DRUG FORM SELECTION IN ALBUTEROL-CONTAINING METERED-DOSE INHALER FORMULATIONS AND ITS IMPACT ON CHEMICAL AND PHYSICAL STABILITY

New albuterol-containing metered-dose inhaler (MDI) formulations were under development to replace chlorofluorocarbon (CFC) propellants with more environmentally friendly hydrofluoroalkane (HFA) propellants. Po achieve good chemical and physical stability of MDI formulations with HFA propellants, different drug forms were evaluated irt model formul ations (drug, oleic acid, and one of the following. P12/P11, P12/ethan ol, P12, P134a/ethanol, P134a). The effects of drug form (base versus sulfate), propellant type (P12 versus P134a), and cosolvent type (Pit or ethanol versus none) on the chemical and physical stability were ex amined. The chemical stability of the formulations was determined by m onitoring the percent drug remaining in the formulations using HPLC. T he physical stability of the formulations was followed by visually ass essing the suspension appearance, and by determining the mass median d iameter (MMD) of the suspended particles using laser: diffraction anal ysis. The drug form has a great impact on the chemical and physical st ability of the formulations. The sulfate formulations were chemically stable up to 12 months when stored at 30 degrees C and 40 degrees C/85 % relative humidity (RH). Poor chemical stability was observed for the base formulations, except for ethanol-free formulations (P12/P11, P12 , and P134a) at 30 degrees C and a P134a formulation at 40 degrees C/8 5% RH. The chemical instability of albuterol base formulations at 30 d egrees C correlates with its solubility, The presence at a cosolvent g reatly improved the dispersion characteristics of both sulfate and bas e formulations. The sulfate formulations in the presence of a cosolven t (P12/P11, P12/ethanol, and P134a/ethanol) snowed good physical stabi lity when stored for up to 12 months at 30 degrees C and 40 degrees C/ 85% RH. The physical stability of the base formulations was nor accept able due to crystal growth/agglomeration in all formulations, except t ar the P12/P11 formulation. The physical instability of both sulfate a nd base formulations not only correlates with the drug solubility, but also with panicle agglomeration. In conclusion! good chemical and phy sical stability of albuterol containing suspension formulations can De achieved with the appropriate choice of drug form and formulation con stituents.