Center of Excellence for Modern Analytical Technologies (CEMAT), Zhejiang Huahai Pharmaceutical Co. Ltd., Xunqiao, Linhai, Zhejiang, 317204, China.
Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 210009, China.
Rapid Commun Mass Spectrom. 2021 May 15;35(9):e9062. doi: 10.1002/rcm.9062.
The focus of this work was to study glycosylamine and Amadori rearrangement products (ARPs), the two major degradants in the Maillard reactions of pharmaceutical interest, and utilize their MS fingerprints by liquid chromatography/high-resolution tandem mass spectrometry (LC/HRMS ) to quickly distinguish the two isomeric degradants. These two types of degradants are frequently encountered in the compatibility and stability studies of drug products containing primary or secondary amine active pharmaceutical ingredients (APIs), which are formulated with excipients consisting of reducing sugar functionalities.
Vortioxetine was employed as the primary model compound to react with lactose to obtain the glycosylamine and ARP degradants of the Maillard reaction, and their MS spectra (MS fingerprints) were obtained by LC/MS . Subsequently, the two degradants were isolated via preparative HPLC and their structures were confirmed by one- and two-dimensional (1D and 2D) nuclear magnetic resonance (NMR) determination.
The MS fingerprints of the two degradants display significantly different profiles, despite the fact that many common fragments are observed. Specifically, protonated glycosylamine shows a prominent characteristic fragment of [M + C H O] at m/z 341 (M is the vortioxetine core), while protonated ARP shows a prominent characteristic fragment of [M + CH] at m/z 311. Further study of the Maillard reactions between several other structurally diverse primary/secondary amines and lactose produced similar patterns.
The study suggests that the characteristic MS fragment peaks and their ratios may be used to differentiate the glycosylamine and ARP degradants, the two isomeric degradants of the Maillard reaction, which are commonly encountered in finished dosage forms of pharmaceutical products containing primary and secondary amine APIs.
本研究的重点是研究糖胺和麦拉德反应中两种主要降解产物（Amadori 重排产物，ARPs），这两种降解产物在具有医药应用价值的 Maillard 反应中经常遇到，利用它们的 MS 指纹图谱通过液相色谱/高分辨串联质谱（LC/HRMS）快速区分这两种非对映异构体降解产物。这两种类型的降解产物经常出现在含有伯胺或仲胺活性药物成分（APIs）的药物产品的相容性和稳定性研究中，这些 API 与含有还原糖功能的赋形剂一起配制成制剂。
采用文拉法辛作为主要模型化合物与乳糖反应，得到 Maillard 反应的糖胺和 ARP 降解产物，并通过 LC/MS 获得它们的 MS 图谱（MS 指纹）。随后，通过制备高效液相色谱（HPLC）分离这两种降解产物，并通过一维（1D）和二维（2D）核磁共振（NMR）确定其结构。
尽管观察到许多常见的碎片，但两种降解产物的 MS 指纹图谱显示出明显不同的特征。具体来说，质子化糖胺在 m/z 341 处显示出一个显著的特征碎片[M+C HO]（M 是文拉法辛的核心），而质子化 ARP 在 m/z 311 处显示出一个显著的特征碎片[M+CH]。对几种其他结构不同的伯/仲胺与乳糖之间的 Maillard 反应进行进一步研究，得到了类似的图谱。
该研究表明，特征 MS 碎片峰及其比值可用于区分 Maillard 反应中常见的两种非对映异构体降解产物——糖胺和 ARP。这些降解产物存在于含有伯胺和仲胺 API 的药物制剂的成品剂型中。
