PharmTech: What formulation considerations are required for multilayer tablet manufacturing (e.g., levels of fines, bulk densities
and granulation properties)?
Behrens (IMA):
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):
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 nonlayered 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 because 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. Precompression of the first layer is required for clear demarcation lines between the layers. If
the press does not have sufficient upper-punch penetration to precompress the first layer, 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):
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.
PharmTech: How can common formulation challenges (e.g., combining incompatible products), be overcome?
Kirsch (Natoli):
Incompatible APIs are the main driver for layered tablets. They enable incompatible ingredients to be administered in the
same tablet without degrading the actives. As for excipient choice, this is why we have R&D; use what works.
Ethirajan (Tedor):
Incompatibility between the tablet components can be overcome by having the incompatible ingredients in different layers.
It is critical to understand the physicochemical properties of the drug substance, and preformulation compatibility studies
will help identify such incompatibilities so that certain excipients can be avoided or be separated into different layers
for better drug product stability. Multilayered technology is used in many instances to overcome incompatibilities between
drug substances that need to be administered in a single dosage. Occasionally, in the case of three-layer tablets, a thin
placebo layer may be used between the outer active layers to avoid incompatibilities.
Another vital part in developing multilayered tablets is excipient selection. It is preferable to use excipients that are
compatible with the drug substances in both the layers to maximize drug-product stability. Generally, scrapers present in
the multilayered machines are non-metallic in nature; hence, it is imperative that the use of abrasive excipients that may
ruin these scrapers is avoided. Using excessive amounts of lubricants should also be avoided because these may interfere with
adhesion between layers. Excipient choices should be based on the functionality of a particular layer (e.g., immediate release).
