Date Available
2-11-2022
Year of Publication
2021
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Pharmacy
Department/School/Program
Pharmaceutical Sciences
First Advisor
Dr. Patrick Marsac
Second Advisor
Dr. Younsoo Bae
Abstract
The successful delivery of chemical compounds for the purpose of therapeutic treatments and prophylactics is a substantial undertaking in modern drug development. Notably, the adoption of high throughput screening techniques has led to the proliferation of poorly water soluble and/or highly potent molecules which further complicate development activities. Spray dried amorphous solid dispersions are an increasingly important formulation strategy to overcome solubility issues while wet granulation approaches are the method of choice for the preparation of highly potent APIs in oral solid dosage forms.
A common connection between these critical techniques is their reliance on solvent-based processing that can often result in unexpected outcomes on product quality and performance. Solvent choice has been shown to influence API form, habit, stabilizing interactions, and physical and chemical properties of drug product intermediates, which requires greater understanding. The objective of this dissertation is to provide a general overview and assessment of the role of solvents in the important methods of spray dried dispersions (SDDs) and highly potent compounds by wet shear granulations (HP-WSG) to address concerns related to poorly soluble and/or highly potent APIs.
Light scattering (LS) and dilute solution viscometry (DSV) techniques have been utilized to assess critical drug-polymer-solvent interactions in the solution state and explore the mechanisms by which solvent choice may influence SDD physical stability. Next, solid-state characterization techniques were leveraged to understand how the interplay between wet granulation processing parameters, API physical form, and environmental moisture may dictate chemical stability issues of a highly potent API. Conclusions and future work are presented with next steps that can be pursued in expanding our knowledge of complex multi-component solutions which are frequently encountered in pharmaceutical development.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2021.011
Funding Information
Pharmaceutical Research and Manufacturers of America (PhRMA) Predoctoral Fellowship in Pharmaceutics, Jan 2018 - Dec 2020
Center for Pharmaceutical Development (CPD), 2016-2020
US World Meds, LLC, May 2019 - May 2020)
Recommended Citation
Defrese, Matthew Kyle, "Understanding the Impact of Solvents in Oral Solid Dosage Formulation and Process Development" (2021). Theses and Dissertations--Pharmacy. 122.
https://uknowledge.uky.edu/pharmacy_etds/122
