Advances in Double-Layer Tablet Manufacturing

Pharmaceutical tablet manufacturers have long sought to refine and optimize the processes utilized for producing double-layer tablets. Whether driven by capacity requirements, marketing-based ideas or simple physics, there are always unique factors to be considered when developing a standard procedure for a repeatable manufacturing process. The creation of one solid dosage form, in particular, has long been thought of as a process that could be more accurately described as an art form (or as a pain in the neck, depending on who the speaker is). Certainly it poses technical challenges as manufacturers seek greater assurances of tighter control while simultaneously looking for higher output rates. Inherent in the successful manufacturing of this dosage form are numerous subtleties, nuances and potential headaches. We're speaking, of course, about the double-layer tablet.

Double-layer (or bi-layer) tablets have been around for some time. Quite possibly the earliest uses of this dosage form were driven from a marketing perspective, with emphasis placed on the perception of the consumer who would be utilizing the product. A tablet with two mutually exclusive "layers," represented by two clearly different colors, provided manufacturers with a way to produce a product that looked more interesting than a standard white "pill." While this motivation still has its place in modern pharmaceutical manufacturing the double-layer dosage form has evolved into much more than a product with purely visual appeal. Some double-layer products are ultimately coated, anyway, with the final form appearing to be comprised of one uniform substance.

Potential Reasons for Considering the Double-layer Dosage Form

One of the more common reasons that have developed for wishing to manufacture a double-layer product centers on sustained versus immediate release active ingredients and the related bio-availability of each within the human body. It is the intention of the manufacturer in some cases to formulate products that utilize two different actives --- one whose pharmacological effect is available to the body shortly after it is ingested (immediate release) and another that fulfills its role more slowly over a longer period of time (sustained release). These two functions can be neatly delivered in the same tablet by separating the actives into two distinct layers.

Some active ingredient combinations for a tablet may also be better suited to the double-layer form if they cannot easily be blended into the same final formulation. Certain ingredients may simply need to be physically separated due to incompatibility. An example of a characteristic that might foster such incompatibility would be disparate dissolution rates.

Another modern catalyst for utilization of the double-layer form focuses on the idea of product line extension. As patent protection begins to wane manufacturers can sometimes breathe new life into a product line by modifying its format or presentation. This can in some cases be achieved by creating a double-layer version of what was historically a mono-layer tablet. The best cases may result in a new patent for the revised form, thereby extending the life of the product line. ?Perhaps the most interesting emerging use for a double-layer tablet focuses on the desire to thwart abuse of a constituent ingredient. Abusers of pharmaceutical preparations have been increasingly successful and inventive in their ability to extract powerful ingredients for uses not intended by the manufacturer. 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.

Basic Principle of Double-layer Manufacturing

The most oversimplified 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.

Typical Considerations for Double-layer Manufacturing

While the aforementioned 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 color "bleeding" - 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 colors bleeding together. This is especially important in the case of an uncoated tablet that utilizes different color granulations, and can also be necessitated in cases where mixing the granulations can compromise product efficacy.

• Layer binding - 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.

Protection against "second-layer-only" tablets - new features are just now being made available that are intended to eliminate or greatly reduce the chances of a partial tablet (i.e. one that may be formed during a sampling interval) making its way into the final, "good" discharge chute

• Minimize transition rejects - it is desirable to reduce the amount of waste (rejected partial tablets or uncompressed granule) produced during the transition period that occurs while the press moves from normal manufacturing mode to sampling mode and back

• Load cell resolution - new features are also being engineered for greater accuracy in compression force monitoring and control, especially at the first-layer stage, where applied forces are often minimal

• Weight control for individual layers - early double-layer tablet presses were outfitted with weight control systems that would monitor and adjust total weight only (if any at all), rather than that of the individual layers. Tablet manufacturers now expect compression equipment to have systems on board that will allow for greater accuracy and control in the adjustment of independent layers.

• Yield optimization through re-circulation - yields for double-layer products have historically been terrible. The typical concerns about keeping one layer separate from the other can often result in scraping off any and all product that doesn't find its way into a die cavity and then discarding it. Systems are now available for double-layer presses that allow for the re-circulation of one layer, resulting in significant cost savings.

• Ease of conversion from mono to double-layer (or vice versa) - a shortcoming inherent in many double-layer presses is that they are not easy to convert back to a mono-layer configuration, or it simply takes too long to do so. A modern double-layer machine must offer maximum flexibility for running the greatest number of tablet forms, and the number of change parts necessitated by converting the machine should be kept to a minimum.
Modern Solutions for Classic Problems

While Fette has long been at the vanguard of double-layer technology, newly emerging needs in the pharmaceutical industry have served as the catalyst for development of even more advanced double-layer features. Areas of focus, as mentioned earlier, include tighter weight control (for both layers), the ability to quickly produce and take accurate first-layer samples, and the assurance that partial tablets cannot make their way into the final, good tablet discharge chute.
Editor's Note:

Fette offers many solutions and advances for double-layer tablet production. For further in-depth information on this topic please contact please contact Laura Frain, VP Sales at 973-586-8722