Solid State Kinetics of Nitrosation Using Native Sources of Nitrite.

Area of Science:

• Pharmaceutical Chemistry
• Chemical Kinetics
• Drug Product Stability

Background:

• Nitrite (NO2-) in pharmaceutical excipients can act as a source of nitrosating agents.
• N-nitrosation is a critical concern for drug product safety and stability.
• The specific salt form of nitrite can influence nitrosamine formation pathways.

Purpose of the Study:

• To investigate the influence of nitrite salt form on nitrosamine formation kinetics.
• To determine the impact of ammonium nitrite (NH4NO2) as a native nitrite source in pharmaceutical formulations.
• To model nitrosamine formation under realistic conditions using metformin as a model drug.

Main Methods:

• Solid-state kinetic studies of nitrosamine formation.
• Utilizing microcrystalline cellulose with native levels of ammonium nitrite (NH4NO2).
• Kinetic modeling to predict nitrosamine formation over a hypothetical 3-year shelf-life.

Main Results:

• The degradation of NH4NO2 into N2 and H2O significantly limited nitrosamine formation.
• Empirical modeling predicted a maximum of 1.6% nitrosamine conversion over a 3-year shelf-life.
• Using other nitrite sources (e.g., NaNO2) can lead to unrealistic worst-case scenarios.

Conclusions:

• The salt form of nitrite is a crucial factor in assessing nitrosamine formation risk.
• Ammonium nitrite (NH4NO2) in excipients presents a lower nitrosamine formation risk compared to other sources.
• Accurate measurement of nitrite in excipients is essential to avoid biased high content readings and ensure realistic risk assessments.