Development of multiple-unit pellet systems by employing the SeDeM expert diagram system

Abstract

Conventional tablets and capsules are considered the most common and acceptable drug delivery systems, however, in recent years multiple unit pellet systems (MUPS) have become more popular and are considered to be an interesting alternative for oral drug administration. MUPS provide several therapeutic advantages over other solid oral single-unit dosage forms such as conventional tablets and capsules. MUPS exhibit a reduced risk of local irritation and toxicity, predictable bioavailability, reduced likelihood of dose dumping and minimised fluctuations in the plasma concentration of the drug. MUPS comprises of a number of small uncoated or coated, spherical or semi-spherical particles (referred to as pellets or beads) which are prepared by different methods including drug layering, cryopelletisation, freeze pelletisation, spray drying, spray congealing, compression, balling and extrusion-spheronisation. The pellets are then compressed into tablets (MUPS tablets) or filled into capsules (MUPS capsules) using the same principles and equipment that are used in the manufacturing of conventional tablets and capsules. The technology used in MUPS formulations combine the advantages of conventional single unit dosage forms with that of small spherical or semi-spherical solid units into one multiple-unit dosage form. The production of MUPS tablets present various challenges including damage or deformation of the pellets during the compression process as well as variations in tablet weight and content uniformity due to segregation of the pellets and added powder excipients. These challenges can however be resolved by using specialised tablet compression machines and/or optimised tablet formulations. Application of MUPS technology has led to the successful formulation of various marketed MUPS products with increased bioavailability and improved pharmacological response. Several sustained drug release MUPS products are available on the market today. Formulation studies of tablets are often done by trial and error. The SeDeM Expert Diagram System (SeDeM EDS), however, provides information about the selection of the most appropriate excipient and the optimal amount thereof which is required in direct compression tablet formulations. This system provides an indication of the degree to which powder substances can be successfully compressed and also predicts which properties of the end product formulations needs to be adjusted to yield the optimal formulation for direct compression. The aim of this study was to apply the SeDeM EDS to different size pellets (i.e. 0.5, 1.0, 1.5, 2.0 and 2.5 mm) containing different APIs (i.e. doxylamine, ibuprofen or paracetamol) to determine which properties should be corrected to yield MUPS tablet formulations. The SeDeM parameter tests were conducted on the pellets, selected excipients, intermediate blends and final blends. The study showed that the properties of the pellets depended on the active ingredient and pellet size. The SeDeM compressibility indices indicated that the final pellet blends should be suitable for compression into MUPS tablets. MUPS tablets were prepared from the final blends and evaluated in terms of physicochemical properties and dissolution profiles. Only three of the MUPS tablet formulations containing ibuprofen and one MUPS tablet formulation containing paracetamol failed content uniformity. All the other MUPS tablet formulation showed acceptable results for friability, hardness, and mass variation. The water solubility of the APIs as well as the pellet size (surface area exposed to the dissolution medium) attributed to the difference in drug dissolution rate. The study concluded that compression of the pellets into MUPS tablets could be achieved and the SeDeM EDS could be applied with success in the formulation of MUPS tablets