Abstract
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.
Similar content being viewed by others
References
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.
Newman S. Respiratory drug delivery: essential theory and practice. Richmond: RDD Online; 2009.
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.
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.
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. https://doi.org/10.1016/j.ijpharm.2018.05.011.
Ferziger JH, Peric M. Computational methods for fluid dynamics. Berlin: Springer; 1999.
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.
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.
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.
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.
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.
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.
Sommerfeld M, Schmalfuß S. Numerical analysis of carrier particle motion in a dry powder inhaler. J Fluids Eng. 2016;138(4):041308.
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.
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.
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.
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.
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.
Voss AP, Finlay WH. Deagglomeration of dry powder pharmaceutical aerosols. Int J Pharm. 2002;248:39–40.
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.
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.
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.
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.
Louey MD, VanOort M, Hickey AJ. Standardized entrainment tubes for the evaluation of pharmaceutical dry powder dispersion. J Aerosol Sci. 2006;37:1520–33.
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.
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.
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.
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. https://doi.org/10.1016/j.jaerosci.2018.02.007.
Longest PW, Vinchurkar S. Validating CFD predictions of respiratory aerosol deposition: effects of upstream transition and turbulence. J Biomech. 2007;40(2):305–16.
Wilcox DC. Turbulence modeling for CFD. 2nd ed. California: DCW Industries, Inc.; 1998.
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.
Longest PW, Vinchurkar S, Martonen TB. Transport and deposition of respiratory aerosols in models of childhood asthma. J Aerosol Sci. 2006;37:1234–57.
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.
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.
Gosman AD, Ioannides E. Aspects of computer simulation of liquid-fueled combustors. J Energ. 1981;7:482–90.
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.
Matida EA, Finlay WH, Grgic LB. Improved numerical simulation of aerosol deposition in an idealized mouth-throat. J Aerosol Sci. 2004;35:1–19.
Vinchurkar S, Longest PW. Evaluation of hexahedral, prismatic and hybrid mesh styles for simulating respiratory aerosol dynamics. Comput Fluids. 2008;37(3):317–31.
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.
Longest PW, Kleinstreuer C, Buchanan JR. Efficient computation of micro-particle dynamics including wall effects. Comput Fluids. 2004;33(4):577–601.
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.
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.
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.
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. https://doi.org/10.1089/jamp.2018.1454.
Dhand R. Inhalation therapy in invasive and noninvasive mechanical ventilation. Curr Opin Crit Care. 2007;13(1):27–38.
Ari A, Fink JB. Inhalation therapy in patients receiving mechanical ventilation: an update. J Aerosol Med Pulm Drug Deliv. 2012;25(6):319–32.
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.
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.
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.
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.
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.
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.
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.
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.
Chan H-K. Dry powder aerosol delivery systems: current and future research directions. J Aerosol Med. 2006;19(1):21–7.
Acknowledgements
Dr. Michael Hindle is gratefully acknowledged for reviewing the manuscript and making helpful suggestions.
Funding
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic Supplementary Material
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)
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)
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)
Rights and permissions
About this article
Cite this article
Longest, W., Farkas, D. Development of a New Inhaler for High-Efficiency Dispersion of Spray-Dried Powders Using Computational Fluid Dynamics (CFD) Modeling. AAPS J 21, 25 (2019). https://doi.org/10.1208/s12248-018-0281-y
Received:
Accepted:
Published:
DOI: https://doi.org/10.1208/s12248-018-0281-y