Regional deposition of inhaled medicines in the respiratory tract is heavily influenced by inertial impaction. Despite this, the current convention is to convert impaction parameter cutoffs on stages in impactors to size cutoffs by operating the impactor at a fixed flow rate. While such a practice has utility when using impactors as a quality control tool, a focus on size metrics (e.g., mass median aerodynamic diameter [MMAD] and fine particle fraction [FPF<5µm]) may lead to misconceptions in the interpretation of impactor data. In contrast, using metrics based on impaction parameter cutoffs (MMIP and FPFS3-F) enables a more accurate prediction of trends in in vivo deposition with variations in device resistance, flow rate, airway size, and other dependent variables. Using impaction parameter cutoffs also eliminates the need to run the impactor at a fixed flow rate, thereby allowing realistic inspiratory flow profiles to be utilized. This, combined with the use of more realistic anatomical throats and impaction parameter metrics, enables improved in vitro–in vivo correlations to guide early formulation and device development in the spirit of Quality by Design principles.
DarquenneC, CorcoranTE, LavoriniF, et al.The effects of airway disease on the deposition of inhaled drugs. Expert Opin Drug Deliv, 2024; 21(8):1175–1190; doi: 10.1080/17425247.2024.2392790
MartinAR, FinlayWH. A general, algebraic equation for predicting total respiratory tract deposition of micrometer-sized aerosol particles in humans. J Aerosol Sci, 2007; 38(2):246–253; doi: 10.1016/jjaerosci.2006.11.002
4.
WeersJ. Regional deposition of particles within the respiratory tract should be linked to impaction parameter, not aerodynamic size. J Aerosol Med Pulm Drug Deliv, 2018; 31(2):116–118; doi: 10.1089/jamp.2018.1452
5.
RuzyckiCA, TaverniniS, MartinAR, et al.Characterization of dry powder inhaler performance through experimental methods. Adv Drug Deliv Rev, 2022; 189:114518; doi: 10.1016/j.addr.2022.114518
6.
EinsteinA. On the movement of small particles suspended in stationary liquids required by the molecular kinetic theory of heat. Annalen Der Physik, 1905; 322(8):549–560.
7.
LaubeBL, JanssensHM, de JonghFH, et al.; International Society for Aerosols in Medicine. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J, 2011; 37(6):1308–1331; doi: 10.1183/09031936.00166410
8.
ClarkAR, HollingworthAM. The relationship between powder inhaler resistance and peak inspiratory conditions in healthy volunteers—Implications for in vitro testing. J Aerosol Med, 1993; 6(2):99–110; doi: 10.1089/jam.1993.6.99
9.
PedersenS, HansenOR, FuglsangG. Influence of inspiratory flow rate upon the effect of a Turbuhaler. Arch Dis Child, 1990; 65(3):308–310; doi: 10.1136/adc.65.3.308
10.
NewmanSP, MorénF, TrofastE, et al.Terbutaline sulphate Turbuhaler: Effect of inhaled flow rate on drug deposition and efficacy. Int J Pharm, 1991; 74(2–3):209–213; doi: 10.1016/0378-5173(91)90239-K
11.
NewmanSP, HollingworthA, ClarkAR. Effect of different modes of inhalation on drug delivery from a dry powder inhaler. Int J Pharm, 1994; 102(1–3):127–132; doi: 10.1016/0378-5173(94)90047-7
12.
BorgströmL, BondessonE, MorénF, et al.Lung deposition of budesonide inhaled via Turbuhaler®: A comparison with terbutaline sulphate in normal subjects. Eur Respir J, 1994; 7(1):69–73; doi: 10.1183/09031936.94.07010069
13.
DolovichMB, VanzieleghamM, HidingerK-G, et al.Influence of inspiratory flow rate on the response to terbutaline sulphate inhaled via the Turbuhaler. Am Rev Respir Dis, 1988; 137:A433.
14.
WeersJ, ClarkA. The impact of inspiratory flow rate on drug delivery to the lungs with dry powder inhalers. Pharm Res, 2017; 34(3):507–528; doi: 10.1007/s11095-016-2050-x
15.
ClarkAR. The role of inspiratory pressures in determining the flow rate through dry powder inhalers; a review. Curr Pharm Des, 2015; 21(27):3974–3983; doi: 10.2174/1381612821666150820105800
16.
ClarkAR, WeersJG, DhandR. The confusing world of dry powder inhalers: It is all about inspiratory pressures, not inspiratory flow rates. J Aerosol Med Pulm Drug Deliv, 2020; 33(1):1–11; doi: 10.1089/jamp.2019.1556
17.
WeersJG. Suboptimal inspiratory flow rates with passive dry powder inhalers: Big issue or overstated problem? Front Drug Deliv, 2022; 2:855234; doi: 10.3390/fddev.2022.855234
18.
BroedersMEAC, MolemaJ, HopWCJ, et al.The course of inhalation profiles during an exacerbation of obstructive lung disease. Respir Med, 2004; 98(12):1173–1179; doi: 10.1016/j.rmed.2004.04.010
19.
VartiainenVA, TikkakoskiA, MalmbergP, et al.Inspiratory flow profiles through Easyhaler during acute bronchoconstriction. J Aerosol Med Pulm Drug Deliv, 2025; 38(2):83–89; doi: 10.1089/jamp.2024/0045
20.
StapletonKW, GuentschE, HoskinsonMK, et al.On the suitability of the turbulence model for aerosol deposition in the mouth and throat: A comparison with experiments. J Aerosol Sci, 2000; 31(6):739–749; doi: 10.1016/S0021-8502(99)00547-9
21.
GrgicB, FinlayW, HeenanA. Regional aerosol deposition and flow measurements in an idealized mouth and throat. J Aerosol Sci, 2004; 35(1):21–32; doi: 10.1016/S0021-8502(03)00387-2
22.
StevensonC, BennettD. Development of Exubera insulin pulmonary delivery system Chapter 21. In: (das NevesJ, and SarmentoB., eds). Mucosal Delivery of Biopharmaceuticals. Springer: New York (NY); 2014. pp. 461–481.
23.
LiCalsiC, ChristensenT, BennettJV, et al.Dry powder inhalation as a potential delivery method for vaccines. Vaccine, 1999; 17(13–14):1796–1803; doi: 10.1016/S0264-410X(98)00438-1
24.
CicilianiA-M, DennyM, LangguthP, et al.Lung deposition using the Respimat® Soft Mist™ Inhaler mono and fixed-dose combination therapies. J COPD, 2021; 18(1):91–100; doi: 10.1080/15412555.2020.1853091
25.
PitcairnG, LunghettiG, VenturaP, et al.A comparison of the lung deposition of salbutamol inhaled from a new dry powder inhaler, at two inhaled flow rates. Int J Pharm, 1994; 102(1–3):11–18; doi: 10.1016/0378-5173(94)90034-5
26.
PitcairnGR, LankinenT, SeppäläO-P, et al.Pulmonary drug delivery from the Taifun® dry powder inhaler is relatively independent of the patient’s inspiratory effort. J Aerosol Med, 2000; 13(2):97–104; doi: 10.1089/089426800418622
27.
NewmanS, MalikS, HirstP, et al.Lung deposition of salbutamol in healthy human subjects from the MAGhaler® dry powder inhaler. Respir Med, 2002; 96(12):1026–1032; doi: 10.1053/rmed.2002.1387
28.
NewmanSP, SuttonDJ, SegarraR, et al.Lung deposition of aclidinium bromide from Genuair®, a multidose dry powder inhaler. Respiration, 2009; 78(3):322–328; doi: 10.1159/000219676
29.
WeersJG, ClarkAR, RaoN, et al.In vitro–in vivo correlations observed with indacaterol-based formulations delivered with the Breezhaler®. J Aerosol Med Pulm Drug Deliv, 2015; 28(4):268–280; doi: 10.1089/jamp.2014.1178
30.
UngKT, RaoN, WeersJG, et al.In vitro assessment of dose delivery performance of dry powders for inhalation. Aerosol Sci Technol, 2014; 48(10):1099–1110; doi: 10.1080/02786826.2014.962685
31.
UngKT, RaoN, WeersJG, et al.Design of spray-dried insulin microparticles to bypass deposition in the extrathoracic region and maximize total lung dose. Int J Pharm, 2016; 511(2):1070–1079; doi: 10.1016/j.ijpharm.2016.07.073
32.
NewmanSP, HirstPH, PitcairnGR. Scintigraphic evaluation of lung deposition with a novel inhaler device. Curr Opin Pulm Med, 2001; 7(Suppl 1):S12–S14.
33.
PitcairnGR, LimJ, HollingworthA, et al.Scintigraphic assessment of drug delivery from the Ultrahaler dry powder inhaler. J Aerosol Med, 1997; 10(4):295–306; doi: 10.1089/jam.1997.10.295
34.
PitcairnG, ReaderS, PaviaD, et al.Deposition of corticosteroid aerosol in the human lung by Respimat soft mist inhaler compared to deposition by metered dose inhaler or by Turbuhaler dry powder inhaler. J Aerosol Med, 2005; 18(3):264–272; doi: 10.1089/jam.2005.18.264
35.
YangMY, VerschuerJ, ShiY, et al.The effect of device resistance and inhalation flow rate on the lung deposition of orally inhaled mannitol dry powder. Int J Pharm, 2016; 513(1–2):294–301; doi: 10.1016/j.ijpjarm.2016.09.047
36.
SonY-J, MillerDP, WeersJG. Optimizing spray-dried powders for high dose delivery with a portable dry powder inhaler. Pharmaceutics, 2021; 13(9):1528; doi: 10.3390/pharmaceutics13091528
37.
DudduSP, SiskSA, WalterYH, et al.Improved lung delivery from a passive dry powder inhaler using an engineered PulmoSphere powder. Pharm Res, 2002; 19(5):689–695; doi: 10.1023/a:1015322616613
38.
DeLongM, WrightJ, DawsonM, et al.Dose delivery characteristics of the AIR® pulmonary delivery system over a range of inspiratory flow rates. J Aerosol Med, 2005; 18(4):452–459; doi: 10.1089/jam.2005.18.452
39.
HaynesA, GellerD, WeersJ, et al.Inhalation of tobramycin using simulated cystic fibrosis patient profiles. Pediatr Pulmonol, 2016; 51(11):1159–1167; doi: 10.1002/ppul.23451
40.
StassH, NagelschmitzJ, KappelerD, et al.Ciprofloxacin dry powder for inhalation in patients with non-cystic fibrosis bronchiectasis or chronic obstructive pulmonary disease, and in healthy volunteers. J Aerosol Med Pulm Drug Deliv, 2017; 30(1):53–63; doi: 10.1089/jamp.2018.1464
41.
WeersJG, MillerDP, TararaTE. Spray-dried PulmoSphere formulations for inhalation comprising crystalline drug particles. AAPS PharmSciTech, 2019; 20(3):103; doi: 10.1208/s12249-018-1280-0
42.
TararaTE, LyonsSW, MillerDP, et al.Minimization of flow rate dependence of dry powder inhalers (DPIs) by tuning device resistance. Inhalation Magazine, 2024.
43.
WeersJG, SonY-J, GluskerM, et al.Idealhalers versus realhalers: Is it possible to bypass deposition in the upper respiratory tract? J Aerosol Med Pulm Drug Deliv, 2019; 32(2):55–69; doi: 10.1089/jamp.2018.1497
44.
MillerDP, TararaTE, WeersJG. Targeting of inhaled therapeutics to the small airways: Nanoleucine carrier formulations. Pharmaceutics, 2021; 13(11):1855; doi: 10.3390/pharmaceutics13111855
45.
McEvoyC, ArgulaR, SahayS, et al.Tyvaso DPI: Drug device characteristics and patient clinical consideration. Pulm Pharmacol Ther, 2023; 83:102266; doi: 10.1016/j.pupt.2023.102266
46.
CapstickTGD, GudimetlaS, HarrisDS, et al.Demystifying dry powder inhaler resistance with relevance to optimal patient care. Clin Drug Investig, 2024; 44(2):109–114; doi: 10.1007/s40261-023-01330-2
47.
VartiainenVA, LavoriniF, MurphyAC, et al.High inhaler resistance does not limit successful inspiratory maneuver among patients with asthma or COPD. Expert Opin Drug Deliv, 2023; 20(3):385–393; doi: 10.1080/1742547.2023.2179984
48.
NewmanSP. Fine particle fraction: The good and the bad. J Aerosol Med Pulm Drug Deliv, 2022; 35(1):2–10; doi: 10.1089/jamp.2021.29056.spn
49.
WeersJG. Design of dry powder inhalers to improve patient outcomes: It’s not just about the device. Expert Opin Drug Deliv, 2024; 21(3):365–380; doi: 10.1080/17425247.2024.2343894
50.
DalbyR, ByronP. In vitro Assessment of Inhaled Products. Respiratory Drug Delivery: Essential Theory & Practice. RDD Online: Richmond, Virginia, USA; 2009. pp. 59–96.
OlssonB, BorgströmL, LundbäckH, et al.Validation of a general in vitro approach for prediction of total lung deposition in healthy adults for pharmaceutical inhalation products. J Aerosol Med Pulm Drug Deliv, 2013; 26(6):355–369.
53.
DelvadiaRR, LongestPW, ByronPR. 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 Pulm Drug Deliv, 2012; 25(1):32–40; doi: 10.1089/jamp.2011.0905
54.
WeiX, HindleM, KaviratnaA, et al.In vitro tests for aerosol deposition. VI: Realistic testing of 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; 31(6):358–371; doi: 10.1089/jamp.2018.1454
55.
UsmaniOS, BiddiscombeMF, BarnesPJ. Regional lung deposition and bronchodilator response as a function of beta2-agonist particle size. Am J Respir Crit Care Med, 2005; 172(12):1497–1504; doi: 10.1164/rccm.200410-1414OC
56.
WeersJG, UngK, LeJ, et al.Dose emission characteristics of placebo PulmoSphere® particles are unaffected by a subject’s inhalation maneuver. J Aerosol Med Pulm Drug Deliv, 2013; 26(1):56–68; doi: 10.1089/jamp.2012.0973
57.
WeersJG, TararaTE, ClarkAR. Design of fine particles for pulmonary drug delivery. Expert Opin Drug Deliv, 2007; 4(3):297–313; doi: 10.1517/17425247.4.3.297
58.
TaiW, YauGTY, ArnoldJC, et al.High-loading cannabidiol powders for inhalation. Int J Pharm, 2024; 660:124370; doi: 10.1016/ijpharm.2024.124370
59.
HoppentochtM, HagedoornP, FrijlinkHW, et al.Technological and practical challenges of dry powder inhalers and formulations. Adv Drug Deliv Rev, 2014; 75:18–31; doi: 10.1016/j.addr.2014.04.004
60.
HaughneyJ, LeeAJ, McKnightE, et al.Peak inspiratory flow measured at different inhaler resistances in patients with asthma. J Allergy Clin Immunol Pract, 2021; 9(2):890–896; doi: 10.1016/j.jaip.2020.09.026
61.
UsmaniOS. Treating the small airways. Respiration, 2012; 84(6):441–453; doi: 10.1159/000343629
62.
LeachCL, DavidsonPJ, BoudreauRJ. Improved airway targeting with the CFC-free HFA-beclomethasone metered dose inhaler compared with CFC-beclomethasone. Eur Respir J, 1998; 12(6):1346–1353; doi: 10.1183/09031936.98.12061346
63.
SonnappaS, McQueenB, PostmaDS, et al.Extrafine versus fine inhaled corticosteroids in relation to asthma control: A systematic review and meta-analysis of observational real-life studies. J Allergy Clin Immunol Pract, 2018; 6(3):907–915.e7; doi: 10.1016/j.jaip.2017.07.032
64.
ScichiloneN, SpataforaM, BattagliaS, et al.Lung penetration and patient adherence considerations in the management of asthma: Role of extra-fine formulations. J Asthma Allergy, 2013; 6:11–21; doi: 10.2147/JAA.S14743
65.
MolimardM, RaherisonC, LignotS, et al.Assessment of handling of inhaler devices in real life: An observational study in 3811 patients in primary care. J Aerosol Med, 2003; 16(3):249–254; doi: 10.1089/08942680376901761342
66.
PriceDB, Román-RodríguezM, McQueenRB, et al.Inhaler errors in the CRITIKAL study: Type, frequency, and associated with asthma outcomes. J Allergy Clin Immunol Pract, 2017; 5(4):1071–1081.e9; doi: 10.1016/j.jaip.201701.00443
67.
LavoriniF, JansonC, BraidoF, et al.What to consider before prescribing inhaled medications: A pragmatic approach for evaluating the current inhaler landscape. Ther Adv Respir Dis, 2019; 13:1753466619884532–1753466619884528; doi: 10.1177/1753466619884532
68.
LeachCL, KuehlPJ, ChandR, et al.Respiratory tract deposition of HFA-beclomethasone and HFA-fluticasone in asthmatic patients. J Aerosol Med Pulm Drug Deliv., 2016; 29(2):127–133; doi: 10.1089/jamp.2014.1199
69.
ClarkAR, EganM. Modelling the deposition of inhaled powdered drug aerosols. J Aerosol Sci, 1994; 25(1):175–186; doi: 10.1016/0021-8502(94)90189-9
70.
GolshahiL, FinlayWH. An idealized child throat that mimics average pediatric oropharyngeal deposition. Aerosol Sci Technol, 2012; 46(5):i–iv; doi: 10.1080/02786826.2012.667170
71.
TaverniniS, ChurchTK, LewisDA, et al.Deposition of micrometer-sized particles in neonatal nasal airway replicas. Aerosol Sci Tech, 2018; 52(4):407–419; doi: 10.1080/02786826.2017.1413489
72.
ClarkAR, McKennaC, MacLoughlinR. Aerosol delivery in term and preterm infants: The final frontier. Proc Respir Drug Deliv, 2018; 1:159–168.
73.
ClarkAR. Essentials for aerosol delivery to term and pre-term infants. Ann Transl Med, 2021; 9(7):594; doi: 10.21037/atm-20-7265
74.
ClarkAR. Half a century of technological advances in pulmonary drug delivery. Front Drug Deliv, 2022; 2:871147; doi: 10.3389/fddev.2022.871147
75.
ClarkAR, ChambersCB, MuirD, et al.The effect of biphasic inhalation profiles on the deposition of coarse (6.5 µm) bolus aerosols. J Aerosol Med, 2007; 20(1):75–82; doi: 10.1089/jam.2006.0557
76.
DolovichMB, MitchellJP, RobertsDL. Re: “Harmonizing the nomenclature for therapeutic aerosol particle size: a proposal” by Hillyear et al. J Aerosol Med Pulm Drug Deliv, 2018; 31(4):266–268; doi: 10.1089/jamp.2018.1479
77.
Metered dose inhaler (MDI) and dry powder inhaler (DPI) products—Quality considerations—FDA Draft Guidance for Industry, 2018.
78.
KonstanMW, FlumePA, KapplerM, et al.Safety, efficacy, and convenience of tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial. J Cyst Fibros., 2011; 10(1):54–61; doi: 10.1016/j.jcf.2010.10.003
79.
GalevaI, KonstanMW, HigginsM, et al.Tobramycin inhalation powder manufactured by improved process in cystic fibrosis: The randomized EDIT trial. Curr Med Res Opin., 2013; 29(8):947–956; doi: 10.1185/03007995.2013.805122
80.
MillerDP, TanT, TararaTE, et al.Physical characterization of tobramycin inhalation powder: I. Rational design of a stable engineered-particle formulation for delivery to the lungs. Mol Pharm, 2015; 12(8):2582–2593; doi: 10.1021/acs.molpharmaceut.5b00147
81.
SahakijpijarnS, SmythHDC, MillerDP, et al.Post-inhalation cough with therapeutic aerosols: Formulation considerations. Adv Drug Deliv Rev, 2020; 165–166:127–141; doi: 10.1016/j.addr.2020.05.003
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