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Date of Award

2011

Document Type

Dissertation - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Xiaoling Li

First Committee Member

Shaoling Li

Second Committee Member

Wade Russu

Third Committee Member

Silvio Rodriguez

Abstract

In this dissertation, the mechanisms of nanosuspension stabilization via polymer adsorption on nanoparticle surface were investigated. As the electrokinetic behavior and colloidal stability depend on the surface characteristics, altering the surface adsorbed polymers affords the different surface properties of nanoparticles and leads to the insight on the mechanism of nanoparticle stabilization. Drug nanosuspensions were prepared by wet milling of drug with water as medium and polymers as stabilizers. Block copolymers were evaluated based on varying the hydrophobic and hydrophilic amounts, polymer concentration, and polymer affinity differences onto the nanoparticle surface. Specifically, block copolymers of ethylene oxide (EO) and propylene oxide (PO) with different EO chain lengths were used to modify the nanoparticle surface and investigate the mechanisms of stabilization by varying the ratio of hydrophobic (PO) and hydrophilic (EO) units. It was hypothesized that the PO chain of block copolymers adsorb at the solid-solution interface and the EO chain provides steric hindrance preventing aggregation. Block copolymer adsorption layer thicknesses were experimentally determined with adsorption layer thicknesses increasing from 4.7 to 9.5 nm as the number of EO increase from 26 to 133 monomer units. Nanoparticle aggregation occurred with insufficient polymer monolayer coverage and electrokinetic zeta potential greater than -20 mV. The amount of block copolymers on the surface of nanoparticles was quantified and the affinity of polymer adsorption increased as the copolymer hydrophobic units increased. The amount adsorbed and affinity provides a qualitative ranking of the affinities between a specific polymer and nanoparticle substrate to provide a method in determining the mechanism of stabilization, where specific functional groups for adsorption could be selected for maximum nanoparticle stability. A molecular modeling was conducted to visualize and support the mathematical model and the proposed mechanism of block copolymer adsorption onto a nanoparticle surface. The time lapse molecular modeling of a block copolymer in an aqueous media showed the hydrophobic units adsorbing onto the nanoparticle surface with the hydrophilic units projecting into the aqueous media. For the first time in pharmaceutical research, a systematic series of studies were conducted to elucidate the mechanisms of adsorption with both surface charge and polymer affinity analyses. A series of studies evaluating the adsorption properties polymer stabilizers provided useful information on how a block copolymer comprised of both hydrophilic and hydrophobic domains adsorbs onto an active pharmaceutical ingredient. A systematic set of experimental techniques were presented with novel analysis tools and predictors to construct stable nanoparticle formulations.

Pages

134

ISBN

9781124634326

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