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

Abstract

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 R 2 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).

Atomic spectrometry update. Review of advances in the analysis of metals, chemicals and functional materials

“…Some signicant analytical developments in this eld are reviewed, including two papers which reported novel methods for trace-level determination of genotoxic impurities in APIs by LC-ICP-MS employing iodo-derivatization. Harigaya et al 81 presented a novel sensitive determination of 4-chloro-1-butanol, a genotoxic alkylating agent. This compound originates from tetrahydrofuran, which is frequently used as a solvent in API synthesis, by reaction with hydrouoric acid.…”

“…Ohata and Miura 271 developed an ID-ICP-MS system for the determination of Br in polypropylene pellets that are to be used by the National Metrology Institute of Japan to develop a reference material. The pellets and a spike of 81 Br were digested using nitric acid in a microwave oven. Two microwave units were tested, one of which used PTFE digestion bombs and the other a quartz vessel.…”

Sensitive Quantitation of Residual Phenylhydrazine in Antipyrine by LC-ICP-MS with Iodo Derivatization

“…The HPLC instrumental setup was the same as in the previous study. 28 An L-column C8 (3 μm, 2.0 mm i.d. × 150 mm, CERI, Tokyo, Japan) (for the first LC system) and an InertSustain C18 (3 μm, 2.1 mm i.d.…”

“…26,27 Based on these perspectives, we have developed a novel analytical method for one GTI, 4-chloro-1-butanol, using ICP-MS with iodo derivatization. 28 The use of iodine for sensitive detection by ICP-MS is advantageous because of the low background, which is a result of the slight interference of polyatomic ions at m/z 127 (iodine). The developed method can also be applied to other GTIs such as phenylhydrazine.…”

“…In the previous study, 3-iodobenzoyl chloride was utilized as an iodo derivatization reagent, and it can be applied to phenylhydrazine analysis. 28 However, in order to expand the range of options of the iodo derivatization reagents, 3-iodophenyl isocyanate was investigated. Incidentally, sensitivity for an ICP-MS analysis is considered to be almost the same between the reagents because both reagents have one iodine atom in the structure.…”