Analytical Sciences

Novel Sensitive Determination Method for a Genotoxic Alkylating Agent, 4-Chloro-1-butanol, in Active Pharmaceutical Ingredients by LC-ICP-MS Employing Iodo Derivatization

Koki HARIGAYA,* Hiroyuki YAMADA,* Koji YAKU,* Hiroyuki NISHI,** and Jun HAGINAKA***

*Analytical Research Laboratories, CMC Division, Mitsubishi Tanabe Pharma Corp., 3-16-89 Kashima, Yodogawa, Osaka 532-8505, Japan
**Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yasuda Women’s University, 6-13-1 Yasuhigashi, Asaminami, Hiroshima 731-0153, Japan
***School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien Kyuban-cho, Nishinomiya 663-8179, Japan

An alkylating agent, 4-chloro-1-butanol, is a genotoxic impurity (GTI); it may be generated during the synthesis of active pharmaceutical ingredients (APIs). For the trace-level detection of GTIs in APIs, usually, gas chromatography–mass spectrometry (GC-MS) or liquid chromatography–mass spectrometry (LC-MS) is employed. In this study, a novel LC-inductively coupled plasma (ICP)-MS method was developed and validated. Linearity was observed over the 0.5 – 50 ppm (μg/g API) range, with an R² value of 0.9994. The detection limit (DL) and quantitation limit (QL) were 0.2 and 0.5 ppm, respectively. The DL and QL values are well over the thresholds specified in the guidelines. The accuracy was 95.1 – 114.7% for concentrations of 1 – 50 ppm, and the relative standard deviation of the spiked recovery test’s repeatability was 6.2%. In addition, six lots of an API were analyzed, and all results were lower than the reported threshold (1 ppm).

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