Original enantioseparation of illicit fentanyls with cellulose-based chiral stationary phases under polar-ionic conditions

• Published in: Journal of Chromatography A Vol. 1643; p. 462088
• Main Authors: Varfaj, Ina, Protti, Michele, Cirrincione, Marco, Carotti, Andrea, Mercolini, Laura, Sardella, Roccaldo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 26.04.2021
• Subjects: cellulose; Cellulose - chemistry; Chloromethyl phenylcarbamate-based chiral stationary phases; chromatography; Chromatography, High Pressure Liquid - methods; enantiomers; ethanol; fentanyl; Fentanyl - analogs & derivatives; Fentanyl - analysis; Fentanyl - isolation & purification; formic acid; heroin; High-resolution mass spectrometry; Ionic additives; isopropyl alcohol; Mass Spectrometry; New Psychoactive Substances (NPSs); Stereoisomerism; therapeutics; Ionic additives; Chloromethyl phenylcarbamate-based chiral stationary phases; High-resolution mass spectrometry; New Psychoactive Substances (NPSs)
• ISSN: 0021-9673; 1873-3778
• DOI: 10.1016/j.chroma.2021.462088

•Cellulose chloromethyl phenylcarbamate CSPs enable the enantioseparation of fentanyls.•Polar-ionic conditions are suitable to obtain high levels of enantioselectivity.•The developed methods are fully compatible with HRMS detectors. Fentanyl analogues used in therapy and a range of highly potent non-pharmaceutical fentanyl derivatives are subject to international control, as the latter are increasingly being synthesized illicitly and sold as ‘synthetic heroin’, or mixed with heroin. A significant number of hospitalizations and deaths have been reported in the EU and USA following the use of illicitly synthesized fentanyl derivatives. It has been unequivocally demonstrated that the enantiomers of fentanyl derivatives exhibit different pharmaco-toxicological profiles, which makes crucial to avail of suitable analytical methods enabling investigations at a “stereochemical level”. Chromatographic methods useful to discriminate the enantioseparation of fentanyls and their derivatives are still missing in the literature. This is the first study in which the enantioseparation of four fentanyl derivatives, that is, (±)-trans-3-methyl norfentanyl, (±)-cis-3-methyl norfentanyl, β-hydroxyfentanyl, and β-hydroxythiofentanyl, has been obtained under polar-ionic conditions. Indeed, the use of ACN-based mobile phases with minor amounts of either 2-propanol or ethanol (plus diethylamine and formic acid as ionic additives) allowed obtaining enantioseparation and enantioresolution factors up to 1.83 and 7.02, respectively. For the study, the two chiral stationary phases cellulose tris(3-chloro-4-methylphenylcarbamate) and cellulose tris(4-chloro-3-methylphenylcarbamate) were used, displaying a remarkably different performance towards the enantioseparation of (±)-cis-3-methyl norfentanyl. Chiral LC analyses with a high-resolution mass spectrometry detector were also carried out in order to confirm the obtained data and demonstrate the suitability and compatibility of the optimized mobile phases with mass spectrometric systems.