Construction of a modified Arrhenius equation for predicting drug nitrosation in solid dosage form.

To prevent contamination by nitrosamine drug substance-related impurities (NDSRIs) in solid dosage forms, the modeling of drug nitrosation reactions was investigated. The nitrosation reaction rate of desloratadine (DES) in the physical mixtures (PMs) was measured under various temperature, relative humidity, and alkaline excipient (AE) content conditions. The nitrosation reaction rate increased with increasing relative humidity and temperature. In contrast, an increase in AE content resulted in a decreased nitrosation reaction rate. The relationship between these three conditions and reaction rate was analyzed by multiple regression analysis using the least-squares method. The modified Arrhenius equation was expressed as ln k = 41.38 -13026 × (1/T) + 0.038 × (%RH) - 0.44 × (% w/w(AE)). The values predicted by the modified Arrhenius equation were in good agreement with the experimental values, indicating that the model equation was valid. The prediction accuracy of the modified Arrhenius equation was higher than that of the original Arrhenius equation. The modified Arrhenius equation can be applied to the nitrosation reactions of various drugs and is expected to improve the quality, safety, and efficiency of drug research, development, and manufacturing processes.