Accelerating development of suspension pressurized metered dose inhaler formulations: innovative techniques to evaluate particle stability

Abstract

This thesis presents several innovative techniques to rapidly evaluate particle stability in suspension-based pressurized metered dose inhalers (pMDIs). Chapter 1 reviews techniques available to evaluate particle stability in pMDIs, discussing categories such as particle properties, suspension quality, polymorphism, and long term stability. Emerging techniques such as Liquid Colloidal Probe Microscopy (CPM), Nano X-ray Computer Tomography (NanoXCT), and Pressurized Isothermal Microcalorimetry possess the potential for accelerating pMDI formulation and are developed through the work embodied within this thesis. Chapters 2, 3, and 4 discuss the improvement and application of liquid CPM to evaluate nano-scale interactions between particles of various porosities in a model propellant. Particle porosity/morphology was found to have a significant effect on these interactions; however, direct measurement of internal particle architecture can be challenging. Thus, in chapter 5, a novel technique using NanoXCT was developed to visualize and quantify the internal porosity of inhalable sized particles with a resolution of 50 nm. It is necessary to control morphology through various manufacturing processes such as freeze and spray drying, since these processes can affect particle physical stability in propellant; thus, in chapter 6 an innovative technique using isothermal microcalorimetry was developed to directly evaluate particle stability in actual pMDI formulations. The versatility of the technique is further demonstrated in Chapter 7, through the evaluation of various other pMDI particle parameters such as amorphicity, excipient compatibility, and moisture ingress.