The AAPS Journal

, 21:25 | Cite as

Development of a New Inhaler for High-Efficiency Dispersion of Spray-Dried Powders Using Computational Fluid Dynamics (CFD) Modeling

  • Worth LongestEmail author
  • Dale Farkas
Research Article


Computational fluid dynamics (CFD) modeling offers a powerful tool for the development of drug delivery devices using a first principles approach but has been underutilized in the development of pharmaceutical inhalers. The objective of this study was to develop quantitative correlations for predicting the aerosolization behavior of a newly proposed dry powder inhaler (DPI). The dose aerosolization and containment (DAC) unit DPI utilizes inlet and outlet air orifices designed to maximize the dispersion of spray-dried powders, typically with low air volumes (~ 10 mL) and relatively low airflow rates (~ 3 L/min). Five DAC unit geometries with varying orifice outlet sizes, configurations, and protrusion distances were considered. Aerosolization experiments were performed using cascade impaction to determine mean device emitted dose (ED) and mass median aerodynamic diameter (MMAD). Concurrent CFD simulations were conducted to predict both flow field-based and particle-based dispersion parameters that captured different measures of turbulence. Strong quantitative correlations were established between multiple measures of turbulence and the experimentally observed aerosolization metrics of ED and MMAD. As expected, increasing turbulence produced increased ED with best case values reaching 85% of loaded dose. Surprisingly, decreasing turbulence produced an advantageous decrease in MMAD with values as low as approximately 1.6 μm, which is in contrast with previous studies. In conclusion, CFD provided valuable insights into the performance of the DAC unit DPI as a new device including a two-stage aerosolization process offering multiple avenues for future enhancements.


aerosol delivery to children aerosolization with low air volumes dry powder inhalers pharmaceutical aerosols quantitative analysis and design spray-dried powders 



Dr. Michael Hindle is gratefully acknowledged for reviewing the manuscript and making helpful suggestions.

Funding Information

Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number R01HD087339 and by the National Heart, Lung and Blood Institute of the National Institutes of Health under Award Number R01HL139673. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Compliance with Ethical Standards

Conflict of Interest

Virginia Commonwealth University is currently pursuing patent protection of devices and methods described in this study, which if licensed and commercialized, may provide a future financial interest to the authors.

Supplementary material

12248_2018_281_Fig9_ESM.png (4.3 mb)
Figure S1

Contours of turbulent kinetic energy (k) on two axial planes for designs (a) Case 1, (b) Case 2, (c) Case 3, (d) Case 4, and (e) Case 5. Different patterns and magnitudes are observed with Case 2 experiencing the highest levels of overall k and Cases 1, 4 and 5 having lowest k in the region of the initial powder bed. (PNG 4436 kb)

12248_2018_281_MOESM1_ESM.tif (279 kb)
High resolution image (TIF 278 kb)
12248_2018_281_Fig10_ESM.png (3.7 mb)
Figure S2

Contours of specific dissipation rate (ω) on two axial planes for designs (a) Case 1, (b) Case 2, (c) Case 3, (d) Case 4, and (e) Case 5. Profiles appear similar among the designs with values increasing significantly at the wall, where differences among the geometries are expected to be greater. (PNG 3819 kb)

12248_2018_281_MOESM2_ESM.tif (232 kb)
High resolution image (TIF 232 kb)
12248_2018_281_MOESM3_ESM.jpg (350 kb)
Figure S3 Contours of total wall shear stress (WSS) on surfaces of the DAC unit inner walls for designs (a) Case 1, (b) Case 2, (c) Case 3, (d) Case 4, and (e) Case 5. Values differ among cases and are highly non-uniform for each case. (JPG 350 kb)


  1. 1.
    De Boer A, Hagedoorn P, Hoppentocht M, Buttini F, Grasmeijer F, Frijlink H. Dry powder inhalation: past, present and future. Expert Opin Drug Deliv. 2017;14(4):499–512.CrossRefGoogle Scholar
  2. 2.
    Newman S. Respiratory drug delivery: essential theory and practice. Richmond: RDD Online; 2009.Google Scholar
  3. 3.
    Islam N, Cleary MJ. Developing an efficient and reliable dry powder inhaler for pulmonary drug delivery—a review for multidisciplinary researchers. Med Eng Phys. 2012;34:409–27.CrossRefGoogle Scholar
  4. 4.
    Farkas D, Hindle M, Longest PW. Development of an inline dry powder inhaler that requires low air volume. J Aerosol Med Pulm Drug Deliv. 2018;31(4):255–65.CrossRefGoogle Scholar
  5. 5.
    Farkas D, Hindle M, Longest PW. Application of an inline dry powder inhaler to deliver high dose pharmaceutical aerosols during low flow nasal cannula therapy. Int J Pharm. 2018;546:1–9. Scholar
  6. 6.
    Ferziger JH, Peric M. Computational methods for fluid dynamics. Berlin: Springer; 1999.CrossRefGoogle Scholar
  7. 7.
    Longest PW, Holbrook LT. In silico models of aerosol delivery to the respiratory tract—development and applications. Adv Drug Deliv Rev. 2012;64:296–311.CrossRefGoogle Scholar
  8. 8.
    Shur J, Lee SL, Adams W, Lionberger R, Tibbatts J, Price R. Effect of device design on the in vitro performance and comparability for capsule-based dry powder inhalers. AAPS J. 2012;14(4):667–76.CrossRefGoogle Scholar
  9. 9.
    Wong W, Fletcher DF, Traini D, Chan HK, Young PM. The use of computational approaches in inhaler development. Adv Drug Deliv Rev. 2012;64(4):312–22.CrossRefGoogle Scholar
  10. 10.
    Ariane M, Sommerfeld M, Alexiadis A. Wall collision and drug-carrier detachment in dry powder inhalers: using DEM to devise a sub-scale model for CFD calculations. Powder Technol. 2018;334:65–75.CrossRefGoogle Scholar
  11. 11.
    Cui Y, Sommerfeld M. Forces on micron-sized particles randomly distributed on the surface of larger particles and possibility of detachment. Int J Multiphase Flow. 2015;72:39–52.CrossRefGoogle Scholar
  12. 12.
    Cui Y, Sommerfeld M. Application of lattice-Boltzmann method for analysing detachment of micron-sized particles from carrier particles in turbulent flows. Flow, Turbul. Combust. 2018;100(1):271–97.Google Scholar
  13. 13.
    Sommerfeld M, Schmalfuß S. Numerical analysis of carrier particle motion in a dry powder inhaler. J Fluids Eng. 2016;138(4):041308.CrossRefGoogle Scholar
  14. 14.
    Longest PW, Son Y-J, Holbrook LT, Hindle M. Aerodynamic factors responsible for the deaggregation of carrier-free drug powders to form micrometer and submicrometer aerosols. Pharm Res. 2013;30:1608–27.CrossRefGoogle Scholar
  15. 15.
    Coates MS, Chan H-K, 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.CrossRefGoogle Scholar
  16. 16.
    Coates MS, Chan H-K, 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.CrossRefGoogle Scholar
  17. 17.
    Coates MS, Fletcher DF, Chan H-K, 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.CrossRefGoogle Scholar
  18. 18.
    Wong W, Fletcher DF, Traini D, Chan HK, Crapper J, Young PM. Particle aerosolisation and break-up in dry powder inhalers: evaluation and modelling of impaction effects for agglomerated systems. J Pharm Sci. 2011;100(7):2744–54.CrossRefGoogle Scholar
  19. 19.
    Voss AP, Finlay WH. Deagglomeration of dry powder pharmaceutical aerosols. Int J Pharm. 2002;248:39–40.CrossRefGoogle Scholar
  20. 20.
    Xu Z, Mansour HM, Mulder T, McLean R, Langridge J, Hickey AJ. Dry powder aerosols generated by standardized entrainment tubes from drug blends with lactose monohydrate: 1. Albuterol sulfate and disodium cromoglycate. J Pharm Sci. 2010;99(8):3398–414.CrossRefGoogle Scholar
  21. 21.
    Xu Z, Mansour HM, Mulder T, McLean R, Langridge J, Hickey AJ. Dry powder aerosols generated by standardized entrainment tubes from drug blends with lactose monohydrate: 2. Ipratropium bromide monohydrate and fluticasone propionate. J Pharm Sci. 2010;99(8):3415–29.CrossRefGoogle Scholar
  22. 22.
    Coates MS, Fletcher DF, Chan H-K, Raper JA. The role of capusle on the performance of a dry powder inhaler using computational and experimental analyses. Pharm Res. 2005;22(6):923–32.CrossRefGoogle Scholar
  23. 23.
    Coates MS, Chan H-K, Fletcher DF, Chiou H. Influence of mouthpiece geometry on the aerosol delivery performance of a dry powder inhalation. Pharm Res. 2007;24(8):1450–6.CrossRefGoogle Scholar
  24. 24.
    Louey MD, VanOort M, Hickey AJ. Standardized entrainment tubes for the evaluation of pharmaceutical dry powder dispersion. J Aerosol Sci. 2006;37:1520–33.CrossRefGoogle Scholar
  25. 25.
    Son Y-J, Longest PW, Hindle M. Aerosolization characteristics of dry powder inhaler formulations for the excipient enhanced growth (EEG) application: effect of spray drying process conditions on aerosol performance. Int J Pharm. 2013;443:137–45.CrossRefGoogle Scholar
  26. 26.
    Son Y-J, Longest PW, Tian G, Hindle M. Evaluation and modification of commercial dry powder inhalers for the aerosolization of submicrometer excipient enhanced growth (EEG) formulation. Eur J Pharm Sci. 2013;49:390–9.CrossRefGoogle Scholar
  27. 27.
    Behara SRB, Longest PW, Farkas DR, Hindle M. Development of high efficiency ventilation bag actuated dry powder inhalers. Int J Pharm. 2014;465:52–62.CrossRefGoogle Scholar
  28. 28.
    Bass K, Longest PW. Recommendations for simulating microparticle deposition at conditions similar to the upper airways with two-equation turbulence models. J Aerosol Sci. 2018;119:31–50. Scholar
  29. 29.
    Longest PW, Vinchurkar S. Validating CFD predictions of respiratory aerosol deposition: effects of upstream transition and turbulence. J Biomech. 2007;40(2):305–16.CrossRefGoogle Scholar
  30. 30.
    Wilcox DC. Turbulence modeling for CFD. 2nd ed. California: DCW Industries, Inc.; 1998.Google Scholar
  31. 31.
    Longest PW, Hindle M, Das Choudhuri S, Byron PR. Numerical simulations of capillary aerosol generation: CFD model development and comparisons with experimental data. Aerosol Sci Technol. 2007;41(10):952–73.CrossRefGoogle Scholar
  32. 32.
    Longest PW, Vinchurkar S, Martonen TB. Transport and deposition of respiratory aerosols in models of childhood asthma. J Aerosol Sci. 2006;37:1234–57.CrossRefGoogle Scholar
  33. 33.
    Longest PW, Hindle M, Das Choudhuri S, Xi J. Comparison of ambient and spray aerosol deposition in a standard induction port and more realistic mouth-throat geometry. J Aerosol Sci. 2008;39(7):572–91.CrossRefGoogle Scholar
  34. 34.
    Longest PW, Xi J. Effectiveness of direct Lagrangian tracking models for simulating nanoparticle deposition in the upper airways. Aerosol Sci Technol. 2007;41(4):380–97.CrossRefGoogle Scholar
  35. 35.
    Gosman AD, Ioannides E. Aspects of computer simulation of liquid-fueled combustors. J Energ. 1981;7:482–90.CrossRefGoogle Scholar
  36. 36.
    Longest PW, Tian G, Delvadia R, Hindle M. Development of a stochastic individual path (SIP) model for predicting the deposition of pharmaceutical aerosols: effects of turbulence, polydisperse aerosol size, and evaluation of multiple lung lobes. Aerosol Sci Technol. 2012;46(12):1271–85.CrossRefGoogle Scholar
  37. 37.
    Matida EA, Finlay WH, Grgic LB. Improved numerical simulation of aerosol deposition in an idealized mouth-throat. J Aerosol Sci. 2004;35:1–19.CrossRefGoogle Scholar
  38. 38.
    Vinchurkar S, Longest PW. Evaluation of hexahedral, prismatic and hybrid mesh styles for simulating respiratory aerosol dynamics. Comput Fluids. 2008;37(3):317–31.CrossRefGoogle Scholar
  39. 39.
    Longest PW, Vinchurkar S. Effects of mesh style and grid convergence on particle deposition in bifurcating airway models with comparisons to experimental data. Med Eng Phys. 2007;29(3):350–66.CrossRefGoogle Scholar
  40. 40.
    Longest PW, Kleinstreuer C, Buchanan JR. Efficient computation of micro-particle dynamics including wall effects. Comput Fluids. 2004;33(4):577–601.CrossRefGoogle Scholar
  41. 41.
    Delvadia R, Hindle M, Longest PW, Byron PR. In vitro tests for aerosol deposition II: IVIVCs for different dry powder inhalers in normal adults. J Aerosol Med Pulm Drug Deliv. 2013;26(3):138–44.CrossRefGoogle Scholar
  42. 42.
    Delvadia R, Longest PW, Byron PR. In vitro tests for aerosol deposition. I. Scaling a physical model of the upper airways to predict drug deposition variation in normal humans. J Aerosol Med. 2012;25(1):32–40.CrossRefGoogle Scholar
  43. 43.
    Longest PW, Tian G, Walenga RL, Hindle M. Comparing MDI and DPI aerosol deposition using in vitro experiments and a new stochastic individual path (SIP) model of the conducting airways. Pharm Res. 2012;29:1670–88.CrossRefGoogle Scholar
  44. 44.
    Wei X, Hindle M, Kaviratna A, Huynh BK, Delvadia RR, Sandell D, et al. In vitro tests for aerosol deposition. VI: realistic testing with different mouth-throat models and in vitro–in vivo correlations for a dry powder inhaler, metered dose inhaler, and soft mist inhaler. J Aerosol Med Pulm Drug Deliv. 2018.
  45. 45.
    Dhand R. Inhalation therapy in invasive and noninvasive mechanical ventilation. Curr Opin Crit Care. 2007;13(1):27–38.CrossRefGoogle Scholar
  46. 46.
    Ari A, Fink JB. Inhalation therapy in patients receiving mechanical ventilation: an update. J Aerosol Med Pulm Drug Deliv. 2012;25(6):319–32.CrossRefGoogle Scholar
  47. 47.
    Laube BL, Sharpless G, Shermer C, Sullivan V, Powell K. Deposition of dry powder generated by solovent in Sophia anatomical infant nose-throat (SAINT) model. Aerosol Sci Technol. 2012;46:514–20.CrossRefGoogle Scholar
  48. 48.
    Hoppentocht M, Hoste C, Hagedoorn P, Frijlink HW, De Boer AH. In vitro evaluation of the DP-4M PennCentury insufflator. Eur J Pharm Biopharm. 2014;88(1):153–9.CrossRefGoogle Scholar
  49. 49.
    Duret C, Wauthoz N, Merlos R, Goole J, Maris C, Roland I, et al. In vitro and in vivo evaluation of a dry powder endotracheal insufflator device for use in dose-dependent preclinical studies in mice. Eur J Pharm Biopharm. 2012;81(3):627–34.CrossRefGoogle Scholar
  50. 50.
    Morello M, Krone CL, Dickerson S, Howerth E, Germishuizen WA, Wong Y-L, et al. Dry-powder pulmonary insufflation in the mouse for application to vaccine or drug studies. Tuberculosis. 2009;89(5):371–7.CrossRefGoogle Scholar
  51. 51.
    Farkas D, Hindle M, Longest PW. Application of an inline dry powder inhaler to deliver nhigh dose pharmaceutical aerosols during low flow nasal cannula therapy. Int J Pharm. 2018;546(1–2):1–9.CrossRefGoogle Scholar
  52. 52.
    Farkas D, Hindle M, Longest PW. Efficient nose-to-lung aerosol delivery with an inline DPI requiring low actuation air volume. Pharm Res. 2018;35(10):194.CrossRefGoogle Scholar
  53. 53.
    Walenga RL, Longest PW, Kaviratna A, Hindle M. Aerosol drug delivery during noninvasive positive pressure ventilation: effects of intersubject variability and excipient enhanced growth. J Aerosol Med Pulm Drug Deliv. 2017;30(3):190–205.CrossRefGoogle Scholar
  54. 54.
    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
  55. 55.
    Chan H-K. Dry powder aerosol delivery systems: current and future research directions. J Aerosol Med. 2006;19(1):21–7.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  1. 1.Department of Mechanical and Nuclear EngineeringVirginia Commonwealth UniversityRichmondUSA
  2. 2.Department of PharmaceuticsVirginia Commonwealth UniversityRichmondUSA

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