title: Outsmarted by nootropics? An investigation into the thermal degradation of modafinil, modafinic acid, adrafinil, CRL-40,940 and CRL-40,941 in the GC injector: formation of 1,1,2,2-tetraphenylethane and its tetra fluoro analog.
abstract: 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 by1H and13C 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.
authors.affiliation: 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.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Dowling
authors.affiliation: Department of Pharmacology and Therapeutics, School of Medicine, Trinity Centre for Health Sciences, St. James's Hospital, James's Street, Dublin, D08 W9RT, Ireland.
authors.forename: Pierce V
authors.initials: PV
authors.lastname: Kavanagh
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, College Green, Dublin, D02 EV57, Ireland.
authors.forename: Brian
authors.initials: B
authors.lastname: Talbot
authors.affiliation: School of Chemistry, Trinity College Dublin, College Green, Dublin, D02 EV57, Ireland.
authors.forename: John
authors.initials: J
authors.lastname: O'Brien
authors.affiliation: School of Chemistry, Trinity College Dublin, College Green, Dublin, D02 EV57, Ireland.
authors.forename: Gary
authors.initials: G
authors.lastname: Hessman
authors.affiliation: Department of Pharmacology and Therapeutics, School of Medicine, Trinity Centre for Health Sciences, St. James's Hospital, James's Street, Dublin, D08 W9RT, Ireland.
authors.forename: Gavin
authors.initials: G
authors.lastname: McLaughlin
authors.affiliation: School of Chemistry, Trinity College Dublin, College Green, Dublin, D02 EV57, Ireland.
authors.forename: Brendan
authors.initials: B
authors.lastname: Twamley
authors.affiliation: School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Brandt
mesh_terms: D001559:Benzhydryl Compounds / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004355:Drug Stability; D008401:Gas Chromatography-Mass Spectrometry; D006358:Hot Temperature; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D000077408:Modafinil; D008958:Models, Molecular; D018697:Nootropic Agents / Q000737:chemistry*; D013267:Stilbenes / Q000737:chemistry*; D013696:Temperature; D064690:Wakefulness-Promoting Agents / Q000737:chemistry*
chemical_list: D001559:Benzhydryl Compounds; D006877:Hydroxamic Acids; D018697:Nootropic Agents; D013267:Stilbenes; D064690:Wakefulness-Promoting Agents; C022116:adrafinil; D000077408:Modafinil
keywords: CRL-40,940; CRL-40,941; adrafinil; forensic; modafiendz; modafinic acid; modafinil; nootropic; smart drugs