Insights into Spray Development from Metered-Dose Inhalers Through Quantitative X-ray Radiography
Typical methods to study pMDI sprays employ particle sizing or visible light diagnostics, which suffer in regions of high spray density. X-ray techniques can be applied to pharmaceutical sprays to obtain information unattainable by conventional particle sizing and light-based techniques.
We present a technique for obtaining quantitative measurements of spray density in pMDI sprays. A monochromatic focused X-ray beam was used to perform quantitative radiography measurements in the near-nozzle region and plume of HFA-propelled sprays.
Measurements were obtained with a temporal resolution of 0.184 ms and spatial resolution of 5 μm. Steady flow conditions were reached after around 30 ms for the formulations examined with the spray device used. Spray evolution was affected by the inclusion of ethanol in the formulation and unaffected by the inclusion of 0.1% drug by weight. Estimation of the nozzle exit density showed that vapour is likely to dominate the flow leaving the inhaler nozzle during steady flow.
Quantitative measurements in pMDI sprays allow the determination of nozzle exit conditions that are difficult to obtain experimentally by other means. Measurements of these nozzle exit conditions can improve understanding of the atomization mechanisms responsible for pMDI spray droplet and particle formation.
KEY WORDSpressurised metered dose inhaler radiography synchrotron radiation X-ray
Electronic metering inhaler
Phase doppler anemometry
Pressurised metered-dose inhaler
Standard litres per minute
ACKNOWLEDGMENTS AND DISCLOSURES
The authors gratefully acknowledge the support given to the project by the Australian Research Council. The authors wish to thank Dr. Chris Powell and Dr. Andrew Swantek, Energy Systems Division, Argonne National Laboratory. This research was performed at the 7-BM beamline 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. DEAC02-06CH11357. 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.
- 3.Dunbar C. An experimental and theoretical investigation of the spray issued from a pressurised metered-dose inhaler. Manchester: University of Manchester; 1996.Google Scholar
- 10.Wigley G, Versteeg H, Hodson D. Near-orifice PDA measurements and atomisation mechanism of a pharmaceutical pressurised metered dose inhaler. In: 18th Annual Conference on Liquid Atomization & Spray Systems. Zaragoza, Spain: Institute for Liquid Atomization & Spray Systems. 2002. .Google Scholar
- 12.Kastengren AL, Tilocco FZ, Duke DJ, Powell CF, Zhang X, Moon S. Time-resolved X-ray radiography of sprays from engine combustion network spray A diesel injectors. Atomization Sprays. 2014;24(3);251–72.Google Scholar
- 13.Duke DJ, Kastengren AL, Tilocco FZ, Swantek AB, Powell CF. X-ray radiography measurements of cavitating nozzle flow. Atomization Sprays. 2013;23(9).Google Scholar
- 22.Majer V, Svoboda V, Kehiaian HV. Enthalpies of vaporization of organic compounds: a critical review and data compilation. vol. 32. Oxford: Blackwell Scientific; 1985.Google Scholar
- 25.Lewis DA. Method and system for electronic MDI model. Google Patents; 2013. WO Patent App. PCT/EP2012/074,278. Available from: http://www.google.com/patents/WO2013083530A2?cl=en.
- 26.Clark AR. Metered atomisation for respiratory drug delivery. Loughborough University of Technology. 1991.Google Scholar
- 30.Duke DJ, Kastengren AL, Mason-Smith N, Chen Y, Young PM, Traini D, et al. Temporally and spatially resolved x-ray fluorescence measurements of in-situ drug concentration in metered-dose inhaler sprays. Pharm Res. 2015.Google Scholar
- 31.Kastengren AL, Powell CF, Cheong SK, Wang Y, Im KS, Liu X, et al. Determination of diesel spray axial velocity using X-ray radiography. SAE Trans. 2007-01-0666. 2007.Google Scholar
- 33.Duke D, Swantek A, Tilocco Z, Kastengren A, Fezzaa K, Neroorkar K, et al. X-ray imaging of cavitation in diesel injectors. SAE Trans. 2014.Google Scholar