Understanding HFO-1234ze and HFA-152a: A Formulator's Comparison Guide

Release 23rd February 2026

The Urgency of Propellant Transition

The 2025 HFC phasedown regulations have created an immediate challenge for pharmaceutical formulators developing pressurised metered dose inhalers (pMDIs). As traditional HFA-134a faces restricted availability, development teams must evaluate low-global warming potential (GWP) alternatives, but the two leading candidates, HFO-1234ze and HFA-152a, present fundamentally different formulation profiles. This isn’t a simple substitution exercise. Each propellant demands distinct approaches to API solubility, excipient compatibility, and device integration. With regulatory deadlines approaching and reformulation timelines extending 18-24 months, the propellant selection you make today will determine whether your product reaches patients on schedule. This guide compares the practical formulation considerations that matter most to development teams navigating this transition.

What Is HFO-1234ze?

HFO-1234ze (trans-1,3,3,3-tetrafluoropropene) represents the hydrofluoroolefin class of propellants specifically developed as an environmentally sustainable alternative to traditional HFCs. With a GWP of less than 1, comparable to carbon dioxide, HFO-1234ze addresses climate concerns whilst maintaining pharmaceutical-grade purity standards required for inhalation products.

Physical and Chemical Properties

HFO-1234ze exhibits a vapour pressure of approximately 4.7 bar at 20°C, notably lower than HFA-134a’s 5.7 bar. This difference affects valve design, actuator force requirements, and ultimately the aerosol plume characteristics your patients will experience. The propellant’s density (1.16 g/mL at 25°C) influences suspension formulation behaviour and particle settling rates during storage.

From a formulation perspective, HFO-1234ze’s polarity differs significantly from HFA-134a, which directly impacts API solubility. According to studies published in the International Journal of Pharmaceutics, HFO-1234ze generally demonstrates lower solvating capacity for many common respiratory APIs compared to HFA-134a, though this varies considerably by molecular structure (Stein et al., 2020). For suspension formulations, this reduced solubility can actually prove advantageous by minimising valve deposition and maintaining dose consistency as HFO-1234ze can help minimise particle growth, particularly in suspension-based aerosol formulations.

Because its lower solvating power reduces API dissolution in the propellant, there is less risk of dissolved drug recrystallising over time, a common cause of Ostwald ripening. This helps maintain a stable particle size distribution, which directly supports dose uniformity, consistent aerosol performance, and predictable lung deposition.

That said, particle growth is still influenced by other formulation factors (surfactants, moisture content, micronisation quality, storage conditions), so the propellant alone doesn’t fully control it.

 

Regulatory Status and Safety Profile

HFO-1234ze carries an A2L flammability classification under ASHRAE Standard 34, indicating low toxicity and low flammability under standard conditions. This classification requires specific handling protocols during manufacturing but remains acceptable for pharmaceutical applications. Regulatory agencies such as the FDA and EMA have acknowledged the industry transition toward low-global-warming-potential propellants in pressurised metered-dose inhalers and have initiated scientific guidance discussions and regulatory engagement pathways. However, HFO-1234ze-based inhalers are largely still in development, and widespread marketing authorisations remain limited, with most currently approved pMDIs continuing to use established HFA propellants. The propellant’s environmental credentials extend beyond GWP. Its atmospheric lifetime of approximately 16 days means minimal long-term accumulation, addressing both climate and ozone depletion concerns that drove the original CFC phaseout.

Formulation Advantages

For development teams, HFO-1234ze offers several practical benefits:

• Reduced valve deposition – it is attributed to lower API solubility in many cases. The physicochemical properties of propellants significantly influence API solubility, suspension stability, and interactions with valve and canister surfaces, all of which impact deposition behaviour. 
• Improved dose consistency in suspension formulations– Its density and solvency characteristics support better suspension stability, limiting particle agglomeration and sedimentation over time. This helps maintain a uniform delivered dose throughout the product’s shelf life and repeated actuation cycles.
• Compatibility with existing valve technologies- HFO-1234ze can be used with standard metering valve platforms when elastomer and gasket materials are appropriately selected and validated. Proper material compatibility testing ensures minimal swelling, extractables risk, and sustained valve functionality.
• Very low environmental impact (GWP <1)- HFO-1234ze has an ultra-low global warming potential compared with traditional pharmaceutical propellants, aligning with evolving environmental regulations. This supports long-term regulatory acceptability while maintaining aerosol performance.
• Established regulatory pathway: HFO-1234ze has already been evaluated by regulatory agencies for pharmaceutical aerosol use, providing a growing body of toxicological, environmental, and formulation-safety data. This prior regulatory experience helps streamline risk assessment, stability requirements, and approval discussions, reducing uncertainty compared with entirely novel propellant systems.

However, these advantages come with formulation complexity that requires specialized expertise to navigate effectively.

What Is HFA-152a?

HFA-152a (1,1-difluoroethane) has been investigated as a pharmaceutical propellant for over two decades, though commercial adoption has remained limited compared to HFA-134a. With a GWP of 138, significantly lower than HFA-134a’s 1,430 but higher than HFO-1234ze, it represents a pragmatic environmental improvement whilst offering distinct formulation characteristics.

Physical and Chemical Properties

HFA-152a demonstrates a vapour pressure of approximately 5.0 bar at 20°C, positioning it between HFO-1234ze and HFA-134a. This intermediate vapour pressure can facilitate device transition strategies, potentially allowing reformulation with minimal valve and actuator modifications. The propellant’s density (0.90 g/mL at 25°C) differs notably from those of HFA-134a and HFO-1234ze, affecting suspension stability and formulation density-matching requirements.

Conference proceedings from the Respiratory Drug Delivery series have noted that the solvating behaviour of HFA-152a is generally closer to that of HFA-134a than to that of HFO-1234ze, which can facilitate reformulation of APIs with established solubility profiles. These reports indicate that several small-molecule bronchodilators show comparable solubility in HFA-152a and HFA-134a; however, API–excipient compatibility and solubility must still be confirmed experimentally for each formulation (Smyth et al., 2019)

Regulatory Status and Safety Profile

HFA-152a is classified as an A2 flammable propellant, indicating greater flammability compared with the mildly flammable A2L classification of HFO-1234ze. While this necessitates implementing appropriate safety controls for manufacturing, storage, and handling, regulatory agencies routinely assess such propellants within established pharmaceutical risk management frameworks.

Clinical development programs, including GSK’s next-generation Ventolin inhaler, have demonstrated therapeutic equivalence and comparable safety to existing HFA-134a-based inhalers, with regulatory submissions underway. Current evidence suggests that HFA-152a can be safely used in pressurized metered dose inhalers when supported by appropriate toxicological, clinical, and manufacturing safety data.

Consequently, adoption is now driven more by environmental and formulation considerations than by flammability alone, with regulatory approvals proceeding on a case-by-case basis as supporting data emerge.

Formulation Advantages

For specific development contexts, HFA-152a presents compelling attributes:

• Similar solvating properties to HFA-134a for many APIs
• Potential for simplified reformulation from existing HFC-134a products
• Intermediate vapour pressure facilitating device design continuity
• Lower cost compared to HFO-1234ze in current market conditions
• Established analytical methods adapted from HFC-134a programmes-The analytical framework already exists. 

Formulation teams must weigh these practical advantages against flammability management requirements and potential regulatory complexity.

Head-to-Head Comparison

The following table compares critical parameters that influence formulation development decisions:

These technical differences fundamentally shape development strategy, timeline, and risk profile. Our experience across multiple low-GWP formulation programmes demonstrates that propellant selection should occur during feasibility assessment, not after API synthesis or device selection. The downstream implications of choosing the wrong propellant can add 12-18 months to development timelines.

For teams evaluating these options, i2c’s formulation development services offer early-stage compatibility screening to identify potential formulation challenges before significant resources are committed.

Formulation Challenges in Practice

Challenges with HFO-1234ze

The primary formulation challenge with HFO-1234ze in solution systems stems from its solvent properties, which can limit API solubility relative to traditional HFA propellants. While reduced solubility can favour suspension stability, solution MDI development often requires careful co-solvent optimization and device compatibility assessment to ensure formulation stability, dose consistency, and aerosol performance. Our formulation work has identified several practical strategies:

• Co-solvent screening to enhance API solubility whilst maintaining pharmaceutical acceptability
• Excipient selection optimized for HFO-1234ze’s polarity profile
• Particle engineering to achieve optimal aerodynamic properties in suspension formulations
• Valve material compatibility testing to prevent extractables/leachables issues

The lower vapour pressure requires attention to spray pattern characteristics and plume geometry. In our experience, formulation teams often need to modify the critical actuator dimensions to achieve dosing performance equivalent to that of HFA-134a products. This isn’t necessarily disadvantageous—it provides an opportunity to optimize patient experience, but it does require appropriate expertise and timeline planning.

Analytical testing is especially important when working with HFO-1234ze formulations because this propellant behaves differently from HFA-134a. Since it evaporates at a different rate and has a different density, standard testing methods, especially cascade impaction, used to measure aerosol particle size, often need adjustments to ensure accurate results.

Challenges with HFA-152a

The flammability profile represents HFA-152a’s most significant practical challenge. Manufacturing facilities require enhanced safety systems, including explosion-proof equipment, appropriate ventilation, and rigorous process hazard analysis. These requirements increase capital investment and operational complexity compared to non-flammable propellants.

Material compatibility testing must account for HFA-152a’s specific chemical properties. Whilst similarities to HfcA-134a exist, assuming complete equivalence can lead to unexpected stability issues or extractables concerns. Comprehensive compatibility programmes should evaluate:

• Elastomer swelling and mechanical property changes
• Valve component extractables under accelerated conditions
• Container material interactions during long-term storage
• Leak rate testing under ICH stability conditions
• Moisture ingress assessment over the intended shelf life

Regulatory submissions require detailed flammability risk assessments that address manufacturing, transportation, storage, and patient-use scenarios. This documentation burden can extend regulatory timelines compared to HFO-1234ze submissions, though precedents are being established.

For programmes prioritizing speed to clinic, our Fast2Clinic service enables rapid formulation iteration whilst maintaining appropriate safety protocols for both propellant options.

Decision Framework: Choosing Your Propellant

The optimal propellant selection depends on project-specific factors that extend beyond simple property comparisons. Consider the following decision criteria:

Choose HFO-1234ze When:

• Environmental sustainability is a regulatory or marketing priority – The near-zero GWP provides maximum future regulatory security
• Your API demonstrates adequate solubility, or when suspension formulation is appropriate for physicochemical characteristics
• You’re developing a novel device platform – The opportunity exists to optimize valve and actuator design specifically for HFO-1234ze properties
• Long-term market presence is planned – HFO-1234ze’s environmental profile best positions products for evolving regulations
• Your organization can invest in formulation optimization – The potential development complexity is acceptable, given the sustainability goals

Choose HFA-152a When:

• The reformulation timeline is critical – HFA-152a exhibits physicochemical properties, including vapour pressure and solubility, that are closer to HFA-134a than those of many next-generation propellants. This similarity can reduce formulation redevelopment complexity, enabling faster optimization of suspension stability, valve performance, and dose uniformity.
• Your facility has existing flammability management capabilities; HFA-152a is classified as a flammable propellant, requiring explosion-proof equipment, ventilation controls, and validated safety protocols for manufacturing and filling operations. Facilities already equipped with these controls can incorporate HFA-152a with lower incremental capital expenditure and reduced operational disruption.
• Device transfer is a priority – Its intermediate vapour pressure profile allows HFA-152a to deliver aerosol performance characteristics comparable to legacy propellants, often permitting reuse or minor modification of existing metering valves and actuator designs. This can minimize engineering redesign cycles and reduce regulatory bridging requirements for device equivalence.
• You can address valve compatibility challenges – Compatibility between HFA-152a and elastomeric valve components must be carefully evaluated due to potential swelling, extractables, or permeability differences. Access to advanced elastomer formulations and robust extractables/leachables testing infrastructure helps mitigate risks to long-term stability and container-closure integrity.
• Cost sensitivity is significant – Current commercial supply dynamics generally position HFA-152a at a lower cost relative to newer ultra-low-GWP propellants. This can improve overall product cost efficiency, although long-term pricing may evolve with regulatory shifts and market demand.
• Regulatory pathway uncertainty is acceptable – While regulators do not prohibit HFA-152a, its flammability classification can lead to additional scrutiny regarding safety, risk assessment, and manufacturing controls. Organizations with regulatory expertise and flexibility in development timelines are better positioned to manage potential extended review cycles.

When Either Option Requires Expert Evaluation:

Many formulation programmes don’t clearly favour one propellant based on these general criteria. In such cases, parallel feasibility studies provide the most reliable basis for decision-making. Early-stage solubility screening, preliminary stability assessment, and device compatibility evaluation with both propellants can be completed within 8-12 weeks, providing empirical data to inform strategic decisions.

i2C’s patented Respitab® technology specifically addresses formulation challenges with both HFO-1234ze and HFA-152a, providing a proven platform for sustainable pMDI development regardless of propellant selection.

Conclusion

The transition from HFA-134a to low-GWP propellants represents more than regulatory compliance—it’s an opportunity to optimize formulation performance whilst addressing environmental concerns. HFO-1234ze and HFA-152a each offer distinct advantages, but neither provides a universal solution. Your optimal choice depends on API properties, device requirements, regulatory strategy, and development timeline constraints.

The formulation complexity inherent in these propellant transitions shouldn’t be underestimated. What appears as a straightforward substitution often reveals unexpected solubility, stability, or device compatibility challenges that can derail development programmes. Early engagement with formulation specialists who have practical experience with both propellants provides the technical foundation for confident decision-making.

At i2c, we’ve supported pharmaceutical companies through MDI development for over three decades. Our integrated capabilities—from formulation development through gamma scintigraphy validation—enable comprehensive development programmes under one roof.

Ready to evaluate HFO-1234ze or HFA-152a for your specific formulation? Contact our formulation team for a technical consultation on your API and device requirements, or download our comprehensive whitepaper on low-GWP propellant formulation strategies.

 

Frequently Asked Questions

Can I simply replace HFA-134a with HFO-1234ze or HFA-152a without reformulation?

No. Whilst some formulation components may transfer directly, differences in physical properties—particularly vapour pressure, density, and solvating characteristics—typically require formulation optimization and device adjustments. Treating low-GWP propellants as drop-in replacements risks stability failures or suboptimal device performance.

Which propellant will regulators prefer?

Regulatory authorities typically do not prescribe a specific propellant choice; approval decisions are based on demonstrated safety, efficacy, quality, and environmental impact. However, the very low global warming potential (GWP <1) of HFO-1234ze is increasingly relevant in environmental policy, sustainability reporting, and reimbursement discussions.

HFA-152a remains a viable and acceptable option from a regulatory standpoint, though its flammability classification means manufacturers must provide robust safety controls, risk assessments, and appropriate manufacturing and handling mitigation strategies as part of the approval process.

How long does propellant transition typically require?

Development timelines vary considerably with formulation complexity, but expect 18-24 months from propellant selection through clinical batch manufacturing for a well-planned programme. Parallel feasibility work and early formulation optimization can compress timelines significantly.

Are there other low-GWP propellant options beyond these two?

HFO-1234ze and HFA-152a are currently the most developed pharmaceutical propellant alternatives. Other candidates are at various stages of research, but regulatory pathways and commercial availability remain limited. For programmes requiring near-term market entry, these two options dominate practical consideration.

What compatibility testing is essential before committing to a propellant?

At minimum, conduct API solubility screening, preliminary stability assessment (accelerated conditions), valve component compatibility testing, and spray pattern characterization. Comprehensive programmes should evaluate extractables/leachables, long-term stability, and moisture sensitivity across the full container-closure system.