Persistent Link:
http://hdl.handle.net/10150/282897
Title:
Principles of formulation physical stability in aqueous media
Author:
Johnson, Jennifer Lynne Huff
Issue Date:
2005
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:
Drugs often require formulation techniques to increase their solubility and/or increase their stability in aqueous media. In cases where solubility enhancement is necessary, ideally, the physical stability of the formulation should be maintained upon administration. Unfortunately, in some cases, drugs precipitate out of solution when the formulation is introduced into aqueous media. Intravenously, drug precipitation can cause phlebitis and orally, it can hinder absorption. In order to avoid phlebitis, new intravenous (IV) parenterals are commonly screened by injection into animals. An in vitro dynamic injection model is introduced and validated. Twenty-one currently marketed IV products were used to investigate the validity of the model. Logistic regression and a receiver operator curve (ROC) indicate a value of 0.003 to best delineate phlebitic and non-phlebitic products. Measures of sensitivity (0.83), specificity (0.93), positive predictive value (0.93) and negative predictive value (0.78) indicate the model's accuracy and reliability. The model was tested to screen different formulations of a new proprietary antibiotic, Van-An. The opacities obtained for the formulation with acetate addition were significantly smaller than for the phosphate buffered formulation at 4 injection rates. In general the results suggest acetate as a better buffer species than phosphate for the pH range defined. The solubilization and stabilization of an orally administered formulation of a new anti-hepatitis C drug, PG301029, is established through a novel method of complexation. Hydroxypropyl-beta-cyclodextrin (HPbetaCD) and PG301029 are dissolved in glacial acetic acid. The acetic acid is removed by roto-evaporation such that the drug exists primarily in the complexed form. Formulated PG301029 is found to be stable upon storage and, once reconstituted, the powder dissolves rapidly and PG301029 remains stable for 21 hours. Acetic acid and HPbetaCD provide several formulation advantages. PG301029 and HPbetaCD are both soluble in acetic acid. Once prepared, the formulation can be stored in solid form. Upon reconstitution, the cyclodextrin both protects the drug from water and enhances the solubility of PG301029. This unique method results in a solid dosage form of PG301029 which is soluble, stable and highly bioavailable in mice when given orally.
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.titlePrinciples of formulation physical stability in aqueous mediaen_US
dc.creatorJohnson, Jennifer Lynne Huffen_US
dc.contributor.authorJohnson, Jennifer Lynne Huffen_US
dc.date.issued2005en_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.abstractDrugs often require formulation techniques to increase their solubility and/or increase their stability in aqueous media. In cases where solubility enhancement is necessary, ideally, the physical stability of the formulation should be maintained upon administration. Unfortunately, in some cases, drugs precipitate out of solution when the formulation is introduced into aqueous media. Intravenously, drug precipitation can cause phlebitis and orally, it can hinder absorption. In order to avoid phlebitis, new intravenous (IV) parenterals are commonly screened by injection into animals. An in vitro dynamic injection model is introduced and validated. Twenty-one currently marketed IV products were used to investigate the validity of the model. Logistic regression and a receiver operator curve (ROC) indicate a value of 0.003 to best delineate phlebitic and non-phlebitic products. Measures of sensitivity (0.83), specificity (0.93), positive predictive value (0.93) and negative predictive value (0.78) indicate the model's accuracy and reliability. The model was tested to screen different formulations of a new proprietary antibiotic, Van-An. The opacities obtained for the formulation with acetate addition were significantly smaller than for the phosphate buffered formulation at 4 injection rates. In general the results suggest acetate as a better buffer species than phosphate for the pH range defined. The solubilization and stabilization of an orally administered formulation of a new anti-hepatitis C drug, PG301029, is established through a novel method of complexation. Hydroxypropyl-beta-cyclodextrin (HPbetaCD) and PG301029 are dissolved in glacial acetic acid. The acetic acid is removed by roto-evaporation such that the drug exists primarily in the complexed form. Formulated PG301029 is found to be stable upon storage and, once reconstituted, the powder dissolves rapidly and PG301029 remains stable for 21 hours. Acetic acid and HPbetaCD provide several formulation advantages. PG301029 and HPbetaCD are both soluble in acetic acid. Once prepared, the formulation can be stored in solid form. Upon reconstitution, the cyclodextrin both protects the drug from water and enhances the solubility of PG301029. This unique method results in a solid dosage form of PG301029 which is soluble, stable and highly bioavailable in mice when given orally.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.proquest3177539en_US
dc.identifier.bibrecord.b49001061en_US
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