Future success

PharmTech: Considering the split drivers of compliance and patent extension, do you think multilayer tablets will continue to be successful in the future?

Behrens (IMA Kilian): If we think of fixed-dose combination drugs as a way to treat two closely related diseases, or to improve compliance and thus efficacy of prescribed medicines, we believe that this trend will continue. However, multilayer tablets could be a less frequent option if, in the future, the drugs are designed to be mixed into a unique powder that can be processed in a standard tablet press.

Calvin (Elizabeth Companies): I believe that the demand for multilayer and tablet-in-tablet technology will continue for many years to come, particularly as new high-potency drugs, which are often combined with other drugs in a single multilayer tablet generate a demand for layer technology. Many matrices are incompatible with one another, but with multilayer tablets, formulators can insert an inert barrier layer between the incompatible matrices to prevent an interaction. Also, developments in the technology have made multilayer tablets easier to produce. For instance, for core tablets, developments now enable the core to be positioned more precisely within the tablet.

Kirsch (Natoli): Multilayer tablets have been manufactured for a long time; more than 50 years that I know of. They are not going away.

A new possible need for layered tablets is the recent FDA draft guidance for industry on tablet scoring. Uniform dosage and assurance that a patient is capable of splitting the tablet properly are two of its concerns. Accu-Break Pharmaceuticals developed and patented a unique method using layered tablets to address these issues. The first (bottom) layer is a drug-free placebo. The second (top) layer containing the API(s) is scored deep enough to reach the second layer. The first inactive layer is merely a holder for the active second layer and when broken, result in a uniform dose. A trilayer tablet with an inactive center layer for split dose combinations has also been developed. Simple, yet brilliant.

Ethirajan (Tedor Pharma): Multilayer technology will continue to be an option in the future for several reasons:

• Pharmaceutical companies will file new patents or extend existing patents on their company name on combination product to win market exclusivities.
• Generic-drug makers may use new technology as an option to work around existing patents for markets product.
• Advancements in the technology by equipment manufacturers who recognized the importance of meeting regulatory requirements to market their high speed machines for production.

Most importantly, a single tablet containing multiple medications can be both cheaper and more convenient than separate tablets.

Formulation

PharmTech: When formulating multilayer tablets, what special considerations are required for factors such as levels of fines, bulk densities, and granulation properties?

Behrens (IMA Kilian): For efficient tableting, granule flow is crucial and a certain amount of fines is needed to guarantee proper filling and binding of the tablet. It is also important that the tableting machine is designed so that the filling range can cope with bulk density. In addition, the system should avoid the carry-over of particles or fines.

Calvin (Elizabeth Companies): When utilizing a tablet press with the proper powder-feed system, there is usually no need for any special considerations or factors such as levels of fines or granulation properties to be determined. The only consideration would be the bulk density of the granulation. Depending upon which layer is the lighter density granulation, it would normally be used on the first layer if the tableting press has a limitation of the upper punch penetration of the layer tamping stations that regulate the depth of fill of the consecutive layers.

Kirsch (Natoli): The level of fines must always be considered, even for non-layered tablets. Excessive fines will result in poor tablet quality, as well as tool binding and tablet press overheating, which exacerbates sticking and picking issues. Although fines are a necessary evil for proper tablet compressibility, it is critical that these are kept to a minimum when compressing layered tablets otherwise cross contamination from one layer to the next will be increased as fines will pass under feeders and scraper blades. Bulk densities are also a consideration because light or airy granulations require increased depth of fill and precompression. Pre-compression of the first layer is required for clear demarcation lines between the layers. If the press does not have sufficient upper punch penetration to pre-compress/tamp the first layer, then the desired weight may not be achieved and there will be insufficient volume in the die bore for the next layer. Some modern presses are only capable of 4 mm upper punch penetration, whereas many older presses were capable of almost 10 mm penetration, which, in many cases, made them better suited for layered tablets. Granulation properties would be much the same as with non-layered tablets with the exception of reduced fines; good flow and compressibility are always desired.

Ethirajan (Tedor Pharma): It is beneficial if both layers have relatively equal physical properties, such as the amount of fines, bulk density and granulation properties. It is also ideal to maintain granule size less than one half of the layer thickness to achieve a clear scrape-off. Specifically, fines below 200 meshes can smear or coat the turntable surface and it may not be possible to achieve a clean scrape-off, which can lead to layer cross-contamination.