Solid-State Stability of Spray-Dried Insulin Powder for Inhalation: Chemical Kinetics and Structural Relaxation Modeling of Exubera Above and Below the Glass Transition Temperature

ABSTRACTThe effect of temperature on the chemical stability of an amorphous spray-dried insulin powder formulation (Exubera)® was evaluated in the solid state at constant moisture content. The chemical stability of the powder was assessed using reversed-phase high-performance liquid chromatography (RP-HPLC) and high-performance-size exclusion chromatography (HP-SEC). The major degradants in spray-dried insulin produced during heat stressing were identified as A21-desamidoinsulin (A21) and high molecular weight protein (HMWP). As expected, the rates of formation of A21 and HMWP were observed to increase with temperature. A stretched-time kinetic model (degradation rate is proportional to the square root of time) was applied to the degradant profiles above and below the glass transition temperature (Tg) and apparent reaction rate constants were determined. Below Tg, isothermal enthalpy of relaxation measurements were used to assess the effect of temperature on molecular mobility. The formation of A21 and HMWP was found to follow an Arrhenius temperature dependence above and below the Tg. Comparison of reaction rate constants to those estimated from structural relaxation experiments suggests that the reaction pathways to form A21 and HMWP below the Tg may be coupled with the molecular motions involved in structural relaxation. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3698–3710, 2010