Samira Dowlatshah,a, b, Frederik André Hansen,a, Stig Pedersen-Bjergaard,a, c, Roger Trones,b, Olav
Bøyum,d,
Albena
Mihailovad
a Department of Pharmacy, University of Oslo, 0316 Oslo, Norway; Department of Pharmacy
b Extraction Technologies Norway, Verkstedveien 29, 1424 Ski, Norway
c Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen,
Denmark
d The Norwegian Medical Products Agency, Oslo, Norway
Email: samira.dowlatshah@farmasi.uio.no
Nitrosamines are classified as Class 1 impurities under the ICH M7 (R1) guideline due to their high mutagenic and carcinogenic potency, and their presence in pharmaceutical products has become a major public health concern following their detection in several widely used medicines. Stringent acceptable intake limits established by regulatory authorities such as the FDA and EMA necessitate highly sensitive and selective analytical methods for trace-level determination of nitrosamines. Liquid chromatography–mass spectrometry (LC–MS) is the preferred analytical technique; however, direct analysis of pharmaceutical formulations is challenged by severe matrix effects arising from high concentrations of active pharmaceutical ingredients (APIs) and excipients, which can lead to ion suppression, compromised quantitative accuracy, and contamination of analytical systems. Consequently, efficient sample preparation is essential.
This study investigates the applicability of liquid membrane extraction (LME) as a selective sample preparation technique for the determination of nitrosamine impurities in pharmaceutical tablets prior to LC–MS analysis. LME employs a supported liquid membrane that acts as both a physical and chemical barrier, enabling effective separation of trace-level nitrosamines from highly concentrated APIs. A commercially available ETN EME device was operated as an LME system using an applied potential of 1 V to ensure controlled mass transfer across the membrane. The extraction approach was evaluated for small-molecule nitrosamines in metformin and candesartan tablet formulations, and the selectivity between an active pharmaceutical ingredient and its corresponding nitrosamine drug substance-related impurity was assessed using mirabegron as a model compound. The developed LME–LC–MS methodology demonstrates the potential of membrane-based extraction for efficient matrix clean-up and reliable determination of nitrosamines in pharmaceutical products.