Failure of stability prediction for minodronic acid injectable by accelerated stability testing.

Abstract A liquid formulation containing 0.5 mg/ml minodronic acid, 40 mM, pH 4.5, citrate, and sodium chloride added to adjust the osmolarity of the final formulation was stored in flint glass ampoules at 25, 40, 50, and 60 °C. At specified times, the drug potency and pH, and the tendency to generate particulate matter, were measured. Test samples stored at 40 °C for 6 months or at 50 and 60 °C for 3 months were stable with no potency loss and no particulate increase. However, despite the satisfactory stability at high temperatures, the amount of particulate matter increased when the formulation was stored at 25 °C. Scanning electron microscopy-energy dispersive X-ray analysis of the particulate matter revealed that it contains aluminum and phosphorus, the latter thought to be derived from minodronic acid. In contrast, the number of the particulate matter did not increase, when the formulation was stored in either plastic containers or in SiO 2 -treated glass ampoules . The spike of minodronic acid solution with aluminum ions led to the particulate generation. These results demonstrate that the particulate matter is a complex of minodronic acid molecules and aluminum ions, which apparently leached from the glass of regular ampoules. Since the particulate generation could not be observed at higher temperatures, it was suggested that the complex formation was exothermic and accelerated testing did not predict the stability in terms of particulate generation.