Kinetics of human insulin degradation in the solid-state: An investigation of the effects of temperature and humidity

Abstract

With the increasing development of oral peptide dosage forms, a comprehensive understanding of factors affecting peptide drug stability in the solid-state is critical. This study used human insulin, as a model peptide, to examine the individual and interactive effects of temperature and humidity on its solid-state stability. Insulin was stored at temperature (25 °C, 40 °C, and 6 °C) and humidity (1 %, 33 % and 75 %) over 6 months. Primary degradation pathways were deamidation and covalent aggregation. Degradation product formation rates were determined empirically and modelled using the humidity-corrected Arrhenius equation. Temperature had a major impact on deamidation and covalent aggregation rates, with the reaction rates increasing with temperature. The effect of humidity was temperature dependent. Moisture induced degradation was minimal at 25 °C and 40 °C, but an important factor at 60 °C. Dynamic vapour sorption analysed determined a clear differences in insulin moisture sorption characteristics at 60 °C relative to 25 °C and 40 °C. The findings suggest that the effect of moisture on insulin deamidation and covalent aggregation rates was not a function of water content but the nature of the insulin moisture interaction.