DOI

10.17077/etd.loh331xh

Document Type

Dissertation

Date of Degree

Fall 2017

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmaceutical Sciences and Experimental Therapeutics

First Advisor

Kirsch, Lee E.

First Committee Member

Wurster, Dale E.

Second Committee Member

Salem, Aliasger K.

Third Committee Member

Stevens, Lewis L.

Fourth Committee Member

Egito, Socrates

Abstract

Amphotericin B (AmB) is an amphiphile antifungal agent composed of lipophilic and hydrophilic structures and is known to aggregate in aqueous solution. The effect of substrate aggregation on the degradation kinetics of aqueous AmB was studied.

Aggregation state of AmB (0.0108 mM) in 10.0%v/v methanol aqueous solutions were pH dependent. The dissociation equilibrium constant (Kd) values suggested that monomeric form was predominant in acidic and alkaline condition and aggregated form appeared predominantly in neutral condition. At methanol concentration above 35.0%v/v, 0.0108 mM AmB in reaction mixtures presented in a monomeric form regardless of pH.

The degradation pathways of AmB were found to be pH-dependent. The effect of oxidants, antioxidants, oxidation initiators and chelators suggested that AmB was susceptible to oxidation in acidic and neutral pH regions which led spectral changes associated with the heptaene moiety. In basic conditions (pH > 9), AmB underwent hydroxide-catalyzed ring-opening lactone hydrolysis.

A degradation model describing substrate loss was constructed based on the kinetics of substrate loss. The pH-rate profile displayed three regions: specific acid-catalyzed degradation at pH below 4, a specific basic-catalyzed hydrolysis at pH above 9 and a pH-independent degradation in the neutral pH range 4 – 9. The effect of methanol on degradation kinetics in the neutral pH region indicated that aggregated AmB was more susceptible to oxidative degradation than monomeric AmB.

Pages

xvii, 128 pages

Bibliography

Includes bibliographical references (page 128).

Copyright

Copyright © 2017 Phawanan Sawangchan

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