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T Tablets & Capsules April 2017 33 multi-layer tablets Tips for success with bi-layer tablets Robert Sedlock Natoli Engineering Important considerations include selecting which granulation to use in which layer, monitoring layer weights, and preventing cross-contamination. he pharmaceutical industry's interest in bi-layer tablets has grown because they promote patient convenience and compliance. They do so by combining multiple active pharmaceutical ingredients (APIs) in a single dosage form while avoiding chemical incompatibilities between APIs by physically separating them. Bi-layers also enable pharmaceutical manufacturers to create controlled-release drug profiles and apply osmotic push-layer technology. Other benefits include patent extensions, marketing advantages, and brand recognition. But making bi-layers presents some challenges. This arti- cle discusses some tools and techniques to help you over- come them. Bi-layer tabletting follows a principle similar to that of single-layer compression, except that the bi-layer opera- tion compresses two granulations, one on top of another in layers. This process requires two systems of feeders, dosing stations, and compression rollers. Selecting APIs for layers To develop a bi-layer tablet, you first must determine which granulation will be which layer. The bottom layer, or layer one, allows a greater weight and typically, tablet presses permit up to 19 millimeters of fill depth. The layer-one dosing process is identical to that of single- layer operations, and selecting the fill cam size is critical because excessive overfill can lead to material waste and unacceptable product yields [1]. The punch penetration allowed by the upper compres- sion roller limits the weight of layer two, the top layer of the tablet. Eight millimeters is a typical maximum value for the industry's multi-layer tablet presses, but you can increase that value by increasing the overall length of the upper punch. It is possible to increase that value by another 2 to 4 millimeters if the tablet press allows it. To determine if it does, inspect the upper punch's clearance as you manually rotate it 360 degrees on the tablet press, with all parts installed, including the feeders. The additional length requires adjustments in the human- machine interface software to increase the values of the upper punch's penetration above what the Tableting Specification Manual lists as the standard operating limit for the upper punch, which is 133.35 millimeters. In the Eurostandard the limit is of 133.60 millimeters. Compaction characteristics Another factor to consider in layer selection is the granulation's compaction characteristics. Layer one expe- riences two compression events, whereas layer two experi- ences only the final compression stage. Undergoing two compression events—one of which is essentially the pre- compression stage—means that a granulation that com- pacts poorly or that is strain-rate sensitive may be better as layer one. That may also pay off if you scale up to a high-speed bi-layer tablet press because any challenges you face on a small-scale R&D machine will worsen on a larger-scale machine due to its higher loading rates and shorter dwell times and because the two compression events will increase total compression time [2].