Issue link: https://www.e-digitaleditions.com/i/1349974
Tablets & Capsules March/April 2021 37 Flexibility in release profiles Multilayer tablets allow a single dose to deliver two APIs with unique in vivo release profiles or to release the same API in two or more different release profiles. Essentially, formulators can develop products that offer both immediate and sustained release for an API. A common approach is to use hydrogels (cross-linked polymer networks), which swell in liquid and sustain release in one portion of the tablet, while the API releases immediately in the other portion. Fixed-dose combinations also offer formulators the opportunity to create products where APIs potentiate each other to increase efficacy at lower doses and/or change therapeutic indications. Vicoprofen (the brand name for the combination of hydrocodone and ibuprofen) is an excellent example of a combination product in which two APIs work synergistically to enhance effect—ibuprofen reduces inflammation in an area, which facilitates access for the hydrocodone and improves analgesic performance. This combination of several APIs, release profiles, and potentiating effects of APIs in one tablet simplifies the dosing regimen and contributes to better patient adherence. Regulatory pathways To extend the patents on their products and accelerate development, manufacturers are increasingly filing new drug applications following the FDA NDA 505(b)2 path- way, which offers relatively shorter clinical development times as well as economic incentives. Products pursuing this pathway most commonly include new indications and improvements to existing products' bioavailability. Multi- layer tableting can play a critical role in formulating such improved products by increasing dosing convenience and, therefore, improving patient adherence and allowing for new fixed-dose combinations and controlled-release products. Summary of key challenges Common problems associated with multilayer tableting include delamination at the interface between the layers due to insufficient adhesion, incomplete segregation of tablet portions, relatively low yield compared with conventional single-layer tablets, and difficulty in achieving the desired weight of individual layers. Delamination most commonly occurs between adjacent layers but can occur internally in an individual layer after compression, at any point during subsequent processing, or even during storage. This may result in patients receiving an inadequate dose. Compression Multilayer tablet presses use a standard upper punch, lower punch, and die assembly on a rotating turret. Whether the tablet has two, three, or four layers, initial layers are compressed with relatively light forces, while the final layer is compressed using the main compression force. A successful multilayer tableting process requires careful selection of the excipients and process parameters as well as careful study of the mechanical properties of the materials being used. Understanding the nature and physicochemical of combining patient medications. The efficacy of current treatments is often limited by poor patient compliance resulting from the burden of taking multiple medications daily. Combining multiple active pharmaceutical ingredients (APIs) or combining more than one release profile for the same API in a single dose is often a win for both patients and drug product developers. Multilayer tablets have emerged as an elegant way to deliver multiple therapeutic payloads in a single dose. Mul- tilayer tablets consist of two to four separate formulations compressed into a single tablet in layers (although three- and four-layer products are rare). Each layer can have a different API and/or release profile, allowing developers to create more effective combination products than with standard tablets. The API levels in the different layers can be the same or different. Multilayer tablets are also particularly relevant as the industry moves toward more patient-centric therapies. Creating such simplicity for patients poses challenges for developers and manufacturers. Formulation considerations include API incompatibility, the compression requirements of different materials, and excipient selection. Multilayer tablets must also have adequate mechanical strength and hardness to endure processing, handling, packaging, and transport. Difficulties include inadequate hardness, imprecise control of layers and tablet weight, elastic mismatch between conterminous layers, and susceptibility to delamination during manufacture. Combining incompatible APIs The main advantage of multilayer tableting is the ability to combine two or more chemically or physically incom- patible APIs into a single tablet. Though matrices may be incompatible with one another, multilayer tablets allow formulators to insert an inert barrier layer between incompatible matrices to prevent interactions. In this connection, formulators have leverage to develop combination products. If the APIs' chemical stability is still not acceptable, an alternative is to add a buffer layer between the two API-containing layers. The buffer layer blocks activity at the interface between the two APIs. This approach often leads to a final drug product with superior chemical stability. The main advantage of multilayer tableting is the ability to combine two or more chemically or physically incompatible APIs into a single tablet.