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.

A study on the impact of HPMC viscosity grade and proportion on the functional properties of co-freeze-dried mannitol-HPMC cushioning excipients for compacted MUPS.

The co-processing of multiple excipients is driven by the potential of diversifying the properties and functionality of excipients when they are combined. Bulk freeze-drying-milling is a novel secondary processing approach to develop co-processed excipients. It offers a significant advantage of formulation flexibility. This study was designed to systematically investigate the impact of 3 factors, hydroxylpropyl methyl cellulose (HPMC) viscosity grade, mannitol to HPMC ratio and particle size fraction on the functional properties of freeze-dried (FD) mannitol-HPMC cushioning excipients produced for multi-unit pellet system tableting. Based on the results, the investigated formulation variables were significant in determining the functional properties of the FD-mannitol-HPMC cushioning excipients. Among the formulations, FD-mannitol-HPMC F4M (3:1 ratio) excipients exhibited the best cushioning performance. It was postulated that the protective effects of the cushioning excipient were brought about by its propensity for rearrangement around the coated pellets to reduce detrimental pellet-pellet contact and ability to absorb damaging compressive forces. Conversely, FD-mannitol-HPMC vLV (3:1 ratio) had cushioning effects but showed short disintegration time while maintaining adequate tablet tensile strength. Overall, the results of this study highlighted the impact of formulation variables on the functional properties of the cushioning excipients, arising from an interplay of the freeze-dried particle properties.

Probing the impact of HPMC viscosity grade and proportion on the physical properties of co-freeze-dried mannitol-HPMC tableting excipients using multivariate analysis methods.

This study investigated the impact of hydroxypropyl methylcellulose (HPMC) viscosity grade, HPMC proportion and particle size fraction on the physical properties of the freeze-dried mannitol-HPMC excipients produced, using multivariate analysis methods. Solutions containing 20%, w/w mannitol-HPMC were freeze-dried and milled to obtain excipients of size fractions 125-355 µm and 355-710 µm to understand the impact of the formulation variables on the molecular, particle and bulk properties of the excipients. Results showed that the freeze-dried mannitol-HPMC excipients were mainly differentiated by 3 overarching properties, in the order of their contribution to the variation in the principal component analysis (PCA) model: (i) freeze-dried cake strength and bulk fill-related properties, (ii) compression behaviour-related properties, and (iii) flow-related properties. These properties were influenced by the HPMC viscosity grade, HPMC proportion and size fraction of excipient used. Freeze-dried excipients containing vLV or lower HPMC proportions had higher bulk densities, thus displaying better packing within the die. For larger excipients, densification by plastic deformation was likely preceded by fragmentation, thus accounting for the higher yield pressure values. The establishment of inter-variable relationships between the physical properties would be useful in further studies on the functional properties of tablets containing these co-freeze-dried mannitol-HPMC tableting excipients.