Effect of Packaging Materials and the Leached Iron on the Stability of Butorphanol Tartrate Injection.

The aim of this study was to investigate the effect of various parameters on the stability of butorphanol tartrate injection and to screen the optimal packaging material. The effect of the headspace oxygen levels, ampoule color, manufacturer, and size on the stability of butorphanol tartrate formulation were evaluated. The headspace oxygen levels controlled by nitrogen purging were found to be particularly effective in improving stability of the butorphanol formulation, especially below 2%. Although it is a photolabile drug, butorphanol tartrate was getting degraded at much higher extent in amber color ampoules in comparison to clear ampoules. The degradation by oxidation was found to be a free radical-mediated process catalyzed by the presence of iron ions leached from the amber ampoules. The ampoule manufacturers also had a significant effect on the stability of butorphanol. Two-milliliter ampoules provided a better stability of the butorphanol tartrate injection than 1mL ampoules as 2-mL ampoules had the lower headspace oxygen level at the same level of oxygen content. The oxidation mechanism of the butorphanol tartrate injection was investigated under various conditions, which include iron powder spiking, removal of excipients, exposure to oxygen/nitrogen, exposure to stainless steel and at different pH. Iron powder spiking, presence of citric acid, exposure to oxygen, exposure to stainless steel, and high pH accelerated the oxidative degradation. The effect of oxygen, iron ion and citric acid is in agreement with a metal-catalyzed oxidation mechanism called Udenfriend reaction. Based on the formulation test results, limiting headspace oxygen level, ampoule color, manufacturer, size, controlling iron ion contamination, and pH are recommended for formulation development. In conclusion, it can be suggested that this study can lead to a better understanding of the degradation mechanism of butorphanol tartrate; hence, it would contribute to the development of butorphanol tartrate injection with improved stability. Virous packaging materials have different effects on the stability of butorphanol tartrate injection, and the leached iron of packaging ampoules and stainless steel can trigger Udenfriend reaction with butorphanol tartrate and citric acid (CA), which lead to the oxydative degradation of butorphanol tartrate injection.