1.The core function of the propellant 

Before selecting the propellant , its core role needs to be clarified:

• provide spray power: generate pressure through its own vapor pressure to promote the contents of the spray;  regulate droplet characteristics: affect the particle size, distribution and morphology of the sprayed material (e.g., mist, foam);
• maintain the stability of the system: with the drug, excipients to form a homogeneous or stabilized dispersed system, to prevent stratification or precipitation.

2.Principles of selecting propellant

The following key factors should be considered when selecting propellant :

(1) Vapor pressure: determines the spraying ability and stability 

The vapor pressure of ejection agent is the core parameter, which needs to be matched with the demand for the use of aerosol:

lToo high vapor pressure: it may lead to too fast jetting speed, too fine droplets (e.g. inhalation aerosol may not be able to be deposited in the lungs because of small particle size), and even the container rupture due to excessive pressure;

lToo low vapor pressure: insufficient power of jetting, much residue of the content, and may not be able to be properly sprayed at low temperatures.

 Note: In practice, the total vapor pressure is often adjusted by mixing propellant with different vapor pressures (e.g. HFA-134a and HFA-227ea) to adapt to different scenarios (e.g. inhalants need medium vapor pressure to ensure that the droplet size is in the range of 1-5 μm, which is conducive to the lungs' deposition).

(2)  Safety: non-toxic, non-irritant, low risk

l Acute toxicity: Especially for inhalation aerosol, the propellant needs to be non-respiratory toxicity (e.g. HFA-134a is non-irritant to respiratory mucous membranes and is suitable for inhalation);

l Flammability and explosiveness: Hydrocarbons (e.g. propane, butane) are flammable, so they need to be avoided to be used in the vicinity of fire or confined space; while HFCs (e.g. HFA-134a) are non-flammable and non-explosive HFCs (e.g. HFA-134a) are non-flammable and non-explosive and are safer;

Local irritation: topical aerosol propellant  need to be non-irritating to the skin and mucous membranes (e.g., avoid high concentrations of hydrocarbons to prevent drying of the skin or allergies).

(3)  Compatibility: no interaction with drugs and excipients

The propellant needs to be compatible with drugs, solvents, preservatives and other excipients to avoid chemical reactions (e.g., oxidation, hydrolysis) or physical incompatibility (e.g., delamination, precipitation, container corrosion):

l For example, some fat-soluble drugs may be miscible with HFCs (e.g., HFA-134a) to form a homogeneous solution, while water-soluble drugs may require the addition of co-solvents, such as ethanol, to enhance compatibility with the dispersant.

l The propellant should be non-corrosive to the container material (e.g., aluminum cans, plastic valves) or leakage or contamination of the contents may result.

(4)  Environmental protection: Compliance with regulations and sustainable requirements

l Chlorofluorocarbons (CFCs, e.g. Freon) have been completely banned by the Montreal Protocol due to ozone layer depletion, and their use is only limited in a few exempted scenarios (e.g. some inhalation first aid medicines);

l Hydrofluorocarbons (HFCs, e.g. HFA-134a, HFA-227ea) are not ozone depleting, but some of them are greenhouse gases, and need to comply with national environmental regulations (e.g. EU F-gas regulations on emission limitations); hydrocarbons (e.g. propane) or compressed gases (e.g. CO HFCs (e.g. HFA-134a, HFA-227ea) do not damage the ozone layer, but some HFCs are greenhouse gases and need to comply with national environmental regulations (e.g., the EU F-gas regulation limits emissions);

l Hydrocarbons (e.g., propane) or compressed gases (e.g., CO₂), although environmentally friendly, are used in a narrow range of scenarios due to their properties (e.g., flammability, unstable vapor pressure). 

(5)  Droplet characteristics: matching the needs of the drug delivery site

The volatility and density of the propellant will affect the droplet size and distribution of the ejected material, which needs to be matched with the drug delivery site:

l Inhalation aerosol: droplet size 1-5μm is needed to be deposited in the alveoli of the lungs; too high volatility of the projectile will lead to too fine droplets (<1μm), which will be easily expelled with the exhaled breath;

l Topical aerosol (e.g., dermal administration): droplets need to be a little larger (10-50μm), to avoid drifting and to improve the local adherence rate;

l Cavity administration (e.g., vaginal, rectal): it may need to be sprayed with a foamy shape, and projectile needs to be coordinated with surfactants to form a stable foam. to form a stable foam.

(6)  Dosage Accuracy: Ensuring Consistency of Drug Delivery

The pressure stability of the propellant directly affects the uniformity of the drug dosage for each injection. For example, the vapor pressure of compressed gases (e.g., nitrogen) varies significantly with temperature (a sudden increase in pressure at elevated temperatures), which can lead to fluctuations in dosage; whereas the vapor pressure of HFCs varies more gently with temperature, making them more suitable for aerosols requiring precise dosage (e.g., inhalers for asthma treatment).

3.Common types of propellant and application scenarios

4.Selection points for special scenarios 

l Inhalation aerosol: prefer HFA-134a or HFA-227ea, need to meet the non-toxic, no respiratory tract irritation, droplet size of 1-5μm, and good compatibility with drugs (e.g., salbutamol);

l Topical aerosol: hydrocarbons (low-cost) or HFCs (high safety), need to avoid skin irritation, and need to avoid skin irritation, and need to have uniform droplets and strong adhesion in the case of sunscreen spray.

l Foam aerosol: need to use propellant with surfactant, e.g. HFA-134a mixed with sodium lauryl sulfate to form stable foam (e.g. gynecological antimicrobial foam).