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Industry experts discuss formulation and technical challenges in multilayer tablet manufacture.
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).
PharmTech: How can the weight of individual layers be monitored and controlled accurately?
Behrens (IMA): When producing bilayer tablets, the in-line control of production, combining compression force measurement and statistical weight check are challenging for several reasons. If the compaction force for layer one is extremely low, it could be difficult to obtain a clear signal from the strain gauges. Low-force compression rollers are available to help deal with this. The reduced mass ensures more accurate and reliable measurements. Another critical point is statistical sampling of the layers for weight checking. For sampling, the first layer has to be compressed at a higher force to achieve enough hardness to make sampling and weighing possible. Some systems can achieve this by using specialized systems. For example, to avoid the production of second-layer-only tablets during layer one sampling, lower punches can remain in the up position while the fill-shoe for layer two is stopped.
Calvin (Elizabeth): Usually, two different process-control methods are employed to achieve this. The first standard method is to utilize force control, which monitors the layer tamping pressure by means of a strain gauge transducer that, in turn, provides feedback to the press controller. This information is used to automatically adjust the metering cam to keep the set pressure constant to maintain the correct weight and tamping pressure. The strain gauge should be sized so that it will be sensitive enough to "sense" the lighter tamping pressures required for producing a tablet layer compared to the strain gauge that would be required for final tablet compression. The secondary method is to select a multilayer tablet press that automatically collects sample tablets from each layer at regular intervals and sends them to a weight testing unit, which would be included in the press control feedback loop, to provide in-process checks and weight control.
Kirsch (Natoli): Tablet press manufactures will be responsible for this through improved technology and engineering. By utilizing quality by design, the science of the formulation is understood and the design space can be exploited to deliver a controllable process. Controlled processes deliver a product with the required critical quality attributes that define what is to be delivered to the patient.
PharmTech: How can layer cross-contamination be avoided?
Behrens (IMA): Product losses can be very high when making layered tablets. Usually strong vacuum aspiration is used to clean the residual product on the die table after the dosage of each layer, thus preventing cross contamination. Over the years, vendors have developed several technical solutions that minimize the quantity of powder remaining on the die plate that needs to be removed by suction.
Calvin (Elizabeth): This can be avoided in a few ways. Ensuring the feed frame is correctly adjusted and not leaking powder, properly adjusting the vacuum being applied to the front of the feedframe to keep the die table clean, and installing dies that are manufactured to the high limit on overall die height. Whenever the granulation characteristics and tablet size deem it necessary, a "Tail Over Die Scraper" (a delrin cover that is held in place against the die table with spring steel to keep any granulation form slinging out of the die through centrifugal force) may be needed if any powder loss is incurred due to centrifugal force.
Kirsch (Natoli): Proper press setup is essential. Turret die tables have a certain amount of vertical run out. Often overlooked is the simple task of indicating a die table to locate the high point. Feeder clearance must be set at this point to achieve a minimal amount of clearance between the feeder and die table to reduce granulation loss. Scraper blades must be in good condition and free floating on the die table to reduce cross contamination. Die tables must also be in excellent condition as any wear or damage will contribute to granulation crossover. Proper dust extraction is also needed as presses suited for layered tablets generally have more and/or specifically designed vacuum nozzles. Skilled press setup technicians and operators are a must.
Ethirajan (Tedor): Scraper and seal conditions of the feed frames are very important. It is also essential that excess granulation passing the scrape-off be vacuum cleaned so that fines from one layer don't cross contaminate the other. Reduced fill cams may be used to reduce the amount of granulation that needs to be scraped off from overfill of the die.
PharmTech: What are the unique challenges of applying in-process controls and process analytical technologies (PAT) to multilayer tablets?
Behrens (IMA): PAT systems based on transmission or reflection are seldom used on monolayer tablets. The amount of validation is high, and even more complex for bilayer or multilayers. It is also difficult to repeat the measuring results on each layer. The industry has to put more efforts into this issue.
Kirsch (Natoli): PAT is best used during development to understand the variables involved in achieving the formulation design for a quality tablet.... However, PAT measurements can provide information for feedback control, which can offer the manufacturer an opportunity to move toward real-time release of a product. If traditional tablet press variables are properly controlled and a quality granulation is delivered to the tablet press, then the due diligence time spent in process development pays off with a robust manufacturing process that does not require process analytical instrumentation.
Read the full version of this article and other related content online at PharmTech.com/multilayer.