Bulk Freeze-Drying Milling: a Versatile Method of Developing Highly Porous Cushioning Excipients for Compacted Multiple-Unit Pellet Systems (MUPS).

The compaction of multiple-unit pellet system (MUPS) is a challenging process due to the ease of coat damage under high compression pressure, thereby altering drug release rates. To overcome this, cushioning excipients are added to the tablet formulation. Excipients can be processed into pellets/granules and freeze-dried to increase their porosity and cushioning performance. However, successful formation of pellets/granules has specific requirements that limit formulation flexibility. In this study, a novel top-down approach that harnessed bulk freeze-drying milling was explored to avoid the challenges of pelletization/granulation. Aqueous dispersions containing 20%, w/w hydroxypropyl methylcellulose (HPMC), partially pregelatinised starch or polyvinylpyrrolidone alone, and with lactose (Lac) in 1:1 ratio, were freeze-dried and then milled to obtain particulate excipients for characterization and evaluation of their cushioning performance. This study demonstrated that bulk freeze-drying milling is a versatile method for developing excipients that are porous and directly compressible. The freeze-drying process modified the materials in a unique manner which could impart cushioning properties. Compared to unprocessed excipients, the freeze-dried products generally exhibited better cushioning effects. The drug release profile of drug-loaded pellets compacted with freeze-dried Lac-HPMC excipients was similar to that of the uncompacted drug-loaded pellets (f 2 value = 51.7), indicating excellent cushioning effects. It was proposed that the specific balance of brittle and plastic nature of the freeze-dried Lac-HPMC composite conferred greater protective effect to the drug-loaded pellets, making it advantageous as a cushioning excipient.