Date of Award

2008

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

First Advisor

Thomas Needham

Abstract

This research compared a traditional drug development approach with an enhanced "Quality by Design" (QbD) approach to foster greater process and formulation understanding. Propranolol HCl extended release capsules and Metoprolol Succinate extended release tablets served as targets for development. The formulation and process parameters utilized well-established techniques, such as wet granulation, extrusion, spheronization, and fluid bed processing with commercially available aqueous or organic polymeric systems.

Propranolol HCl extended release capsules were a benchmark for current generic pharmaceutical process development to identify basic parameters for a suitable product. Metoprolol Succinate extended release tablets utilized the ICH Q8 annex guidelines approach to identify target profiles, and then; define, test, and link Critical Quality Attributes (CQAs). Preliminary data supported factor and level selections for the 23 full factorial and Box-Behnken experimental designs for elements of a conceptual design space.

Physical and chemical characterization of commercially available competitors established product target profiles. Particle size distribution, sphericity, moisture content, and dissolution profiles were studied as CQA's. Preliminary studies for the immediate release beads identified the water quantity during granulation, kneading time during granulation, and the duration of spheronization as significant factors for particle size generation, and sphericity. The traditional approach determined an organic system was necessary for Propranolol HCl to yield a stable extended release product. The aqueous sustained release coating studies for Metoprolol Succinate found the polymer coating level, humidified curing condition, and curing duration were important factors. Altering the excipient blend formulation during initial tabletting trials minimized segregation and bead damage.

The full factorial design for the development of immediate release beads identified spheronization time as a statistically significant factor in determining the standard deviation and relative standard deviation for sphericity. The Box-Behnken design for sustained release beads found the polymer coating levels to be a statistically significant main effect for the dissolution profile. Significant surface damage was apparent throughout the full factorial tabletting design, with a "best case" approach yielding an improved dissolution profile. Traditional approaches incorporated into the QbD approach facilitate variable and level selection throughout the development process. Data generated via these statistical methods supports process understanding and future decision-making.

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