Analysis of impurities of cannabidiol from hemp. Isolation, characterization and synthesis of cannabidibutol, the novel cannabidiol butyl analog

• Published in: Journal of pharmaceutical and biomedical analysis 2019-10, Vol.175, p.112752-112752, Article 112752
• Main Authors: Citti, Cinzia, Linciano, Pasquale, Forni, Flavio, Vandelli, Maria Angela, Gigli, Giuseppe, Laganà, Aldo, Cannazza, Giuseppe
• Format: Article
• Language: English
• Subjects: Cannabidibutol; Cannabidiol; Cannabidiol - chemistry; Cannabidivarin; Cannabinoids - chemistry; Cannabis - chemistry; CBD-C4; Chromatography, High Pressure Liquid - methods; LC-HRMS; LC-UV; Tandem Mass Spectrometry - methods
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2019.06.049

•Cannabidivarin (CBDV) and cannabidibutol (CBDB) are the two major impurities in cannabidiol (CBD) extracted from hemp.•CBDB was isolated and fully characterized for the first time.•A stereoselective synthesis was carried out and absolute configuration assigned to natural CBD.•A perfect match of all properties of isolated CBDB and synthesized CBDB was obtained.•A simple and selective HPLC-UV method was developed, validated and applied to ten batches of commercial CBD. Cannabidiol (CBD), one of the two major active principles present in Cannabis sativa, is gaining great interest among the scientific community for its pharmaceutical, nutraceutical and cosmetic applications. CBD can be prepared either by chemical synthesis or extraction from Cannabis sativa (hemp). The latter is more convenient from several points of view, including environmental and economic, but mainly for the absence of harmful organic solvents generally employed in the chemical synthesis. Although CBD produced by hemp extraction is the most widely employed, it carries two major impurities. The first one is the already known cannabidivarin (CBDV), whereas the second one is supposed to be the butyl analog of CBD with a four-term alkyl side chain. In this work, we report the isolation by semi-preparative liquid chromatography and the unambiguous identification of this second impurity. A comprehensive spectroscopic characterization, including NMR, UV, IR, circular dichroism and high-resolution mass spectrometry (HRMS), was carried out on this natural cannabinoid. In order to confirm its absolute configuration and chemical structure, the stereoisomer (1R,6R) of the supposed cannabinoid was synthesized and the physicochemical and spectroscopic properties, along with the stereochemistry, matched those of the natural isolated molecule. According to the International Nonproprietary Name, we suggested the name of cannabidibutol (CBDB) for this cannabinoid. Lastly, an HPLC-UV method was developed and validated for the qualitative and quantitative determination of CBDV and CBDB in samples of CBD extracted from hemp and produced according to Good Manufacturing Practices regulations for pharmaceutical and cosmetic use.