Simple and Practical Method for the Quantitative High-Sensitivity Analysis of N-Nitroso Duloxetine in Duloxetine Drug Products Utilizing LC-MS/MS.

The high-sensitivity analytical method for the determination of N-nitroso duloxetine (NDXT), which can be carcinogenic and harmful in duloxetine drug products, was successfully developed utilizing liquid chromatography-tandem mass spectrometry (LC-MS/MS). Tandem mass spectrometric detection at positive electrospray ionization in multiple reaction monitoring (MRM) mode was then employed for the determination of NDXT. The quantitative range for NDXT was found in 0.075-3.75 ng/mL in terms of concentration in the dilution solvent for duloxetine active pharmaceutical ingredient (API) and capsules and 0.075-1.875 ng/mL for duloxetine tablets, and the recovery rates were in the range of 82.5-91.6% for the API, 91.0-113.4% for capsules, and 70.6-109.1% for tablets, respectively. The repeatability was 6.9% with a %RSD of n = 9 for the API, 10.9% with a %RSD of n = 9 for capsules, and 21.6% with a %RSD of n = 9 for tablets, respectively. For reproducibility, the %RSD of the n = 6 measurements between the two sites was 3.5%. The calibration curve of NDXT in the concentration range of 0.075-3.75 ng/mL was carried out, and the correlation coefficient (R) was found to be 1.000. The sample solution was stable for 7 days. The applicability of the determination of the content of NDXT in a variety of duloxetine drug products was demonstrated. This manuscript seeks to aid the risk assessment process of NDXT in duloxetine drug products through providing a fast and reliable quantitative LC-MS/MS analytical method.