目的:氧化是药物制剂中活性药物成分(API)最常见的降解途径之一,主要涉及通过过氧自由基的1电子过程和通过过氧化物的2电子过程。在液体药物制剂中,几个因素可以影响氧化不稳定性,包括pH,赋形剂杂质,顶部空间氧气,和光氧化的潜力。光氧化对于表征可能发生的氧化机制的数量可能是特别具有挑战性的。这是在新化学实体的配方开发过程中观察到的,MK-1454,其中在光稳定性研究中观察到降解峰,而在过氧化物和过氧自由基强制应力研究中以前没有观察到。
方法:为了基本了解活性氧的产生及其在MK-1454降解中的作用,对产生或测量活性氧的材料进行了实验,包括有机氢过氧化物,单线态氧,和超氧化物,以从根本上了解在原始配方中观察到的光降解机理。LC-MS实验进一步阐明了这种观察到的降解途径的结构和机理。
结果:在曝光后溶解氧的减少与MK-1454的损失之间建立了明确的关系。数据表明单线态氧是特定光降解产物的最可能的贡献者。单线态氧是由配方中的非活性成分产生的,和LC-MS证实这是最可能的途径。
结论:这项工作强调了了解溶液配方中原料药光化学降解的重要性,并提供了可以更好地阐明这些机制并从而控制策略的方法。
OBJECTIVE: Oxidation is one of the most common degradation pathways for active pharmaceutical ingredients (APIs) in pharmaceutical formulations, mostly involving 1-electron processes via peroxy radicals and 2-electron processes by peroxides. In liquid pharmaceutical formulations, several factors can impact oxidative instabilities including pH, excipient impurities, headspace oxygen, and the potential for photo-oxidation. Photo-oxidation can be particularly challenging to characterize given the number of oxidative mechanisms which can occur. This was observed during formulation development of a new chemical entity, MK-1454, where a degradation peak was observed during photostability studies which was not previously observed during peroxide and peroxyradical forced stress studies.
METHODS: To gain a fundamental understanding of reactive oxygen species generation and its role in degradation of MK-1454, experiments were performed with materials which either generate or measure reactive oxygen species including organic hydroperoxides, singlet oxygen, and superoxide to fundamentally understand a
photodegradation mechanism which was observed in the original formulation. LC-MS experiments further elucidated the structure and mechanism of this observed degradation pathway.
RESULTS: A clear relationship between the decrease in dissolved oxygen after light exposure and the loss of MK-1454 was established. The data indicate that singlet oxygen is the most likely contributor of a particular
photodegradation product. The singlet oxygen was generated by the inactive ingredients in the formulation, and LC-MS confirm this as the most likely pathway.
CONCLUSIONS: This work highlights the importance of understanding photochemical degradation of APIs in solution formulations and provides approaches which can better elucidate those mechanisms and thereby control strategies.