Quantification of Nitrite in Excipients and Chemicals: A Versatile and Highly Sensitive Method Using Headspace Gas Chromatography Coupled to Mass Spectrometry

The trace level quantification of nitrite in excipients and chemicals is of major interest to the pharmaceutical industry due to the formation of carcinogenic nitrosamines from potentially present secondary amines and nitrite in the API and/or drug product. The aim of this work was the development of a method for the quantification of nitrite down to a level of 0.05 mg nitrite per kg material (ppm) that can be versatilely used for a wide range of excipients and chemicals. The detection of cyclohexene from the reaction of cyclamate with nitrite in water by gas chromatography coupled with mass spectrometry was selected due to its presumed great potential in terms of sensitivity, robustness, reliability, and specificity. The root cause for the presence of a significant blank peak, which was the key limiting factor, was identified and eliminated to achieve the desired sensitivity. Consequently, a method for the quantification of nitrite down to the targeted level of 0.05 ppm was developed and validated for 19 different excipients and chemicals. Specific sample preparation for challenging excipients and chemicals, such as magnesium stearate and carbonates, was developed and successfully applied. It was shown that the quantification range can be expanded up to 50 ppm covering a wide concentration range.