Pharmaceutical Research

, Volume 31, Issue 11, pp 2963–2974 | Cite as

A Novel High-Speed Imaging Technique to Predict the Macroscopic Spray Characteristics of Solution Based Pressurised Metered Dose Inhalers

  • Nicolas A. Buchmann
  • Daniel J. Duke
  • Sayed A. Shakiba
  • Daniel M. Mitchell
  • Peter J. Stewart
  • Daniela Traini
  • Paul M. Young
  • David A. Lewis
  • Julio Soria
  • Damon Honnery
Research Paper
First Online:
Received:
Accepted:

ABSTRACT

Purpose

Non-volatile agents such as glycerol are being introduced into solution-based pMDI formulations in order to control mean precipitant droplet size. To assess their biopharmaceutical efficacy, both microscopic and macroscopic characteristics of the plume must be known, including the effects of external factors such as the flow generated by the patient’s inhalation. We test the hypothesis that the macroscopic properties (e.g. spray geometry) of a pMDI spray can be predicted using a self-similarity model, avoiding the need for repeated testing.

Methods

Glycerol-containing and glycerol-free pMDI formulations with matched mass median aerodynamic diameters are investigated. High-speed schlieren imaging is used to extract time-resolved velocity, penetration and spreading angle measurements of the pMDI spray plume. The experimental data are used to validate the analytical model.

Results

The pMDI spray develops in a manner characteristic of a fully-developed steady turbulent jet, supporting the hypothesis. Equivalent glycerol-containing and non glycerol-containing formulations exhibit similar non-dimensional growth rates and follow a self-similar scaling behaviour over a range of physiologically relevant co-flow rates.

Conclusions

Using the proposed model, the mean leading edge penetration, velocity and spreading rate of a pMDI spray may be estimated a priori for any co-flow conditions. The effects of different formulations are captured in two scaling constants. This allows formulators to predict the effects of variation between pMDIs without the need for repeated testing. Ultimately, this approach will allow pharmaceutical scientists to rapidly test a number of variables during pMDI development.

KEY WORDS

co-flow glycerol HFA high-speed schlieren imaging modelling pMDI 

ABBREVIATIONS

ACI

Andersen Cascade Impactor

BDP

Beclomethasone dipropionate

FPD

Fine particle dose

HFA

Hydrofluoroalkane

MMAD

Mass median aerodynamic diameter

pMDI

Pressurised Metered Dose Inhaler

This is a preview of subscription content, log in to check access.

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to acknowledge the financial support of the Australian Research Council (grant number DP120103510).

REFERENCES

  1. 1.
    Newhouse M. Advantages of pressurized canister metered dose inhalers. J Aerosol Med. 1991;4(3):139–50.PubMedCrossRefGoogle Scholar
  2. 2.
    Finlay WH. The mechanics of inhaled pharmaceutical aerosols - an introduction. Academic Press; 2001.Google Scholar
  3. 3.
    Ross DL, Schultz RK. Effect of inhalation flow rate on the dosing characteristics of dry powder inhaler (DPI) and metered dose inhaler (MDI) products. J Aerosol Med. 1996;9(2):215–26.PubMedCrossRefGoogle Scholar
  4. 4.
    Lewis DA, Young PM, Buttini F, Church T, Colombo P, Forbes B, et al. Towards the bioequivalence of pressurised metered dose inhalers 1: design and characterisation of aero-dynamically equivalent beclomethasone dipropionate inhalers with and without glycerol 2 as a non-volatile excipient. Eur J Pharm Biopharm. 2013.Google Scholar
  5. 5.
    Keller M. Innovations and perspectives of metered dose inhalers in pulmonary drug delivery. Int J Pharm. 1999;186:81–90.PubMedCrossRefGoogle Scholar
  6. 6.
    Haghi M, Bebawy M, Colombo P, Forbes B, Lewis DA, Salama R, et al. Towards the bioequivalence of pressurised metered dose inhalers 2. Aerodynamically equivalent particles (with and without glycerol) exhibit different biopharmaceutical profiles in vitro. Eur J Pharm Biopharm. 2013.Google Scholar
  7. 7.
    Brambilla G, Ganderton D, Garzia R, Lewis D, Meakin B, Ventura P. Modulation of aerosol clouds produced by pressurised inhalation aerosols. Int J Pharm. 1999;186(1):53–61.PubMedCrossRefGoogle Scholar
  8. 8.
    Versteeg HK, Hargrave GK, Kirby M. Internal flow and near-orifice spray visualisations of a model pharmaceutical pressurised metered dose inhaler. J Phys Conf Ser. 2006;45(1):207.CrossRefGoogle Scholar
  9. 9.
    Tzou TZ. Aerodynamic particle size of metered-dose inhalers determined by the quartz crystal microbalance and the Andersen cascade impactor. Int J Pharm. 1999;186:71–9.PubMedCrossRefGoogle Scholar
  10. 10.
    May KR. Multistage liquid impinger. Bacteriol Rev. 1966;30:559–70.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Marple VA, Roberts DL, Romay FJ, Miller NC, Truman KG, Van Oort M, et al. Next generation pharmaceutical impactor (a new impactor for pharmaceutical inhaler testing). Part I: design. J Aerosol Med. 2003;16:283–99.PubMedCrossRefGoogle Scholar
  12. 12.
    Liu X, Doub WH, Guo C. Evaluation of metered dose inhaler spray velocities using Phase Doppler Anemometry (PDA). Int J Pharm. 2012;423:235–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Dunbar CA, Hickey AJ. Selected parameters affecting characterization of nebulized aqueous solutions by inertial impaction and comparison with phase-Doppler analysis. Eur J Pharm Biopharm. 1999;48(2):171–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Ma Z, Merkus HG, de Smet JG, Heffels C, Scarlett B. New developments in particle characterization by laser diffraction: size and shape. Powder Technol. 2000;111(1):66–78.CrossRefGoogle Scholar
  15. 15.
    Dunbar CA. Atomization mechanisms of the pressurized metered dose inhaler. Part Sci Technol. 1997;15(3–4):253–71.CrossRefGoogle Scholar
  16. 16.
    Crosland BM, Johnson MR, Matida EA. Characterization of the spray velocities from a pressurized metered-dose inhaler. J Aerosol Med Pulm Drug Deliv. 2009;22(2):85–98.PubMedCrossRefGoogle Scholar
  17. 17.
    Roisman IV, Araneo L, Tropea C. Effect of ambient pressure on penetration of a diesel spray. Int J Multiphase Flow. 2007;33:904–20.CrossRefGoogle Scholar
  18. 18.
    Sweeney TD, Blanchard JD, Zeltner TB, Cater JE, Brain JD. Delivery of aerosolized drugs to the lungs with a metered-dose inhaler: quantitative analysis of regional deposition. J Aerosol Sci. 1990;21(3):350–4.CrossRefGoogle Scholar
  19. 19.
    Clark AR. MDIs: physics of aerosol formation. J Aerosol Med. 1996;9(S1):19–26.CrossRefGoogle Scholar
  20. 20.
    Smyth H, Hickey AJ, Brace G, Barbour T, Gallion J, Grove J. Spray pattern analysis for metered dose inhalers I: orifice size, particle size, and droplet motion correlations. Drug Dev Ind Pharm. 2006;32(9):1033–41.PubMedCrossRefGoogle Scholar
  21. 21.
    Dhand R, Malik SK, Balakrishnan M, Verma SR. High speed photographic analysis of aerosols produced by metered dose inhalers. J Pharm Pharamcol. 1988;40:429–30.CrossRefGoogle Scholar
  22. 22.
    Hajialimohammadi A, Honnery D, Abdullah A, Mirsalim MA. Time resolved characteristics of gaseous jet injected by a group-hole nozzle. Fuel. 2013;113:497–505.CrossRefGoogle Scholar
  23. 23.
    Kostas J, Honnery D, Soria J. A correlation image velocimetry-based study of high-pressure fuel spray tip evolution. Exp Fluids. 2011;51:667–78.CrossRefGoogle Scholar
  24. 24.
    Settles GS. Schlieren and shadowgraph techniques. experimental fluid mechanics. Springer-Verlag; 2001.Google Scholar
  25. 25.
    Mitchell D, Honnery D, Soria J. The visualization of the acoustic feedback loop in impinging underexpanded supersonic jet flows using ultra-high frame rate Schlieren. J Vis. 2012;15(7):333–41.CrossRefGoogle Scholar
  26. 26.
    Buchmann NA, Willert CE, Soria J. Pulsed, high-power LED illumination for tomographic particle image velocimetry. Exp Fluids. 2012;53:1545–60.CrossRefGoogle Scholar
  27. 27.
    Willert CE, Mitchell DM, Soria J. An assessment of high-power light-emitting diodes for high frame rate schlieren imaging. Exp Fluids. 2012;53(2):413–21.CrossRefGoogle Scholar
  28. 28.
    Canny J. A computational approach to edge detection. IEEE Trans Pattern Anal Mach Intell. 1986;8(6):679–98.PubMedCrossRefGoogle Scholar
  29. 29.
    Duke D, Honnery D, Soria J. A comparison of subpixel edge detection and correlation algorithms for the measurement of sprays. Int J Spray Combust Dyn. 2011;3(2):93–109.CrossRefGoogle Scholar
  30. 30.
    Duke D, Honnery D, Soria J. A cross-correlation velocimetry technique for breakup of an annular liquid sheet. Exp Fluids. 2010;49:435–45.CrossRefGoogle Scholar
  31. 31.
    Duke D, Honnery D, Soria J. Experimental investigation of nonlinear instabilities in annular liquid sheets. J Fluid Mech. 2011;691:594–604.CrossRefGoogle Scholar
  32. 32.
    Westerweel J, Scarano F. Universal outlier detection for PIV data. Exp Fluids. 2005;39(6):1096–100.CrossRefGoogle Scholar
  33. 33.
    Clark AR. Metered atomisation for respiratory drug delivery. Loughborough University; 1991.Google Scholar
  34. 34.
    Hiroyasu H, Arai M. Structures of fuel sprays in diesel engines. SAE J. 1990 Feb;900475.Google Scholar
  35. 35.
    Pastor JV, López JJ, García J, Pastor JM. A 1D model for the description of mixing-controlled inert diesel sprays. Fuel. 2008;87(13–14):2871–85.CrossRefGoogle Scholar
  36. 36.
    Ricou FP, Spalding DB. Measurements of entrainment by axisymmetrical turbulent jets. J Fluid Mech. 1961;11(1):21–32.CrossRefGoogle Scholar
  37. 37.
    Shaik AQ. Numerical modeling of two-phase flashing propellant flow inside the twin-orifice system of pressurized metered dose inhalers (PMDIs). Loughborough University; 2010.Google Scholar
  38. 38.
    Kostas J, Honnery D, Soria J. Time resolved measurements of the initial stages of fuel spray penetration. Fuel. 2009;88(11):2225–37.CrossRefGoogle Scholar
  39. 39.
    White FM. Fluid mechanics. 4th ed. Singapore: McGraw-Hill; 1999.Google Scholar
  40. 40.
    Ihmels EC, Horstmann S, Fischer K, Scalabrin G, Gmehling J. Compressed liquid and supercritical densities of 1, 1, 1, 2, 3, 3, 3-heptafluoropropane (R227ea). Int J Thermophys. 2002;23(6):1571–85.CrossRefGoogle Scholar
  41. 41.
    Huber ML, McLinden MO. Thermodynamic properties of R134a (1, 1, 1, 2-tetrafluoroethane). In: International Refridgeration and Air Conditioning Conference; 1992.Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Nicolas A. Buchmann
    • 1
    • 6
  • Daniel J. Duke
    • 1
  • Sayed A. Shakiba
    • 1
  • Daniel M. Mitchell
    • 1
  • Peter J. Stewart
    • 2
  • Daniela Traini
    • 3
    • 4
  • Paul M. Young
    • 3
    • 4
  • David A. Lewis
    • 5
  • Julio Soria
    • 1
    • 7
  • Damon Honnery
    • 1
  1. 1.Department of Mechanical and Aerospace EngineeringMonash UniversityMelbourneAustralia
  2. 2.Faculty of Pharmacy and Pharmaceutical SciencesMonash UniversityMelbourneAustralia
  3. 3.Respiratory Technology, Woolcock Insititute of Medical ResearchUniversity of SydneySydneyAustralia
  4. 4.Discipline of Pharmacology, School of MedicineThe University of SydneySydneyAustralia
  5. 5.Chiesi LimitedChippenhamUK
  6. 6.Institute of Fluid Dynamics and AerodynamicsUniversität der Bundeswehr MünchenNeubibergGermany
  7. 7.Department of Aeronautical EngineeringKing Abdulaziz UniversityJeddahKingdom of Saudi Arabia

Personalised recommendations