目的: 建立青霉胺片的有关物质检测方法,并分析国产青霉胺片的有关物质质量及存在的问题。方法: 建立HPLC-ELSD法检测31批次青霉胺片和6批次青霉胺原料的有关物质,色谱柱为GRACE Apollo C18(250 mm×4.6 mm,5 μm),流速0.6 mL·min-1,柱温25 ℃,进样量20 μL。采用二维色谱柱切换HPLC-MSn法推测6个杂质的化学结构并分析其来源,并采用ADMET Predictor软件对这6个杂质进行毒性预测。结果: 青霉胺片的有关物质个数和含量均远高于原料。推测的6个杂质中,青霉胺二硫化物为已知杂质,其余5个为未知杂质,所有杂质均为降解杂质。ADMET Predictor软件毒性预测结果显示4个杂质的毒性均较青霉胺大,2个杂质的毒性与青霉胺相当。结论: 建立的HPLC-ELSD法可有效检测青霉胺片的有关物质。制剂中的杂质主要来源于制剂的生产过程。青霉胺片有关物质的风险比较大,根据各杂质的毒性预测结果,建议制剂生产企业应高度重视制剂生产的各个环节。
Objective: To establish an HPLC-ELSD method for detection of related substances in penicillamine tablets, and analyze the quality of related substances in domestic penicillamine tablets. Methods: HPLC-ELSD method was established for the detection of related substances in 31 batches of penicillamine tablets and 6 batches of penicillamine raw materials. The chemical structures of six impurities were predicted by HPLC-MSn with double ternary column switching, and their sources were analyzed. Results: The number and content of related substances in penicillamine tablets were much higher than those in raw materials. Among the six impurities, penicillamine disulfide was known impurity, five were unknown impurities, and all of them were degradation impurities. ADMET Predictor results showed that the toxicity of 4 impurities were greater than penicillamine, 2 impurities were equivalent to that of penicillamine. Conclusion: The HPLC-ELSD method is suitable for the detection of related substances in penicillamine tablets. The impurities in the preparation mainly come from the production process of the preparation. The risk of related substances in penicillamine tablets is relatively high. Based on the results of toxicity prediction of impurities, it is suggested that pharmaceutical manufacturers should attach great importance to all aspects of pharmaceutical production.
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