2023 FDA Science Forum
Development and Validation of an Analytical Method to Identify and Quantitate Novel Modafinil Analogs in Dietary Supplements
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Contributing OfficeOffice of Regulatory Affairs
Abstract
Drugs that boost concentration or wakefulness (nootropics, eugeroics) are prescribed for specific medical conditions. Nootropics have been used as recreational drugs and have also been found in dietary supplements. Modafinil (brand name Provigil®) is a Schedule IV drug used for the treatment of narcolepsy and sleep disorders in the U.S. Analogs of modafinil, including adrafinil, remain unapproved and/or unscheduled.
The lack of scheduling has made these analogs a popular target for recreational use and inclusion in dietary supplements. However, the use of controlled substances without the care of a physician presents a public health risk. A preliminary untargeted analysis in our laboratory revealed the presence of adrafinil in several dietary supplements. A liquid chromatography high resolution mass spectrometry (LC-HRMS) method was developed to separate modafinil from four novel unscheduled modafinil analogs: adrafinil, CRL-40,940, CRL-40,941, and N-methyl-4,4-difluoromodafinil.
The mass resolution of the Thermo Q-Exactive platform can differentiate unknowns of similar mass better than unit mass resolution instruments. The method discussed here can differentiate different modafinil analogs from one another, determining whether those drugs are scheduled drugs or unscheduled novel analogs. For this method, dietary supplement tablets containing no modafinil analogs were ground to a fine powder and used as blank matrix. The extraction consisted of weighing 100 mg of supplement powder, adding 20 mL acetonitrile, and shaking for 30 minutes. The mixture was allowed to settle.
Then 10 µL was diluted to 50 mL with a 90:10 mixture of water: acetonitrile containing 0.1% formic acid. The extract was subsequently separated on a Thermo Hypersil Gold C18 column, and identities were confirmed using retention time, exact mass of parent ions, and exact mass of fragment ions. Our standard curve spanned 10 ng/mL – 450 ng/mL with good linearity over this range. This LC-HRMS method could be used alone or as a confirmatory method after suspected modafinil analogs are detected in our laboratory through HRMS untargeted screening of dietary supplements. The identification of modafinil and its analogs in this context important so that consumers are not, knowingly or unknowingly, consuming these active pharmaceutical ingredients in dietary supplements.
