Determination of enantiomerization barriers of desloratadine and its N-oxide derivative by dynamic enantioselective high-performance liquid chromatography and off-column racemization experiments

IF 3.1 3区医学 Q2 CHEMISTRY, ANALYTICAL

Journal of pharmaceutical and biomedical analysis Pub Date : 2025-09-24 DOI:10.1016/j.jpba.2025.117159

Francesca Romana Mammone , Simone Manetto , Giulia Mazzoccanti , Daniele Sadutto , Marco Pierini , Roberto Cirilli

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Abstract

Desloratadine, a tricyclic histamine H₁-receptor antagonist, is employed in the treatment of asthma and other allergic conditions. Its efficacy against various types of tumors has also been demonstrated. The molecule possesses a non-planar central seven-membered ring, devoid of a plane of symmetry, which confers planar stereogenicity. In this study, the energy barriers for the inversion of the pR and pS enantiomers, which occurs via a near-planar transition state, have been determined by on-column dynamic high-performance liquid chromatography and parallel kinetic off-column experiments based on electronic circular dichroism measurements. The kinetic and thermodynamic data pertinent to enantiomerization process were compared with those obtained for the N-oxide derivative of desloratadine. The results indicated that the targeted oxidation increased the activation enantiomerization barriers, thus conferring configurational stability to enantiomers. To complete the work, the absolute configuration of the enantiomers of the N-oxide derivative of desloratadine was established by comparing their experimental and theoretical chiroptical properties.

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动态对映选择高效液相色谱法和柱外消旋实验测定地氯雷他定及其n -氧化物衍生物的对映异构化障碍

地氯雷他定是一种三环组胺h1受体拮抗剂，用于治疗哮喘和其他过敏性疾病。它对各种类型肿瘤的疗效也已得到证实。该分子具有一个非平面的中心七元环，没有对称平面，从而具有平面立体性。在本研究中，通过基于电子圆二色性测量的柱上动态高效液相色谱和柱外平行动力学实验，确定了pR和pS对映体通过近平面过渡态发生反转的能垒。对地氯雷他定n -氧化物衍生物对映异构化过程的动力学和热力学数据进行了比较。结果表明，靶向氧化增加了活化对映异构化障碍，从而赋予对映体构型稳定性。为了完成这项工作，通过比较地氯雷他定n -氧化物衍生物的实验和理论热学性质，确定了它们的绝对构型。

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来源期刊

Journal of pharmaceutical and biomedical analysis 医学-分析化学

CiteScore

6.70

自引率

5.90%

发文量

588

审稿时长

37 days

期刊介绍： This journal is an international medium directed towards the needs of academic, clinical, government and industrial analysis by publishing original research reports and critical reviews on pharmaceutical and biomedical analysis. It covers the interdisciplinary aspects of analysis in the pharmaceutical, biomedical and clinical sciences, including developments in analytical methodology, instrumentation, computation and interpretation. Submissions on novel applications focusing on drug purity and stability studies, pharmacokinetics, therapeutic monitoring, metabolic profiling; drug-related aspects of analytical biochemistry and forensic toxicology; quality assurance in the pharmaceutical industry are also welcome. Studies from areas of well established and poorly selective methods, such as UV-VIS spectrophotometry (including derivative and multi-wavelength measurements), basic electroanalytical (potentiometric, polarographic and voltammetric) methods, fluorimetry, flow-injection analysis, etc. are accepted for publication in exceptional cases only, if a unique and substantial advantage over presently known systems is demonstrated. The same applies to the assay of simple drug formulations by any kind of methods and the determination of drugs in biological samples based merely on spiked samples. Drug purity/stability studies should contain information on the structure elucidation of the impurities/degradants.