Date of Completion

9-14-2015

Embargo Period

12-15-2015

Major Advisor

Dr. Bodhisattwa Chaudhuri

Associate Advisor

Dr Bruno Hancock

Associate Advisor

Dr. Mike Pikal

Associate Advisor

Dr Robin Bogner

Field of Study

Pharmaceutical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Despite solid oral and inhaled dosage forms making a significant proportion of marketed pharmaceutical products, a better understanding of particulate processes will enable more science-based product optimization and scale up. A combination of experimental and computational approaches can be used to improve our current understanding of particulate processes. The current dissertation aims at improving understanding of particulate systems by investigating applications in several multiphase multicomponent flow regimes, each capturing a fundamental force, by systematic experiments and computational modeling.

Computational Fluid Dynamics (CFD) modeling of aerosol flow through pressurized metered dose inhaler (pMDI) – spacer systems and correlation of fluid flow patterns with drug transport and deposition through the Recirculation Index (RCI), a dimensionless variable developed during the course of our studies, improved our understanding in the dilute flow regime. Increased discharge of co-flow air and the smaller spacer were associated with smaller spacer deposition.

In the dense flow regime, the effect of material (cohesion/adhesion) and process variables on formation ordered mixtures were investigated in low shear and high shear double cone (DCN) and a high shear mixer (HSM) using experiments and Discrete Element Method (DEM) based modeling. Segregation of ordered mixtures was studied upon flow from hoppers in both mass and funnel flow regimes. Ordered mixtures formed quickly in the HSM, however the high velocity in the HSM also caused greater sticking of fines and abrasion of carrier fines compared to DCN. DEM studies demonstrated different flow fields for the blenders, which also responded differently to change in adhesive properties of the mixture components. Press-on forces holding the carrier and the fines decreased as a function of drug load but not differentiated between the blenders .No segregation of ordered mixtures was observed upon discharge from either hopper.

The impact of electrostatic forces was investigated during tribocharging of binary mixtures in a hopper-chute assembly. The work function difference, determined computationally from Molecular Dynamics (MD) simulations for chemically pure materials, between contacting materials was tested as a predictor for tribocharging of insulators. The work function difference model was found to be a good predictor for pure systems, but not for binary mixtures where the system net charge was additionally influenced by material hygroscopicity and segregation patterns.

Capillary forces impacting high shear wet granulation (HSWG) performance were investigated in a simple lactose-water system. This was done through experiments and a dynamic 3D DEM model capable of including dynamic process variables and incorporating material property changes upon liquid addition. The effects of liquid addition rate and impeller speed were well-correlated with experimental observations. The DEM model also predicted poor agglomeration for a cohesive material in contrast with a non-cohesive powder. The importance of incorporating modification of material properties of granular material with binder addition was also elucidated.

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