Science and Technology of Pressurized Metered-Dose Inhalers

Solvation in hydrofluoroalkanes: how can ethanol help?

“…HFA‐227 (1,1,1,2,3,3,3‐heptafluoropropane) and HFA‐134a (1,1,1,2‐tetrafluoroethane) are the two propellants currently used commercially in pMDIs [8,11] . They were selected on the basis of several criteria, including biological compatibility and inertness [12] . However, due to their unique chemistry, [10] HFAs have significantly different solvent properties compared with CFCs, [8] including larger dielectric constant and dipole moment [13] .…”

“…HFAs have a dual character, being somewhat lipophobic, and at the same time hydrophobic [11,14] . Thus, most therapeutics of interest, and excipients used in previous CFC formulations, have very low solubility in HFAs [10,12] …”

“…To overcome solubility limitations, the industry has resorted to a large extent to the use of cosolvents, especially ethanol, [12] not only as solubility enhancer for drugs in the development of solution formulations, but also as solubility enhancer for other excipients, for both solution and suspension formulations [12,15] . However, there are also many issues surrounding the use of ethanol [1,7,12,15,16] .…”

“…To overcome solubility limitations, the industry has resorted to a large extent to the use of cosolvents, especially ethanol, [12] not only as solubility enhancer for drugs in the development of solution formulations, but also as solubility enhancer for other excipients, for both solution and suspension formulations [12,15] . However, there are also many issues surrounding the use of ethanol [1,7,12,15,16] . In solution‐based formulations, ethanol may reduce the chemical stability of the system and, depending on its concentration, the presence of such a low‐volatile compound mixed with the propellant can adversely impact the aerosol characteristics of the formulation [12,13,17] .…”

“…However, there are also many issues surrounding the use of ethanol [1,7,12,15,16] . In solution‐based formulations, ethanol may reduce the chemical stability of the system and, depending on its concentration, the presence of such a low‐volatile compound mixed with the propellant can adversely impact the aerosol characteristics of the formulation [12,13,17] . In suspension‐based formulations, ethanol may also affect its physical stability and aerosol performance of the device [1,18] .…”