Pharmaceutical Research

, Volume 32, Issue 6, pp 2086–2096 | Cite as

Multi-Scale Modelling of Powder Dispersion in a Carrier-Based Inhalation System

  • Zhenbo Tong
  • Hidehiro Kamiya
  • Aibing Yu
  • Hak-Kim Chan
  • Runyu YangEmail author
Research Paper



Carrier-based dry powder inhalers (DPIs) are widely used for rapid and convenient delivery of drug to the site of action. This work aimed to predict powder aerosolisation in DPIs through numerical modelling.


A multi-scale modelling technique based on the combined computational fluid dynamics (CFD) and discrete element method (DEM) approach was developed.


The simulation results of the detachments of the drug particles from single carrier under different impact velocities and angles were comparable with those measured in the experiments in terms of fine particle fraction FPF loaded . Empirical equations were developed to link the detachment performance with impact velocity and impact angle. Then the dynamics of the carrier particles in Aerolizer® was simulated. The results indicated that the carrier-wall impaction was the dominant mechanism for drug aerosolisation performance. By linking the empirical equations with the carrier-wall impact energy, the predictions showed that for a given formulation mass with a fixed carrier/drug ratio, the inhaler performance decreased with carrier size and increased with air flow rate. Device empty efficiency, however, was independent with carrier size and flow rate.


The multi-scale model was able to provide quantitative information to better understand the aerosolisation mechanisms of carrier-based formulation.


carrier-based formulation computational fluid dynamics discrete element method dry powder inhaler numerical modelling powder dispersion 



Authors are grateful to the Japan Society for the Promotion of Science (JSPS) and the Australia Research Council (ARC) for the financial support through the Discovery Project.


  1. 1.
    Patton J. Breathing life into protein drugs. Nat Biotechnol. 1998;16(2):141–3.CrossRefPubMedGoogle Scholar
  2. 2.
    Clark AR. Pulmonary delivery technology: recent advances and potential for the new millennium. In: Hickey AJ, editor. Pharmaceutical Inhalation aerosol technology. New York: Marcel Dekker, Inc.; 2004. p. 571–91.Google Scholar
  3. 3.
    Chan H-K. Dry powder aerosol drug delivery-opportunities for colloid and surface scientists. Colloids Surf A Physicochem Eng Asp. 2006;284–285:50–5.CrossRefGoogle Scholar
  4. 4.
    Chan HK. Dry powder aerosol delivery systems: current and future research directions. J Aerosol Med-Depos Clearance Eff Lung. 2006;19(1):21–7.CrossRefGoogle Scholar
  5. 5.
    Islam N, Gladki E. Dry powder inhalers (DPIs)–A review of device reliability and innovation. Int J Pharm. 2008;360(1–2):1–11.CrossRefPubMedGoogle Scholar
  6. 6.
    Frijlink HW, De Boer AH. Dry powder inhalers for pulmonary drug delivery. Expert Opin Drug Deliv. 2004;1(1):67–86.CrossRefPubMedGoogle Scholar
  7. 7.
    Bell JH, Hartley PS, Cox JS. Dry powder aerosols. I: a new powder inhalation device. J Pharm Sci. 1971;60(10):1559–64.CrossRefPubMedGoogle Scholar
  8. 8.
    Malcolmson RJ, Embleton JK. Dry powder formulations for pulmonary delivery. Pharm Sci Technol. 1998;1(9):394–8.CrossRefGoogle Scholar
  9. 9.
    Hersey JA. Ordered mixing: a new concept in powder mixing practice. Powder Technol. 1975;11(1):41–4.CrossRefGoogle Scholar
  10. 10.
    Kawashima Y, Serigano T, Hino T, Yamamoto H, Takeuchi H. Effect of surface morphology of carrier lactose on dry powder inhalation property of pranlukast hydrate. Int J Pharm. 1998;172(1–2):179–88.CrossRefGoogle Scholar
  11. 11.
    Young PM, Kwok P, Adi H, Chan HK, Traini D. Lactose composite carriers for respiratory delivery. Pharm Res. 2009;26(4):802–10.CrossRefPubMedGoogle Scholar
  12. 12.
    Traini D, Young PM, Thielmann F, Acharya M. The influence of lactose pseudopolymorphic form on salbutamol sulfate-lactose interactions in dpi formulations. Drug Dev Ind Pharm. 2008;34(9):992–1001.CrossRefPubMedGoogle Scholar
  13. 13.
    Dickhoff BHJ, De Boer AH, Lambregts D, Frijlink HW. The effect of carrier surface and bulk properties on drug particle detachment from crystalline lactose carrier particles during inhalation, as function of carrier payload and mixing time. Eur J Pharm Biopharm. 2003;56(2):291–302.CrossRefPubMedGoogle Scholar
  14. 14.
    Donovan MJ, Smyth HDC. Influence of size and surface roughness of large lactose carrier particles in dry powder inhaler formulations. Int J Pharm. 2010;402(1–2):1–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Ooi J, Traini D, Hoe S, Wong W, Young PM. Does carrier size matter? A fundamental study of drug aerosolisation from carrier based dry powder inhalation systems. Int J Pharm. 2011;413(1–2):1–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Guenette E, Barrett A, Kraus D, Brody R, Harding L, Magee G. Understanding the effect of lactose particle size on the properties of DPI formulations using experimental design. Int J Pharm. 2009;380(1–2):80–8.CrossRefPubMedGoogle Scholar
  17. 17.
    De Boer AH, Dickhoff BHJ, Hagedoorn P, Gjaltema D, Goede J, Lambregts D, et al. A critical evaluation of the relevant parameters for drug redispersion from adhesive mixtures during inhalation. Int J Pharm. 2005;294(1–2):173–84.CrossRefPubMedGoogle Scholar
  18. 18.
    Islam N, Stewart P, Larson I, Hartley P. Lactose surface modification by decantation: are drug-fine lactose ratios the key to better dispersion of salmeterol xinafoate from lactose-interactive mixtures? Pharm Res. 2004;21(3):492–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Young PM, Edge S, Traini D, Jones MD, Price R, El-Sabawi D, et al. The influence of dose on the performance of dry powder inhalation systems. Int J Pharm. 2005;296(1–2):26–33.CrossRefPubMedGoogle Scholar
  20. 20.
    Young PM, Wood O, Ooi J, Traini D. The influence of drug loading on formulation structure and aerosol performance in carrier based dry powder inhalers. Int J Pharm. 2011;416(1):129–35.CrossRefPubMedGoogle Scholar
  21. 21.
    Jones MD, Price R. The influence of fine excipient particles on the performance of carrier-based dry powder inhalation formulations. Pharm Res. 2006;23(8):1665–74.CrossRefPubMedGoogle Scholar
  22. 22.
    Hoe S, Traini D, Chan H-K, Young P. The contribution of different formulation components on the aerosol charge in carrier-based dry powder inhaler systems. Pharm Res. 2010;27(7):1325–36.CrossRefPubMedGoogle Scholar
  23. 23.
    Young P, Sung A, Traini D, Kwok P, Chiou H, Chan H-K. Influence of humidity on the electrostatic charge and aerosol performance of dry powder inhaler carrier based systems. Pharm Res. 2007;24(5):963–70.CrossRefPubMedGoogle Scholar
  24. 24.
    Ganderton D, Kassem, N.M. DRY Powder inhalers: Advances in Pharmaceutical Sciences. London: Academic Press; 1992. P. 165–191.Google Scholar
  25. 25.
    Coates MS, Fletcher DF, Chan HK, Raper JA. Effect of design on the performance of a dry powder inhaler using computational fluid dynamics. part 1: grid structure and mouthpiece length. J Pharm Sci. 2004;93(11):2863–76.CrossRefPubMedGoogle Scholar
  26. 26.
    Coates MS, Chan HK, Fletcher DF, Raper JA. Effect of design on the performance of a dry powder inhaler using computational fluid dynamics. part 2: air inlet size. J Pharm Sci. 2006;95(6):1382–92.CrossRefPubMedGoogle Scholar
  27. 27.
    Tong ZB, Yang RY, Yu AB, Adi S, Chan HK. Numerical modelling of the breakage of loose agglomerates of fine particles. Powder Technol. 2009;196(2):213–21.CrossRefGoogle Scholar
  28. 28.
    Tong ZB, Yang RY, Chu KW, Yu AB, Adi S, Chan HK. Numerical study of the effects of particle size and polydispersity on the agglomerate dispersion in a cyclonic flow. Chem Eng J. 2010;164(2–3):432–41.CrossRefGoogle Scholar
  29. 29.
    Tong ZB, Zheng B, Yang RY, Yu AB, Chan HK. CFD-DEM investigation of the dispersion mechanisms in commercial dry powder inhalers. Powder Technol. 2013;240:19–24.CrossRefGoogle Scholar
  30. 30.
    Yang J, Wu C-Y, Adams M. A. three-dimensional DEM–CFD analysis of air-flow-induced detachment of api particles from carrier particles in dry powder inhalers. Acta Pharm Sinica B. 2014;4:52–9.CrossRefGoogle Scholar
  31. 31.
    Zhu HP, Zhou ZY, Yang RY, Yu AB. Discrete particle simulation of particulate systems: theoretical developments. Chem Eng Sci. 2007;62(13):3378–96.CrossRefGoogle Scholar
  32. 32.
    Gidaspow D. Multiphase flow and fluidization. San Diego: Academic; 1994.Google Scholar
  33. 33.
    Chu KW, Wang B, Yu AB, Vince A. Cfd-dem modelling of multiphase flow in dense medium cyclones. Powder Technol. 2009;193(3):235–47.CrossRefGoogle Scholar
  34. 34.
    Launder BE, Reece GJ, Rodi W. Progress in development of a Reynolds-stress turbulence closure. J Fluid Mech. 1975;68:537–66.CrossRefGoogle Scholar
  35. 35.
    Wang B, Xu DL, Chu KW, Yu AB. Numerical study of gas-solid flow in a cyclone separator. Appl Math Model. 2006;30(11):1326–42.CrossRefGoogle Scholar
  36. 36.
    Adi S, Tong Z, Chan H-K, Yang R, Yu A. Impact angles as an alternative way to improve aerosolisation of powders for inhalation? Eur J Pharm Sci. 2010;41(2):320–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Tong Z, Adi S, Yang R, Chan H, Yu A. Numerical investigation of the de-agglomeration mechanisms of fine powders on mechanical impaction. J Aerosol Sci. 2011;42(11):811–9.CrossRefGoogle Scholar
  38. 38.
    Coates M, Chan H-K, Fletcher D, Raper J. The role of capsule on the performance of a dry powder inhaler using computational and experimental analyses. Pharm Res. 2005;22(6):923–32.CrossRefPubMedGoogle Scholar
  39. 39.
    Chew NYK, Bagster DF, Chan HK. Effect of particle size, air flow and inhaler device on the aerosolisation of disodium cromoglycate powders. Int J Pharm. 2000;206(1–2):75–83.CrossRefPubMedGoogle Scholar
  40. 40.
    Chew NYK, Chan HK. Influence of particle size, air flow, and inhaler device on the dispersion of mannitol powders as aerosols. Pharm Res. 1999;16(7):1098–103.CrossRefPubMedGoogle Scholar
  41. 41.
    Bronsky EA, Grossman J, Henis MJ, Gallo PP, Yegen Ü, Cioppa GD, et al. Inspiratory flow rates and volumes with the Aerolizer dry powder inhaler in asthmatic children and adults. Curr Med Res Opin. 2004;20(2):131–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Coates MS, Chan HK, Fletcher DF, Raper JA. Influence of air flow on the performance of a dry powder inhaler using computational and experimental analyses. Pharm Res. 2005;22(9):1445–53.CrossRefPubMedGoogle Scholar
  43. 43.
    Tong Z, Yang R, Yu A, Adi S, Chan H. Numerical modelling of the breakage of loose agglomerates of fine particles. Powder Technol. 2009;196(2):213–21.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Zhenbo Tong
    • 1
    • 2
  • Hidehiro Kamiya
    • 1
  • Aibing Yu
    • 2
    • 3
  • Hak-Kim Chan
    • 4
  • Runyu Yang
    • 2
    Email author
  1. 1.Graduate School of Bio-Applications and Systems Engineering (BASE)Tokyo University of Agriculture and TechnologyTokyoJapan
  2. 2.School of Materials Science and EngineeringUniversity of New South WalesSydneyAustralia
  3. 3.Department of Chemical EngineeringMonash UniversityClaytonAustralia
  4. 4.Faculty of PharmacyUniversity of SydneySydneyAustralia

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