Issue link: https://www.e-digitaleditions.com/i/1349974
38 March/April 2021 Tablets & Capsules layer ratios of up to 1:6 have been formulated, but com- mercializing such a ratio would be incredibly challenging. To minimize the risk of delamination, it is recommended to keep the weights of the layers similar or if that is not possible, to maintain consistency in terms of the inactive ingredients used in the layers. Patient variability API absorption and bioavailability can be substantially affected by a dosage form's transit through the gastroin- testinal tract, so variability in the rate of gastric emptying between patients is one of the most critical parameters. For delayed-release products, variability between patients is especially important, as release begins when the dosage form comes into contact with the higher pH environment in the proximal small intestine. For multilayer tablets, the pharmacokinetic profiles of each layer must be fully understood and considered during formulation, as patient variability can lead to missed ther- apeutic windows and variability of the dosages received. Highly potent APIs The development pipeline for highly potent APIs has become one of the strongest revenue-generating segments in the pharmaceutical industry, and the market holds enor- mous potential. Highly potent APIs are often combined with others in fixed-dose combination products—often as a means of managing side effects or improving a prod- uct's safety profile with multiple release profiles. Highly potent APIs create a further challenge for manufacturers, who must ensure that appropriate containment strategies and technologies are in place to handle such materials and protect employees. Conclusion As with many new drug products and dosage forms, the formulation and manufacturing challenges presented by multilayer tablets are plentiful. Success requires careful formulation that considers downstream processing and the physical performance of all the materials involved. Following that, understanding the different compression requirements and having the equipment to handle them is a must. As multilayer tablets and other fixed-dose combinations gain more prominence, the industry is likely to see more innovation as manufacturers push the boundaries to deliver better products to patients. T&C Thomas B. Gold, PhD, is vice president of pharmaceutical development at Metrics Contract Services (252 752 3800, www. metricscontractservices.com). He holds a PhD in pharmaceutics and medicinal chemistry from the University of Kentucky. properties of both the active and inactive ingredients and how those properties determine the strength and integrity of the multilayer tablet is key. Parameters such as brittle- ness, viscoelasticity, plasticity, and compaction properties significantly affect the amount of compression required for each layer during manufacture. Selecting the tablet's first layer is important because the weight and control of the subsequent layers depend on the fill of the first layer. Compression force significantly influences the strength and interfacial adhesion between the layers, which further influences the mechanical integrity of the tablet. Often, the strength of the interface between the layers decreases as the compaction force on the first layer increases, so it is recommended to only lightly compress the first layer. Since the first layer is subjected to compression more than once, manufacturers prefer to use materials that exhibit greater compressibility and offer good compaction under minimal force, which also allows for enough space for the second layer. If layers require different ingredients, formulating the layers to have similar properties and compactibility is rec- ommended to encourage superior compaction and layer adhesion. Layers that relax differently after compaction or expand differently after exposure to stressed conditions are less likely to adhere successfully. Layer ratios The ratio between the layers and the sequence of their arrangement also affects multilayer tablet compression. A ratio at or near 1:1 (where each layer is the same size) often creates the most physically robust tablets, but in practice, different APIs and/or profiles require different formulations, which impacts layer size. To ensure accurate weight control of each layer during manufacturing, the particle size distribution, flow properties, and compressibility must be optimized. Compressibility is also a decisive factor in ensuring acceptable content uniformity of the APIs. The relative weight and sequencing of layers are as important as compression, as they directly impact inter-layer delamination or intra-layer capping. To obtain satisfactory API content uniformity, it is recommended to prioritize the compression setting of the layer with the smaller API dose or weight. Weight ratios for bilayer tablets are most commonly 1:1 or 1:2 but can be 1:3 or even 1:4. During development, Layers that relax differently after compaction or expand differently after exposure to stressed conditions are less likely to adhere successfully.