DMAP-NITROSO Impurity Method Development and Validation in Dapagliflozin Propanediol Monohydrate Drug Substance

Abstract

N-Nitrosamine, the probable carcinogen has been reported with an type-II diabatic drug. dapagliflozin propanediol monohydrate, N-Methyl-N-Nitrosopyridin-4-amine (DMAP-nitroso) impurities play a vital role in the pharmaceutical in the separation, purification and cleaning process for manufacturing of dapagliflozin propanediol monohydrate drug Substance. According to the FDA and EMA guideline (EMA Q&A document EMA/40981/2020), the drug manufacturing process are potential root cause of N- Nitrosamine impurity. Hence, monitoring of N-Nitrosamine for manufacturing of dapagliflozin propanediol monohydrate drug substance. A sensitive LCMS/MS an essential analytical tool for low level N-Nitrosamine quantification in dapagliflozin propanediol monohydrate drug substance, method development by multiple reaction monitoring mode (MRM). A novel method was developed to optimize the critical parameters of LCMS/MS according to the dapagliflozin propanediol monohydrate samples. The method validation was performed through the following parameters, specificity, sensitivity, linearity, accuracy, precision and stability. The quantification of N-Methyl-N-Nitrosopyridin-4-amine (DMAP-nitroso) in dapagliflozin propanediol monohydrate drug substance ranged from 0.18 ppm to 2.12 ppm with respect to the sample concentration of 1 mg/mL with good sensitivity in LOQ level.  Hence, it will be useful to quantify the trace level DMAP-nitroso in dapagliflozin propanediol monohydrate drug substance.