Author ORCID Identifier

https://orcid.org/0000-0002-9372-3595

Date Available

5-23-2022

Year of Publication

2022

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Pharmacy

Department/School/Program

Pharmaceutical Sciences

Advisor

Dr. Eric J. Munson

Abstract

Amorphous formulations, including amorphous solid dispersions (ASDs), consisting of the active pharmaceutical ingredient (API) intimately mixed in a polymeric matrix, are an attractive formulation approach to improve drug delivery, dissolution, and solubility. However, an amorphous API in an ASD is in a higher energy state compared to the crystalline drug and results in most ASDs being inherently unstable. The polymer helps to stabilize the amorphous drug against crystallization such that the resulting homogenous mixture maintains its solubility advantage relative to the crystalline form. One challenge of ASDs is that the presence of impurities including crystals or residual solvent, variations in the ingredients, or changes in storage conditions can all affect physical stability and bioavailability. There is a clear need for advanced analytical techniques that can both detect, characterize, and quantify the components of amorphous formulations, especially ASDs. This research focuses on methods to detect and quantify crystallinity, ensure consistency between manufactured lots of amorphous formulations, and predict shelf life and drug substance properties. Poorly soluble model drug compounds such as nifedipine, indomethacin, and patiromer were studied using multiple analytical techniques including solid-state nuclear magnetic resonance (SSNMR) spectroscopy. First, SSNMR was used to develop a method to quantify the monomeric makeup of an insoluble polymeric API which can be used to demonstrate API sameness during generic drug development. Second, crystallinity was detected, quantified, and compared using a variety of analytical techniques with SSNMR and powder X-ray diffraction being used to predict drug-polymer solubility form the first time. Third, an extensive investigation into the effect of hydrogen bonding, drug loading, and storage temperature on crystallization tendency was conducted around the glass transition temperature (Tg) and found that hydrogen bonding plays a particularly important role in stability near Tg. Lastly, the impact of multiple absorbed solvents on the physicochemical properties of pharmaceutical polymers was investigated using dynamic vapor sorption. In conclusion, this research proposes new methods and new applications of existing analytical techniques for the advanced characterization of pharmaceutical amorphous formulations. The results provide an improved understanding of the factors affecting the physical stability of ASDs and should aid in their successful formulation.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2022.194

Funding Information

  • This research was supported by the David E. Burgio and Thalia McMillen Endowed Graduate Pharmacy Scholarship, awarded by the UK College of Pharmacy in 2017.
  • These studies were supported by a National Science Foundation grant (CHE-1710453) in 2017.
  • Funding for this research was made possible by a U.S. Food and Drug Administration grant (5U01FD004275-07) in 2018.

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