Drug-surfactant-propellant interactions in HFA-formulations

The required replacement of chlorofluorocarbon (CFC) with hydrofluoroalkane (HFA) propellants has challenged formulators of pressurized metered dose inhalers in several major respects. Conventional (CFC soluble) surfactants are effectively insoluble in the major CFC replacement candidates, HFA 134 and HFA 227ea, in the absence of co-solvents. While these ethane and propane derivatives have comparable boiling points and vapor pressures to dichlorodifluoromethane (CFC 12), their increased polarity demands that formulators use either alternative (soluble) surfactants, or co-solvents along with traditional surfactants, in order to stabilize pressurized suspension products. The use of either approach is complicated by the existence of many competing patents and the fact that the science in the area is empirical; predictive theoretical approaches are frustrated by the lack of an adequate database. Technical developments in this area must also take into account the need to avoid crystal growth and/or adhesion of micronized, suspended drugs to internal container surfaces, problems which may be catalyzed by some combinations of surfactant type/concentration, vehicle(s) and physical form/type(s) of drug substance. For some drugs, it appears simpler to use co-solvents with HFA propellants to dissolve the drug, avoiding the need for suspension stabilization. This article presents an overview of the present state of the art with respect to the formulation of MDIs.