Greater Poland Oncology Center, 15th Garbary Street, 61-866 Poznań, Poland; Poznan University of Medical Sciences, Department of Pharmaceutical Chemistry, 6th Grunwaldzka Street, 60-780 Poznan, Poland.
Int J Pharm. 2013 Nov 18;456(2):332-9. doi: 10.1016/j.ijpharm.2013.09.002. Epub 2013 Sep 8.
Stability study for imidapril hydrochloride (IMD) was performed under stress conditions of increased temperature (T=373 K) and decreased relative air humidity (RH=0%) in order to obtain and identify its degradation product. The degradation sample stored for 15 days under the above environmental conditions was analyzed by LC-MS technique and it was found that the only degradation impurity formed in the course of the investigated drug degradation was IMD diketopiperazine derivative (DKP) which was produced by dehydration and intramolecular cyclization. The kinetics of its formation was analyzed by a revalidated RP-HPLC method and the kinetic model of this reaction was established. It was concluded that the DKP formation follows Prout-Tompkins kinetics with the rate constant k±Δk=2.034±0.157×10(-6) [s(-1)]. The obtained degradation impurity was further assessed with respect to its mutagenic potential using commercial Ames MPF 98/100 microplate format mutagenicity assay kit equipped with Salmonella typhimurium strains TA 98 and TA 100. Both strains were exposed to six concentrations (in a range of 0.16-5.0mg/mL) of DKP in the presence and absence of metabolic activation system. No mutagenic effect was observed confirming that the presence of DKP in IMD final dosage form has no impact on cancer initiation.
为了获得并鉴定盐酸依那普利（IMD）的降解产物，在升高的温度（T=373 K）和降低的相对空气湿度（RH=0%）的应激条件下对 IMD 进行了稳定性研究。将在上述环境条件下储存 15 天的降解样品通过 LC-MS 技术进行分析，结果发现，在所研究的药物降解过程中形成的唯一降解杂质是 IMD 二酮哌嗪衍生物（DKP），它是通过脱水和分子内环化形成的。通过重新验证的反相高效液相色谱法（RP-HPLC）分析了其形成动力学，并建立了该反应的动力学模型。结果表明，DKP 的形成遵循 Prout-Tompkins 动力学，速率常数 k±Δk=2.034±0.157×10(-6) [s(-1)]。进一步使用配备有鼠伤寒沙门氏菌 TA 98 和 TA 100 菌株的商业 Ames MPF 98/100 微孔板格式致突变性检测试剂盒，对获得的降解杂质的致突变潜力进行了评估。两种菌株均在存在和不存在代谢激活系统的情况下，暴露于 DKP 的六个浓度（0.16-5.0mg/mL 范围内）。未观察到致突变作用，证实 IMD 最终剂型中 DKP 的存在不会对癌症的发生产生影响。
