Pharmaceutical Chemistry Department, Faculty of Pharmacy, Nahda University, Sharq El-Nile, Beni-Suef, 62511, Egypt.
Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Beni-Suef University, Alshaheed Shehata Ahmad Hegazy St, Beni-Suef, 62514, Egypt.
J Fluoresc. 2022 May;32(3):993-1003. doi: 10.1007/s10895-022-02897-3. Epub 2022 Mar 3.
Cyclizine (CYZ); an antiemetic compound; is widely misused for its euphoric or hallucinatory effects, either by oral or intravenous routes. The concomitant abuse of CYZ among addicted adolescents contributes to neuromuscular disorders that are life-threatening. Consequently, with the company of 1-Methylpiperazine (MPZ) and diphenylmethanol (DPM, Benzhydrol) as pharmacopoeia-reported CYZ impurities, a novel spectrofluorimetric assay for the detection of CYZ, has been established either in human plasma samples or in its parenteral formulation. The native fluorescence of CYZ has been investigated under various conditions. Different parameters affecting relative fluorescence intensity of CYZ including diluting solvent, surfactant, plasma protein solvent, and pH were studied and optimized. The linearity obtained between the fluorescence intensity at emission wavelength 350 nm after excitation at 244 nm and the corresponding CYZ concentrations was in the range 10-1000 ng/mL for measurement of CYZ either in pure form or in human plasma samples, with a appropriate correlation coefficient (r = 0.9999) and 3.10 ng/mL as the limit of detection and 9.41 ng/mL as the limit of quantitation. The suggested procedure was created and validated in accordance with ICH guidelines for quantification of CYZ either in its pure form or its dosage form, and FDA guidelines for the assay of CYZ in human plasma. Finally, in silico study and ADMET predictions were conducted for the studied drug impurities to estimate their pharmacokinetic behaviors. The results showed that both CYZ impurities have higher cellular permeability and maximum tolerated doses, DPM has higher BBB and CNS permeability than MPZ, while MPZ exceeds DPM in total clearance and volume of distribution.
克赛嗪（CYZ）是一种止吐化合物，因其欣快或致幻作用而被广泛滥用，无论是通过口服还是静脉途径。成瘾青少年同时滥用 CYZ 会导致危及生命的神经肌肉紊乱。因此，本研究以 1-甲基哌嗪（MPZ）和二苯甲醇（DPM，苯甲醇）作为药典报告的 CYZ 杂质，建立了一种检测人血浆样品或其注射剂中 CYZ 的新型荧光分光光度法。在各种条件下研究了 CYZ 的本征荧光。研究并优化了影响 CYZ 相对荧光强度的不同参数，包括稀释溶剂、表面活性剂、血浆蛋白溶剂和 pH 值。在 244nm 激发波长下，在 350nm 发射波长处获得的荧光强度与相应的 CYZ 浓度之间的线性关系，在纯品或人血浆样品中测定 CYZ 的范围为 10-1000ng/mL，具有适当的相关系数（r=0.9999），检测限为 3.10ng/mL，定量限为 9.41ng/mL。该方法符合 ICH 关于测定 CYZ 纯品或制剂的定量指导原则，以及 FDA 关于测定人血浆中 CYZ 的分析方法指导原则。最后，对研究药物杂质进行了计算化学研究和 ADMET 预测，以估计其药代动力学行为。结果表明，两种 CYZ 杂质均具有较高的细胞通透性和最大耐受剂量，DPM 具有较高的 BBB 和 CNS 通透性，而 MPZ 的总清除率和分布容积均高于 DPM。
