The Role Of Molecular Mobility And Hydrogen Bonding Interactions On The Physical Stability Of Amorphous Pharmaceuticals
2014-09
Loading...
View/Download File
Persistent link to this item
Statistics
View StatisticsJournal Title
Journal ISSN
Volume Title
Title
The Role Of Molecular Mobility And Hydrogen Bonding Interactions On The Physical Stability Of Amorphous Pharmaceuticals
Authors
Published Date
2014-09
Publisher
Type
Thesis or Dissertation
Abstract
The physical instability of amorphous pharmaceuticals and our inability to reliably predict their crystallization propensity is a major impediment to their use in solid oral dosage forms. The central goal of this thesis work is to gain a fundamental insight into the roles of (i) specific molecular mobility (global or local) on the observed physical instability (crystallization) in the supercooled as well as glassy states of amorphous pharmaceuticals and (ii) the influence of hydrogen bonding on molecular mobility and thereby the physical stability. Our ultimate objective is to be able to use molecular mobility as a predictor of drug crystallization from complex multi-component solid dispersions. The different modes of molecular motions were comprehensively characterized using broadband dielectric spectroscopy (BDS). Since, BDS is traditionally conducted with film samples, we first validated the use of powder samples for measuring molecular mobility. Crystallization kinetics was monitored by powder X-ray diffractometry using either a laboratory or a synchrotron X-ray source. Physical instability, both above and below Tg in our model systems (griseofulvin, nifedipine and nifedipine-PVP dispersion), increased with a decrease in structural relaxation time. Next, a causal relationship between hydrogen bonding interactions and molecular mobility was established. The higher physical stability in felodipine as compared to nifedipine was attributed to the reduced molecular mobility brought about by the stronger and more extensive hydrogen bonding interactions in the former. In solid dispersions of nifedipine with each PVP, HPMCAS and PAA, the drug-polymer interactions, by modulating molecular mobility, influenced the drug crystallization kinetics. The strength of drug-polymer hydrogen bonding, the structural relaxation time and the crystallization kinetics were rank ordered as: PVP > HPMCAS > PAA. Finally a model derived from the relationship between diffusion and relaxation time was used to predict drug crystallization from solid dispersions. Molecular mobility proved to be an effective predictor of drug crystallization in nifedipine solid dispersions.
Description
University of Minnesota Ph.D. dissertation.September 2014. Major: Pharmaceutics. Advisor: RONALD SIEGEL. 1 computer file (PDF); xvi, 239 pages.
Related to
Replaces
License
Collections
Series/Report Number
Funding information
Isbn identifier
Doi identifier
Previously Published Citation
Suggested citation
Kothari, Khushboo. (2014). The Role Of Molecular Mobility And Hydrogen Bonding Interactions On The Physical Stability Of Amorphous Pharmaceuticals. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/183354.
Content distributed via the University Digital Conservancy may be subject to additional license and use restrictions applied by the depositor. By using these files, users agree to the Terms of Use. Materials in the UDC may contain content that is disturbing and/or harmful. For more information, please see our statement on harmful content in digital repositories.