Stability studies represent an essential component of pharmaceutical development, enabling critical evaluation of the therapeutic potential of an active pharmaceutical ingredient (API) or a final pharmaceutical product under the influence of various environmental factors. The aim of the present study was to investigate the chemical stability of cannabidiol (CBD) in the form of a solid powder (hereinafter referred to as CBD powder) and also dissolved in sunflower oil. We performed stress studies in accordance with the International Conference on Harmonization (ICH) guidelines, where 5 mg of marketed CBD in the form of a solid powder and in form of oil solution were exposed for 7 and 14, 30, 60, 90, 180, 270, and 365 days to precisely defined temperature and humidity conditions, 25 °C ± 2 °C/60% RH ± 5% and 40 °C ± 2 °C/75% RH ± 5% in both open and closed vials in the dark. CBD powder was significantly more stable than CBD in oil solution. Such finding is important because CBD is often administered dissolved in oil matrix in practice due to very good bioavailability. Thus, the knowledge on admissible shelf time is of paramount importance.

Department of Analytical Chemistry University of Chemistry and Technology Prague Technická 5 16628 Prague Czech Republic

Forensic Laboratory of Biologically Active Substances Department of Chemistry of Natural Compounds University of Chemistry and Technology Prague Technická 5 16628 Prague Czech Republic

Institute of Chemical Process Fundamentals of CAS v v i Rozvojová 135 16502 Prague Czech Republic

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Lee G., Grovey B., Furnish T., Wallace M. Medical Cannabis for Neuropathic Pain. Curr. Pain Headache Rep. 2018;22:8. doi: 10.1007/s11916-018-0658-8. PubMed DOI

Tomida I., Pertwee R.G., Azuara-Blanco A. Cannabinoids and glaucoma. Br. J. Ophthalmol. 2004;88:708–713. doi: 10.1136/bjo.2003.032250. PubMed DOI PMC

Sansone R.A., Sansone L.A. Marijuana and body weight. Innov. Clin. Neurosci. 2014;11:50–54. PubMed PMC

Parker L.A., Rock E.M., Limebeer C.L. Regulation of nausea and vomiting by cannabinoids. Br. J. Pharmacol. 2011;163:1411–1422. doi: 10.1111/j.1476-5381.2010.01176.x. PubMed DOI PMC

Pacifici R., Marchei E., Salvatore F., Guandalini L., Busardo F.P., Pichini S. Evaluation of cannabinoids concentration and stability in standardized preparations of cannabis tea and cannabis oil by ultra-high performance liquid chromatography tandem mass spectrometry. Clin. Chem. Lab. Med. 2017;55:1555–1563. doi: 10.1515/cclm-2016-1060. PubMed DOI

Beardsley P.M., Brands B., Ekwere I.T., Elliott S., Gysling K., Jain R., Kaduri P., Kitanaka J., Rahimi-Movaghar A., Nudmamud-Thanoi S., et al. WHO Expert Committee on Drug Dependance: No. 1013, Cannabidiol. WHO Press; Geneva, Switzerland: 2018. pp. 1–27.

Szaflarski J.P., Bebin E.M., Comi A.M., Patel A.D., Joshi C., Checketts D., Beal J.C., Laux L.C., De Boer L.M., Wong M.H., et al. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results. Epilepsia. 2018;59:1540–1548. doi: 10.1111/epi.14477. PubMed DOI PMC

Leweke F.M., Piomelli D., Pahlisch F., Muhl D., Gerth C.W., Hoyer C., Klosterkotter J., Hellmich M.R., Koethe D. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl. Psychiatry. 2012;2:94. doi: 10.1038/tp.2012.15. PubMed DOI PMC

Sulé-Suso J., Watson N.A., Van Pittius D.G., Jegannathen A. Striking lung cancer response to self-administration of cannabidiol: A case report and literature review. SAGE Open Med. Case Rep. 2019;7:2050313X19832160. doi: 10.1177/2050313X19832160. PubMed DOI PMC

Martinez-Martinez E., Martin-Ruiz A., Martin P., Calvo V., Provencio M., Garcia J.M. CB2 cannabinoid receptor activation promotes colon cancer progression via AKT/GSK3beta signaling pathway. Oncotarget. 2016;7:68781–68791. doi: 10.18632/oncotarget.11968. PubMed DOI PMC

Lindholst C. Long term stability of cannabis resin and cannabis extracts. Aust. J. Forensic Sci. 2010;42:181–190. doi: 10.1080/00450610903258144. DOI

Carbone M., Castelluccio F., Daniele A., Sutton A., Ligresti A., Di Marzo V., Gavagnin M. Chemical characterisation of oxidative degradation products of Δ9-THC. Tetrahedron. 2010;66:9497–9501. doi: 10.1016/j.tet.2010.10.025. DOI

Layton C., Runco J., Aubin A. Forced Degradation of Cannabidiol. Volume 6. Waters Corporation; Milford, MA, USA: 2016. p. 720005766EN.

International Conference on Harmonization Guideline: Impurities: Guideline for Residual Solvents Q3C (R5) Volume 4. ICH Steering Committee; London, UK: 2005. [(accessed on 25 July 2020)]. pp. 1–25. Available online: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-33.pdf.

Guidance for Industry Q1A(R2): Stability Testing of New Drug Substances and Products. US. Food and Drug Administration; Rockville, MD, USA: 2003. [(accessed on 25 July 2020)]. Available online: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q1ar2-stability-testing-new-drug-substances-and-products.

Palazzoli F., Citti C., Licata M., Vilella A., Manca L., Zoli M., Vandelli M.A., Forni F., Cannazza G. Development of a simple and sensitive liquid chromatography triple quadrupole mass spectrometry (LC–MS/MS) method for the determination of cannabidiol (CBD), Δ9-tetrahydrocannabinol (THC) and its metabolites in rat whole blood after oral administration of a single high dose of CBD. J. Pharm. Biomed. Anal. 2018;150:25–32. PubMed

Citti C., Ciccarella G., Braghiroli D., Parenti C., Vandelli M.A., Cannazza G. Medicinal cannabis: Principal cannabinoids concentration and their stability evaluated by a high performance liquid chromatography coupled to diode array and quadrupole time of flight mass spectrometry method. J. Pharm. Biomed. Anal. 2016;128:201–209. doi: 10.1016/j.jpba.2016.05.033. PubMed DOI

Deidda R., Avohou H.T., Baronti R., Davolio P.L., Pasquini B., Del Bubba M., Hubert C., Hubert P., Orlandini S., Furlanetto S. Analytical quality by design: Development and control strategy for a LC method to evaluate the cannabinoids content in cannabis olive oil extracts. J. Pharm. Biomed. Anal. 2019;166:326–335. doi: 10.1016/j.jpba.2019.01.032. PubMed DOI

Nemeškalová A., Hajkova K., Mikulu L., Sykora D., Kuchar M. Combination of UV and MS/MS detection for the LC analysis of cannabidiol-rich products. Talanta. 2020;219:121250. doi: 10.1016/j.talanta.2020.121250. PubMed DOI

Zgair A., Wong J.C., Sabri A., Fischer P.M., Barrett D.A., Constantinescu C.S., Gershkovich P. Development of a simple and sensitive HPLC-UV method for the simultaneous determination of cannabidiol and Delta(9)-tetrahydrocannabinol in rat plasma. J. Pharm. Biomed. Anal. 2015;114:145–151. doi: 10.1016/j.jpba.2015.05.019. PubMed DOI

Turner C.E., Hadley K.W., Fetterman P.S., Doorenbos N.J., Quimby M.W., Waller C. Constituents of Cannabis sativa L. IV: Stability of cannabinoids in stored plant material. J. Pharm. Sci. 1973;62:1601–1605. doi: 10.1002/jps.2600621005. PubMed DOI

Trofin I., Dabija G., Vaireanu D.I., Laurentiu F. The influence of long-term storage conditions on the stability of cannabinoids derived from cannabis resin. Rev. Chim. 2012;63:422–427.

Maskan M. Change in colour and rheological behaviour of sunflower seed oil during frying after adsorbent treatment of used oil. Eur. Food Res. Technol. 2003;218:20–25. doi: 10.1007/s00217-003-0807-z. DOI

Tan Y.A., Ong S.H., Berger K.G., Oon H.H., Poh L.B. A study of the cause of rapid color development of heated refined palm oil. J. Am. Oil Chem. Soc. 1985;62:999–1006. doi: 10.1007/BF02935701. DOI

Stevenson S.G., Vaisey-Genser M., Eskin N.A.M. Quality control in the use of deep frying oils. J. Am. Oil Chem. Soc. 1984;61:1102–1108. doi: 10.1007/BF02636232. DOI

Pavlovic R., Nenna G., Calvi L., Panseri S., Borgonovo G., Giupponi L., Cannazza G., Giorgi A. Quality traits of “Cannabidiol oils”: Cannabinoids tontent, terpene fingerprint and oxidation stability of European commercially available preparations. Molecules. 2018;23:1230. doi: 10.3390/molecules23051230. PubMed DOI PMC

Fairbairn J.W., Liebmann J.A., Rowan M.G. The stability of cannabis and its preparations on storage. J. Pharm. Pharmacol. 1976;28:1–7. doi: 10.1111/j.2042-7158.1976.tb04014.x. PubMed DOI

Turner C.E., Henry J.T. Constituents of Cannabis sativa L. IX: Stability of synthetic and naturally occurring cannabinoids in chloroform. J. Pharm. Sci. 1975;64:357–359. doi: 10.1002/jps.2600640244. PubMed DOI