title: Dynamics of aerosol size during inhalation: hygroscopic growth of commercial nebulizer formulations.
abstract: The size of aerosol particles prior to, and during, inhalation influences the site of deposition within the lung. As such, a detailed understanding of the hygroscopic growth of an aerosol during inhalation is necessary to accurately model the deposited dose. In the first part of this study, it is demonstrated that the aerosol produced by a nebulizer, depending on the airflows rates, may experience a (predictable) wide range of relative humidity prior to inhalation and undergo dramatic changes in both size and solute concentration. A series of sensitive single aerosol analysis techniques are then used to make measurements of the relative humidity dependent thermodynamic equilibrium properties of aerosol generated from four common nebulizer formulations. Measurements are also reported of the kinetics of mass transport during the evaporation or condensation of water from the aerosol. Combined, these measurements allow accurate prediction of the temporal response of the aerosol size prior to and during inhalation. Specifically, we compare aerosol composed of pure saline (150 mM sodium chloride solution in ultrapure water) with two commercially available nebulizer products containing relatively low compound doses: Breath®, consisting of a simple salbutamol sulfate solution (5 mg/2.5 mL; 1.7 mM) in saline, and Flixotide® Nebules, consisting of a more complex stabilized fluticasone propionate suspension (0.25 mg/mL; 0.5 mM in saline. A mimic of the commercial product Tobi© (60 mg/mL tobramycin and 2.25 mg/mL NaCl, pH 5.5-6.5) is also studied, which was prepared in house. In all cases, the presence of the pharmaceutical was shown to have a profound effect on the magnitude, and in some cases the rate, of the mass flux of water to and from the aerosol as compared to saline. These findings provide physical chemical evidence supporting observations from human inhalation studies, and suggest that using the growth dynamics of a pure saline aerosol in a lung inhalation model to represent nebulizer formulations may not be representative of the actual behavior of the aerosolized drug solutions.
authors.affiliation: School of Chemistry, University of Bristol, Bristol BS8 1TS, UK. Electronic address: a.haddrell@bristol.ac.uk.
authors.forename: Allen E
authors.initials: AE
authors.lastname: Haddrell
authors.affiliation: School of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
authors.forename: James F
authors.initials: JF
authors.lastname: Davies
authors.affiliation: School of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
authors.forename: Rachael E H
authors.initials: RE
authors.lastname: Miles
authors.affiliation: School of Chemistry, University of Bristol, Bristol BS8 1TS, UK.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Reid
authors.affiliation: Institute of Pharmaceutical Science, King's College London, London SE1 9NH, UK.
authors.forename: Lea Ann
authors.initials: LA
authors.lastname: Dailey
authors.affiliation: University of Hertfordshire, Research Centre in Topical Drug Delivery and Toxicology, Department of Pharmacy, Hatfield AL10 9AB, UK.
authors.forename: Darragh
authors.initials: D
authors.lastname: Murnane
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000420:Albuterol / Q000737:chemistry; D000730:Androstadienes / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D000068298:Fluticasone; D006813:Humidity; D008962:Models, Theoretical; D009330:Nebulizers and Vaporizers; D010316:Particle Size; D012965:Sodium Chloride / Q000737:chemistry; D014031:Tobramycin / Q000737:chemistry; D017155:Wettability
chemical_list: D000336:Aerosols; D000730:Androstadienes; D012965:Sodium Chloride; D000068298:Fluticasone; D000420:Albuterol; D014031:Tobramycin
keywords: Commercial formulations; Hygroscopic growth; Inhalation; Mass flux; Nebulizer