Document Type


Date of Award

Fall 2017

Degree Name

Doctor of Philosophy in Chemical Engineering - (Ph.D.)


Chemical, Biological and Pharmaceutical Engineering

First Advisor

Ecevit Atalay Bilgili

Second Advisor

Rajesh N. Dave

Third Advisor

Robert Benedict Barat

Fourth Advisor

Piero M. Armenante

Fifth Advisor

Dan Zhang


Nanoparticle-based formulations (nanocomposites) and amorphous solid dispersions, shortly ASDs, are two major pharmaceutical formulation platforms used for the bioavailability enhancement of poorly water-soluble drugs. While they both have several advantages-disadvantages, a scientific comparative assessment of their drug release performance and dissolution mechanisms at different drug doses is not available. With the goal of addressing this issue, the dissertation aims to achieve three major objectives: (1) develop a processing-formulation understanding of wet media milling process for fast-efficient production of drug nanoparticles in stable nanosuspension form, (2) elucidate the impact of various classes dispersants on drug release rate and mechanisms during the redispersion-dissolution of nanocomposites prepared via dying of the drug nanosuspensions, and (3) assess the dissolution enhancement imparted by drug nanocomposites vs. ASDs prepared via drying of drug nanosuspensions by a novel nanoextrusion process, which allows for a scientific, head-to-head assessment of the two formulation platforms at various drug doses.

In achieving the first objective, this dissertation work firstly establishes a general stabilization strategy for ensuring the physical stability of five different wet-milled drug nanosuspensions via combined use of a polymer (HPC: hydroxypropyl cellulose)-anionic surfactant (SDS: sodium dodecyl sulfate). A microhydrodynamic model is used for enhanced process understanding of the wet media milling process and rational selection of bead sizes. Then, the media milling process is intensified with the guidance of the microhydrodynamic model for fast production of sub-100 nm drug particles with reduced specific energy consumption and low bead wear. In achieving the aforementioned second objective, drug nanosuspensions prepared by the media milling are processed into nanocomposite microparticles with various classes of dispersants via either fluidized bed coating/drying or spray drying process. The drug nanosuspensions stabilized by HPC-SDS or HPC alone are coated on Pharmatose® carrier particles, which allows us to elucidate the impact of the physical stability of drug nanosuspensions and different dispersants on drug dissolution from the nanocomposites. It is found that good physical stability of a drug nanosuspension is a necessary condition for fast nanoparticle recovery and drug dissolution, but it is insufficient; dispersant concentration/type plays a critical role for fast drug release. Fast drug dissolution from the nanocomposites is also attained by high drug-loaded, surfactant-free nanocomposites with a co-milled superdisintegrant-HPC prepared via spray drying. The drug release rate is found to correlate positively with the dispersant concentration and the swelling capacity of the superdisintegrant. In achieving the last objective, drug nanosuspensions are dried in an identical nanoextrusion process with two polymers, which enables to produce both a nanocomposite (poor polymer-drug miscibility) and an ASD of the same drug (good polymer-drug miscibility). Nanocomposites outperforms the ASDs at low drug dose, whereas ASDs exhibits much higher supersaturation, outperforming the nanocomposites at high dose. Overall, this dissertation has established a platform approach (nanoextrusion) for a scientific comparison of drug nanocomposites vs. ASDs and the prerequisite processing–materials knowledge and methodology needed for such scientific comparison.



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