Abstract
A novel HPLC method with fluorimetric detection was developed for the determination of potentially carcinogenic N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in active pharmaceutical ingredient enalapril maleate. N-nitrosamines were subject to denitrosation followed by derivatisation with dansyl chloride or fluorenylmethoxycarbonyl chloride (Fmoc-Cl). Fmoc-Cl offers much better sensitivity and repeatability than dansyl chloride derivatisation. A satisfactory linearity was obtained for the method, with R2 = 0.9994 for NDMA and 0.9990 for NDEA, and a limit of quantification level of 0.038 μg/g for NDMA and 0.050 μg/g for NDEA. The precision decreased with the concentration to a maximum level of about 10%. The recoveries were in the range of 74.2 ± 4.2% to 101.6 ± 16.1% for NDMA and 90.6 ± 2.9% to 125.4 ± 7.4% for NDEA. Dansyl chloride was found to be an inappropriate derivatisation agent, mainly due to potential contamination with dimethylamine, leading to unrepeatable peaks in the blank solution. Since the method involves the derivatisation of amines liberated from the N-nitrosamines, it was necessary to remove the amines from the test sample. Several critical points in the standard/sample preparation have been mentioned, which affect the reproducibility of the method and are not covered in similar articles.
Highlights
N-nitrosamines are carcinogenic compounds that were detected in drugs for the first time in July 2018 [1]
The aim of our research is to develop a reproducible analytical method that would provide an appropriate limits of quantification (LOQ), as required by the European Medicines Agency (EMA), and would not require expensive and sophisticated equipment, such as gas chromatography (GC)-mass spectrometer (MS) and LC-MS
This pH value was chosen on the basis of the pKa values for N-nitrosamines and amines, which provides intermediate conditions in which N-nitrosamines should be neutral, while amines should be charged
Summary
N-nitrosamines are carcinogenic compounds that were detected in drugs for the first time in July 2018 [1]. Classified these two compounds into Category B2 (possibly carcinogenic to humans). The identification of these impurities in angiotensin receptor blockers (ARBs), mainly sartans with a tetrazole ring, and in metformin and ranitidine has led to the recall of certain batches of active pharmaceutical ingredients (APIs) from the market [2]. In February 2021, the European Pharmacopeia (Ph. Eur.) commission revised the five monographs on sartans with a tetrazole ring, namely Valsartan (2423), Losartan potassium (2232), Irbesartan (2465), Candesartan cilexetil (2573) and Olmesartan medoxomil (2600), using the rapid revision process. N-Nitrosamines in APIs” was introduced in the “Production” section to assist manufacturers. The five revised monographs became legally binding on 1 April 2021 [3]
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