Influence of formulation technique for hydroxypropyl- β-cyclodextrin on the stability of aspirin in HFA 134a

Abstract

The objective of this study was to determine the influence of the formulation technique for 2-hydroxypropyl- β-cyclodextrin (HP βCD) on the stability of aspirin in a suspension-based pressurized metered-dose inhaler (pMDI) formulation containing a hydrofluoroalkane (HFA) propellant. HP βCD was formulated in a pMDI as a lyophilized inclusion complex or a physical mixture with aspirin. A pMDI formulation containing aspirin alone was used as the control. The chemical stability of aspirin in each pMDI formulation was determined over 6-months storage at 5, 25 and 40°C. The quantity of water taken up into the pMDI canister was determined by Karl Fisher titration after storage for 6 months. Differential scanning calorimetry (DSC) was used to confirm the formation of a complex between HP βCD and aspirin. Aspirin in the lyophilized inclusion complex exhibited the most significant degree of degradation during the 6-months storage, while aspirin alone in the pMDI demonstrated a moderate degree of degradation. Aspirin formulated in the physical mixture displayed the least degree of degradation. The water uptake study showed that water ingress occurred to the greatest extent for formulations containing aspirin and HP βCD physical mixture, and to the least extent for formulations containing aspirin alone. Finally, the DSC study indicated that an inclusion complex was formed in situ in the pMDI formulations containing the HP βCD and aspirin physical mixture. In conclusion, HP βCD may be used to enhance the stability of a chemically labile drug, but the drug stability may be affected by the method of preparation of the formulation.