Dowling Geraldine, Kavanagh Pierce V, Talbot Brian, O'Brien John, Hessman Gary, McLaughlin Gavin, Twamley Brendan, Brandt Simon D
School of Chemical and Pharmaceutical Sciences, Dublin Institute of Technology, Kevin Street, Dublin, D08 NF82, Ireland.
Department of Pharmacology and Therapeutics, School of Medicine, Trinity Centre for Health Sciences, St. James's Hospital, James's Street, Dublin, D08 W9RT, Ireland.
Drug Test Anal. 2017 Mar;9(3):518-528. doi: 10.1002/dta.2142. Epub 2016 Dec 29.
2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil) is commonly prescribed for the treatment of narcolepsy. Increasing popularity and off-label use as a cognitive enhancer has resulted in a reputation as an intelligence boosting 'wonder drug'. Common alternatives available from online shops and other retail outlets include 2-[(diphenylmethyl)sulfinyl]-N-hydroxyacetamide (adrafinil), 2-{[bis(4-fluorophenyl)methyl]sulfinyl}acetamide (CRL-40,940), 2-{[bis(4-fluorophenyl)methyl]sulfinyl}-N-hydroxyacetamide (CRL-40,941), and N-methyl-4,4-difluoro-modafinil (modafiendz), respectively. Gas chromatography-mass spectrometry (GC-MS) is a common tool used in forensic and clinical analysis but there is a potential for inducing analysis-related ambiguities. This study reports on the thermal degradation of modafinil, modafinic acid, adrafinil, CRL-40,940, and CRL-40,941 due to exposure to the heated GC injection port dissolved in a variety of solvents. Key degradation products common to modafinil, modafinic acid, and adrafinil analysis included diphenylmethanol and 1,1,2,2-tetraphenylethane (TPE), the latter of which was verified by its synthesis and characterization by x-ray crystallography. The investigated compounds were also characterized by H and C NMR. Diphenylmethane and thiobenzophenone were also identified in some instances. TPE formation was suggested to involve the generation of a benzhydrylium ion and its reaction with the sulfoxide oxygen of the parent compound to give an oxysulfonium intermediate. Correspondingly, the fluorinated TPE analogue was formed during heat-induced degradation of modafiendz, CRL-40,940 and CRL-40,941, respectively. When a mixture of modafinil (non-fluorinated) and modafiendz (fluorinated) were subjected to GC analysis, 4,4'-(2,2-diphenylethane-1,1-diyl)bis(fluorobenzene) was detected as a third cross reaction product in addition to the two expected TPE analogues. These observations served as a reminder that the seemingly straightforward implementation of GC-MS analysis can lead to challenges during routine analysis.
2-[(二苯甲基)亚磺酰基]乙酰胺（莫达非尼）通常用于治疗发作性睡病。随着其作为认知增强剂的知名度不断提高和非标签使用的增加，它赢得了能提升智力的“神奇药物”的声誉。网上商店和其他零售渠道常见的替代药物分别包括2-[(二苯甲基)亚磺酰基]-N-羟基乙酰胺（阿屈非尼）、2-{[双(4-氟苯基)甲基]亚磺酰基}乙酰胺（CRL-40,940）、2-{[双(4-氟苯基)甲基]亚磺酰基}-N-羟基乙酰胺（CRL-40,941）以及N-甲基-4,4-二氟莫达非尼（莫达非尼类似物）。气相色谱-质谱联用仪（GC-MS）是法医和临床分析中常用的工具，但存在引发与分析相关的模糊性的可能性。本研究报告了莫达非尼、莫达非尼酸、阿屈非尼、CRL-40,940和CRL-40,941在溶解于多种溶剂的情况下，因暴露于加热的GC进样口而发生的热降解情况。莫达非尼、莫达非尼酸和阿屈非尼分析中常见的关键降解产物包括二苯甲醇和1,1,2,2-四苯基乙烷（TPE），后者通过X射线晶体学合成和表征得到了验证。所研究的化合物还通过氢核磁共振和碳核磁共振进行了表征。在某些情况下还鉴定出了二苯甲烷和二苯甲硫酮。TPE的形成被认为涉及苯甲鎓离子的生成及其与母体化合物亚砜氧的反应，从而生成氧硫鎓中间体。相应地，在莫达非尼类似物、CRL-40,940和CRL-40,941的热诱导降解过程中分别形成了氟化TPE类似物。当对莫达非尼（非氟化）和莫达非尼类似物（氟化）的混合物进行GC分析时，除了两种预期的TPE类似物外，还检测到4,4'-（2,2-二苯基乙烷-1,1-二基）双（氟苯）作为第三种交叉反应产物。这些观察结果提醒人们，GC-MS分析看似简单的实施在常规分析过程中可能会带来挑战。
