Skip to main content
SpringerLink
Log in

Measurement of Aerodynamic Particle Size Distribution of Orally Inhaled Products by Cascade Impactor: How to Let the Product Specification Drive the Quality Requirements of the Cascade Impactor

  • Research Article
  • Theme: Paul Myrdal Memorial Issue - Pharmaceutical Formulation and Aerosol Sciences
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The multi-stage inertial cascade impactor is used to determine the mass-weighted aerodynamic particle size distribution (APSD) as a critical quality attribute for orally inhaled products (OIPs). These apparatuses progressively size-fractionate the aerosol passing through a series of stages containing one or more nozzles, by increasing particle velocity. Nozzle sizes for a given multi-nozzle stage can be described collectively by effective diameter (\( \overset{\sim }{W_0} \)), related to the cut-point size, providing the link to aerodynamic diameter. Users undertake stage mensuration periodically to assure that each stage \( \overset{\sim }{W_0} \) remains within the manufacturer’s tolerance, but there is no guidance on how frequently such checks should be made. We examine the philosophy that particle size-related specifications of the OIP should determine when an impactor is mensurated. Taking an example of a dry powder inhaler-generated aerosol sampled via a Next Generation Impactor with pre-separator, we find that there are only three critical stages that could have a material effect on the measured APSD specified as four groupings of stages following current regulatory practice. Furthermore, \( \overset{\sim }{W_0} \) for the most critical stage having the smallest nozzle sizes could be relaxed by a factor of four or more before risking an inability to measure the mass fraction of API in the group containing the finest particles to a specification within ± 10% of nominal. We therefore conclude that users should consider letting the specification for APSD performance of an OIP in terms of accepted stage groupings drive the impactor quality requirements and frequency that stage mensuration is undertaken.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Mitchell J, Newman S, Chan H-K. In vitro and in vivo aspects of cascade impactor tests and inhaler performance: a review. AAPS PharmSciTech. 2007;8(4):110. https://doi.org/10.1208/pt0804110 Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750696/ Accessed September 27th 2018.

    Article  Google Scholar 

  2. Hinds WC. Aerosol technology properties, behavior, and measurement of airborne particles. 2nd ed. New York: Wiley; 1999. p. 134–8.

    Google Scholar 

  3. Marple VA, Liu BYH. Characteristics of laminar jet impactors. Environ Sci Technol. 1974;8(7):648–54.

    Article  CAS  Google Scholar 

  4. Dechraksa J, Suwandecha T, Maliwan K, Srichana T. The comparison of fluid dynamics parameters in an Andersen cascade impactor equipped with and without a preseparator. AAPS PharmSciTech. 2014;15(3):792–801.

    Article  Google Scholar 

  5. United States Food and Drug Administration. Draft guidance for industry: metered dose inhaler (MDI) and dry powder inhaler (DPI) products—quality considerations. Silver Spring, MD, USA. 2018. available at: https://www.fda.gov/downloads/drugs/guidances/ucm070573.pdf , visited September 28, 2018.

  6. Nichols SC, Mitchell JP. An assessment of the comparative efficiency of abbreviated versus full resolution cascade impactor measurements: a survey of European Pharmaceutical Aerosol Group (EPAG) members. Drug delivery to the Lungs-24. Edinburgh: The Aerosol Society; 2013. p. 237–40.

  7. US Pharmacopeial Convention. United States Pharmacopeia 41/National Formulary 36, Chapter <601> Aerosols, nasal sprays, metered-dose inhalers, and dry powder inhalers. Rockville. 2018.

  8. Marple VA, Roberts DL, Romay FJ, Miller NC, Truman KG, Van Oort M, et al. Next generation pharmaceutical impactor. Part 1: design. J Aerosol Med. 2003;16(3):283–99.

  9. Marple VA. A fundamental study of inertial impactors. PhD Dissertation, Minneapolis: University of Minnesota, 1970.

  10. Rader DJ, Marple VA. Effect of ultra-Stokesian drag and particle interception on impactor characteristics. Aerosol Sci Technol. 1985;4(2):141–56.

    Article  Google Scholar 

  11. Roberts DL, Mitchell JP. The Next Generation Impactor (NGI™)—manufacturing control: Part 1—nozzles. Inhalation. 2016;10(2):12–9.

    Google Scholar 

  12. Nichols SC, Mitchell JP. Stimulus to revision: a rational approach to cascade impactor mensuration in a good cascade impactor practice (GCIP) environment. Pharm Forum. 2014;40(1) on line at: https://www.uspnf.com/pharmacopeial-forum, visited September 28, 2018.

  13. Roberts DL, Romay FJ. Relationship of stage mensuration data to the performance of new and used cascade impactors. J Aerosol Med. 2005;18(4):396–413.

    Article  Google Scholar 

  14. Mitchell JP, Nagel MW. Cascade impactors for the size characterization of aerosols from medical inhalers: their uses and limitations. J Aerosol Med. 2003;16(4):341–77.

    Article  CAS  Google Scholar 

  15. McRobbie DW, Pritchard S, Quest RA. Studies of the human oropharyngeal airspaces using magnetic resonance imaging. I. Validation of a three-dimensional MRI method for producing ex vivo virtual and physical casts of the oropharyngeal airways during inspiration. J Aerosol Med. 2003;16(4):401–15.

    Article  Google Scholar 

  16. Zhang Y, Finlay WH, Matida EA. Particle deposition measurements and numerical simulation in a highly-idealized mouth-throat. J Aerosol Sci. 2004;35(7):789–803.

    Article  CAS  Google Scholar 

  17. Dunbar CA, Hickey AJ, Holzner P. Dispersion and characterization of pharmaceutical dry powder aerosols. KONA Powder and Particle Journal. 1998;16:7–45.

  18. Hickey AJ. Complexity in pharmaceutical powders for inhalation: a perspective. KONA-Powder and Particle. 2018;35:3–13.

    Article  CAS  Google Scholar 

  19. Marple VA, Olson BA, Santhanakrishnan K, Mitchell JP, Murray SC, Hudson-Curtis BL. Next generation pharmaceutical impactor. Part II: archival calibration. J Aerosol Med. 2003;16(3):301–24.

    Article  Google Scholar 

  20. Mitchell JP, Sandell D, Suggett J, Christopher JD, Leiner S, Walfish S, et al. Stimulus to revision: proposals for data interpretation in the context of determination of aerodynamic particle size distribution profile for orally inhaled products. Pharm Forum. 2017;43(3) on line at: https://www.uspnf.com/pharmacopeial-forum , visited September 28, 2018.

  21. United States Food and Drug Administration. Guidance for industry: Q8(R2)—pharmaceutical development. 2009. available at: https://www.fda.gov/downloads/drugs/guidances/ucm073507.pdf , visited September 28, 2018.

  22. United States Pharmacopeial Convention. Product monograph for fluticasone propionate and salmeterol inhalation powder. Rockville, USP41-NF36; 2018. Available at: https://online.uspnf.com/uspnf/document/GUID-A54661A3-DF23-400A-8763-0213D19A10C6_1_en-US, visited October 15, 2018

  23. United States Pharmacopeial Convention. Product monograph for fluticasone propionate inhalation aerosol. Rockville: USP41-NF36; 2018. Available at: https://online.uspnf.com/uspnf/document/GUID-39375AC5-C31B-4C74-AB80-75FD5D95A6A0_1_en-US, visited October 15, 2018

    Google Scholar 

  24. United States Pharmacopeial Convention. Product monograph for fluticasone propionate and salmeterol inhalation aerosol. Rockville: USP41-NF36; 2018. Available at: https://online.uspnf.com/uspnf/document/GUID-5BD2B30C-5CC9-4003-8ED1-59E4FF6B0CAF_1_en-US, visited October 15, 2018

    Google Scholar 

  25. United States Pharmacopeial Convention. Product monograph for fluticasone propionate inhalation powder. Rockville: USP41-NF36; 2018. Available at: https://online.uspnf.com/uspnf/document/GUID-A54661A3-DF23-400A-8763-0213D19A10C6_1_en-US, visited October 15, 2018

    Google Scholar 

  26. Nasr MM, Ross DL, Miller NC. Effect of drug load and plate coating on the particle size distribution of a commercial albuterol metered dose inhaler (MDI) determined using the Andersen and Marple-Miller cascade impactors. Pharm Res. 1997;14:1437–43.

    Article  CAS  Google Scholar 

  27. Dunbar C, Kataya A, Tiangbe T. Reducing bounce effects in the Andersen cascade impactor. Int J Pharm. 2005;301:25–32.

    Article  CAS  Google Scholar 

  28. Roberts DL. Theory of multi-nozzle impactor stages and the interpretation of stage mensuration data. Aerosol Sci Technol. 2009;43(11):1119–29.

    Article  CAS  Google Scholar 

  29. Byron PR, Weers JG, Clark AR, Sandell D, Mitchell JP. Achieving deposition equivalence: the state of the art. In: Dalby RN, Peart J, Suman JD, Young PM, Traini D, editors. Respiratory drug delivery Europe 2017. River Grove: Davis Horwood Publishing LLC; 2017. p. 101–18.

    Google Scholar 

  30. Olsson B, Asking L. Methods of setting and measuring flow rates in pharmaceutical impactor experiments. Pharm Forum. 2003;29(3):879–84.

    Google Scholar 

  31. Roberts DL, Mitchell JP. The effect of non-ideal impactor stage collection efficiency curves on the interpretation of the size of inhaler-generated aerosols. AAPS PharmSciTech. 2013;14(2):497–510.

    Article  CAS  Google Scholar 

  32. Zhou Y, Sun J, Cheng Y-S. Comparison of deposition in the USP and physical mouth-throat models with solid and liquid particles. J Aerosol Med Pulmon Drug Deliv. 2011;24(6):277–84.

    Article  CAS  Google Scholar 

  33. Twomey S. Comparison of constrained linear inversion and an iterative nonlinear algorithm applied to the indirect estimation of particle size distributions. J Comput Phys. 1975;18:188–200.

    Article  Google Scholar 

  34. Picknett RG. A new method of determining aerosol size distributions from multistage sampler data. J Aerosol Sci. 1972;3:185–98.

    Article  Google Scholar 

  35. Nichols SC, Mitchell JP, Shelton CM, Roberts DL. Good cascade impactor practice (GCIP) and considerations for “in-use” specifications. AAPS PharmSciTech. 2013;14(1):375–90.

    Article  CAS  Google Scholar 

  36. Roberts DL, Maidment M, Copley MA. Improved protocol for relating impactor stage pressure drop to the suitability for routine use. Drug delivery to the lungs. Edinburgh: The Aerosol Society; 2017. p. 94–7.

    Google Scholar 

  37. Williams G, Blatchford C, Mitchell JP. Evaluation of nasal inlet ports having simplified geometry for the pharmacopeial assessment of mass fraction of dose likely to penetrate beyond the nasopharynx: a preliminary investigation. AAPS PharmSciTechnol. 2018; 19(8):3723–3733

Download references

Author information

Authors and Affiliations

  1. Applied Particle Principles LLC, 17347 Westham Estates Court, Hamilton, Virginia, 20158, USA

    Daryl L. Roberts

  2. Jolyon Mitchell Inhaler Consulting Services Inc., 1154 St. Anthony Road, London, Ontario, N6H 2R1, Canada

    Jolyon P. Mitchell

Authors
  1. Daryl L. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jolyon P. Mitchell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jolyon P. Mitchell.

Additional information

Guest Editors: Philip J. Kuehl and Stephen W. Stein

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Roberts, D.L., Mitchell, J.P. Measurement of Aerodynamic Particle Size Distribution of Orally Inhaled Products by Cascade Impactor: How to Let the Product Specification Drive the Quality Requirements of the Cascade Impactor. AAPS PharmSciTech 20, 57 (2019). https://doi.org/10.1208/s12249-018-1276-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-018-1276-9

KEY WORDS

Search

Navigation