Abstract
A sensitive and selective hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) method was developed and validated for trace analysis of potential genotoxic impurities (PGIs): 2,3-dichloroaniline (PGI-1), bis(2-chloroethyl) amine (PGI-2), and 2-chloroethylamine (PGI-3), in aripiprazole (APZ) active drug substance. Separation of analytes was achieved on ACE HILIC–N Column (HILN-5-1046U, 100 × 4.6 mm, 5 μm) in gradient elution mode with mobile phase A [acetonitrile:ammonium formate buffer (95:5 v/v)] and mobile phase B [acetonitrile:ammonium formate buffer (50:50 v/v)] at a flow rate of 0.8 mL/min. Developed method was linear in the concentration range of 8–100 ppm for PGI-1, 11–100 ppm for PGI-2, and 12.5–100ppm for PGI-3 with R2 > 0.996. The developed method was accurate for quantification of each PGI with percent recoveries greater than 96% and RSD (%) not more than 5%. The developed method was precise for quantification of PGIs in aripiprazole with RSD (%) of not more than 4% for any of the PGIs. There was no interference of diluent peaks at the retention time of the PGIs and APZ in the method. All the PGIs and sample solutions were found to be stable at ambient laboratory temperature (25 ± 5 °C) and refrigerated condition (2–8 °C) for a period of 48 h. The developed HILIC-MS/MS method can be used for trace quantification of PGIs in aripiprazole drug in quality control laboratories of the pharmaceutical industry.
Highlights
The assessment and control of impurities in pharmaceutical products, especially genotoxic/mutagenic impurities have received considerable attention in the recent years
Optimization of chromatographic and mass spectrometric method conditions Considering the small molecular size and polar nature of the analytes under investigation, hydrophilic interaction liquid chromatography (HILIC) was applied. Different stationary phases such as Inertsil HILIC, Luna HILIC, Zic HILIC, and ACE HILIC–N columns with varied polarity were evaluated with LC-Mass spectrometer (MS) compatible aqueous mobile phases such as ammonium formate and ammonium acetate buffers to optimize the separation of Potential genotoxic impurity (PGI) from the active pharmaceutical ingredient (API) and to obtain better sensitivity in their MS response
Better peak shapes and resolution of PGIs and APZ were obtained with ACE HILIC–N Column (100 mm × 4.6 mm × 5 μm) in gradient elution mode using mobile phase A consisting of acetonitrile:ammonium formate buffer (95: 5 v/v) and mobile phase B comprising of acetonitrile:ammonium formate buffer (50:50 v/v)
Summary
The assessment and control of impurities in pharmaceutical products, especially genotoxic/mutagenic impurities have received considerable attention in the recent years. International Council on Harmonization (ICH) provides guidance on assessment of genotoxic impurities in pharmaceuticals (International Council for Harmonization, n.d.-a; United states food and drug administration, n.d.). Aripiprazole (APZ), 7-{4-[4-(2,3-dichlorophenyl) piperazin1-yl] butoxy}-3,4-dihydroquinolin-2(1H)-one (Fig. 1), is a D2/5-HT 1A/5-HT 2C partial agonist and a D3/4/5-HT 2A/ 5-HT 7 antagonist, with moderate serotonin transporter inhibitory, antihistaminic H1, and adrenolytic activities (Sharif et al, 2009). It is a member of a class of typical antipsychotic agents and is indicated in the treatment of positive and negative symptoms of schizophrenia and Mullangi et al Journal of Analytical Science and Technology (2021) 12:21. Several double-blind, placebo-controlled trials have proved the efficacy and safety of APZ for the said treatments (Keck et al, 2003; Sachs et al, 2006; Vieta et al, 2008; Keck et al, 2009)
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