Document Type


Date of Award


Degree Name

Doctor of Philosophy in Materials Science and Engineering - (Ph.D.)


Chemical and Materials Engineering

First Advisor

Piero M. Armenante

Second Advisor

Costas G. Gogos

Third Advisor

N. M. Ravindra

Fourth Advisor

Nicolas Ioannidis

Fifth Advisor

Ken Keunhyuk Ahn

Sixth Advisor

Munir Hussain


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 processes.

Four blends are prepared to investigate how fme API (micronized theophylline) interacts with a coarse polymer (HPC MF), how coarse API (theophylline) interacts with a fine polymer (HPC EXF), and the effects when both components in the blend are fine and coarse. When each formulation is granulated, the torque, product temperature, and particle size are found to be strongly dependent on heating temperature, screw speed, screw design and, ultimately, the input material properties.

Finally, to elucidate the effects from just the input material, the four formulations are granulated under controlled conditions, in a batch mixer, at room temperature. This provides a "time-dilating" effect where the granulation process happened in order of minutes vs. seconds as observed in the extruder. The product temperature and torque traces vary for all four formulations, evident that PED and FED are a function of the formulation. The formulations with theophylline reach the maximum torque limit approximately twice as fast as the formulations containing the micronized theophylline. Particle size growth and rate of densification is also different between all the formulations. All observations correlate that the following input material properties: particle size, cohesion, inter-particle coefficient of friction, f, influence the ensemble and structure of the granules.



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