Smart drugs crack up due to GC heat

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  • Published: Feb 1, 2017
  • Author: Ryan De Vooght-Johnson
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thumbnail image: Smart drugs crack up due to GC heat

Modafinil and its analogues increasingly traded on the internet

Modafinil has legitimate medical uses for combating sleeping disorders, but it is increasingly being used, along with a number of its analogues, as a so-called ‘smart drug’ or ‘nootropic’, in order to improve mental performance.

Modafinil, or 2-[(diphenylmethyl)sulfinyl]acetamide, is a pharmaceutical prescribed for conditions such as narcolepsy (where a sufferer tends to suddenly fall asleep at inappropriate times) and sleep disorders caused by shift work. However, there is a growing illicit market for modafinil as a ‘smart drug’ or ‘nootropic’ to augment mental performance. Students taking exams and employees with high-pressure jobs are typical customers, often buying products over the internet. In addition to modafinil itself, a variety of analogues are also sold, some of which have undergone little or no safety testing, so could have unexpected side effects. Impurities in these analogues may also be a problem since unregulated manufacturers have a higher risk of producing contaminated pills than those working under GMP guidelines.

Regulatory agencies, such as police and customs, need fast, reliable analytical methods in order to identify unknown substances. GC-MS is typically used in forensic laboratories for rapid identification of suspect tablets or powders. Prior to the current work, both GC-MS and LC-MS were applied by other researchers to modafinil, although the former method gave decomposition.

GC-MS identification of modafinil presents challenges

As thermally unstable compounds, modafinil and its analogues tend to decompose in GC injection ports. GC-MS analysis only shows degradation compounds, which can make distinguishing between the different analogues difficult. The Dublin/Liverpool researchers found that modafinil gave two main GC peaks (injection port at 250 °C, initial column temperature 60 °C for two minutes, ramped up to 295 °C), identified as diphenylmethanol and 1,1,2,2-tetraphenylethane by their mass spectra. Various difluorinated analogues of modafinil, with fluorine atoms at the para positions of the aromatic rings, are in current use as ‘smart drugs’. These gave analogous fluorinated peaks on GC: bis(4-fluorophenyl)methanol and 1,1,2,2-tetrakis(4-fluorophenyl)ethane. Samples of 1,1,2,2-tetraphenylethane and its tetrafluorinated analogue, 1,1,2,2-tetrakis(4-fluorophenyl)ethane, were synthesised for comparison, in order to confirm the identification.

Modafinil, adrafinil (the NOH analogue) and modafinic acid (the acetic acid analogue) gave similar GC results, with the two main peaks due to diphenylmethanol and 1,1,2,2-tetraphenylethane dominating. Adrafinil also showed a distinct peak due to thiobenzophenone, not noted or very weak with the other two compounds.

Three difluorinated analogues of modafinil were examined by GC-MS: CRL 40,490 (difluorinated modafinil), CRL 40,491 (the difluorinated NOH compound) and ‘modafiendz’ (the difluorinated N-Me compound). There was little difference between them, all three giving GC peaks for bis(4-fluorophenyl)methanol and 1,1,2,2-tetrakis(4-fluorophenyl)ethane.

A mixture of the fluorinated compound ‘modafienz’ and modafinil co-injected onto the GC-MS gave mixtures of 1,1,2,2-tetraphenylmethane, 1,1,2,2-tetrakis(4-fluorophenyl)ethane and the ‘cross coupling’ product, 4,4’-(2,2-diphenylethane-1,1-diyl)-bis(fluorobenzene). This pattern will show up when unfluorinated and fluorinated analogues have been mixed in a formulation.

For modafinil and adrafinil, more diagnostic adducts were obtained by high-resolution electrospray, using direct injection into an LTQ Orbitrap Discovery instrument. In this case, adducts of the molecular ions were seen for modafinil and adrafinil (M + benzhydrilium ion, Ph2CH+).

Analytical techniques for modafinil analogues need improvement

The thermal instability of modafinil and its analogues under standard GC conditions makes distinguishing it from its analogues difficult. Although fluorinated analogues were clearly distinguishable from non-fluorinated compounds, it was not possible to clearly distinguish between the similar fluorinated compounds. It might be beneficial to see if there were better signals at lower injection temperatures, although this may give problems with incomplete volatilisation. When identification of the exact species present is required, other techniques, such as LC-MS, may have to be employed.

Related Links

Drug Testing and Analysis, 2016, Early View paper. Dowling et al. Outsmarted by nooptropics? 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 analogue.

Indian Journal of Pharmacology, 2009, 41, 278-283. Dubey et al. A novel study of screening and confirmation of modafinil, adrafinil and their metabolite modafinilic acid under EI-GC-MS and ESI-LC-MS-MS ionization.

Wikipedia, Modafinil.

Article by Ryan De Vooght-Johnson

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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