Factors affecting the stability and performance of ipratropium bromide; fenoterol hydrobromide pressurized-metered dose inhalers

Abstract

The aim of the study was to investigate the factors affecting the stability and performance of ipratropium bromide and fenoterol hydrobromide in a pressurized-metered dose inhaler (pMDI). A factorial design was applied to investigate the effects of three parameters (propellant, water, and ethanol) on the performance of 27 designed formulations of a solution-based pMDI. The formulations that contained a hydrofluoroalkane (HFA) propellant lower than 72% v/v and an ethanol concentration higher than 27% v/v remained as clear solutions. Nine formulations that contained the HFA propellant higher than 74% v/v precipitated. The results indicated that it was not only the HFA propellant content of the formulations that was related to the formulation instability but also ethanol content. Only six formulations from the 18 formulations, that did not precipitate, produced drug contents that were within the acceptable range (80-120%). These six formulations generated aerosols with mass median aerodynamic diameters (MMAD) of approximately 2 μm with a fine particle fraction (FPF; particle size, <6.4 μm) between 45% and 52%. The MMAD and FPF did not change significantly after 6 months of storage (P > 0.05).

Fig. 1

Schematic diagram showing the method used to assay active pharmaceutical ingredients by depositing the formulation onto a centrally located disk sampler

Fig. 2

Contents of the active ingredients delivered by actuation of the valve at initial and after storage at 25°C after 3 and 6 months of selected formulations. Doses were collected at the beginning, mid, and end of the ipratropium bromide (white circle, white triangle, white square) and fenoterol hydrobromide (black circle, black triangle, black square). The dashed lines are the upper limit (120%) and the lower limit (80%) of the drug content stated in the British Pharmacopoeia

Fig. 3

Uniformity of the delivery dose at initial and after storage at 25°C after 3 and 6 months of selected formulations. Doses were collected at the beginning, mid, and end of the total dose of ipratropium bromide (white circle, white triangle, white square) and fenoterol hydrobromide (black circle, black triangle, black square). The dashed lines are the upper limits (120%) and lower limits (80%) of the drug content stated in British Pharmacopoeia