Low-frequency and macro-Raman analysis of respirable dosage forms and their sampling with a low flow rate single-nozzle cascade impactor Open Access
- Other title
solid state analysis
minimum sample volume
low-frequency Raman spectroscopy
- Type of item
- Degree grantor
University of Alberta
- Author or creator
- Supervisor and department
Vehring, Reinhard (Mechanical Engineering)
- Examining committee member and department
Martin, Andrew (Mechanical Engineering)
Nobes, David (Mechanical Engineering)
Department of Mechanical Engineering
- Date accepted
- Graduation date
Master of Science
- Degree level
Applications of Raman spectroscopy to respirable dosage forms are explored in this thesis. First, a high performance Raman system enabling low-frequency Raman signal detection is described and used for pharmaceutical sample analysis. Applications to species identification and solid state differentiation are presented, including solid phase identification and differentiation of glycopyrronium bromide and formoterol fumarate in pharmaceutical powders, and identification of active pharmaceutical ingredients, e.g., salmeterol xinafoate, fluticasone propionate, mometasone furoate, and salbutamol sulphate, as well as excipients, e.g., amino acids, in different formulations, are presented. For the first time, low-frequency shift Raman spectra of mannitol polymorphs were measured and used for solid phase identification. Unambiguous identification of two similar bronchodilator metered dose inhalers, Ventolin® HFA and Airomir®, was accomplished. The low-frequency shift Raman signals can be used for the analysis of crystallinity of small samples (< 5 mg) of respiratory dosage forms in a multi-component formulation matrix containing less than 3% by weight of the component of interest.
Second, quantitative macro-Raman spectroscopy was applied to the analysis of bulk compositions of pharmaceutical drug powders. A custom designed dispersive macro-Raman instrument with a large sample volume of 0.16 µL was utilized to quantitatively evaluate the composition of multi-component powder samples extracted from commercial products. A Monte-Carlo model was developed to predict the minimum sample volume required for representative sampling from heterogeneous samples with variable particle size distributions and compositions. For typical carrier-free respirable powder samples the required minimum sample volume was on the order of 0.0001 µL to achieve representative sampling with less than 3% relative error. However, dosage forms containing non-respirable carriers, e.g., lactose, required sample volume on the order of microliter for representative measurements. Error analysis of the experimental results showed good agreement with the error predicted by the simulation.
Finally, a low volume flow rate single-nozzle impactor was designed and manufactured for the collection of aerosols in the respirable range for subsequent macro-Raman characterization. The impactor utilized standard scanning electron microscopy stubs as the impaction plate, allowing easy removal and sample analysis. The impactor was designed to operate at a volume flow rate of 0.5 L/min, and included multiple stages to allow aerodynamic diameter measurements in the range from 0.6 µm to 10 µm. Preliminary tests showed satisfactory performance of the new impactor, which was capable of collecting a single dose (300µg) of respirable particulate drugs actuated from a commercial pressurized metered dose inhaler.
- Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
- Citation for previous publication
Hui Wang, Mohammed A. Boraey, Lisa Williams, David Lechuga-Ballesteros, and Reinhard Vehring. "Low-frequency Shift Dispersive Raman Spectroscopy for the Analysis of Respirable Dosage Forms." International Journal of Pharmaceutics 469 (1). 2014: 197-205.Hui Wang, Lisa Williams, Susan Hoe, David Lechuga-Ballesteros, and Reinhard Vehring. "Quantitative Macro-Raman Spectroscopy on Microparticle-based Pharmaceutical Dosage Forms". Applied Spectroscopy. (Accepted)
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