Optimizing low GWP pMDI sprays for enhanced performance & sustainability

In response to changing legislative requirements due to environmental concerns, pharmaceutical companies are exploring switching to more environmentally friendly pressurized 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 pMDI products.

Low-GWP candidate propellants have different physicochemical and thermodynamic properties than current hydrofluorocarbon (HFC) gases, which means a change in propellant may necessitate adjustments to formulation and/or hardware. Here, we take a look at the low-GWP propellants available and their implications on pMDI performance.

From Green to Greener

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. That agreement led to a transition from ozone-depleting chlorofluorocarbons (CFCs) to HFC-based propellants.

The current drive toward 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. Current pMDI propellants, HFA-134a and HFA-227, have relatively high GWP values. The industry is exploring alternative propellants like HFA-152a and/or HFO-1234ze(E), which have significantly lower GWP values and will significantly reduce the carbon footprint of pMDI products. These propellants have 90% and 99.9% lower GWP than HFA-134a, the greenest pMDI propellant currently used.

The Impact of Low-GWP Propellants on Product 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 product. Similarly, the higher surface tension values of HFA-152a and HFO-1234ze(E) could impact the initial droplet size formed upon atomization and, subsequently, the final residual droplet size that reaches the lungs. The differences in properties indicate low-GWP propellants may have a less aggressive atomization process.

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

A Collaborative Approach to Understanding Low-GWP Propellants

Kindeva is seeking to better understand the physics behind pMDI atomization 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 optimize performance using current hardware and formulation toolbox parameters
• Exploring new opportunities to improve pMDI performance through novel hardware developments

Analyzing the performance of pMDIs is complex due to the transient nature of the atomization process both inside the device and in the spray itself. The propellant liquid rapidly depressurizes when a pMDI is actuated, which leads to chaotic atomization.

Vapor pressure, density, surface tension, specific heat capacity, and latent heat of vaporization of low-GWP propellants may all impact pMDI product 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 one to capture the dynamics of the spray both inside the actuator and outside the device.

By analyzing 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 optimize low-GWP pMDI performance.

Aerodynamic particle size distribution (APSD) is considered a critical quality attribute (CQA) 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 vapor 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 optimize 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 atomization and spray breakup process. Computer simulations have shown that by increasing the nozzle length, the spray width can be narrowed, providing another variable for optimizing pMDI performance.

Recent Advances in Spray Formation Optimization

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

Building a Sustainable Future

The transition to low-GWP propellants in pMDIs represents a significant step toward more sustainable medical products. Before we fully implement these greener propellants, we must understand and adjust for the impact on product functionality.

Kindeva is leading the charge in this transition. We have installed pilot scale manufacturing lines as well as two new commercial manufacturing lines capable of filling inhalers with HFA-152a and/or HFO-1234ze propellants. The expansion ties with one of Kindeva’s near-term goals: to have one of the first commercial scale green propellant lines by 2024.

As you transition your pMDIs from green to greener, partner with a CDMO that has been a leader in this space since its inception.

Learn more about Kindeva’s ongoing work with more sustainable pulmonary & nasal drug delivery services here.

References

1 The Montreal Protocol on Substances That Deplete the Ozone Layer.” U.S. Department of State, 2024. https://www.state.gov/key-topics-office-of-environmental-quality-and-transboundary-issues/the-montreal-protocol-on-substances-that-deplete-the-ozone-layer/

2 IPCC. “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.

3 Pritchard, J.N. “The Climate is Changing for Metered-Dose Inhalers and Action is Needed.” Drug Design, Development and Therapy, 2020, 14, pp 3043-3055.