HILIC-SPE and LC–HRMS Method Used for N-Nitrosamine Detection in Pharmaceuticals

Author：JIANGXI AIYI HI-TECH CO., LTD. Click： Time：2024-12-25 19:22:01

Recently, a research team from the University of Ljubljana in Slovenia successfully developed a new method that can effectively detect N-nitrosamines (NA) in drugs. This breakthrough discovery will completely change the quality control system of the pharmaceutical industry.

In 2018, the discovery of N-nitrosodimethylamine (NDMA) in valsartan shocked the entire pharmaceutical industry. The average level of NDMA detected in daily quality control was as high as 66.5 parts per million, forcing pharmaceutical companies to re-examine their production processes. Subsequently, multiple drug recalls around the world have triggered the industry's continued attention to nitrosoamine drug impurities (NDSRIs).

N-nitrosoamines are potential highly carcinogenic substances. They are formed during drug synthesis or degradation, and even at extremely low levels, they pose a serious threat to human health. Therefore, extremely strict methods must be used to detect these substances. However, most existing detection methods can only target a single active pharmaceutical ingredient (API), and there is a lack of a universal method for detecting multiple N-nitrosoamines in multiple drugs.

The new method developed by the University of Ljubljana team combines hydrophilic interaction chromatography (HILIC)-based solid phase extraction (SPE) and liquid chromatography-high resolution mass spectrometry (LC–HRMS) to achieve accurate detection of N-nitrosamines in pharmaceutical products. During the SPE step, multiple APIs and polar excipients are retained, while N-nitrosamines pass through. This clean-up step significantly reduces matrix interferences and removes excess API.

The SPE process uses sequential elution steps optimized for different N-nitrosamines, ensuring good recoveries and high precision, even in complex matrices. After sample clean-up, the samples were analyzed using LC–HRMS, which showed good linearity (R² > 0.999), accuracy (85–115%), and repeatability (RSD < 10%). Recovery rates of more than 80% and detection limits as low as 42.5% of the regulatory threshold highlight the effectiveness of the method.

The team validated these parameters on 59 APIs and 15 tested N-nitrosamines, including multi-API formulations. They also tested both marketed and expired drug products and found that N-nitrosamine levels in active drug products were within the acceptable limit, but NDMA levels in expired ranitidine products were as high as 32 times the acceptable level. This finding highlights the importance of proper storage and immediate sample preparation to prevent the generation of N-nitrosamines during degradation.

The research team pointed out that the adaptability of the method is one of its greatest advantages. It is the first method to overcome the difficulties in analyzing such compounds, such as the different physicochemical properties of N-nitrosamines, low concentrations relative to the API, and the complexity of the matrix. By modifying the SPE elution protocol, the method can accommodate newly discovered NDSRIs and customize the detection for specific APIs. As the pharmaceutical industry continues to address this challenge, this method provides continued flexibility for daily quality control and regulatory compliance.

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HILIC-SPE and LC–HRMS Method Used for N-Nitrosamine Detection in Pharmaceuticals

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