Photostability testing using online reactor HPLC hyphenation and mass spectrometric compound identification illustrated by ketoprofen as model compound
Photostability testing using online reactor HPLC hyphenation and mass spectrometric compound identification illustrated by ketoprofen as model compound
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DOI：
10.1016/j.jpba.2017.07.006
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发表时间：
2017-10-25
影响因子：
3.4
通讯作者：
Parr, Maria Kristina
中科院分区：
文献类型：
--
作者：
Assaf, Jaber;Gomes, Diego Zulkiewicz;Parr, Maria Kristina
在药物开发和许可中，必须对药物物质的光化学稳定性进行研究，因为活性药物成分（API）的光诱导降解不仅可能导致API浓度降低，还可能导致有毒或反应性产物。因此，美国食品药品监督管理局（FDA）和人用药品技术要求国际协调理事会（ICH）发布了行业指南Q1B "新原料药和产品的光稳定性试验"，用于检测纯药物和包装药物。然而，光产物也是已知的，在体内产生的阳光照射下的皮肤，并导致相当数量的药物不良反应。在此，我们提出了一种替代系统，可用于模拟这两种情况下的光稳定性测试。它结合了定制的光反应器与可更换的笔光源和改进的HPLC系统与在线SPE。光产物的鉴定可以使用质谱法进行。精确的质谱作为鉴定光产物的工具的潜力也得到了证明。使用酮洛芬对在线光反应器系统和传统光室照射进行比较以验证概念。在这两种设计中，乙酰基二苯甲酮和乙基二苯甲酮被检测到作为主要的光产物。新设备允许快速和简单的光稳定性研究，这可能有助于减少体外实验和动物试验的时间消耗。使用最先进的仪器，动力学研究也可以很容易地进行，定性和定量的观点结合到一个实验设计中，只需要非常少量的API。这在早期药物开发中可能是有用的，其中只有少量的API可用。也可以很容易地实现规模放大，以生成用于定量和质量控制（QC）过程以及毒性测试的参考材料。(C)2017爱思唯尔B.V.保留所有权利。
Investigations on the photochemical stability of pharmaceutical substances are mandatory in drug development and licensing as photo-induced degradation of an active pharmaceutical ingredient (API) may not only lead to decreased API concentrations but also to toxic or reactive products. Thus, the US Food and Drug Administration (FDA) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) issued Guidance for Industry Q1B "Photostability Testing of New Drug Substances and Products" for testing of pure but also packed drugs. However, photoproducts are also known to be generated in vivo under sunlight exposure of the skin and lead to considerable amounts of adverse drug effects.Herein we present an alternative system that may be used for photostability testing mimicking both situations. It combines a tailored photoreactor with an exchangeable pen light source and a modified HPLC system with online-SPE. Identification of photoproducts may be performed using mass spectrometry. The potential of accurate mass spectrometry as a tool for identification of photoproducts was demonstrated as well. A comparison of the online photoreactor system and the traditional photochamber irradiation was performed using ketoprofen for proof of concept. In both designs acetylbenzophenone and ethylbenzophenone were detected as main photoproducts. The new device allows for fast and easy photostability studies that may help to reduce time consuming in vitro experiments and animal trials. Using state of the art instruments kinetic studies could also easily be performed with qualitative and quantitative perspectives combined into one experimental design with only very low amounts of API needed. This may be useful in early drug development, where only small amounts of API are available. Scale-up may also be easily realized for the generation of reference material for quantification and quality control (QC) processes as well as for toxicity testing. (C) 2017 Elsevier B.V. All rights reserved.