To Issue 159


Citation: Myatt B, Duke D, “Optimising low-GWP pMDI Sprays for Enhanced Performance and Sustainability”. ONdrugDelivery, Issue 159 (Apr/May 2024), pp 40–42.

Benjamin Myatt and Daniel Duke explore the low-global-warming-potential propellants available and their implications for the performance of pressurised metered dose inhalers.

In response to changing legislative requirements due to environmental concerns, pharmaceutical companies are exploring switching to more environmentally friendly pressurised metered dose inhaler (pMDI) propellants. Now, the search is on to understand how these new, low-global-warming-potential (GWP) propellants affect the performance of pMDIs.

Low-GWP candidate propellants have different physicochemical and thermodynamic properties from current hydrofluorocarbon (HFC) gases, which means a change in propellant may necessitate adjustments to formulation and/or hardware.


The industry made a significant shift in propellant gas use with the signing of the Montreal Protocol on Substances That Deplete the Ozone Layer in 1987.1 That agreement led to a transition from ozone-depleting chlorofluorocarbons (CFCs) to HFC-based propellants.

The current drive towards low-GWP propellants is motivated by the Kigali Amendment to the Montreal Protocol, which aims to phase down the use of HFCs with high GWPs.1 Current pMDI propellants, HFA-134a and HFA-227, have relatively high GWP values.2 The industry is exploring alternative propellants, such as HFA-152a and/or HFO-1234ze(E), which have significantly lower GWP values and will significantly reduce the carbon footprint of pMDIs These propellants have 90% and 99.9% lower GWP than HFA-134a, the greenest pMDI propellant currently used.3

“Understanding the properties of low-GWP propellants is essential for preserving performance.”


Propellant properties affect all fundamental aspects of pMDIs. The differences in thermodynamic, physical and chemical properties can all impact pMDI functionality. For example, the lower density of certain low-GWP propellants could affect the physical suspension stability of a pMDI. Similarly, the higher surface tension values of HFA-152a and HFO-1234ze(E) could impact the initial droplet size formed upon atomisation and, subsequently, the final residual droplet size that reaches the lungs. The differences in properties indicate low-GWP propellants may have a less aggressive atomisation process.

Understanding the properties of low-GWP propellants is essential for preserving performance (Figure 1). Kindeva Drug Delivery, in partnership with Monash University, the Woolcock Institute of Medical Research and Macquarie University, are benchmarking low-GWP propellant products against current systems. To do this, the team of research partners uses a range of novel measurement methodologies alongside compendial techniques to better understand the pMDI performance of various gases.

Figure 1: Evaluating low-GWP propellants.


Kindeva is seeking to understand the physics behind pMDI atomisation better,  and how these processes change with the switch to low-GWP propellants. This research is focused on the following:

  • Benchmarking to understand the differences in product performance when switching propellants
  • Investigating mitigation strategies to optimise performance using current hardware and formulation toolbox parameters
  • Exploring new opportunities to improve pMDI performance through novel hardware developments.

“Vapour pressure, density, surface tension, specific heat capacity and latent heat of vapourisation of low-GWP propellants may all impact pMDI performance.”

Analysing the performance of pMDIs is complex due to the transient nature of the atomisation process, both inside the device and in the spray itself. The propellant liquid rapidly depressurises when a pMDI is actuated, which leads to chaotic atomisation. Vapour pressure, density, surface tension, specific heat capacity and latent heat of vapourisation of low-GWP propellants may all impact pMDI performance.

Kindeva has partnered with the team at Monash University, who have developed an ultra-high-speed imaging facility that goes beyond the resolution and capabilities of any spray pattern and plume geometry system currently available. This facility collects extremely large volumes of data from various test formulations comprising each propellant, which are then mined to extract the differences between propellants.

The facility uses a custom 100-nanosecond pulsed LED light source – a pulse of light that travels through the sprayed droplets and particles. The spray is imaged by a high-speed camera that runs at over 100,000 images per second. This device allows the dynamics of the spray to be captured, both inside the actuator and outside the device. By analysing the stability and repeatability of the spray plumes, Kindeva will gain insight into how changing the propellant alters the plume characteristics, which can then guide hardware and formulation adjustments that will optimise low-GWP pMDI performance.

Aerodynamic particle size distribution (APSD) is considered a critical quality attribute for orally inhaled and nasal drug products. When the APSD was examined with different ethanol concentrations, variations in droplet size and plume structure were found, both of which may impact drug efficacy.

A potential approach to modulate performance is to adjust the ethanol cosolvent concentration in the formulation. Additionally, the vapour pressure of mixtures of low-GWP propellant formulations with ethanol is less sensitive to the addition of ethanol than HFA-134a-ethanol binary mixtures. This suggests that, within the bounds of formulation and solubility constraints, adjusting the ethanol concentration may be one avenue to optimise pMDI performance.

Kindeva has also been experimenting with differences in pMDI hardware. Adjusting the orifice length of the pMDI alters the condition of the fluid as it exits the orifice and changes the atomisation and spray break-up process. Computer simulations have shown that, by increasing the nozzle length, the spray width can be narrowed, providing another variable for optimising pMDI performance.


Kindeva’s researchers are continuously working to develop new strategies for optimising spray formation with low-GWP propellants. Recent advances in this area include computational fluid dynamics to simulate the flow of propellant and medication through the MDI valve and actuator. This information can be used to optimise the design of the actuator to improve spray formation.


The transition to low-GWP propellants in pMDIs represents a significant step towards more sustainable medical products. However, before these greener propellants are fully implemented, it is important to understand and adjust for the impact on product functionality.

Kindeva is leading the charge in this transition. It has installed pilot-scale manufacturing lines as well as two new commercial manufacturing lines capable of filling inhalers with HFA-152a and/or HFO-1234ze(E) propellants. The expansion ties in with one of Kindeva’s near-term goals: to have one of the first commercial green propellant lines by 2025.


  1. “The Montreal Protocol on Substances That Deplete the Ozone Layer”. Web Page, U.S. Department of State, accessed Mar 2024.
  2. “Climate Change 2007: Synthesis Report. Contribution of Working Groups I, II and II to the Fourth Assessment Report of the Intergovernmental Panel on Climate Change”. IPCC, 2007.
  3. Pritchard JN, “The Climate is Changing for Metered-Dose Inhalers and Action is Needed”. Drug Des Devel and Ther, 2020, Vol 14, pp 3043–3055.