Document Type

Dissertation

Date of Degree

Summer 2015

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmacy

First Advisor

Douglas R. Flanagan

Abstract

The dissolution behavior of a drug substance is an important part of its bioavailability. Three solid dissolution mechanisms are recognized: transport control, interface control and mixed-kinetic control. The mixed-kinetic control mechanism is not well studied as the majority of dissolution phenomena in pharmaceutical research are assumed to be transport-controlled. A phenomenological model for mixed-kinetic control was developed in which the interfacial step comprises molecular detachment and re-deposition and is described by chemical kinetic theory. This model encompasses interface control and transport control as limiting cases.

Experimental studies on three organic compounds showed that they dissolved by transport control at 37°C, but exhibited certain degrees of interface control at lower temperatures (10°C and 3°C), which, according to the model, indicates that reducing the dissolution temperature slowed down re-deposition more than transport. Using mathematical approaches derived from the model, up to 27% interface control was calculated from the experimental results.

The second experimental investigation showed significant degrees of interface control in benzoic acid dissolution in sodium dodecyl sulfate (NaDS) solutions at 25°C. The dissolution behavior was well described by the mixed-kinetic control model and up to 73% interface control was calculated. An extension of the model was proposed to describe a potential micelle-interface interaction mechanism indicated by the model-fitted parameters.

The third investigation showed that FD&C Blue #1, a water-soluble dye, inhibited sulfathiazole dissolution in acidic media but not in water. The inhibition was attributed to the blocking of dissolution sites by dye adsorption. A potential pH-dependent adsorption mechanism was proposed in which protonation at sulfathiazole solid surface gives rise to preferential dye adsorption on detachment rates and thus reduced dissolution rates.

Public Abstract

The dissolution behavior of a drug substance is an important part of its bioavailability. Three solid dissolution mechanisms are recognized: transport control, interface control and mixed-kinetic control. The mixed-kinetic control mechanism is not well studied as the majority of dissolution phenomena in pharmaceutical research are assumed to be transport-controlled. A phenomenological model for mixed-kinetic control was developed in which the interfacial step comprises molecular detachment and re-deposition and is described by chemical kinetic theory. This model encompasses interface control and transport control as limiting cases.

Experimental studies on three organic compounds showed that they dissolved by transport control at 37°C, but exhibited certain degrees of interface control at lower temperatures (10°C and 3°C), which, according to the model, indicates that reducing the dissolution temperature slowed down re-deposition more than transport. Using mathematical approaches derived from the model, up to 27% interface control was calculated from the experimental results.

The second experimental investigation showed significant degrees of interface control in benzoic acid dissolution in sodium dodecyl sulfate (NaDS) solutions at 25°C. The dissolution behavior was well described by the mixed-kinetic control model and up to 73% interface control was calculated. An extension of the model was proposed to describe a potential micelle-interface interaction mechanism indicated by the model-fitted parameters.

The third investigation showed that FD&C Blue #1, a water-soluble dye, inhibited sulfathiazole dissolution in acidic media but not in water. The inhibition was attributed to the blocking of dissolution sites by dye adsorption. A potential pH-dependent adsorption mechanism was proposed in which protonation at sulfathiazole solid surface gives rise to preferential dye adsorption on detachment rates and thus reduced dissolution rates.

Keywords

publicabstract, dissolution, mechanism, model, surfactants

Pages

xiii, 116 pages

Bibliography

Includes bibliographical references (pages 113-116).

Copyright

Copyright 2015 Yang Qiu

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