Low‐level determination of 4‐chlorobutyl‐(S)‐[4‐chloro‐2‐(4‐cyclopropyl‐1,1,1‐trifluoro‐2‐hydroxy‐but‐3yn‐2‐yl)phenyl] carbamate (4‐CTHC) in efavirenz drug substance by LC–MS

Abstract

A rapid, simple, sensitive, and selective liquid chromatography-tandem mass spectrometry (LC-MS) test method was developed and validated for the trace level. 4-CTHC is a potential genotoxic impurity in efavirenz drug substance and the acceptable level is 2.5 μg ml −1 with respect to analyte concentration according to ICH M7(R1) Multidisciplinary Guidelines M7(R1). The LC-MS/MS analysis of 4-CTHC impurity was carried out on a Kinetex C 18 (150 × 4.6 mm, 5.0 μm) column. In this test procedure, the mobile phase was prepared with buffer (0.1% formic acid in water) and acetonitrile in the ratio of 1:3 (v/v). The method set flow rate was 0.4 ml min −1 . The method was developed with a short run time of <10 min. Selective ion monitoring acquisition mode and negative polarity electrospray ionization mode were used as an MS method to quantify genotoxic impurities at 422.25 Da. The method showed linearity in a range of 0.64-3.71 μg ml −1 with a correlation coefficient of 0.9992. The RSD for intra-day and inter-day precision was found to be <5%. The method's accuracy was in the range of 106.5-112.4% for the genotoxic impurity of 4-CTHC. The procedure was validated as per the current ICH Q2 (R1) guidelines and proved suitable for stability testing in the quality control laboratory for pharmaceutical preparations.

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“…An example could be the determination of 4‐phenoxyphenyl‐boronic in ibrutinib samples using ammonium formate with unmodified pH in ESI ‐ (Mullangi et al, 2021). In the absence of one well‐ionizing functional group (Mallavarapu et al, 2021), the situation is much less clear, and thus, a trial‐and‐error approach is usually implemented.…”

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