A new on-line reverse-phase high-performance liquid chromatography method to determine the solubility of compounds in propellant-based metered-dose inhaler (MDI) formulations was developed. The new method uses a direct injection from an MDI vial into the port of a manual injector. The MDI vials were coupled with a filtration and injection assembly to filter the excess compound, and deliver the filtrate of the MDI vials to the injector port of the manual injector. A backpressure regulator was connected to the manual injector, to maintain the propellant in the liquid state after injection from the MDI vial. Phase separation studies were conducted to investigate the miscibility of hydrofluoroalkane 134a with different mobile-phase solvent compositions. Characterization of the new direct injection method was done by evaluating sample presentation and chromatography variables to determine the robust nature of the method. Beclomethasone dipropionate in ethanol/hydrofluoroalkane 134a was used as a model system for development. A chemically diverse set of nine compounds was used to evaluate solubility measurement reproducibility. Solubilities were determined at two different temperatures (25 and 378C) and the average relative standard deviation for all of the solubility measurements was <4%.