Abstract
In July 2018, certain valsartan-containing drugs were voluntary recalled in Japan owing to contamination with N-nitrosodimethylamine (NDMA), a probable human carcinogen. In this study, an HPLC method was developed for the quantitative detection of NDMA simultaneously eluted with valsartan. Good linearity with a correlation coefficient (R2) > 0.999 was achieved over the concentration range of 0.011–7.4 µg/mL. The limits of detection and quantification were 0.0085 μg/mL and 0.0285 μg/mL, respectively. When the recalled valsartan samples were subjected to this method, the observed NDMA contents were in agreement with the reported values, indicating that our method achieved sufficient linearity, accuracy, and precision to detect NDMA in valsartan drug substances and products. Moreover, six samples (valsartan drug substances and tablet formulations), which had a possibility for NDMA contamination, were analyzed; none of the samples contained NDMA at detectable levels. Our method would be useful for the rapid screening and quantification of NDMA impurity in valsartan drug substances and products.
Highlights
Valsartan-containing drugs contain the active pharmaceutical ingredient (API) valsartan
The API valsartan is listed in the Japanese Pharmacopoeia (JP)[19] with methods for testing identity, purity, and assay; it is listed in the US and European Pharmacopoeias[20,21]
Valsartan, we first assayed each standard solution according to the high-performance liquid chromatography (HPLC) condition for the quantitative assay for valsartan API and its tablet formulation defined in the JP19
Summary
The standardized limits of NDMA impurity in valsartan drug substances, which was set as 0.559 ppm by the MHLW2, was equivalent to 0.02995 μg/mL when 0.1 g of sample was extracted with 2 mL methanol This concentration was almost equal to the LOQ. When a sample solution of drug substance (50 mg/mL in methanol) was analyzed using the developed method, the peak at 7.8 min was identified by comparing its retention time and UV spectrum with those of the NDMA reference standard (Fig. 3). Five replicates of the spiked samples and triplicates of blanks (samples not spiked) were analyzed, and the recovery rate was determined to be 96.5% with 0.67% relative standard deviation (RSD) These results indicate that the developed method has sufficient linearity, Product name VALSARTAN TABLETS 80 mg [SAWAI]. We successfully developed a practical method for the rapid screening and quantification of NDMA impurity in valsartan-containing products
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