DOI
https://doi.org/10.25772/8T33-N442
Author ORCID Identifier
https://orcid.org/0000-0002-6947-658X
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Chemistry
First Advisor
B. Frank Gupton
Abstract
The synthesis of active pharmaceutical ingredients is often a time-consuming and expensive process. Due to the nature of pharmaceutical manufacturing, these costs are carried forward to the final purchase price by the consumer. Although there are many factors which are involved in the final costing of a pharmaceutical, the cost associated with the synthesis is the primary one which can be managed by chemists and engineers.
This work discusses the synthetic routes of four active pharmaceutical ingredients as well as the synthetic techniques and equipment used with an emphasis on how the application of specific techniques can be applied to decrease the cost of the drug. Four main factors: reagent cost, reaction yield, atom and step economy, and operation costs, are used to guide the work being performed and the routes which are chosen.
Using these variables, we apply process intensification to the synthesis of dolutegravir, glycidyl pivalate, albuterol, and the fluoroquinolone class of antibiotics. Through this, we are able to optimize reaction conditions to improve the final yield of reactions as well as improve purification to allow for direct utilization of our material in solution for subsequent reactions. We also utilize continuous flow chemistry techniques to streamline the synthesis of pharmaceuticals through the application of different flow reactor vessels and peripheral devices.
Lastly, in order to address factors outside of science’s control, we develop an alternative synthesis in order to strengthen the drug synthesis against shifts in availability and costing of currently available reagents. By identifying a convergent synthesis using different starting materials and reagents early in the synthesis, the overall synthesis is protected from unexpected or sudden increases in the costs of the current route’s starting materials.
Rights
© Jeffrey Michael Noble
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-10-2023