RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology Performance of Pressurized Metered-Dose Inhalers at Extreme Temperature Conditions CHELSEA M. D. MORIN, JAMES W. IVEY, JORDAN T. F. TITOSKY, JONATHAN D. SUDERMAN, JASON S. OLFERT, REINHARD VEHRING, WARREN H. FINLAY Department of Mechanical Engineering, University of Alberta, Edmonton, Alberta Received 16 June 2014; revised 1 August 2014; accepted 11 August 2014 Published online 22 September 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.24145 ABSTRACT: The performance of pressurized metered-dose inhalers (pMDIs) under a variety of temperature conditions was investigated. The effects of both inhaler temperature and ambient temperature were considered. The inhaler temperature ranged from −13.0 ◦ C to 41.7 ◦ C and the ambient temperature ranged from −12.0 ◦ C to 41.7 ◦ C. The in vitro lung dose was measured for four widely available pMDIs: Airomir TM , QVAR TM , Symbicort R  , and Ventolin R  . The in vitro lung dose through an Alberta Idealized Throat was measured by gravimetric assay, which was verified by UV spectroscopic assay. A decrease in the in vitro lung dose was observed for all evaluated pMDIs when ambient temperature and device temperature were simultaneously reduced, decreasing on average by 70% at the coldest temperatures, whereas increasing on average by 25% at the elevated temperature condition. In vitro lung dose is strongly dependent on both inhaler temperature and ambient temperature with the tested pMDIs. C  2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3553–3559, 2014 Keywords: temperature; pressurized metered-dose inhaler (pMDI); aerosols; microparticles; in vitro models; pulmonary drug delivery; Airomir TM ; stability; QVAR TM ; Symbicort R  ; Ventolin R  INTRODUCTION Pressurized metered-dose inhalers (pMDIs) are widely used for treating and controlling asthma and chronic obstructive pulmonary disease. 1 pMDIs are typically formulated as either solutions or suspensions. Solution pMDIs consist of a drug in a solubilized state and may contain dissolved excipients and co- solvents. Suspension pMDIs consist of a drug in a solid phase, suspended in a propellant. Surfactants may be added to re- duce particle aggregation but are typically insoluble in the pure propellant, necessitating the addition of a cosolvent, such as ethanol. 1 It is well known that propellant droplet formation is influ- enced by device parameters including actuator orifice diameter and valve size, as well as drug formulation parameters such as composition, concentration, propellant type, cosolvent, and vapor pressure inside the canister. 2,3 Increases in orifice diam- eter lead to higher plume momentum, 3 which in turn leads to increased oropharyngeal deposition. 4 Propellant choice and co- solvent content determine the vapor pressure within the canis- ter at any given temperature, and an increase in vapor pressure increases evaporation rate after atomization. 5 Increasing vapor pressure also produces a finer atomized droplet distribution. 3 Overall, increased vapor pressure leads to a decrease in ex- trathoracic deposition and an increase in lung deposition. 6 In vitro tests of pMDI delivery efficiency, such as cascade im- paction, have thoroughly explored the effects of manipulating the aforementioned device parameters. Such tests are typically Abbreviations used: pMDI, pressurized metered-dose inhaler; MMAD, mass median aerodynamic diameter; RH, relative humidity. Correspondence to: Warren H. Finlay (Telephone: +780-492-4707; Fax: +780- 492-2200; E-mail: warren.finlay@ualberta.ca) Journal of Pharmaceutical Sciences, Vol. 103, 3553–3559 (2014) C  2014 Wiley Periodicals, Inc. and the American Pharmacists Association performed under controlled laboratory conditions, but there are a number of environmental factors, which also influence deliv- ery efficiency, including temperature and humidity. 7–11 In order to obtain results under realistic use conditions, external fac- tors influencing droplet formation and delivery must also be considered. The effect of reduced temperature on pMDI performance has previously been studied, but in a limited manner. In an early study of pMDIs with chlorofluorocarbon propellant, Wilson et al. 7 showed that as the device temperature decreases, the vapor pressure inside the canister also decreases, leading to a larger initial mass median diameter when actuated in am- bient conditions. They also found the actuated dose increased at lower temperatures and proposed increased propellant den- sity at lower temperatures as a potential explanation. Stein and Cocks 8 showed that the mass median aerodynamic diame- ter (MMAD) of commercially available solution and suspension pMDIs, including QVAR TM and Ventolin R  , increased with de- creased device temperature. They concluded that the MMAD of solution pMDIs increased as a result of an increase in the atomized droplet size, and the MMAD of suspension pMDIs in- creased as a result of a larger number of propellant droplets containing multiple particles of the dispersed phase (so-called multiplets). Because the frequency of multiplets is related to the propellant droplet size distribution, 12 Stein and Cocks 8 es- sentially showed that cold inhalers produce coarser droplet size distributions compared with warmer inhalers. The effects of increasing inhaler temperature have also been investigated, albeit in a limited way. 9–11,13 Shemirani et al. 9 tested pMDIs equilibrated to ambient conditions and observed an increase in lung dose fraction for a BDP HFC 134a formu- lation with an increase in ambient temperature. Hoye 11 also tested pMDIs at increased temperatures, but it is not clear whether they were tested at elevated ambient temperature or Morin et al., JOURNAL OF PHARMACEUTICAL SCIENCES 103:3553–3559, 2014 3553