Stability kinetics of 4-dedimethylamino sancycline, a new anti-tumor drug, in aqueous solutions

Persistent Link:
http://hdl.handle.net/10150/282753
Title:
Stability kinetics of 4-dedimethylamino sancycline, a new anti-tumor drug, in aqueous solutions
Author:
Pinsuwan, Sirirat, 1961-
Issue Date:
1998
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:
4-Dedimethylamino sancycline (col-3) is a new antitumor antibiotic of the tetracycline family. Preformulation studies have indicated that col-3 is not stable in aqueous solutions. The overall purpose of this research project is to investigate the stability kinetics of this drug in aqueous solutions. The physicochemical properties of col-3, including melting point, UV spectrum, mass spectrum, dissociation constants and solubility were determined. Col-3 is an acidic compound with two pKₐ values of 5.9 (pKₐ₁) and 8.1 (pKₐ₂). It is slightly soluble in water (0.01 mg/mL) and readily soluble in organic solvents such as polyethylene glycol and benzyl alcohol. Although the solubility of col-3 increases with increasing pH, its stability decreases with increasing pH. A HPLC assay was developed to quantitate col-3 and separate its degradation products. Four major degradation products of col-3 were detected under alkaline conditions. These degradates were identified by their elution times and their UV-absorption spectra. The kinetics of degradation of col-3 in aqueous solution at 25°C were investigated by HPLC over the pH-range of 2-10. The Influence of pH, buffer concentration, light, temperature and some additives on the degradation rate were studied. The degradation of col-3 was found to follow first-order kinetics at 25°C. A rate expression covering the degradation of the various ionic forms of the drug was derived and shown to account for the shape of the experimental pH-rate profile. Under basic conditions, the degradation of col-3 involves oxidation, which is catalyzed by metal ions. The separation of the four initial degradation products of col-3 was investigated. Partial separation of these compounds is achieved by liquid-liquid extraction. However, due to the instability of these compounds, their complete isolation cannot be successful. The UV spectroscopic analysis of these compounds shows that an absorbance at 360 nm is partially decreased in degradates I and II and totally absent in degradates III and IV. These results suggest that the phenolic diketone moiety, which produces this absorption band, has been altered upon degradation.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Chemistry, Pharmaceutical.; Health Sciences, Pharmacy.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmacy Practice and Science
Degree Grantor:
University of Arizona
Advisor:
Yalkowsky, Samuel H.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleStability kinetics of 4-dedimethylamino sancycline, a new anti-tumor drug, in aqueous solutionsen_US
dc.creatorPinsuwan, Sirirat, 1961-en_US
dc.contributor.authorPinsuwan, Sirirat, 1961-en_US
dc.date.issued1998en_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.abstract4-Dedimethylamino sancycline (col-3) is a new antitumor antibiotic of the tetracycline family. Preformulation studies have indicated that col-3 is not stable in aqueous solutions. The overall purpose of this research project is to investigate the stability kinetics of this drug in aqueous solutions. The physicochemical properties of col-3, including melting point, UV spectrum, mass spectrum, dissociation constants and solubility were determined. Col-3 is an acidic compound with two pKₐ values of 5.9 (pKₐ₁) and 8.1 (pKₐ₂). It is slightly soluble in water (0.01 mg/mL) and readily soluble in organic solvents such as polyethylene glycol and benzyl alcohol. Although the solubility of col-3 increases with increasing pH, its stability decreases with increasing pH. A HPLC assay was developed to quantitate col-3 and separate its degradation products. Four major degradation products of col-3 were detected under alkaline conditions. These degradates were identified by their elution times and their UV-absorption spectra. The kinetics of degradation of col-3 in aqueous solution at 25°C were investigated by HPLC over the pH-range of 2-10. The Influence of pH, buffer concentration, light, temperature and some additives on the degradation rate were studied. The degradation of col-3 was found to follow first-order kinetics at 25°C. A rate expression covering the degradation of the various ionic forms of the drug was derived and shown to account for the shape of the experimental pH-rate profile. Under basic conditions, the degradation of col-3 involves oxidation, which is catalyzed by metal ions. The separation of the four initial degradation products of col-3 was investigated. Partial separation of these compounds is achieved by liquid-liquid extraction. However, due to the instability of these compounds, their complete isolation cannot be successful. The UV spectroscopic analysis of these compounds shows that an absorbance at 360 nm is partially decreased in degradates I and II and totally absent in degradates III and IV. These results suggest that the phenolic diketone moiety, which produces this absorption band, has been altered upon degradation.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectChemistry, Pharmaceutical.en_US
dc.subjectHealth Sciences, Pharmacy.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacy Practice and Scienceen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorYalkowsky, Samuel H.en_US
dc.identifier.proquest9906522en_US
dc.identifier.bibrecord.b38868234en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.