International Journal of Pharmaceutics 405 (2011) 9–15 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm Plume temperature emitted from metered dose inhalers G. Brambilla a , T. Church b , D. Lewis b,∗ , B. Meakin b a Chiesi Farmaceutici SpA, Parma 43100, Italy b Chiesi Limited, Chippenham SN14 0AB, United Kingdom article info Article history: Received 4 August 2010 Received in revised form 18 November 2010 Accepted 24 November 2010 Available online 1 December 2010 Keywords: Aerosol Pressurised metered dose inhaler Plume temperature Hydrofluoroalkane HFAs abstract The temperature of the drug cloud emitted from a pressurised metered dose inhaler (pMDI) may result in patient discomfort and inconsistent or non-existent dose delivery to the lungs. The effects of variations in formulation (drug, propellant, co-solvent content) and device hardware (metering volume, actuator orifice diameter, add-on devices) upon the temperature of pMDI plumes, expressed as replicate mean minimum values (MMPT), collected into a pharmacopoeial dose unit sampling apparatus (DUSA), have been investigated. Ten commercially available and two development products, including chlorofluorocar- bon (CFC) suspensions and hydrofluoroalkane (HFA) solutions or suspensions, were examined together with a number of drug products in late stage development and a variety of HFA 134a placebo pMDIs. Plume temperatures were observed to be lowest in the proximity of the product’s actuator mouthpiece where rapid flashing and evaporation of the formulation’s propellant and volatile excipients cause cooling. The ability to control plume temperature by judicious choice of formulation co-solvent content, metering volume and the actuator orifice diameter is identified. An ethanol based HFA 134a formulation delivered through a fine orifice is inherently warmer than one with 100% HFA 134a vehicle delivered through a coarse actuator orifice. Of the 10 commercial products evaluated, MMPTs ranged from -54 to +4 ◦ C and followed the formulation class rank order, HFA suspensions < CFC suspensions < HFA solutions. For all systems examined it was possible to raise pMDI plume temperature to that of the ambient surroundings by use of an add-on or integrated spacer device. © 2010 Elsevier B.V. All rights reserved. 1. Introduction The temperature of the cloud emitted from a pressurised metered dose inhaler (pMDI) may result in patient discomfort (“cold Freon effect”) and consequent inconsistent or non-existent dose delivery to the lungs (Crompton, 1982). However, there is limited published information on the effects of formulation and device hardware on the temperature of clouds emitted from pMDIs. Gabrio et al. (1999) described methodology in which a PC was used to record the temperature at the centre of a “free” plume using a “quick” response (5 ms) thermocouple positioned at the centre of a 45 mm 2 target plate mounted 50 mm from the exit of a pMDI’s mouthpiece. No attempt was made to examine potential pertur- bation from thermal conduction by the target. The experimental conditions used in this study differ significantly in that the expelled cloud is constrained within a pMDI dose unit sampling apparatus (DUSA; EP/USP), thus more closely mimicking the in vivo scenario; ∗ Corresponding author at: Chiesi Limited, Units T1 & T2, Bath Road Industrial Estate, Chippenham, Wiltshire SN14 0AB, United Kingdom. Tel.: +44 01249 466931; fax: +44 01249 653036; mobile: +44 07957 954379. E-mail address: DLewis@chiesi.uk.com (D. Lewis). also the thermocouple sensing tips were at least 10 mm away from the walls of the DUSA. The plume temperatures of the commercial products previously evaluated by Gabrio et al. (1999) were re-assessed to compare results for the two techniques. Using our technique, the effects of ethanol, widely used as cosolvent, in the formulation vehicle and pMDI hardware variables upon the temperature of plumes emit- ted from HFA 134a solution based pMDIs were then studied using model placebo pMDI systems together with an extended range of commercial suspension and solution products. The effects of add- on “spacer” and “holding chamber” devices on cloud temperature were also determined. 2. Experimental 2.1. Measurement of plume temperature Plumes were collected into a pMDI DUSA constructed from polyethylene terephthalate (PET) in compliance with EP/USP dimensional specifications, operated at a flow rate of 28.3 l min -1 . Temperature profiles were recorded by thermocouples (Omega, UK, K-Type, response time 3 ms) mounted 20 mm from the inlet of the apparatus with their exposed 0.25 mm stainless steel tips 0378-5173/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.ijpharm.2010.11.037