Formulation and Evaluation of Albuterol Metered Dose Inhalers Containing Tetrafluoroethane (P134a), a Non-CFC Propellant

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Abstract
This study was undertaken to evaluate tetrafluoroethane (P134a) as a possible chlorofluorocarbon (CFC) replacement for albuterol metered dose inhaler (MDI) formulations. Preformulation studies using three conventional (oleic acid, sorbitan trioleate, lecithin) and a nonconventional (oleyl alcohol) surfactant indicated that P134a is a poor solvent for these surfactants. A slight improvement in the solubility of oleic acid and oleyl alcohol was observed by the addition of low concentrations of a nonconventional cosolvent diethyl ether (< or = 0.5% w/w). Formulation screening of the prepared albuterol formulations indicated that suspensions containing oleyl alcohol and diethyl ether had a slower rate of separation. Product performance of four albuterol formulations containing oleyl alcohol, diethyl ether, and P134a was evaluated and compared to a leading commercial formulation containing CFC propellants (Ventolin). Ventolin showed excellent agreement between the emitted dose and the expected dose but only a reasonable agreement was observed with one of the better P134a-containing formulations. P134a formulations showed higher internal pressure in comparison to the CFC formulation. The concentrations of the surfactant, drug, and cosolvent appeared to have a significant impact on the uniformity of the emitted dose. Determination of particle size using the time-of-flight and the laser diffraction analyzer revealed that P134a formulations had equal or smaller particle size than the formulation containing CFC. However, the CFC formulation showed a higher respirable fraction than the P134a formulation when measured by the two inertial impaction methods. The observed particle size distribution of the formulation appeared to depend on the measuring method used.