Fixed dose combination drugs are becoming increasingly popular, as part of the life-cycle management strategies to extend intellectual property and minimize generic exposure of mature pharmaceutical products. To combine different actives for a synergic therapeutic effect, or different formulations of the same active in order to achieve a specific release profile, might be a viable way to achieve a product with improved efficacy or less side-effects, for which supplementary patent protection can be granted.
Even if a powder mixture of two or more formulations can be compressed in a single tablet, often a multiple-layer tablet is preferred, in order to avoid interactions between the different drugs and to optimize each formulation in terms of pharmacokinetics and manufacturability. Additionally, layered tablets might be a means to strengthen brand identity, as they clearly differentiate from other products.
Although their popularity is quite recent, bi-layer tablets have been produced for many years for both pharmaceutical and non-pharmaceutical applications, and the criticalities of this style of tableting process are well known. IMA Kilian, has been manufacturing bi-layer tablet presses for many years and has hundreds of working installations world-wide.
The production of a bi-layer tablet entails a double compression cycle
- the first layer powder is fed to the die through a dedicated fill-shoe, the quantity of powder is determined by the position of the lower punch inside the die by using a dosing cam
- precompression is applied to the first layer
- the second layer powder is then fed to the die through a dedicated fill-shoe, the quantity of powder is determined by the position of the first layer inside the die
- precompression and final compression are applied and the final tablet is thus produced
- the bi-layer tablet is ejected
Good layer binding and well defined layer separation
One of the most common problems that may occur is tablet lamination between the two layers. In most cases this is avoided by keeping the compression force for the first layer at a very low value: in fact it is only a de-areation.
In Kilian bi-layer presses this light compaction is carried out by the first layer pre-compression roller, while the main compression station is used as a fill-cam for layer two: the upper and lower punches simultaneously move down to displace layer one to the desired position inside the die. This “guided” movement avoids the risk of bad positioning of the first layer in the die due to centrifugal force.
Samples of tablets with bad positioning of layer one
In order to achieve a well defined layer separation and to avoid mix-up and interactions between the powders composing the two layers, it is very important to remove any powder residue from the die plate. For this purpose dedicated scrapers are located before and after each fill-shoe, to move residual powder dust to the outside of the die table, where the high efficiency suction nozzles are located.
Individual dosage control for each layer
The standard working mode of tablet presses combines compression force measurement and statistical weight check to achieve in-line control of production. When producing bi-layer tablets, this system could be challenging for different reasons:
1) Compaction force for layer one is extremely low, and it could be very difficult to obtain a clear signal from the strain gauges. To solve this problem IMA Kilian has developed over many years a “low force compression roller” that can be fitted at the pre-compression station for layer one. The reduced mass ensures the most accurate and reliable measurements even with standard strain gauges.
2) Statistical sampling of layer one for weight check is another critical point. For sampling, the first layer has to be compressed at a higher force, in order to achieve enough hardness to make sampling and weighing possible. In the IMA Kilian bi-layer presses this is obtained by raising the lower punch through the hydraulic system which is standard on all machines (therefore with no additional parts and at no additional cost). The reaction time of the hydraulic system is extremely fast and ensures minimization of waste. In order to avoid the production of second-layer-only tablets during layer one sampling, the lower punches are maintained in the up position, and the fill-shoe for layer two is stopped.
Yield optimization and Human-Machine Interface
Product losses for bi-layer tableting can be very high as it is necessary to avoid cross contamination between the two layers, the use of strong vacuum suction can help avoid this. Additionally, the recirculation of product is not recommended as it can create more dust and therefore a greater risk of cross contamination – even if some machine manufacturers choose to do this for one layer. Over the years, IMA Kilian has developed a number of technical solutions in order to minimize the quantity of powder remaining on the die plate which therefore needs to be removed by suction. These options can be applied according to the product and include a special surface treatment allowing “zero clearance” between fill-shoe and die plate, as well as size-related closing segments for the fill-shoes.
An additional help to improve yield is granted by the user friendly software, allowing a good process-understanding for the operator and a self-learning function thereby shortening set-up times.
Range of machines for bi-layer tableting
All of the above technical solutions have been developed by IMA Kilian through years of experience in bi-layer tableting. At present multiple layer or core tablets can be produced on the following machines:
- S250 ZS/M
- Synthesis 500
- Synthesis 700
- KTS 1000
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