Eco‐Friendly HPLC Method for Quantifying Genotoxic Impurity 4‐Chlorobenzaldehyde in Baclofen Drug Substance and Tablets

ABSTRACT

4‐Chlorobenzaldehyde (4‐CBA) is used as a key starting material in the synthesis of Baclofen, a widely prescribed anti‐spastic agent, and is recognized as a potential genotoxic impurity. Thus, stringent regulatory expectations necessitate its rigorous control throughout pharmaceutical development to ensure patient safety. To ensure adequate control of this impurity, a green and eco‐friendly high‐performance liquid chromatography method was developed for the determination of trace levels of 4‐CBA in Baclofen active pharmaceutical ingredients and tablets. Chromatographic separation was achieved on a C18 column using a binary gradient system composed of water and acetonitrile (A: 70/30, v/v; B: 30/70, v/v ). The method employed a flow rate of 1.2 mL/min, an injection volume of 10 µL, a column temperature of 35  ±  5°C, and UV detection at 273 ± 3 nm. Method validation was performed in accordance with ICH guidelines. The limit of detection and limit of quantitation for 4‐CBA were 0.6072 ppm and 2.0240 ppm, respectively. Linearity was demonstrated over the concentration range of 2.0240–28.125 ppm with an R ² value greater than 0.999. Recovery and precision results ranged from 97.5%–102.6%. The greenness of the proposed HPLC method was evaluated using the green chemistry tools of AGREE, NEMI, and AMGS.