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To identify the structure and determine the source of unknown impurities present at levels greater than 0.1% in representative pharmaceutical excipient benzalkonium chloride samples, in accordance with ICH Q3A guidelines.
A new LC-MS method suitable for the structure prediction of related substances of benzalkonium chloride was established. The separation was performed on an Acclaim 120 C18 column (250 mm×4.6 mm, 5 μm) using a mobile phase consisting of methanol (mobile phase A) and 20 mmol·L-1 ammonium formate aqueous solution (pH 3.5, mobile phase B) with gradient elution at a flow rate was 1 mL·min-1. The post-column split was set to 1 ：3. MS data were collected in positive ion mode using an electrospray ionization (ESI) source. The structures of unknown impurities were inferred using a “Diagnostic fragment ion extension strategy” and confirmed by comparing the chromatographic and mass spectrometric behaviors of the impurities with those of reference substances. Additionally, the source attribution and genotoxicity prediction of the detected impurities were performed.
A total of five unknown impurities were detected in a representative sample of benzalkonium chloride by the newly established LC-MS method, and their structures were inferred. The structures of four impurities were confirmed using two commercially available reference substances and two reference substances synthesized in a directionally oriented manner. Impurity D was identified as N-benzyl-N,N-dimethyl-1-phenylmethanaminium chloride. Impurity E as N-benzyl-N-methyl-1-phenylmethanamine. The impurity G as N-benzyl-N-methyldodecan-1-amine, and impurity H as N,N-dibenzyl-N-methyldodecane-1-ammonium chloride. Impurity F was hypothesized to be an isomer of the formula C15H17N. Predictions using Nexus 2.6.0 software indicated that all the above impurities fell into category 5 and had no genotoxic potential. Furthermore, the method successfully located four unknown impurities detected by the USP method in benzalkonium chloride related substances using impurity reference standards.
This study systematically examines the structure and safety risks of potential impurities in benzalkonium chloride, providing valuable insights for enhancing quality control standards and pharmacopoeia criteria both domestically and internationally.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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