First Time Exploration of Few Novel Molecules from Oxidative Degradation of Raw and Tableted Quetiapine and Unveiling Their Toxico-Pharmacological Potentials for Future Drug Discovery

IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Dipanwita Bera, Darakhshan Begum, Balaram Ghosh, Susmita Mallick, Souvik Basak, Nandagopal Sahoo
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Abstract

Purpose

Quetiapine (QUE) is an FDA approved antimanic and antischizophrenic active pharmaceutical ingredient (API). However, quetiapine is disseminated worldwide in tablets requiring special attention regarding its stability on storage. Also, as per the official compendium, a maximum ± 10% of such impure or degradation products is allowed in the API as well in tablets. Hence isolation, explicit characterization and toxicological profiling of such products become pertinent. In addition, recycling opportunity of such products into newer bioactive molecules need to be explored in the realm of drug discovery and circular economy.

Methods

Acid, base, oxidative, photolytic and thermal degradation pathways are explored first by subjecting QUE to respective conditions. The products were subsequently analyzedby HPLC. Finally, oxidative pathway was chosen for investigation to isolate and characterize the degradation products. Toxicological studies and in vitro antimicrobial activity investigations were undertaken with the obtained degradation products.

Results

Characterizations revealed, the 3-oxo hydroxyl ethyl chain, two side phenyl rings, the two α-carbon atoms adjacent to piperazine nitrogens and the Sulphur of the central thiazepine ring, have been the most susceptible positions for the oxidation. Different novel degradation products have been obtained from QUE API and QUE tablets. Interestingly, certain degradation products revealed considerable in vitro antimicrobial activity. Mild allergic manifestations were observed afterthe degradation products had been tested on rodents. An overall in silico studies revealed a few adverse effects on human organs.

Conclusion

Molecules explored from our QUE degradation have been novel till date, providing potential scaffolds for novel antimicrobial agents. The degradation products also insinuated a few adverse effects for drug manufacturers. Above all, this is maiden report on investigations of QUE tablet degradation.

Abstract Image

首次从原始和片剂喹硫平氧化降解中发现一些新分子,并揭示其毒理学潜力,为未来的药物发现奠定基础
sequetiapine (QUE)是FDA批准的抗躁狂和抗精神分裂症活性药物成分(API)。然而,喹硫平以片剂形式在世界范围内传播,需要特别注意其储存稳定性。此外,根据官方纲要,原料药和片剂中最多允许±10%的此类不纯或降解产品。因此,分离,明确表征和毒理学分析这些产品成为相关的。此外,需要在药物发现和循环经济领域探索这些产品转化为新的生物活性分子的回收机会。方法首先在不同的条件下探索酸、碱、氧化、光解和热降解途径。用高效液相色谱法对产物进行分析。最后选择氧化途径对降解产物进行分离和表征。对获得的降解产物进行了毒理学研究和体外抗菌活性研究。结果3-氧羟基乙基链、两侧苯基环、与哌嗪氮相邻的两个α-碳原子和中心噻吩环的硫原子是最易发生氧化的位置。从QUE原料药和QUE片剂中获得了不同的新型降解产物。有趣的是,某些降解产物显示出相当大的体外抗菌活性。降解产物在啮齿类动物身上试验后,观察到轻度过敏表现。一项全面的计算机研究揭示了对人体器官的一些不利影响。结论从QUE降解中发现的分子迄今为止是新颖的,为新型抗菌药物的开发提供了潜在的支架。降解产物对药品制造商也有一些不良影响。综上所述,这是QUE片剂降解研究的首次报道。
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来源期刊
Journal of Pharmaceutical Innovation
Journal of Pharmaceutical Innovation PHARMACOLOGY & PHARMACY-
CiteScore
3.70
自引率
3.80%
发文量
90
审稿时长
>12 weeks
期刊介绍: The Journal of Pharmaceutical Innovation (JPI), is an international, multidisciplinary peer-reviewed scientific journal dedicated to publishing high quality papers emphasizing innovative research and applied technologies within the pharmaceutical and biotechnology industries. JPI''s goal is to be the premier communication vehicle for the critical body of knowledge that is needed for scientific evolution and technical innovation, from R&D to market. Topics will fall under the following categories: Materials science, Product design, Process design, optimization, automation and control, Facilities; Information management, Regulatory policy and strategy, Supply chain developments , Education and professional development, Journal of Pharmaceutical Innovation publishes four issues a year.
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