Assessing Colloidal Stability of Pharmaceutical Suspensions with a Shadowgraphic Imaging Method

• Author / Creator

  Wang, Hui

• The colloidal stability of pharmaceutical suspensions is an important attribute that needs to be carefully characterized in order to ensure designed product quality. In the field of respiratory drug delivery, pharmaceutical suspensions contained in pressurized metered-dose inhalers (pMDIs) are the most widely used form of medication for the treatment of various airway diseases such as asthma and chronic obstructive pulmonary diseases (COPD). These inherently unstable drug suspensions can destabilize mainly by particle migration and particle agglomeration, which will cause severe problems such as poor consistencies in delivered drug doses, deviated particle size distribution from the optimum respirable range, off-target drug deposition, and so on. This thesis focuses on a newly developed technique for characterizing the colloidal stability of pressurized pharmaceutical suspensions and its application in the development of stable pharmaceutical suspensions.

  CHAPTER 1 introduces the dispersed system, the applications of suspensions in the pharmaceutical field, the colloidal stability issues associated with solid suspensions, and the approaches that have been employed for the stabilization of these suspensions.

  A shadowgraphic imaging method developed for the colloidal stability characterization of pharmaceutical suspensions, especially pressurized suspensions with relatively poor stability, is introduced in CHAPTER 2. Briefly, the instrument takes sequential shadowgraphic images of samples contained in transparent glass vessels in a bright field, and the images are analyzed for changes in transmission intensity profiles over time. Selected applications demonstrated the instrument’s suitability as a routine tester for non-destructive stability monitoring of pressurized pharmaceutical suspensions with a wide range of stability. This technique offers features that are not currently afforded by any commercially available instruments, namely simultaneous illumination of the complete suspensions, a high image resolution and acquisition rate, and parameters for convenient cross-sample comparison, making this new suspension tester a suitable and reliable instrument for investigating the stability of pressurized pharmaceutical suspensions.

  With the developed shadowgraphic imaging technique, how to make meaningful stability measurements becomes important. CHAPTER 3 highlights the important effects of agitation method on the colloidal stability of pharmaceutical suspensions, which has rarely been discussed in the literature. Three different initial agitation methods—wrist action shaking, which simulates the manual shaking motion of pMDI users, vortex mixing, which delivers moderate shear rate, and ultrasonic agitation, which provides the most effective dispersing capability—were tested using different suspension formulations, and the results were compared. A clear dependence of the suspension stability on the employed initial agitation method was observed unanimously for multiple suspension formulations. It is suggested that colloidal stability testing of suspensions must be based on quantified initial agitation energy or at least consistent agitation method. Suspension stability analysis results must also be presented together with a detailed description of the applied agitation method for any measurement of suspension stability to be fully meaningful. As a promising approach forward, a prototyped built-in ultrasonic agitation device was applied to study the colloidal stability of a commercial pMDI, and results with good repeatability were achieved.

  With the assistance of the shadowgraphic imaging technique, a systematic study of the effects of particle surface roughness on the colloidal stability of pressurized pharmaceutical suspensions is presented in CHAPTER 4. Effects of surface roughness on the colloidal stability of pressurized pharmaceutical suspensions were isolated and investigated using monodisperse spray-dried particles. A surface-active shell-former, trileucine, was used to produce particles with different levels of surface roughness. More rugose particles were found to lead to more stable suspensions, and all of them showed better stability than suspensions containing pure trehalose particles with relatively smooth surfaces. Therefore, increasing the surface roughness of particles, for example, by using shell formers like trileucine, is a promising technique that can potentially be used to stabilize their suspensions. Moreover, because this technique is likely not very dependent on the type of propellant and does not require the use of a surfactant, it offers a new means of transitioning to more environmentally friendly pMDIs.

  CHAPTER 5 summarizes the main conclusions of this work and suggests possible directions for further investigations.

• Subjects / Keywords

  • pharmaceutical suspension
  • colloidal stability
  • agitation method
  • surface roughness
  • pressurised suspension
  • shadowgraphic imaging
  • particle engineering
  • suspension stability
  • surface modification

• Graduation date

  Fall 2019

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-x08k-nm12

• License

  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.