An unknown impurity was detected in olmesartan medoxomil active pharmaceutical ingredient (API), which was determined as 2-methyl-4-oxopentan-2-yl-protected olmesartan medoxomil by NMR and mass spectrometry (MS). The formation mechanism of this impurity was investigated. In summary, the tetrazole of the final product was condensed with the potential genotoxic compound mesityl oxide generated from acetone self-condensation in acidic conditions to form the N-Alkyl impurity. Further quality control of the reaction was investigated using statistical methods (design of experiment, DoE) via a definitive screening design. The key factors of the reaction were determined to control the process parameters. Three batches of validation experiments showed that the generation of the N-Alkyl impurity was suppressed (<0.1%) and the residual mesityl oxide was not detected (<2.5 ppm).

中文翻译：

---

理解和控制奥美沙坦Medoxomil中N-烷基杂质的形成：经由Tetrazole和丙酮生成的间苯三酚氧化物之间的Michael型加成的衍生物

在奥美沙坦medoxomil活性药物成分（API）中检测到未知杂质，通过NMR和质谱（MS）确定该杂质为2-甲基-4-氧戊丹-2-基保护的奥美沙坦medoxomil。研究了该杂质的形成机理。总而言之，将最终产物的四唑与在酸性条件下由丙酮自缩合生成的潜在的遗传毒性化合物异氰酸酯缩合，以形成N-烷基杂质。通过确定的筛选设计，使用统计方法（实验设计，DoE）对反应的进一步质量控制进行了研究。确定反应的关键因素以控制工艺参数。三批验证实验表明，N的生成-烷基杂质被抑制（＜0.1％），并且未检测到残留的均三甲苯氧化物（＜2.5ppm）。