Advertisement

AAPS PharmSciTech

, 20:57 | Cite as

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

  • Daryl L. Roberts
  • Jolyon P. Mitchell
Research Article Theme: Paul Myrdal Memorial Issue - Pharmaceutical Formulation and Aerosol Sciences
  • 43 Downloads
Part of the following topical collections:
  1. Theme: Paul Myrdal Memorial Issue - Pharmaceutical Formulation and Aerosol Sciences

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.

KEY WORDS

cascade impactor inhaler testing product specification aerodynamic particle size distribution 

Notes

References

  1. 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.CrossRefGoogle Scholar
  2. 2.
    Hinds WC. Aerosol technology properties, behavior, and measurement of airborne particles. 2nd ed. New York: Wiley; 1999. p. 134–8.Google Scholar
  3. 3.
    Marple VA, Liu BYH. Characteristics of laminar jet impactors. Environ Sci Technol. 1974;8(7):648–54.CrossRefGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 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. 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.Google Scholar
  7. 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.Google Scholar
  8. 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.Google Scholar
  9. 9.
    Marple VA. A fundamental study of inertial impactors. PhD Dissertation, Minneapolis: University of Minnesota, 1970.Google Scholar
  10. 10.
    Rader DJ, Marple VA. Effect of ultra-Stokesian drag and particle interception on impactor characteristics. Aerosol Sci Technol. 1985;4(2):141–56.CrossRefGoogle Scholar
  11. 11.
    Roberts DL, Mitchell JP. The Next Generation Impactor (NGI™)—manufacturing control: Part 1—nozzles. Inhalation. 2016;10(2):12–9.Google Scholar
  12. 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. 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.CrossRefGoogle Scholar
  14. 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.CrossRefGoogle Scholar
  15. 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.CrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 17.
    Dunbar CA, Hickey AJ, Holzner P. Dispersion and characterization of pharmaceutical dry powder aerosols. KONA Powder and Particle Journal. 1998;16:7–45.Google Scholar
  18. 18.
    Hickey AJ. Complexity in pharmaceutical powders for inhalation: a perspective. KONA-Powder and Particle. 2018;35:3–13.CrossRefGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 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. 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. 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. 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, 2018Google Scholar
  24. 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, 2018Google Scholar
  25. 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, 2018Google Scholar
  26. 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.CrossRefGoogle Scholar
  27. 27.
    Dunbar C, Kataya A, Tiangbe T. Reducing bounce effects in the Andersen cascade impactor. Int J Pharm. 2005;301:25–32.CrossRefGoogle Scholar
  28. 28.
    Roberts DL. Theory of multi-nozzle impactor stages and the interpretation of stage mensuration data. Aerosol Sci Technol. 2009;43(11):1119–29.CrossRefGoogle Scholar
  29. 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. 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. 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.CrossRefGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 34.
    Picknett RG. A new method of determining aerosol size distributions from multistage sampler data. J Aerosol Sci. 1972;3:185–98.CrossRefGoogle Scholar
  35. 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.CrossRefGoogle Scholar
  36. 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. 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):3723–3733Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  1. 1.Applied Particle Principles LLCHamiltonUSA
  2. 2.Jolyon Mitchell Inhaler Consulting Services Inc.LondonCanada

Personalised recommendations