Department of Medicinal Chemistry, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland.
Department of Medicinal Chemistry, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland.
J Pharm Biomed Anal. 2019 Feb 5;164:789-807. doi: 10.1016/j.jpba.2018.11.023. Epub 2018 Nov 15.
Sitagliptin was stored at high temperature/high humidity, dry hot air, UV/VIS light and different pH. Then, a selective LC-UV method was developed for determination of sitagliptin in the presence of degradation products and for estimation of degradation kinetics. Because parent drugs can react with excipients in final pharmaceutical formulations, stability of sitagliptin was also examined in the presence of excipients of different reactivity, using FT-IR and LC-UV methods. Finally, LC-MS method was used for identification of degradation products of sitagliptin. High degradation of sitagliptin, following the first order kinetics, was observed in strongly acidic, alkaline and oxidative media. The quickest degradation was found in 2 M HCl and 2 M NaOH. In addition, all excipients used in the present study, i.e. fumaric acid, lactose, mannitol and magnesium stearate showed potent interactions with sitagliptin. Some of these interactions were shown without any stress while others were accelerated by high temperature/high humidity and dry hot air, and less by UV/VIS light. Some mechanisms for the observed changes were proposed, i.e. the Michael addition in the presence of fumaric acid and the Maillard reaction in the presence of lactose. In addition, degradation of sitagliptin together with the occurrence of its impurities was stated in a broad range of stress conditions.
西他列汀在高温/高湿、干燥热空气、UV/VIS 光和不同 pH 值条件下进行了储存。然后，开发了一种选择性的 LC-UV 方法，用于在存在降解产物的情况下测定西他列汀，并用于估算降解动力学。由于母体药物可能会与最终药物制剂中的赋形剂发生反应，因此还使用 FT-IR 和 LC-UV 方法在不同反应性赋形剂存在的情况下检查了西他列汀的稳定性。最后，使用 LC-MS 方法鉴定了西他列汀的降解产物。在强酸性、碱性和氧化性介质中，西他列汀按照一级动力学发生了高度降解。在 2M HCl 和 2M NaOH 中发现了最快的降解。此外，本研究中使用的所有赋形剂，即富马酸、乳糖、甘露醇和硬脂酸镁，均与西他列汀表现出强烈的相互作用。其中一些相互作用在没有任何压力的情况下显示出来，而另一些则在高温/高湿和干燥热空气的作用下加速，在 UV/VIS 光的作用下则较少。提出了一些观察到的变化的机制，即在富马酸存在下的迈克尔加成反应和在乳糖存在下的美拉德反应。此外，在广泛的应激条件下，西他列汀与杂质的降解一起被陈述。
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