Optimization of cyclodextrin-assisted green extraction of cannabidiol from industrial hemp leaves: Release behavior, permeability, bioactivity, and stability
Graphical Abstract
Introduction
Hemp (Cannabis sativa L.) is an annual herbaceous plant of the Cannabis genus. It is believed that it first appeared in central Asia (Baker et al., 2003). Hemp has been employed as a raw material of textiles, oil, food products, or medicines for thousands of years. Besides, it has a complex chemical composition with more than 500 phytochemicals including flavonoids, fatty acids, cannabinoids, terpenoids, alkaloids, and stilbenoids (Zampachova et al., 2021). Cannabinoids, a group of terpenophenolic compounds containing twenty-one carbon atoms, are the most notable metabolites of hemp. They mainly accumulate in the leaves and inflorescences of the plant. Nowadays, more than 70 cannabinoids have been determined, among which, cannabidiol (CBD) and tetrahydrocannabinol (THC) are the most valuable compounds. Hemp is generally divided into two types based on the cannabinoid profile: a drug-type plant called marijuana (THC ≥ 0.3 wt. %) and a fiber-type plant, namely industrial hemp (THC < 0.3 wt. %) (Zampachova et al., 2021). The cultivation and commercialization of marijuana are strictly controlled or prohibited due to the psychoactive effect of THC. But industrial hemp has been extensively used as a source of functional foods, cosmetics, and drugs. CBD is an abundant cannabinoid and exhibits excellent biological activities, such as antioxidative, anxiolytic, antibacterial, anticancer, and anti-inflammatory activities (Burstein, 2015, Devinsky et al., 2014). Epidiolex®, a drug based on highly purified CBD, was approved by FDA and EMA for treating seizures. Meanwhile, the commercialization of industrial products with CBD has a significant development. There are many kinds of industrial products such as beverages, beer, health products, cosmetics, daily chemical products, drugs, and electronic cigarettes (Peng and Shahidi, 2021). Because of its great applied value, studies about the extraction of CBD are gradually increasing in recent years.
Conventional organic solvents, such as ethyl ether, chloroform, hexane, methanol, and butane were commonly employed for CBD extraction from hemp. For example, 80 % methanol was used as the extractant to obtain CBD from hemp (Agarwal et al., 2018). These methods have the advantages of easy operation and low cost, but long extraction time could not meet the requirements of large-scale production. More importantly, some solvents like chloroform, hexane, and ethyl ether could cause serious pollution. To improve extraction yield, some new methods including microwave-assisted extraction (Fiorini et al., 2020) and supercritical CO2 extraction (Attard et al., 2018, Marzorati et al., 2020) were also developed. However, these methods need high cost and sophisticated equipment, which are not appropriate for industrial production. Recently, deep eutectic solvents (DESs) (Cai et al., 2019) and ionic liquids (ILs) (Cai et al., 2020) were applied to extract CBD. The recovery yield of CBD using DESs could reach 81.46 %. But the selection of suitable DESs or ILs is difficult. Furthermore, most of ILs and DESs could not be used because of their toxicity. Therefore, green, low-cost, and efficient methods are urgently demanded for the extraction of CBD.
The green chemistry method aims to obtain a higher extraction yield with less energy consumption, extraction time, and costs (Fernandes et al., 2021). Cyclodextrin (CD) assisted extraction is an emerging green method with great potential. CDs are non-polluting and non-toxic cyclic oligosaccharides that are generally recognized as safe (GRAS). It is well known that they can improve the solubility and stability of bioactive molecules by encapsulation. Meanwhile, as extraction boosters, CDs can improve the extraction of natural products from plants by forming inclusion complexes with them. In recent years, β-cyclodextrin (β-CD) has been successfully used for the extraction of phytochemicals, such as polyphenols from Punica granatum (Diamanti et al., 2017), functional compounds from Piper nigrum (Favre et al., 2020), and betanin from Beta vulgaris (Tutunchi et al., 2019). It was also found that the total flavonols were extracted from apple pomace at 0.728 mg/g level by β-CD while the aqueous extraction was 0.314 mg/g (Parmar et al., 2015). Therefore, CD-assisted extraction has been proved to be an eco-friendly and efficient method. The extraction ability of aqueous solution of CDs can be enhanced by employing co-solvents. To ensure the green extraction procedure, the co-solvents are limited to food-grade solvents such as ethanol. Based on its advantages, CD-assisted extraction can be used to recover CBD from hemp.
In this study, CD-assisted extraction was studied to improve the extraction yield of CBD (YCBD) from hemp leaves and to enhance the release behavior, permeability, bioactivity, and stability of the extract. Single-factor experiments and response surface methodology (RSM) were used to optimize extraction conditions. Powder X-ray diffraction (PXRD), fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and particle size distribution were employed to speculate the interaction between CDs and CBD. Subsequently, the influence of CDs on the release behavior, permeability, bioactivity, and stability of the extract was explored. The novelty of this manuscript was that CD-assisted extraction was used for the first time to extract CBD from industrial hemp and a high recovery yield was expected. The interaction between CDs and CBD was also studied to explain the efficient extraction. Besides, the permeability, bioactivity, and stability of the extract were studied to evaluate the influence of CD-assisted extraction.
Section snippets
Materials and reagents
Hemp leaves and CBD standard were provided by Yunnan Hempmon Pharmaceutical Co., Ltd. (Yunnan, China). Cannabidiolic acid (CBDA) is not stable and it is easily decomposed to CBD by decarboxylation. At present, the most common method of decarboxylation is heating the sample (Olejar et al., 2021). A study found that maximum CBD conversion from CBDA occurred after 40 min at 140 ℃ (Moreno et al., 2020). And we determined the decarboxylation conditions after consulting the relevant experts. The
Effects of different CDs on YCBD
When the extraction conditions were extraction temperature = 40 ℃, RL/S = 30 mL/g, extraction time = 1 h, RD/H = 1, and ethanol concentration = 60 %, effects of different CDs on YCBD were displayed in Fig. 1(A). Compared with the extraction without CDs (0.448 mg/g), YCBD of CD-assisted extraction had a significant increase. The maximum YCBD of DM-βCD was 1.010 mg/g. The higher YCBD could be attributed to the inclusion by CDs. On the one hand, the hydrophobic cavity of CDs supplied a
Conclusions
The optimal extraction conditions were as follows: extraction temperature was 40 ℃, RL/S was 25.17 mL/g, extraction time was 74.4 min, RD/H was 1.17, and ethanol concentration was 60%. YCBD under the conditions was 1.075 ± 0.012 mg/g and the recovery yield of CBD was about 87.19%, which indicated that the extract had a higher proportion of CBD. Then PXRD, FT-IR, DSC, SEM, and particle size distribution were used to demonstrate that the complexation of DM-βCD promoted the extraction of CBD from
CRediT authorship contribution statement
Hang Li: Investigation, Methodology, Writing – original draft, Data curation, Writing – review & editing. Qing-Sheng Zhao: Investigation, Methodology, Writing – review & editing. Li-Wei Wang: Writing – review & editing, Methodology. Sen-Lin Chang: Writing – review & editing. Pei-Dong Wang: Methodology. Bing Zhao: Investigation, Project administration, Writing – review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors gratefully appreciate the supports from Yunnan Hempmon Pharmaceutical Co., Ltd.
References (44)
- et al.
Utilisation of supercritical fluids for the effective extraction of waxes and Cannabidiol (CBD) from hemp wastes
Ind. Crop. Prod.
(2018) - et al.
The therapeutic potential of cannabis
Lancet Neurol.
(2003) Cannabidiol (CBD) and its analogs: a review of their effects on inflammation
Bioorg. Med. Chem.
(2015)- et al.
Novel gamma-cyclodextrin-metal-organic frameworks for encapsulation of curcumin with improved loading capacity, physicochemical stability and controlled release properties
Food Chem.
(2021) - et al.
Green extraction of polyphenols from whole pomegranate fruit using cyclodextrins
Food Chem.
(2017) - et al.
New deep eutectic solvent assisted extraction of highly pure lignin from maritime pine sawdust (Pinus pinaster Ait.)
Int. J. Biol. Macromol.
(2021) - et al.
Cyclodextrin-based ultrasonic-assisted microwave extraction and HPLC-PDA-ESI-ITMSn separation and identification of hydrophilic and hydrophobic components of Polygonum cuspidatum: a green, rapid and effective process
Ind. Crop. Prod.
(2016) - et al.
Chapter 53 - Cannabis sativa and Hemp
- et al.
Inclusion complexes of cannabidiol with β-cyclodextrin and its derivative: physicochemical properties, water solubility, and antioxidant activity
J. Mol. Liq.
(2021) - et al.
An investigation into the supramolecular structure, solubility, stability and antioxidant activity of rutin/cyclodextrin inclusion complex
Food Chem.
(2013)
Mass transfer during continuous solid–liquid extraction of antioxidants from grape byproducts
J. Food Eng.
Characterization and antioxidant activity of the complexes of tertiary butylhydroquinone with beta-cyclodextrin and its derivatives
Food Chem.
Estimation of effective diffusion and transfer rate during the protopine extraction process from Fumaria officinalis L
Sep. Purif. Technol.
Two green approaches for extraction of dihydromyricetin from Chinese vine tea using beta-Cyclodextrin-based and ionic liquid-based ultrasonic-assisted extraction methods
Food Bioprod. Process.
Development of a myricetin/hydroxypropyl-beta-cyclodextrin inclusion complex: preparation, characterization, and evaluation
Carbohydr. Polym.
Preparation of pectin-tannic acid coated core-shell nanoparticle for enhanced bioavailability and antihyperlipidemic activity of curcumin
Food Hydrocoll.
Ultrasound-Assisted Extraction Of Cannabinoids From Cannabis sativa L. optimized by response surface methodology
J. Food Sci.
Ultrasonicated resveratrol loaded starch nanocapsules: characterization, bioactivity and release behaviour under in-vitro digestion
Carbohydr. Polym.
The antimicrobial potential of cannabidiol
Commun. Biol.
Green extraction of cannabidiol from industrial hemp (Cannabis sativa L.) using deep eutectic solvents coupled with further enrichment and recovery by macroporous resin
J. Mol. Liq.
Ionic liquids simultaneously used as accelerants, stabilizers and extractants for improving the cannabidiol extraction from industrial hemp
Ind. Crop. Prod.
Extraction of epigallocatechin gallate and epicatechin gallate from tea leaves using -cyclodextrin
J. Food Sci.
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