Influence of material properties on granules prepared by dry co-rotating twin screw extrusion and counterrotating batch mixing

Recently, the pharmaceutical industry has shown interest in continuous granulating technology because of the flexibility it offers as an option that bypasses the costly scale-up process associated with batch manufacturing. However, the granulation mechanism(s) using twin screw co-rotating hot melt extrusion (HME) has not been fully explored, and it is not yet well understood. This leads to costly experiments during development and process reliability problem in commercial manufacturing. The main objective of this dissertation is to increase the mechanistic understanding of the twin screw granulation process of systems containing an active pharmaceutical ingredient (API) and a polymer excipient. This is accomplished by demonstrating that the onset of granule growth is driven by frictional energy dissipation (FED) and plastic energy dissipation (PED); where FED is the dominating mechanism for granule growth. The work presented here demonstrates how these mechanisms manifest in the evolving and resulting granule structure. The highlights of this dissertation can be categorized into the following parts: (i) A proof of concept analysis that looks at the morphological evolution of granules formed inside the extruder, specifically across the kneading zone. (ii) A comprehensive understanding of how PED and FED are influenced by the input material properties and the set-up of the extruder and how these interactions manifest themselves through system responses and granule growth. And finally, (iii) an understanding that PED and FED are predominantly responsible for the onset of granulation in batch mixing studies. For the first part, a proof-of-concept trial is explored with a prototype formulation containing approximately 65% (w/w) theophylline and hydroxypropylcellulose (HPC) MF (35% w/w). Granule carcasses collected across the kneading zone reveals the onset of granulation and the morphological differences within the granule, indicating that interacting material properties are playing a part in the granule ensemble ...