Low-frequency and macro-Raman analysis of respirable dosage forms and their sampling with a low flow rate single-nozzle cascade impactor

  • Author / Creator
    Wang, Hui
  • 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.

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Master of Science
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Department of Mechanical Engineering
  • Supervisor / co-supervisor and their department(s)
    • Vehring, Reinhard (Mechanical Engineering)
  • Examining committee members and their departments
    • Martin, Andrew (Mechanical Engineering)
    • Nobes, David (Mechanical Engineering)