achieve swellable/erodible barriers for controlled release.^3,20

· To split incompatible active pharmaceutical ingredients (APIs) from one another so that the functional characteristic of the other layer (such as the osmotic property) can be used to control the release of API from one layer.³

· To control the dosage administration of either a single API or two separate APIs.³

Merits of Bi-layer Tablet:

· Physical separation aids in preventing chemical incompatibilities between APIs.⁴

· Appropriate for mass production.⁴

· It is simple to swallow and has a lower tendency to hang up.⁴

· Highest level of chemical and microbiological stability among all oral dose formulations.⁶

· A bi-layer tablet is useful for limiting direct contact between two medications and so maximising the effectiveness of a two-drug combination.⁸

· Patient compliance increases, which enhances the effectiveness of the treatment regimen.⁸

Demerits of Bi-layer Tablet:

· It is difficult to swallow in the case of children and unconscious patients.⁸

· Due to their amorphous and low density characteristics, several medications avoid compression into dense compacts.⁸

· Bitter testing substances, pharmaceuticals with an unpleasant odour, or drugs sensitive to air may demand encapsulation or coating.¹²

· It may be challenging to construct or manufacture a tablet for a drug with poor wetting, slow dissolution, or optimal absorption that is high in the GIT while maintaining adequate or complete drug bioavailability.¹²

Bi-layer tablets quality and GMP requirements:

The selected press must be capable of the following in order to create a quality bilayer tablet in a certified and GMP manner:

1. Providing the appropriate tablet hardness.^8-12

2. Keeping the two layers from becoming contaminated with one another.²¹

3. Creating a distinct visible separation between the two layers.²²

4. Highest yield control of the two layers weights with accuracy and individuality.²⁵

5. Preventing the two separate layers that make up the bilayer tablet from being capped and separated.⁸

Applications:

1. Two distinct medicines with different release profiles are provided in bilayer tablets.

2. The term "bilayer tablets" refers to tablets with two layers, one of which is a floating layer and the other a rapid drug release layer.

3. The loading dose and maintenance dose of the same or a different drug are distributed using bilayer tablets.

4. Bi-layer tablets are usually administered in combination therapy.²⁵

Bi-Layer Manufacturing Obstacles:

Bilayer tablets can be conceptualised as a combination of two single-layer tablets. There are various manufacturing difficulties in actual situations.

De-lamination- When the link between the two tablet parts is imperfect, the tablet will break. Compression ought to cause the two granulations to stick together.

Cross-Contamination- Cross-contamination happens when the first layer's granulation mixes with the second layer's granulation or the other way around. It may defeat the fundamental aim of the bilayer respectively tablet. Cross contamination can be substantially avoided with proper dust collection.²¹

Production Yields- Dust collection is necessary for preventing cross contamination, yet this causes losses. As a result, single-layer tablets provide higher yields than bilayer tablets.

Cost- There are various reasons why bilayer tableting costs more than single layer tableting. First off, the tablet press is more expensive. Second, the press often works more slowly in bilayer mode. Third, it is necessary to develop two compatible granulations, which requires more time for formulation development, analysis, and validation. These variables will have an effect on the bilayer compression in general and the quality characteristics of the bilayer tablets (sufficient mechanical strength to retain its integrity and particular layer weight control) in one way or another if they are not effectively regulated or optimized. In order to develop a solid product and process, it is crucial to gain insight into the underlying causes.²⁶

Various Techniques of Bilayer Tablet:

1. OROS® Push pull Technology

2. L-OROS^TM Technology

3. EN SO TROL Technology

4. DUROS Technology

5. DUREDAS^TM Technology

1. OROS® Push pull Technology:

This system primarily comprises of two or three layers, one or more of which are necessary for the drug and the other layers of which are push layers. The primary components of the drug layer are drugs and two or more distinct agents. As a result, this drug layer is made up of drug that is in a poorly soluble form. There is also a suspending agent and an osmotic agent added. The tablet core is surrounded by a semipermeable membrane.

Fig 2: Bi-layer and Triple layer OROS Push pull Technology

2. L-OROS^TMTechnology:

This system was used to solve the solubility problem. Alza created the L-OROS system, which involves manufacturing a lipid soft gel product that contains a drug in a dissolved condition and coating it with a barrier membrane, an osmotic push layer, a semi-permeable membrane, and a hole for an exit orifice.

Fig 3: L-OROS^TM Technology

3. EN SO TROL Technology:

Shire laboratory uses an integrated strategy to drug delivery with a focus on identification and implementation of the identified enhancers into controlled drug release technologies to increase solubility by an order of magnitude or to develop optimum dosage forms.

Fig 4: EN SO TROL Technology

4. DUROS Technology:

The system consists of an exterior cylindrical titanium alloy reservoir. Higher intensity strength and enzyme protection are provided by this reservoir for the drug molecules. The DUROS technology is a miniature drug distribution system that works like a little syringe and dispenses a small amount of concentrated drug in a regular and continuous manner across months or years.

Fig 5: DUROS Technology

5. DUREDAS^TM Technology:

A bilayer tablet with (DUREDASTM Technology) can deliver two medications in one dose form at different release rates or with immediate or sustained release. A modified-release hydrophilic matrix complex and an immediate release granulate can be produced by the tableting process as different layers within a single tablet. Many hydrophilic polymers work together to give the dosage form its modified-release features.

Stands to Benefits of DUREDAS^TM Technology

· Produced as a single dose tablet.

· Bi-layer tableting technology.

· Similarity between components with immediate and modified releases identified in a single tablet.

· similarity of two blended different CR formulations.

· Tailored rates of release for two pharmaceutical ingredients.

Types of Bi-Layer Tablet:

1. Singled sided tablet press

2. Double sided tablet press

3. Bi-layer tablet press with displacement monitoring

4. Multi-layer compression basics

1. Single sided tablet press:

Bi-layer presses have been developed in a variety of forms over time. The most basic layout is a single-sided press with two distinct chambers for the double feeder. Each chamber is gravity or force fed with a separate powder, resulting in the tablet's two distinct layers. The first layer of powder and the second layer of powder are put onto the dye as it passes beneath the feeder, and then the entire tablet is squeezed in one or two steps. The simplest method for developing a bilayer tablet involves the two layers of the dye mixing somewhat at their interface and, in most circumstances, bonding sufficiently to prevent layer separation when the tablet is manufactured.^7,16

Limitation:

· There's no weight monitoring or layer-by-layer management.

· There is no obvious visual distinction between the two levels.

· Because to the small compression roller and the extremely short initial layer dwell time, there may be issues with capping, hardness, and de-aeration.

· Extremely complicated first-layer tablet sampling and samples transport to a test unit for in-line standard control and weight recalibration²⁰

2. Double sided tablet press:

The majority of double-sided tablet presses that automate production control track and regulate tablet weights using compression force. The compression system's effective compression force applied to each individual tablet during the layer's primary compression. When necessary, this mechanism helps to adjust the die fill depth and reject out the tolerance tablets.

Advantage:

· To prevent capping and layer separation, a light compression force is applied to the top layer.

· Monitoring of displacement weight enables precise and individual layer-by-layer weight management.

· Maximum cross-contamination prevention between two layers.

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

· A distinct visible distinction between two layers.²⁰

Limitation:

· The first layer must be compressed with a modest compression force to ensure that it still has contact with the subsequent layer during a final compression in order to achieve proper bonding.

· The low compression force required when compressing the first layer, unfortunately, reduces the accuracy of the weight monitoring/control of the initial layer in the case of tablet presses with compression force measurement.

· Bonding is too restricted if the first layer is compressed at a high compression force.²⁰

3. Bi-layer tablet press with displacement monitoring:

A significant distinction must be made between the compression force and bilayer tablet press principles. In this case, accuracy rises as compression force is decreased. An adequate dwell time at each of the four compression stages can lower the risk of capping and separation as production speed increases.

Advantage:

· Displacement weight monitoring and control for precise individual layer weight control, to prevent chapping and the separation of the two layers, just a slight compression force should be applied to the first layer.

· Increased dwell time at first- and second-layer pre-compression to ensure enough hardness at maximum turret speed, maximum cross-contamination prevention between the layers, a distinct visual separation of the layers, increased yield.²⁰

4. Multi-layer Compression basics:

Presses can be modified for multipliers or a conventional double press can be specifically made for multi-layer compression. The idea of a multi-layer tablet has been used for a long time for developing formulations for prolonged release of drugs. These tablets can include a fast-releasing layer as well as players or triple layers to sustain drug release from the tablet. The pharmacokinetics advantage is based on the fact that, while drug release from fast-releasing granules causes an immediate rise in blood concentration, drug release from sustained granules causes the blood level to remain stable.¹⁶

Characteristics of Bi-layer Tablet^10-26

· Photo-Microscopic Analysis

Photo-microscope TGG and GG were images taken by a photo-microscope.

· The distribution of particle sizes

The distribution of particle sizes was determined using the sieve method.

· Angle of repose

The powder cone's diameter was measured, and the following equation was utilized to calculate its angle of repose:

Tan Ø = h / r

Where, h = Height

r = radius

· Density

These formulas were used to calculate the bulk density and tapped bulk density:

Bulk Density = Mass / Volume

· Compressibility

The formula was employed to determine the compressibility index:

Carr’s Index % = 100 (1 – BD / TD)

· Hausner's Ratio

It is determined using the formula:

H = BD / TD

Evaluation of Bi-Layer Tablets:

· General appearance:

The overall appearance of a tablets, its visual identity, and overall "elegance" are critical for consumer acceptability. includes tablet dimensions, form, colour, flavour, texture of the tablet's surface, physical faults, consistency, and readability of any identifying markings.²⁵

· Dimension and thickness:

Vernier callipers were used to measure the diameter and thickness. The consistency of tablet size was mostly dependent on the thickness and width of the tablets.³

· Tablet hardness:

A Monsanto harness tester was used to gauge each formulation's tablet's hardness. The hardness was calculated using kg/cm2 units.^8,25

· Friability:

The friability of 10 tablets will be chosen at random, weighed, and rotated in a Friabilator for 4 minutes at a speed of 25rpm. After resolution, the tablet can be dusted and measured. The strength of a tablet is measured by its friability. The following approach was done to test the friability using an Electro lab EF2 Friabilator (USP). Twenty tablets were precisely weighed and put in the tumbling device, which rotates at 25 revolutions per minute and drops the tablets six inches at a time. The tablets were weighted after 4 minutes to assess the percentage of weight loss.^3,8,25

Friability % loss = {(Initial weight of tablet – Final weight of tablet)/Initial weight of tablet} * 100

· Weight variation:

Twenty tablets are randomly selected for the weight variation test, and the average weight is determined after the weight variation is calculated and the weight variation is compared to the IP standard. The average weight of 20 tablets was determined after a random selection of the tablets. Calculated weight variation was compared to I. P. standards.

The weight variation shown in the tablet below may deviate up to the following percentage.³

Table 1: Weight Variation Parameter

Average weight tablets	Percentage Deviation
Less than 85mg	±10%
85mg – 250mg	±7.5%
More than 250mg	±5%

· Drug Content and Drug Release:

To evaluate a tablet's potential for efficacy, it is necessary to track the amount of drug contained in each tablet from batch to batch as well as to determine how well the tablet releases the drug.^3-10

· In- vitro dissolution study:

A dissolution study is performed in simulated stomach and intestinal fluids to determine their capacity to provide the appropriate controlled drug delivery. Using a USP dissolving test apparatus at a particular RPM and a temperature of 37°C, in-vitro drug release studies are performed as described in the mentioned monograph.^{12, 25,27}

CONCLUSION:

Bi-layer Tablets are frequently a great opportunity for manufacturers to differentiate themselves from their competition, improve the efficacy of their products, and defend against counterfeit items. Bilayer layer tablets have two layers, one for delayed release and one for immediate drug release, with the goal of attaining a significant serum level in a relatively short time. Quality and GMP requirements for bilayer tablets can vary greatly. This explains why a wide variety of presses, from conventional single-sided presses through highly complicated equipment, are used to create bi-layer tablets. The application of an "air compensator" along with displacement control seems like the ideal method where high-quality bi-layer tablets must be made quickly.^3,19

ACKNOWLEDGEMENT:

We are grateful to the teacher’s and principal of Loknete Dr J. D. Pawar College of Pharmacy, Manur, and Tal. Kalwan for their helpful guidance.

CONFLICT OF INTEREST:

The author’s state that have no conflicts of interest.

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Received on 19.05.2023 Modified on 03.07.2023

Asian J. Res. Pharm. Sci. 2024; 14(1):81-86.

DOI: 10.52711/2231-5659.2024.00013