Precipitation of parenteral formulations upon injection or dilution.

Persistent Link:
http://hdl.handle.net/10150/186213
Title:
Precipitation of parenteral formulations upon injection or dilution.
Author:
Ward, Gary Henry.
Issue Date:
1993
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:
A new method for the quantitation of acute phlebitis in superficial veins is investigated. This method capitalizes on local temperature elevations which result from the inflammatory process. The thermally based detection method is more objective than traditional procedures which utilize simple visual evaluations of symptoms. Several irritating parenteral drugs and their vehicles as well as many commonly used cosolvents were tested for their potential to produce phlebitis. The water soluble compounds and the cosolvents produced little if any irritation. In cases where significant phlebitis was produced, it was the drug and not the vehicle which was found to be responsible. This method shows promise as a tool for screening compounds and vehicles for their potential to produce local venous side-effects. The hemolytic method for assessing the venous compatibility of parenterals was compared with the thermal method. It was found that hemolysis testing can give false positive suggestions of phlebitis, which could result in the elimination of promising new formulations. The effect of injection rate on the severity of phlebitis is investigated using parenteral amiodarone HCl. As the injection rate is increased the severity of phlebitis also increases to a limiting value. At rates above this value there is less phlebitis produced. The reason for this behavior is explained below. Amiodarone was found to precipitate upon dilution with physiological fluids. Incomplete dilution of the formulation in the blood results in a physically stable "plug" within the vein. Where there is plug flow, and the drug is soluble in the plug, there is no precipitation. It was shown in vitro that plug flow of the partially diluted formulation correlates with the decrease in phlebitis observed in vivo at rapid injection rates. The immediate precipitation of amiodarone HCl upon dilution is pH dependent. Amiodarone is reformulated in a buffered version of the original vehicle in an attempt to reduce this precipitation. Buffering the amiodarone formulation significantly improved the precipitation problem of this drug. By characterizing the variables which influence the physical stability of amiodarone we were able to produce a new formulation which is resistant to dilution-induced precipitation.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Dissertations, Academic.; Pharmacy.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmaceutical Sciences; Graduate College
Degree Grantor:
University of Arizona
Committee Chair:
Yalkowsky, Samuel H.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titlePrecipitation of parenteral formulations upon injection or dilution.en_US
dc.creatorWard, Gary Henry.en_US
dc.contributor.authorWard, Gary Henry.en_US
dc.date.issued1993en_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.abstractA new method for the quantitation of acute phlebitis in superficial veins is investigated. This method capitalizes on local temperature elevations which result from the inflammatory process. The thermally based detection method is more objective than traditional procedures which utilize simple visual evaluations of symptoms. Several irritating parenteral drugs and their vehicles as well as many commonly used cosolvents were tested for their potential to produce phlebitis. The water soluble compounds and the cosolvents produced little if any irritation. In cases where significant phlebitis was produced, it was the drug and not the vehicle which was found to be responsible. This method shows promise as a tool for screening compounds and vehicles for their potential to produce local venous side-effects. The hemolytic method for assessing the venous compatibility of parenterals was compared with the thermal method. It was found that hemolysis testing can give false positive suggestions of phlebitis, which could result in the elimination of promising new formulations. The effect of injection rate on the severity of phlebitis is investigated using parenteral amiodarone HCl. As the injection rate is increased the severity of phlebitis also increases to a limiting value. At rates above this value there is less phlebitis produced. The reason for this behavior is explained below. Amiodarone was found to precipitate upon dilution with physiological fluids. Incomplete dilution of the formulation in the blood results in a physically stable "plug" within the vein. Where there is plug flow, and the drug is soluble in the plug, there is no precipitation. It was shown in vitro that plug flow of the partially diluted formulation correlates with the decrease in phlebitis observed in vivo at rapid injection rates. The immediate precipitation of amiodarone HCl upon dilution is pH dependent. Amiodarone is reformulated in a buffered version of the original vehicle in an attempt to reduce this precipitation. Buffering the amiodarone formulation significantly improved the precipitation problem of this drug. By characterizing the variables which influence the physical stability of amiodarone we were able to produce a new formulation which is resistant to dilution-induced precipitation.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectDissertations, Academic.en_US
dc.subjectPharmacy.en_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.chairYalkowsky, Samuel H.en_US
dc.contributor.committeememberMartin, Arnolden_US
dc.identifier.proquest9322724en_US
dc.identifier.oclc716215504en_US
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