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Temporally and Spatially Resolved x-ray Fluorescence Measurements of in-situ Drug Concentration in Metered-Dose Inhaler Sprays

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ABSTRACT

Purpose

Drug concentration measurements in MDI sprays are typically performed using particle filtration or laser scattering. These techniques are ineffective in proximity to the nozzle, making it difficult to determine how factors such as nozzle design will affect the precipitation of co-solvent droplets in solution-based MDIs, and the final particle distribution.

Methods

In optical measurements, scattering from the constituents is difficult to separate. We present a novel technique to directly measure drug distribution. A focused x-ray beam was used to stimulate x-ray fluorescence from the bromine in a solution containing 85% HFA, 15% ethanol co-solvent, and 1 \( \mu \mathrm{g} \) / \( \mu \kern-.5pt \mathrm{L} \) IPBr.

Results

Instantaneous concentration measurements were obtained with 1 ms temporal resolution and 5 \( \mu \mathrm{m} \) spatial resolution, providing information in a region that is inaccessible to many other diagnostics. The drug remains homogeneously mixed over time, but was found to be higher at the centerline than at the periphery. This may have implications for oropharyngeal deposition in vivo.

Conclusions

Measurements in the dynamic, turbulent region of MDIs allow us to understand the physical links between formulation, inspiration, and geometry on final particle size and distribution. This will ultimately lead to a better understanding of how MDI design can be improved to enhance respirable fraction.

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Abbreviations

FWHM:

Full width at half maximum

HFA:

Hydrofluoroalkane

IPBr:

Ipratropium bromide

MDI:

Metered dose inhaler

XFS:

X-ray fluorescence spectroscopy

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors thank Dr. Christopher Powell and Dr. Andrew Swantek from the Energy Systems Division at Argonne National Laboratory for their assistance. The authors acknowledge funding support from the Australian Research Council. This research was performed at the 7-BM beam line of the Advanced Photon Source at Argonne National Laboratory. Use of the APS is supported by the U.S. Department of Energy (DOE) under Contract No. DE-AC02-06CH11357.

The submitted manuscript has been created by UChicago Argonne, LLC, Operator of Argonne National Laboratory (“Argonne”). Argonne, a U.S. Department of Energy Office of Science laboratory, is operated under Contract No. DE-AC02-06CH11357. The U.S. Government retains for itself, and others acting on its behalf, a paid-up nonexclusive, irrevocable worldwide license in said article to reproduce, prepare derivative works, distribute copies to the public, and perform publicly and display publicly, by or on behalf of the Government.

Author information

Authors and Affiliations

  1. Energy Systems Division, Argonne National Laboratory, Lemont, Illinois, USA

    Daniel J. Duke

  2. X-ray Science Division, Argonne National Laboratory, Lemont, Illinois, USA

    Alan L. Kastengren

  3. Laboratory for Turbulence Research in Aerospace & Combustion, Department of Mechanical & Aerospace Engineering, Monash University, Melbourne, Victoria, Australia

    Nicholas Mason-Smith, Daniel Edgington-Mitchell & Damon Honnery

  4. Respiratory Technology, Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia

    Yang Chen, Paul M. Young & Daniela Traini

  5. Chiesi Limited, Chippenham, UK

    David Lewis

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  1. Daniel J. Duke
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Correspondence to Daniel J. Duke.

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Duke, D.J., Kastengren, A.L., Mason-Smith, N. et al. Temporally and Spatially Resolved x-ray Fluorescence Measurements of in-situ Drug Concentration in Metered-Dose Inhaler Sprays. Pharm Res 33, 816–825 (2016). https://doi.org/10.1007/s11095-015-1828-6

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