Golob Nejc, Peterlin Simona, Grahek Rok, Roškar Robert
Lek Pharmaceuticals d.d., Sandoz Development Center Slovenia, Ljubljana, Slovenia; University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
Lek Pharmaceuticals d.d., Sandoz Development Center Slovenia, Ljubljana, Slovenia.
J Pharm Sci. 2023 May;112(5):1277-1286. doi: 10.1016/j.xphs.2023.03.007. Epub 2023 Mar 14.
N-nitrosamines are genotoxic compounds which can be found as impurities in drug substances and drug products used in the pharmaceutical industry. To date, several possible nitrosamine sources in drug products have been reported and this study aims to illuminate another one. A case of afatinib drug product was investigated, in which up to 50 ppb N-nitrosodimethylamine (NDMA) traces were detected. Afatinib was found to degrade to the secondary amine dimethylamine (DMA), forming NDMA with traces of nitrite in crospovidone. Two series of film-coated tablets were prepared with crospovidone from two different manufacturers, containing different levels of nitrites. Tablets were subjected to an accelerated stability study (40 °C/75% relative humidity) or stored at room temperature and levels of NDMA, DMA and nitrite in tablets were monitored. NDMA and nitrite were found on ppb levels, whereas DMA was detected on ppm levels. NDMA formation in the drug product was found to be time, temperature and nitrite dependent and it was emphasized that DMA and nitrite should be reduced. The accelerated stability study proved to be a useful tool for predicting nitrosamine formation in the drug product.
N-亚硝胺是具有基因毒性的化合物，在制药行业使用的原料药和药品中可作为杂质被发现。迄今为止，已报道了药品中几种可能的亚硝胺来源，本研究旨在阐明另一种来源。对一例阿法替尼药品进行了调查，其中检测到高达50 ppb的N-亚硝基二甲胺（NDMA）痕量。发现阿法替尼降解为仲胺二甲胺（DMA），在交联聚维酮中与痕量亚硝酸盐形成NDMA。用来自两个不同制造商的交联聚维酮制备了两系列薄膜包衣片，其含有不同水平的亚硝酸盐。将片剂进行加速稳定性研究（40°C/75%相对湿度）或在室温下储存，并监测片剂中NDMA、DMA和亚硝酸盐的水平。发现NDMA和亚硝酸盐的水平为ppb级，而DMA的检测水平为ppm级。发现药品中NDMA的形成与时间、温度和亚硝酸盐有关，并强调应降低DMA和亚硝酸盐的水平。加速稳定性研究被证明是预测药品中亚硝胺形成的有用工具。
