Engineering Nanoparticles for Pharmaceutical Applications: Formulation and Freeze-Drying Techniques

Abstract

This dissertation discusses the use of Flash NanoPrecipitation, a continuous rapid precipitation method, to fabricate pharmaceutical nanoparticles. After introducing the precipitation technique and reviewing the current understanding and applications in the literature of Flash NanoPrecipitation, three chapters exhibiting a methodology for formulating active pharmaceutical ingredients are presented. The main focus is the adaption of Flash NanoPrecipitation techniques for producing final dosage forms that could be feasibly administered at a therapeutic dose, which has not been emphasized in the past. Guided by scientific principles, systematic evaluations of critical formulation and process parameters achieve formulations with maximized loading efficiencies.

This treatment is first given for the production of lyophilized progesterone-loaded nanoparticles for emergency treatment of a traumatic brain injury, followed by a model study investigating how to generate lyophilized nanoparticles loaded with a crystalline weak base, GW771806X. These two chapters are aimed for parenteral administration of nanoparticulate therapeutics, which is why freeze-drying is employed to obtain dry dosage forms. The last chapter focusing on rational formulation details the production of nanoparticles suitable for oral dosage forms, for which traditional Flash NanoPrecipitation formulations would not be cost-effective.

Finally, an evaluation of freeze-drying nanoparticles is presented. This fundamental study elucidates on the effects of various formulation and process parameters on underlying phenomena in the freeze-drying process. The results underscore the need for a rational development of a lyophilized nanoparticle formulation in order to achieve a dosage form that can be easily reconstituted at therapeutic concentrations, starting with nanoparticle composition, choice of protectant excipients, and freeze-drying conditions.

Overall, the methodology put forth by this dissertation exemplifies some of the necessary steps for the Flash NanoPrecipitation technique to be adapted into industrial pharmaceutical practice. While the technique has been highly characterized and promoted as a viable option for the formulation of active pharmaceutical ingredients that have traditionally been difficult to formulate, there has yet to be significant use of Flash NanoPrecipitation in the industry. Therefore, in attempting to marry the particle engineering with the requirements of pharmaceutical formulation development, this dissertation aims to establish a starting point for future industrial adaption of Flash NanoPrecipitation.