cannabinoids; quality by design; Cannabis sativa; HPLC; olive oil extracts; control strategy
Abstract :
[en] Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) are considered as the most interesting cannabinoids in Cannabis sativa L. for the clinical practice. Since 2013, the Italian law allows pharmacists to prepare and dispense cannabis extracts to patients under medical prescription, and requires the evaluation of CBD and Δ9-THC content in cannabis extracts before sale. Cannabis olive oil extracts are prepared from dried female cannabis inflorescences, but a standard protocol is still missing. In this study, a fast RP-HPLC/UV method has been developed to quantify CBD and Δ9-THC in cannabis olive oil extracts. The analytical quality by design strategy has been applied to the method development, setting critical resolution and total analysis time as critical method attributes (CMAs), and selecting column temperature, buffer pH and flow rate as critical method parameters. Information from Doehlert Design in response surface methodology combined to Monte-Carlo simulations led to draw the risk of failure maps and to identify the method operable design region. The method was validated according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines and then implemented in routine analysis. A control strategy based on system control charts was planned to monitor the developed method performances. Evaluation data were recorded over a period of one year of routine use, and both the CMAs showed values within the specifications in every analysis performed. Hence, a new risk evaluation for the future performances of the method was achieved by using a Bayesian approach based on the routine use data, computing the future distribution of the two CMAs. Finally, a study focusing on the monitoring of CBD and Δ9-THC concentrations in cannabis olive oil extracts was carried out. The developed method was applied to 459 extracts. The statistical analysis of the obtained results highlighted a wide variability in terms of concentrations among different samples from the same starting typology of cannabis, underlining the compelling need of a standardised procedure to harmonise the preparation of the extracts.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Deidda, Riccardo ; Université de Liège - ULiège > Département de pharmacie > Chimie analytique
Avohou, Tonakpon Hermane ; Université de Liège - ULiège > Département de pharmacie > Chimie analytique
Baronti, Roberto; Azienda USL Toscana centro - > Laboratory of Clinical Toxicology and Antidoping, Via di San Salvi 12, 50135 Florence, Italy
Davolio, Pier Luigi; Farmacia del Madonnone, Via Aretina 9r, 50135 Florence, Italy
Pasquini, Benedetta; Università degli Studi di Firenze - UniFI > Department of Chemistry “U. Schiff”, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy
Del Bubba, Massimo; Università degli Studi di Firenze - UniFI > Department of Chemistry “U. Schiff”, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy
Hubert, Cédric ; Université de Liège - ULiège > Département de pharmacie > Chimie analytique
Hubert, Philippe ; Université de Liège - ULiège > Département de pharmacie > Chimie analytique
Orlandini, Serena; Università degli Studi di Firenze - UniFI > Department of Chemistry “U. Schiff”, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy
Furlanetto, Sandra; Università degli Studi di Firenze - UniFI > Department of Chemistry “U. Schiff”, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy
Language :
English
Title :
Analytical quality by design: development and control strategy for a LC method to evaluate the cannabinoids content in cannabis olive oil extracts
Flores-Sanchez, I.J., Verpoorte, R., PKS activities and biosynthesis of cannabinoids and flavonoids in Cannabis sativa L. plants. Plant Cell Physiol. 49 (2008), 1767–1782.
Aizpurua-Olaizola, O., Omar, J., Navarro, P., Olivares, M., Etxebarria, N., Usobiaga, A., Identification and quantification of cannabinoids in Cannabis sativa L. plants by high performance liquid chromatography-mass spectrometry. Anal. Bioanal. Chem. 406 (2014), 7549–7560.
Savage, S.R., Romero-Sandoval, A., Schatman, M., Wallace, M., Fanciullo, G., McCarberg, B., Ware, M., Cannabis in pain treatment: clinical and research considerations. J. Pain 17 (2016), 654–668.
Citti, C., Braghiroli, D., Vandelli, M.A., Cannazza, G., Pharmaceutical and biomedical analysis of cannabinoids: a critical review. J. Pharm. Biomed. Anal. 147 (2018), 565–579.
Thomas, B.F., Pollard, G.T., Preparation and distribution of cannabis and cannabis-derived dosage formulations for investigational and therapeutic use in the United States. Front. Pharmacol. 7 (2016), 1–6 Article 285.
Russo, E., Guy, G.W., A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med. Hypotheses 66 (2006), 234–246.
Romano, L.L., Hazekamp, A., Cannabis oil: chemical evaluation of an upcoming cannabis-based medicine. Cannabinoids 1 (2013), 1–11.
Carcieri, C., Tomasello, C., Simiele, M., De Nicolò A., Avataneo, V., Canzoneri, L., Cusato, J., Di Perri, G., D'Avolio, A., Cannabinoids concentration variability in cannabis olive oil galenic preparations. J. Pharm. Pharmacol. 70 (2018), 143–149.
Ambach, L., Penitschka, F., Broillet, A., König, S., Weinmann, W., Bernhard, W., Simultaneous quantification of delta-9-THC, THC-acid A, CBN and CBD in seized drugs using HPLC-DAD. Forensic Sci. Int. 243 (2014), 107–111.
De Backer, B., Debrus, B., Lebrun, P., Theunis, L., Dubois, N., Decock, L., Verstraete, A., Hubert, P., Charlier, C., Innovative development and validation of an HPLC/DAD method for the qualitative and quantitative determination of major cannabinoids in cannabis plant material. J. Chromatogr. B 877 (2009), 4115–4124.
Peschel, W., Politi, M., 1 H NMR and HPLC/DAD for Cannabis sativa L. chemotype distinction, extract profiling and specification. Talanta 140 (2015), 150–165.
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. 128 (2016), 201–209.
Brighenti, V., Pellati, F., Steinbach, M., Maran, D., Benvenuti, S., Development of a new extraction technique and HPLC method for the analysis of non-psychoactive cannabinoids in fibre-type Cannabis sativa L. (hemp). J. Pharm. Biomed. Anal. 143 (2017), 228–236.
Pacifici, R., Marchei, E., Salvatore, F., Guandalini, L., Busardò 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. 55 (2017), 1555–1563.
Casiraghi, A., Roda, G., Casagni, E., Cristina, C., Musazzi, U.M., Franzè S., Rocco, P., Giuliani, C., Fico, G., Minghetti, P., Gambaro, V., Extraction method and analysis of cannabinoids in cannabis olive oil preparations. Planta Med. 84 (2018), 242–249.
Citti, C., Battisti, U.M., Braghiroli, D., Ciccarella, G., Schmid, M., Vandelli, M.A., Cannazza, G., A metabolomic approach applied to a liquid chromatography coupled to high-resolution tandem mass spectrometry method (HPLC-ESI-HRMS/MS): towards the comprehensive evaluation of the chemical composition of cannabis medical extracts. Phytochem. Anal. 29 (2018), 144–155.
Fekete, S., Sadat-Noorbakhsh, V., Schelling, C., Molnár, I., Guillarme, D., Rudaz, S., Veuthey, J.L., Implementation of a generic liquid chromatographic method development workflow: application to the analysis of phytocannabinoids and Cannabis sativa extracts. J. Pharm. Biomed. Anal. 155 (2018), 116–124.
Decreto 9 novembre 2015: Funzioni di Organismo statale per la cannabis previsto dagli articoli 23 e 28 della convenzione unica sugli stupefacenti del 1961, come modificata nel. 1972 (15A08888) (GU Serie Generale n. 279 del 30-11-2015). Available at: http://www.gazzettaufficiale.it/eli/id/2015/11/30/15A08888/sg;jsessionid=p1rnwNujUKlqQ5azhA Q95A__.ntc-as3-guri2a (Accessed 14 November 2018).
Orlandini, S., Pinzauti, S., Furlanetto, S., Application of quality by design to the development of analytical separation methods. Anal. Bioanal. Chem. 405 (2013), 443–450.
Dispas, A., Avohou, H.T., Lebrun, P., Hubert, Ph., Hubert, C., ‘Quality by Design’ approach for the analysis of impurities in pharmaceutical drug products and drug substances. Trends Analyt. Chem. 101 (2018), 24–33.
Deidda, R., Orlandini, S., Hubert, Ph., Hubert, C., Risk-based approach for method development in pharmaceutical quality control context: a critical review. J. Pharm. Biomed. Anal. 161 (2018), 110–121.
ICH harmonised tripartite guideline. Pharmaceutical development Q8(R2). International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, 2009.
Orlandini, S., Gotti, R., Furlanetto, S., Multivariate optimization of capillary electrophoresis methods: a critical review. J. Pharm. Biomed. Anal. 87 (2014), 290–307.
Piepel, G., Pasquini, B., Cooley, S., Heredia-Langner, A., Orlandini, S., Furlanetto, S., Mixture-process variable approach to optimize a microemulsion electrokinetic chromatography method for the quality control of a nutraceutical based on coenzyme Q10. Talanta 97 (2012), 73–82.
Borman, P., Chatfield, M., Nethercote, P., Thompson, D., Truman, K., The application of quality by design to analytical methods. Pharm. Technol. 31 (2007), 142–152.
Tumpa, A., Stajić A., Jančić-Stojanović B., Medenica, M., Quality by Design in the development of hydrophilic interaction liquid chromatography method with gradient elution for the analysis of olanzapine. J. Pharm. Biomed. Anal. 134 (2017), 18–26.
Nompari, L., Orlandini, S., Pasquini, B., Campa, C., Rovini, M., Del Bubba, M., Furlanetto, S., Quality by design approach in the development of an ultra-high-performance liquid chromatography method for Bexsero meningococcal group B vaccine. Talanta 178 (2018), 552–562.
Dispas, A., Desfontaine, V., Andri, B., Lebrun, P., Kotoni, D., Clarke, A., Guillarme, D., Hubert, Ph., Quantitative determination of salbutamol sulfate impurities using achiral supercritical fluid chromatography. J. Pharm. Biomed. Anal. 134 (2017), 170–180.
Jambo, H., Dispas, A., Avohou, H.T., André S., Hubert, C., Lebrun, P., Ziemons, E., Hubert, Ph., Implementation of a generic SFC-MS method for the quality control of potentially counterfeited medicinal cannabis with synthetic cannabinoids. J. Chromatogr. B 1092 (2018), 332–342.
Orlandini, S., Pasquini, B., Caprini, C., Del Bubba, M., Douša, M., Pinzauti, S., Furlanetto, S., Enantioseparation and impurity determination of ambrisentan using cyclodextrin-modified micellar electrokinetic chromatography: visualizing the design space within quality by design framework. J. Chromatogr. A 1467 (2016), 363–371.
Pasquini, B., Orlandini, S., Villar-Navarro, M., Caprini, C., Del Bubba, M., Douša, M., Giuffrida, A., Gotti, R., Furlanetto, S., Chiral capillary zone electrophoresis in enantioseparation and analysis of cinacalcet impurities: use of quality by design principles in method development. J. Chromatogr. A 1568 (2018), 205–213.
ICH harmonised tripartite guideline. Pharmaceutical quality systems Q10. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, 2008.
MODDE v. 10. 2013, MKS Umetrics AB, Sweden.
Mathieu, D., Nony, J., Phan-Tan-Luu, R., NEMROD-W. 2012, LPRAI sarl, Marseille.
R Core Team, R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing, Vienna, Austria, https://www.R-project.org/ (Accessed 22 November 2018).
Avohou, H.T., Hubert, C., Debrus, B., Lebrun, P., Rudaz, S., Boulanger, B., Hubert, P., Statistical methods in quality by design approach to liquid chromatography methods development. Fekete, S., Molnár, I., (eds.) Software-Assisted Method Development in High Performance Liquid Chromatograph, 2018, World Scientific, London, 109–150.
Gelman, A., Carlin, J.B., Stern, H.S., Dunson, D.B., Vehtari, A., Donald, B., Bayesian Data Analysis. 3rd ed., 2013, Chapman and Hall/CRC, New York.
Orlandini, S., Pasquini, B., Caprini, C., Del Bubba, N., Squarcialupi, L., Colotta, V., Furlanetto, S., A comprehensive strategy in the development of a cyclodextrin-modified microemulsion electrokinetic chromatographic method for the assay of diclofenac and its impurities; Mixture-process variable experiments and quality by design. J. Chromatogr. A 1466 (2016), 189–198.
Ishikawa, K., What is total quality control?. The Japanese Way, 1985, Prentice-Hall, Englewood Cliffs.
Eriksson, L., Johansson, E., Kettaneh-Wold, N., Wikström, C., Wold, S., Design of Experiments – Principles and Applications. 2008, MKS Umetrics AB, Umeå Sweden.
ICH harmonised tripartite guideline. Validation of analytical procedures: text and methodology Q2(R1). International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, 2005.
Furlanetto, S., Orlandini, S., La Porta, E., Coran, S., Pinzauti, S., Optimization and validation of a CZE method for rufloxacin hydrochloride determination in coated tablets. J. Pharm. Biomed. Anal. 28 (2002), 1161–1171.
Peterson, J.J., Yahyah, M., Lief, K., Hodnett, N., Predictive distributions for constructing the ICH Q8 design space. Reklaitis, G.V., Seymour, C., García‐Munoz, S., (eds.) Comprehensive Quality by Design for Pharmaceutical Product Development and Manufacture, 2017, John Wiley & Sons, Hoboken, 55–70.
