Issue link: https://www.e-digitaleditions.com/i/541292
Tablets & Capsules July 2015 11 • Adding variety to traditional sold dosage forms, including orally disintegrating tablets (ODTs), mul- tiple-unit pellet system (MUPS) tablets, sachets, stick packs, and drinking straws for pediatric and geriatric use. Coated starter pellets can also be used in oral suspensions. Pellets—typically 100 to 2,000 microns in diameter— are made by extrusion-spheronization, direct pelletiza- tion, prilling, and layering. For use in formulations, the pellets are first subjected to drug layering and coating using well-established techniques, including the Wurster process and other fluid-bed processes, powder layering, and other mechanical processes. Naturally, the characteristics of the starter pellets determine how they will perform in these preparatory coating processes and in the final dosage form. While some characteristics may not seem critical in small-scale development (e.g., friability), those properties can strongly affect the product's success once it reaches com- mercial manufacturing. They can also affect the final product's cost structure. Table 1 lists some characteristics and how they affect the product [1]. In fact, as pellet-based formulations become more complex, the quality aspects of the starter cores and their processability can have a greater impact on the cost of the final product than the base price of the pellets does. For example, if insoluble cores are used, spray rates can be higher and process times shorter. Likewise, opting for low-friability pellets when coating in a fluid-bed process will minimize losses (maximize yields). In short, it is important to evaluate many different fac- tors when choosing starter pellets. Do not only consider the excipient's price per kilogram; study how your choice will affect costs when production is scaled up. Using off- the-shelf products from the warehouse or simply re-speci- fying what worked in earlier formulations may be unwise. Rather, evaluate the application carefully to find the best option right from the start because once the project is underway, time pressure and other limitations may make switching difficult. Types of starter pellets Pellets can be classified as being neutral substrates or functional ingredients, and both can serve as carriers for subsequent drug layering. They can also be manufactured as API-matrix pellets or pure API pellets. Neutral starter pellets should be as inert as possible to prevent them from interacting with the API; they should serve only as a carrier to enable API layering, often fol- lowed by the application of a coating to mask off-tastes and/or modify API release. Functional starter pellets, however, actively support the formulation, such as by improving API solubility, improving dissolution, and enhancing stability. API-matrix pellets combine an excipient and an API and can subsequently be coated to achieve the desired dissolution profile. These matrix pellets can comprise as much as 90 percent API. In addition to binders, API- matrix pellets can include functional polymers that con- trol the dissolution profile based on particle size, thereby eliminating the need for an additional functional coating. In some cases, depending on the API's characteristics and the technology used, it is possible to create pellets of 100 percent API and apply a functional coating to them. A number of manufacturers offer equipment to create these pellets, including ACG, Freund-Vector, and Glatt. A 2011 article described some of the production tech- nologies—aside from extrusion-spheronization—used to create API-matrix and API pellets [1]. Because standard extrusion-spheronization processes produce particles whose sizes vary fairly widely, many pharmaceutical manufacturers often sieve them to narrow the particle size distribution to meet their formulation's requirements. In the case of sugar spheres, the process uses sugar crystals of different sizes, and the target parti- cle size is obtained by using intermediate layered crystals, which prevents large losses to sieving. Usually, the over- and undersize spheres can be used for the next larger or smaller fraction. For the production of some microcrys- talline cellulose (MCC) pellets, the same starting material is used for all size grades, and particle size is defined by the parameters of the process, which is followed by a final sieving step. In general, the narrower the particle Table 1 Effect of pellet characteristics on formulations [1] Characteristic Considerations Size Final dosage form, drug load, and processability Particle size distribution Dissolution profile, batch-to-batch uniformity Surface area Target drug load, film thickness, choice of binder, dissolution profile Solubility Processing (process time) Hardness Compression into tablets (MUPS) Friability Processing (process times and yield) Inertness Compatibility with API This event, held October 24, is offered by the Controlled Release Society and immediately precedes the AAPS Annual Meeting in Orlando, FL. It reviews the advantages of multiparticulate dosage forms in terms of dosing flexibility (i.e., targeted dosing and timed dosing) and offers practical knowledge about formulation and process development of multi- particulate dosage forms, including beads, pellets, and mini-tablets. Receive a discount if you register by August 21. For more information: bit.ly/MultiPart15. Formulation, Processing, and Testing of Functionally Coated Multiparticulates