5. Perhaps the most interesting emerging use for a double-layer tablet focuses on the desire to thwart abuse of a constituent ingredient⁴. Certain new painkillers, for example, provide wonderful benefits to a patient in need who uses them according to the manufacturer’s instructions. When they are mishandled by an abuser, however, they can become dangerous and potentially addictive. The makers of some of these types of products are beginning to investigate the use of double-layer forms, where an “antagonist” layer is formulated in such a way as to foil the would-be abuser’s attempt to extract the active ingredient that they are seeking to abuse.

6. The bilayer system is a unique drug delivery device, which overcomes the major disadvantage of non-linear release associated with most diffusion-controlled matrix devices. This system also has the advantage of being compatible with conventional manufacturing methods⁵.

Manufacturing Of Bilayer Tablets-An Overview Of Process^22,23

Figure 1: An overview of Bilayer Tablet Manufacturing Process

The simplified description of the double-layer manufacturing process can be offered as follows. A tablet press with two different feed hoppers is charged with the two different granulations required for the finished product. The first-layer granulation (also thought of as the bottom layer) is fed into the die as the cavity passes under the first feed frame. This cavity then continues through an initial compression stage, where with a double-layer tablet it is often simply tamped, to form the first layer but not make it so hard as to inhibit good cohesion with the second layer fill. The dies then pass under the second feed frame and are filled with an amount of the second layer granulation, which when combined with the first layer, is appropriate for the desired total tablet weight. The tools then pass through a series of final compression rolls that are set to apply the right amount of force for achieving the target tablet hardness. Finally, the tools proceed through the ejection stage of the press, where the upper and lower punches are raised through the use of raising and ejection cams, ejecting the finished tablets from the die cavities. The schematic diagram of uniaxial compression for preparation of single and bilayer tablets is shown in Figure 2.

Figure 2: Schematic diagram showing the manufacture of single and bilayer tablets utilizing uniaxial compaction. A- die filling, B- compression, C- decompression, D- lower punch removal and reapplication of load to the upper punch, E-tablet fully ejected. 1 refers to the final compaction conditions

Quality and Good manufacturing practice (GMP) requirements of bi-layer tablets¹⁸:

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.

· High yield.

· Accurate and individual weight control of the two layers.

These requirements seem very obvious but are not very easy to observe in manufacturing a bilayer tablet dosage form as there are several critical factors that are to be taken into consideration while manufacturing bilayer tablets.

Critical Factors to Be Considered For Bilayered Tablet Manufacturing:

While the above mentioned process description is technically accurate, it no longer suffices to describe modern double-layer manufacturing requirements. Manufacturers always have a number of concerns that are unique to double- (or multi-) layer processes. Some of these concerns are fairly new, while some have existed since this type of product was first introduced. The most common concerns are addressed briefly below.

Cross-contamination or colour “bleeding”²¹:

It is imperative in virtually all cases of double-layer manufacturing to ensure that the granulations for the different layers are contained effectively by the feed frames and subsequent scraper assemblies so as to minimize or eliminate the possibility of the colours bleeding together. This is especially important in the case of an uncoated tablet that utilizes different colour granulations, and can also be necessitated in cases where mixing the granulations can compromise product efficacy.

Layer binding²⁰:

A tablet press must have versatile compression force capabilities, so as to foster good binding between layers. If good binding cannot be achieved it may result in lamination of the final tablet, where the two layers separate from one another after ejection.

Output capabilities:

The press design must effectively meld all engineering characteristics into a package that optimizes output speeds, while ensuring good final tablet characteristics for criteria such as weight, thickness and hardness.

First-layer sampling:

This feature receives more and more attention these days, as it is critical to the overall integrity of the final product. The tablet press must have, at a minimum, the capability of periodically manufacturing layer samples, where the layers are intentionally (and automatically) kept separate in an effort to ensure good weights. The process must also be fast and accurate, as there is the potential for waste during the sampling interval. Novel methods for optimizing this entire process are now being made commercially available.

“Second-layer-only” tablets:

This is the typical problems observed because of the first layer sampling. A partial tablet is the result of such a sampling. To avoid this, a specifically designed discharge chute is necessary.

Weight control for individual layers :

Early double-layer tablet presses were outfitted with weight control systems that would monitor and adjust total weight only, rather than that of the individual layers. But now systems are available which allow for greater accuracy and control in the adjustment of independent layers.

Compaction principles⁸ governing weight control:

Unlike conventional tablets, bi-layer tablets require three weight controls, namely, individual layers and the final tablet weight control. The complexity in the weight control significantly increases the level of sophistication needed in the rotary press designed for multi-layer tablets. Typically, in closed-loop control systems, two different types of control mechanisms for weight are involved. In the first case, typically called a force control system, a fixed force is applied during compression and the actual exerted force is measured. The measured force on the individual layer is utilized to calculate the acceptable range around the mean during the process set up. The acceptable range of the measured force from the set point is sent as a feedback for weight control during beginning of compression cycle. Alternatively, the layer or tablet thickness is indirectly used as a feedback for weight control. In this case, the peak force encountered during compression for fixed tablet thickness is measured and the acceptable range for the established peak force for given run weight is sent as feedback for the weight contro^l7. For example, the upper punch is programmed to travel a fixed distance in the die cavity. The range for the resulting force is established for the target weight of first layer during set up. The compressed first layer is rejected if the measured force during first compression does not fall within the range. The same cycle is repeated for the second layer compression and both the layers are rejected if the resulting force during second compression does not fall within the range established for total tablet. Though both the approaches are very similar in manufacturing the tablets, the feedback mechanism differs. Ultimately, the compressed tablet is required to retain the adhesiveness between the two layers during the shelf life of the product. The primary process parameter that may impact adhesion as a quality attribute of the drug product is compression force.

Compression force¹⁹:

Since the material in the die cavity is compressed twice to produce a bi-layer tablet, compressed first with layer—one followed by both the layers, the compression force affects the interfacial interaction and adhesion²⁰ between the two layers. A certain amount of surface roughness of the initial layer is required for particle interlocking and adhesion with the second layer. As the surface roughness of the first layer is reduced, the contact area for the second layer is significantly reduced at the interface and makes the adhesion weaker. Immediately after final compaction, the compressed second layer may release the stored elastic energy unevenly and may produce crack on the first layer which could act as a stress concentrator and eventually making the tablet interface weaker. This may result in capping or de-lamination of the tablet along the interface either during manufacturing or immediately after⁹. The level of compression force used in the first layer compaction determines the degree of surface roughness of the first layer. The higher the first layer compression force, the lesser the surface roughness resulting in reduced adhesion with the second layer. Therefore, for a gi0ven final compression force the strength of interfacial adhesion decreases with the increasing first layer compression force. It implies that the extent of plastic/elastic deformation of the first layer has profound effect on the strength of the interface¹⁰. Thus, understanding the interaction and adhesion behaviour between different layers composed of various ingredients with differing physico-chemical properties during compaction is critical to understand the failure mechanisms of bi-layer tablets. Understanding of material attributes of the excipients and API that undergo compression and compaction is decisive in predicting the interaction. It is indicated¹⁴ the compression force on layer I and the compression zone in the die cavity of layer II were two factors needing to be controlled in order to yield bilayer tablets with acceptable physical characteristics.

Material attributes: elastic and plastic deformation:

Compressibility and the tablet breaking force are dependent on the nature of the API, excipients and compaction parameters. Material properties such as brittleness (di-calcium phosphate), ductility (microcrystalline cellulose) and elasticity play central roles. In addition, porosity, shape of the granules and morphology significantly influence the compression process. Significance of material attributes depends on ratio of API to the excipients in the drug product. If the drug product consists predominantly of API, then the material attributes of API need to be evaluated and likewise for a potent or low dose formulation, the attributes of the excipients become increasingly significant. Brittle and plastic deformations of the excipients have significant impact on the compaction process. Compaction of predominantly ductile material is a result of plastic deformation as long as the stress developed by the elastic recovery does not exceed the bond strength¹¹. The additive effect of individual material attributes and the material attributes of a blend, may not be the same as in the binary mixtures and to address this issue, several models are proposed to predict the compressibility behaviour of the binary mixtures with the input of individual material attributes of the excipients. For example, the mean yield pressures during under pressure (in-die) and after the elastic recovery (out-of-die) of the tablet have been calculated¹². However, a proportional relationship was not valid for the mean yield pressures calculated based on the individual yield pressure. A predictive approach was proposed by these authors to indirectly obtain the mean yield pressure of a binary mixture from the data of the individual materials. The predictive approach used the linear mixing rule observed with the porosity. The validity of the model was verified and compared with the experimental values. The interesting fact is that the authors have used predominantly a ductile material such as microcrystalline cellulose and brittle material such as calcium phosphate and lactose for preparing their binary mixtures.

During compression, brittle materials such as dicalcium phosphate, acetaminophen and lactose tend to fracture and fill the voids. On the contrary, the ductile materials, such as microcrystalline cellulose and corn starch tend to undergo deformation. This material attributes impact the surface characteristics of the tablets. It is observed¹³ that the brittle materials generally produced smooth (surface) and brittle compacts, where as the ductile materials produced rough (surface) contacts and ductile compacts. Therefore, if the first layer is predominantly composed of ductile material and the second layer predominantly of brittle material, their interfacial interaction and the tablet breaking force needs additional scrutiny. Thus, for robust manufacturing operation for multi-layer tablets the material attributes such as mechanical and compaction properties individual layers should be similar. Or, alternatively the individual layers may include a well-balanced proportion of both brittle and ductile material. Because there is more than one layer, the precision needed for controlling the individual weight of the layers demands predictable and consistent behaviour of the final blend such as flow property and particle size distribution. Thus, for directly compressible material, material attributes including the flow property and particle size distribution of the ingredients undergoing compaction will play a major role. However, that situation changes when granulation process, such as wet granulation and roller compaction or slugging are utilized to improve the flow properties, blend uniformity or compressibility.

Coating:

Often multi-layered tablets are coated to improve elegance, to protect the cores from ambient conditions or to control the release profile. In either case, exposure of the multi-layered tablets to solvents, high temperatures and affect of loads must be considered in the product development. 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. It has been explained that during the coating process of bi-layered tablets, cracks appeared on the surface of only one layer within few minutes of the coating process, leaving the other layer intact. Upon testing, the authors found that the thermal expansion coefficient of two different layers of the tablet were significantly different. When the authors ran a control, coating the individual layers separately at 40–55 °C, no evidence of cracking was found. To alleviate the cracking, the product was reformulated with each layer having almost the same coefficient of thermal expansion. Thus, multi-layer drug products that are intended to undergo coating process require additional scrutiny that may not be needed for drug products that do not require coating. 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. Thus, it is imperative that the excipients are not only screened for their physical properties such as particle size and compressibility during the pharmaceutical development stage, but also, tested to ensure the individual layers are similar in terms of their thermal expansion coefficient.

Evaluation of Bilayer Tablets:

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.

Size and Shape:

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

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.

Weight variation¹⁶:

Standard procedures are followed as described in the official books.

Friability¹⁶:

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:

Hardness (Crushing strength)¹⁵:

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.

CONCLUSION:

Bilayer tablets provide one of the important design approaches where incompatible drugs, with different indication, and same drug with different release rate (e.g. IR and ER) can be incorporated in a single unit, or two incompatible drugs are needed to be provided in single dosage form. To develop a robust bi-layer tablet a complete mechanistic understanding must be developed through the application of scientific and quality risk management tools. Many critical factors are taken into consideration while manufacturing a robust bilayer tablet dosage form. The problems of delamination, less strength, weight control, layer thickness etc. require serious consideration while formulation and manufacturing of bilayered tablets. A well-developed product will effectively address these issues by including appropriate control strategies and establishing the functional relationships of the material attributes and process parameters critical to the bi-layer tablet quality as discussed in the article. Bi-layer 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.

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Received on 28.04.2012

Accepted on 25.05.2012

Research Journal of Pharmaceutical Dosage Forms and Technology. 4(3): May-June 2012, 160-165