Persistent Link:
http://hdl.handle.net/10150/195941
Title:
SELECTED STUDIES IN PHARMACEUTICS
Author:
Guo, Duoli
Issue Date:
2010
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Three different studies are included in this dissertation.The first chapter is a preformulation study of the anticancer drug NSC-726796. A stability-indicating HPLC method to quantify the compound and its three main degradation products was developed. This method was used to investigate its degradation kinetics and mechanism. The reaction follows first-order kinetics and appears to be base-catalyzed with a maximum stability at pH 1. The degradation products were identified as 2-(2,4-difluorophenylcarbamoyl)-3,4,5,6-tetrafluorobenzoic acid (NSC-749820), 2,4-difluoroaniline and 3,4,5,6-tetrafluorophthalic acid. The mono acid was synthesized and its structure was confirmed by single crystal crystallography. That compound is found to be more soluble and more stable than the parent drug in aqueous media.The purpose of the research reported in the second chapter is to investigate the pH-stability of an anticancer cytidine derivative and a cytidine deaminase inhibitor, individually and in combination. A stability indicating HPLC method for the quantification of 5-fluoro-2-deoxycytidine (FdCyd, NSC-48006), tetrahydrouridine (THU, NSC-112907) and their degradants was developed using a ZIC®-HILIC column. The effect of THU and FdCyd on the in vitro degradation of each other was studied as a function of pH from 1.0 to 7.4. The degradation of FdCyd appears to be first-order and acid-catalyzed. THU equilibrates with at least one of its degradants. Results show that the combination of FdCyd and THU in solution does not affect the stability of either compound. The stability and compatibility of FdCyd and THU in the solid state at 40 C/ 75% relative humidity (RH) and at ambient temperature are also evaluated.In chapter three, the effect of polarity on acid-base dissociation in ionic micellar systems is discussed. The dissociation constant of a compound (i.e., pKa) can shift when it is incorporated in or on a micelle. The magnitude of the pKa shift can be attributed to the effect of the surface potential of the micelle and the dielectric constant of the system. Currently, there is no reliable relationship to quantitate the dependence of pKa on the polarity of the drug. Experimental data for pKa of acids in cationic and anionic micelles were compiled from the literature. The increase in the pKa of weak acids upon incorporation into sodium dodecyl sulphate micellar is shown to be proportional to their ClogP values.
Type:
text; Electronic Dissertation
Keywords:
NSC-726796; preformulation
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmaceutical Sciences; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Yalkowksy, Samuel H.
Committee Chair:
Yalkowksy, Samuel H.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleSELECTED STUDIES IN PHARMACEUTICSen_US
dc.creatorGuo, Duolien_US
dc.contributor.authorGuo, Duolien_US
dc.date.issued2010en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractThree different studies are included in this dissertation.The first chapter is a preformulation study of the anticancer drug NSC-726796. A stability-indicating HPLC method to quantify the compound and its three main degradation products was developed. This method was used to investigate its degradation kinetics and mechanism. The reaction follows first-order kinetics and appears to be base-catalyzed with a maximum stability at pH 1. The degradation products were identified as 2-(2,4-difluorophenylcarbamoyl)-3,4,5,6-tetrafluorobenzoic acid (NSC-749820), 2,4-difluoroaniline and 3,4,5,6-tetrafluorophthalic acid. The mono acid was synthesized and its structure was confirmed by single crystal crystallography. That compound is found to be more soluble and more stable than the parent drug in aqueous media.The purpose of the research reported in the second chapter is to investigate the pH-stability of an anticancer cytidine derivative and a cytidine deaminase inhibitor, individually and in combination. A stability indicating HPLC method for the quantification of 5-fluoro-2-deoxycytidine (FdCyd, NSC-48006), tetrahydrouridine (THU, NSC-112907) and their degradants was developed using a ZIC®-HILIC column. The effect of THU and FdCyd on the in vitro degradation of each other was studied as a function of pH from 1.0 to 7.4. The degradation of FdCyd appears to be first-order and acid-catalyzed. THU equilibrates with at least one of its degradants. Results show that the combination of FdCyd and THU in solution does not affect the stability of either compound. The stability and compatibility of FdCyd and THU in the solid state at 40 C/ 75% relative humidity (RH) and at ambient temperature are also evaluated.In chapter three, the effect of polarity on acid-base dissociation in ionic micellar systems is discussed. The dissociation constant of a compound (i.e., pKa) can shift when it is incorporated in or on a micelle. The magnitude of the pKa shift can be attributed to the effect of the surface potential of the micelle and the dielectric constant of the system. Currently, there is no reliable relationship to quantitate the dependence of pKa on the polarity of the drug. Experimental data for pKa of acids in cationic and anionic micelles were compiled from the literature. The increase in the pKa of weak acids upon incorporation into sodium dodecyl sulphate micellar is shown to be proportional to their ClogP values.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectNSC-726796en_US
dc.subjectpreformulationen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmaceutical Sciencesen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorYalkowksy, Samuel H.en_US
dc.contributor.chairYalkowksy, Samuel H.en_US
dc.contributor.committeememberMayersohn, Michaelen_US
dc.contributor.committeememberMyrdal, Paulen_US
dc.identifier.proquest11104en_US
dc.identifier.oclc752260973en_US
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