In vitro evaluation of solution-based pressurised metered dose inhaler sprays with low GWP propellants

BACKGROUND: The impending transition from high Global Warming Potential (GWP) propellants such as HFA134a to low-GWP alternatives such as HFA152a and HFO1234ze(E) in pressurised metered dose inhalers (pMDIs) poses a number of challenges. Changes in chemicophysical properties will alter spray performance; this study investigates those differences using matched hardware and formulations. METHODS AND MATERIALS: Aerodynamic particle size distribution (APSD) measurements, laser diffraction and high-speed imaging experiments were used to compare the performance of HFA134a, HFA152a and HFO1234ze(E) solution formulations of becamethasone dipropionate (BDP). Propellant-only placebos, cosolvent-free solutions (0.05 mg/mL), 8\% and 15\% w/w ethanol solution formulations (2.0 mg/mL) were investigated. RESULTS: HFA152a formulations were found to have increased actuator and throat deposition while HFO1234ze(E) showed comparable APSD performance to HFA134a. Droplet and particle size increased for both low-GWP propellants. High-speed imaging revealed that HFA152a formulations spread more rapidly and were less stable and repeatable than HFA134a. HFO1234ze(E) formulations were found to spread more slowly than HFA134a, but converged with HFA134a ex-mouthpiece. Propellant effects were moderated by the addition of ethanol. CONCLUSIONS: Stability changes were found to be dominant in the near-orifice region, depending on formulation properties and ex-orifice flashing behaviour. Shot-to-shot repeatability effects were more pronounced in the ex-mouthpiece region where mixing with the ambient air is dominant. As such, modifications to orifice and mouthpiece geometry may provide a route to improved in vitro bioequivalence for low-GWP PMDIs.
Comment: 23 pages single-spaced, 10 figures