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Title: Development and application of single particle mass spectrometry techniques for the analysis of pharmaceutical aerosols
Author: New, Anthony Peter
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2010
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Single particle mass spectrometry techniques were applied to the analysis of aerosol particles originating from inhaler devices, used to deliver pharmaceuticals for the treatment of lung disease such as asthma. The inhalation products studied were Seretide® for which the formulated drug product is composed of a blend of fluticasone propionate (FP) which is a corticosteroid and salmeterol xinofoate (SX) which is a long acting f3- agonist. It has been suggested previously that the formation of particles that are composed of both FP and SX by co- association can give improved efficacy: however in the past it has been difficult to analyze this type of co- associated particle. Hence, the purpose of the work described in this thesis was to develop single particle mass spectrometry methods that could assess the degree of co- association between FP and SX in fine aerosolized particles emitted from the inhaler devices. Two types of inhaler device were investigated and these were pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). The formulated product for pMDIs was a blend of FP and SX held in a suspension of propellant in a pressurized canister. The formulated product for the DPIs is comprised of a blend of FP and SX and an excipient lactose. Two commercial single particle mass spectrometers were used in this work; an Aerosol Time -of- Flight Mass Spectrometer (TSI, Shoreview, MN, USA) and an Aerodyne Aerosol Mass Spectrometer (Aerodyne, Billerica, MA, USA). Although the general layout of these instruments was similar in that they are both comprised of an inlet, a particle sizing region and a mass spectrometer, there were some differences in their design. For example, the ionization source of the Aerosol Time -of- Flight Mass Spectrometer used a single step process involving laser ablation and ionization while the Aerodyne Aerosol Mass Spectrometer used a two step process involving thermal desorption from a hot plate followed by electron ionization. These instruments were compared and evaluated in terms of their design and the characteristics of the data acquired on aerosols of pharmaceutical materials. Data analysis methods for single particle mass spectrometry were developed based on the mass spectrometric fragmentation patterns indicative of either pure or co- associated particles. Data analysis was performed by either using representative ions from the mass spectrum taken from each particle or by using multivariate statistical analysis as a pattern recognition tool applied to the complete mass spectrum for each particle. High levels (above 50 %) of co- association were found in the emitted doses from both pMDI and DPI products. Although the design of each instrument was different, reasonable agreement in the levels of co- association was found as long as the size of particle that was analyzed by the mass spectrometer in each case was taken into account. Finally a comparison of the applicability of each of the commercial single particle mass spectrometers to the analysis of materials taken from pharmaceutical aerosols was made. Recommendations for future work on instrument development and further applications for inhalation products are given.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available