CN110283048B - Preparation method of cannabidiol crystal - Google Patents
Preparation method of cannabidiol crystal Download PDFInfo
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- CN110283048B CN110283048B CN201910577111.1A CN201910577111A CN110283048B CN 110283048 B CN110283048 B CN 110283048B CN 201910577111 A CN201910577111 A CN 201910577111A CN 110283048 B CN110283048 B CN 110283048B
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Abstract
The invention relates to a preparation method of cannabidiol crystals. The method of the invention comprises the following steps: (1) decarboxylating and extracting the flower and leaf powder of industrial hemp to obtain a decarboxylated extract; (2) mixing the decarboxylated extract with a first solvent, standing at low temperature for precipitation, separating to remove the precipitate, and concentrating the solvent containing cannabidiol to obtain a concentrated extract; (3) mixing the concentrated extract with a second solvent, filtering, subjecting the filtrate to high pressure preparative liquid chromatography, collecting a fraction containing cannabidiol, and removing the solvent from the fraction to obtain a cannabidiol crude product; (4) and mixing the cannabidiol crude product with a crystallization solvent, and crystallizing at low temperature to obtain cannabidiol crystals. The method can obtain high-purity cannabidiol crystals with high total extraction rate, has low energy consumption and low organic solvent consumption, is more energy-saving and environment-friendly, and is particularly suitable for industrial application.
Description
Technical Field
The invention relates to the field of industrial preparation of cannabinoids crystals, in particular to a preparation method of high-purity cannabidiol crystals.
Background
Hemp (Cannabis sativa L.) is an annual herb plant of significant economic and medicinal value, also known as hemp, sisal, jute, and industrial hemp. The main active substance in cannabis is cannabinoids, which mainly include Tetrahydrocannabinol (THC), Cannabidiol (CBD), Cannabinol (CBN) and its carboxyl compounds.
Among cannabinoids, CBD is a non-addictive component of cannabis, can inhibit the adverse effects of certain polyphenols on human nervous system, and has a series of physiological activities such as blocking breast cancer metastasis, treating epilepsy, and resisting rheumatoid arthritis. In recent years, cannabidiol has attracted much attention in the fields of medicine, food, health products, cosmetics, etc.
At present, the following methods are generally used in industry for producing cannabidiol crystals: column chromatography, supercritical fluid or subcritical fluid extraction technology, (enzyme-assisted) solvent extraction, biosynthesis, chemical synthesis and the like.
However, the traditional column chromatography process is extremely complex, high in production cost, low in extraction rate, easy to cause resource waste, and large in environmental pollution, and the adopted macroporous adsorption resin and polyamide chromatographic column have short service life. More importantly, the effect of column chromatography depends heavily on the conditions of each operation and the proficiency of operators, so that the quality (purity, impurity types and content, color, crystal morphology and the like) of the obtained product has large fluctuation and cannot meet the requirements of industrial production.
The supercritical fluid or subcritical fluid extraction technology has the problems of high equipment requirement, high production cost, complex operation and the like, and the cannabidiol obtained by the supercritical fluid or subcritical fluid extraction technology has low purity and is not suitable for the field of medicine. The existing solvent extraction usually needs enzymolysis pretreatment on raw materials, so that the solvent consumption is huge, the extraction rate is very low, and the subsequent separation process is complicated and tedious.
The production efficiency of biosynthesis and chemical synthesis is low at present. Moreover, because CBD has a plurality of chiral centers and cis-trans isomeric double bonds, the separation and purification steps are complex and the cost is high. Therefore, biosynthesis and chemical synthesis are only suitable for synthesizing a small amount of sample and are not suitable for industrial large-scale application at present.
In addition, the existing methods are difficult to effectively and stably control the content of the hallucinogenic addiction THC to be less than 0.3 percent, difficult to meet the requirements of safety supervision departments, and are not beneficial to the transportation, storage and use of cannabidiol products.
Thus, there is a need for a high purity, high yield process for preparing cannabidiol crystals.
Disclosure of Invention
The invention aims to provide a preparation method of cannabidiol crystals, which not only can greatly improve the extraction rate and the extraction purity of cannabidiol in industrial cannabis sativa, but also can effectively reduce the THC content in products so as to meet the safety requirement.
In order to achieve the above object, the present invention provides a method for preparing cannabidiol crystals, comprising the steps of:
(1) decarboxylating and extracting the flower and leaf powder of industrial hemp to obtain a decarboxylated extract;
(2) mixing the decarboxylated extract with a first solvent, standing at low temperature for precipitation, separating to remove the precipitate, and concentrating the solvent containing cannabidiol to obtain a concentrated extract;
(3) mixing the concentrated extract with a second solvent, filtering, subjecting the filtrate to high pressure preparative liquid chromatography, collecting a fraction containing cannabidiol, and removing the solvent from the fraction to obtain a cannabidiol crude product;
(4) and mixing the cannabidiol crude product with a crystallization solvent, and crystallizing at low temperature to obtain cannabidiol crystals.
The inventors have found that by skillfully combining the decarboxylation, extraction, precipitation, high-pressure liquid phase preparation and crystallization steps in a specific manner, cannabidiol crystals of high purity can be obtained at a high extraction rate. In particular, the extraction yield and product purity can be further improved by employing specific extraction solvents, precipitation solvents, high pressure preparation of the liquid phase and/or specific process parameters. By adopting the method of the invention, the total extraction rate of more than 80 percent and even more than 92 percent can be obtained, and the purity of more than 99 percent and even more than 99.8 percent can be simultaneously obtained.
The crystals obtained by the process of the invention are almost free of THC, e.g. comprise less than 0.3%, preferably less than 0.1%, more preferably less than 0.05% THC, most preferably less than 0.01% THC.
More importantly, the process of the invention is particularly suitable for industrial mass production. The process of the invention is able to maintain a high degree of purity even in large scale production. Moreover, the method provided by the invention has the advantages of relatively simple operation, low cost, short production period, low energy consumption, low organic solvent consumption, energy conservation, environmental friendliness and the like.
Drawings
Figure 1 is a liquid chromatogram of Cannabidiol (CBD) and Tetrahydrocannabinol (THC) standards.
FIG. 2 is a liquid chromatogram of crude CBD obtained by high pressure preparative liquid chromatography in example 3.
FIG. 3 is a liquid chromatogram of a pure CBD crystal prepared in example 3.
Detailed Description
Definition of
Cannabidiol (CBD) is present in the plant cannabis in the form of (-) -CBD. Unless otherwise indicated, CBD in the present invention refers to (-) -CBD.
Tetrahydrocannabinol (THC), the major addictive component of cannabis, can cause hallucinations and addiction, is a substance which is currently known to determine the properties of cannabis narcotics, and is classified as "narcotics" or "narcotics" by the united nations convention and laws in many countries. Internationally, a hemp variety with a THC content of less than 0.3% is defined as "industrial hemp" which does not have a drug utilization value, and a hemp variety with a THC content of more than 0.3% is defined as "drug hemp". The cannabis which is allowed to be planted in China at present basically belongs to industrial cannabis.
It is particularly noted that, in cannabinoids, THC and CBD are present in relatively high amounts, both being isomers of each other. This also makes it difficult to completely distinguish THC from CBD using conventional methods and to completely remove THC from CBD products.
Herein, "industrial large scale", "large scale" or "industrial application" means that the amount of pollen raw material is above 1 ton, more preferably at least 1.5 ton in a single treatment process or preparation process. In contrast, small-scale production generally uses a charge of 500kg or less or 50kg or more, and laboratories use a charge of 10kg or less.
The terms "preferred" and "preferably" refer to embodiments of the invention that may provide certain benefits under certain circumstances. However, other embodiments may be preferred, under the same or other circumstances. In addition, recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the invention.
Hereinafter, the technical solution of the present invention will be specifically described by some embodiments, but these embodiments are merely illustrative and should not be construed as limiting the present invention.
Specifically, the invention provides a preparation method of cannabidiol crystals, which is characterized by comprising the following steps:
(1) decarboxylating and extracting the flower and leaf powder of industrial hemp to obtain a decarboxylated extract;
(2) mixing the decarboxylated extract with a first solvent, standing at a temperature below 20 deg.C for precipitation, separating to remove the precipitate, and concentrating the solvent containing cannabidiol to obtain a concentrated extract;
(3) mixing the concentrated extract with a second solvent, filtering, subjecting the filtrate to high pressure preparative liquid chromatography, collecting a fraction containing cannabidiol, and removing the solvent from the fraction to obtain a cannabidiol crude product;
(4) mixing the crude cannabidiol product with a crystallization solvent, and crystallizing at a temperature lower than room temperature to obtain cannabidiol crystals.
In the method of the present invention, a powder of leaves of industrial hemp is used as a raw material. The material is either commercially available as such or obtained from industrial cannabis plants by drying, grinding, sieving and the like. In some embodiments, the average particle size of the industrial cannabis sativa leaf powder is 50-100 mesh. Preferably, the particle size of the industrial hemp flower leaf powder is 60-80 mesh. The oversized powder particles require a longer time to process; and the undersized powder particles are easy to absorb moisture and bond, float to the environment, have too high surface energy and have higher safety risk.
In step (1), the decarboxylation step may convert most of the acidic species in the pollen to neutral species. The time and temperature of decarboxylation need to be selected to obtain a material suitable for subsequent processing. Excessive temperatures can cause some active substances to decompose, evaporate, and even carbonize; however, too low a temperature makes it difficult to decarboxylate the acidic substance, or decarboxylation is incomplete, and the time taken for decarboxylation is prolonged. Preferably, the decarboxylation step is performed to convert at least 97% of the acidic cannabinoids to their neutral form whilst ensuring that less than 5% of the active is decomposed or evaporated. In some embodiments, the decarboxylation step may be performed at a temperature of 80 to 130 ℃. Preferably, the decarboxylation step is carried out at a temperature of 90 to 120 ℃. In some embodiments, the decarboxylation step is carried out for 1.5 to 4h, preferably for 2 to 3 h.
In the step (1), the active substances such as cannabidiol and the like in the pollen of the flower leaves are extracted into the organic solvent through the extraction step, and then the organic solvent containing cannabidiol is concentrated to obtain the extract (extractum). The organic solvent may be concentrated by a conventional method such as atmospheric evaporation, reduced pressure evaporation, rotary evaporation and the like. At least one extraction, preferably at least two extractions, may be performed. When multiple extractions are performed, the organic solvents containing cannabidiol obtained from each extraction are combined and concentrated. Generally, the extraction step is carried out under normal pressure for the sake of easy operation and improved safety.
The solvent used for extraction is an organic solvent which can dissolve cannabidiol well, and at the same time it can be easily concentrated by evaporation to obtain extract containing cannabidiol. In some preferred embodiments, the solvent used for extraction is n-hexane, petroleum ether, acetone, or any combination thereof. More preferably, n-hexane is employed as the solvent for extraction.
The amount of solvent used for extraction may be selected as appropriate depending on the amount of the raw material or the content of cannabidiol in the raw material. Preferably, the weight ratio of the weight of the floral leaf powder to the amount of solvent used for each extraction is in the range of 1:4 to 1: 10. More preferably, the weight ratio of the weight of the floral leaf powder to the amount of solvent used for each extraction is in the range of 1:5 to 1: 8.
The temperature and time of extraction may be suitably selected depending on, among other factors, the rate of dissolution and solubility in the solvent of cannabidiol and the solvent used for extraction. Furthermore, at the extraction temperature, the solvent and the active substance do not evaporate to a large extent. Preferably, the extraction step is carried out at a temperature above room temperature so that the cannabidiol exhibits a high dissolution rate and solubility in the solvent. In some embodiments, the extraction step is performed at a temperature of 40 to 65 ℃. Preferably, the extraction may be performed at 45 to 60 ℃. In some embodiments, each extraction is performed for 1 to 3 hours. Preferably, each extraction is carried out for 1.5 to 2.5 hours.
In step (1), an extraction step may be performed before or after the decarboxylation step.
In some embodiments, in step (1), the extraction is performed after decarboxylation. Decarboxylation is carried out on the flower and leaf powder of industrial hemp, and then the decarboxylated flower and leaf powder is extracted to obtain a decarboxylated extract.
In other embodiments, in step (1), the extraction is performed prior to decarboxylation. The method comprises the steps of extracting the flower and leaf powder of industrial cannabis sativa to obtain an extract containing cannabidiol, and decarboxylating the extract containing cannabidiol to obtain a decarboxylated extract.
The inventors have found that under the same conditions (including the same amount of extraction solvent), with different sequences of decarboxylation and extraction steps, substantially the same overall extraction yield is obtained; however, when the decarboxylation after extraction is employed, the raw material for the decarboxylation step is significantly less than when the decarboxylation after extraction is employed, which greatly reduces the energy consumption and processing time of the decarboxylation step. Thus, in some embodiments, a process of extraction followed by decarboxylation is highly advantageous, especially for industrial scale applications.
In the step (2), the decarboxylated extract is mixed with a first solvent, allowed to stand at a low temperature for precipitation, and separated to remove the precipitate. The cannabidiol-containing solvent is then concentrated to give a concentrated extract (also referred to as a "treated extract").
In the precipitation refining process, the first solvent (also referred to as "precipitation refining solvent") used may be absolute ethanol, acetone, dichloromethane, or any combination thereof. Preferably, absolute ethanol, acetone or any combination thereof is used as the first solvent. Most preferably, acetone is used as the first solvent.
The inventors found that by specifically using acetone as a precipitation refining solvent, a significantly better effect is obtained than with other organic solvents. For example, when acetone is used as the first solvent, the total extraction yield is greatly improved. In particular, in large-scale industrial applications, a high overall extraction yield can still be maintained, while the purity is not significantly reduced.
This is highly expected since the total extraction, purity, efficiency of production etc. is often impaired to a different extent, especially if the total extraction is significantly reduced, by a person skilled in the art when scaling up the production (e.g. by a factor of 100, 200 or 500). Moreover, the solvents known in the art are very diverse and have a large number of combinations of solvents.
During the standing precipitation, the amount of the first solvent is 5 to 15 times, preferably 8 to 12 times of the weight of the extract. More preferably, the amount of the first solvent is 10 times of the weight of the extract.
The standing precipitation process is preferably carried out at a temperature of less than 20 ℃, more preferably at a temperature of-20 ℃ to 15 ℃, even more preferably at a temperature of-10 ℃ to 10 ℃. Most preferably at 4 ℃. + -. 1 ℃.
The standing precipitation process is preferably carried out for 2 to 8 hours, more preferably 3-5 hours. In some preferred embodiments, the standing precipitation process is carried out for 4 hours.
The inventors have found that by performing the standing precipitation according to the above preferred embodiment, the other active substances are well precipitated in the first solvent while the majority of cannabidiol remains in the first solvent.
In step (2), the precipitate may be separated and removed in a manner well known in the art. For example, centrifugation, filtration, decantation, etc. are employed. In some embodiments, the precipitate is removed by centrifugation. The person skilled in the art is able to perform the centrifugation using known centrifuges, for example a model number LLW450 horizontal screw centrifuge from model DL-6000B low-freeze centrifuge manufactured by shanghai incessant instruments and devices limited and ultracentrifuge limited manufactured by zhanggang, inc.
In step (3), the concentrated extract is mixed with a second solvent. Preferably, the weight ratio of the concentrated extract to the second solvent is in the range of 1:2 to 1:6, more preferably in the range of 1:3 to 1: 5.
In some preferred embodiments, the second solvent is a mixed solution of petroleum ether and acetone. More preferably, the volume ratio of petroleum ether to acetone is in the range of 15:1 to 10: 1. In some embodiments, the volume ratio of petroleum ether to acetone is 12: 1.
After the concentrated extract is dissolved in the second solvent, it may be filtered. In some embodiments, filtration using a 0.45 micron nylon filter membrane removes solid insolubles.
In step (3), the filtrate is subjected to high pressure preparative liquid chromatography. Collecting the fraction containing cannabidiol, and removing the solvent in the fraction to obtain a cannabidiol crude product.
The high-pressure preparative liquid chromatography is adopted, so that the purification efficiency can be greatly improved, a stable purification effect is obtained, and the deviation caused by manual operation and the introduced extra impurities are obviously reduced. The obtained fraction containing cannabidiol and the subsequent crude cannabidiol have high repeatability, meet the requirements of a quality management system, and are particularly suitable for industrial production. And other chromatographic separation methods such as a conventional column chromatography process and the like cannot meet the requirements of large-scale application.
In high pressure preparative liquid chromatography, preparative columns having a diameter in the range of 200mm to 1500mm may be employed. For example, a preparation column may be employed which may have a diameter of 200mm, 300mm, 500mm, 1000mm, 1200mm or 1500 mm. Accordingly, the loading of the concentrated extract is in the range of 180g-220g, 200g-1200g, 1.0kg-3.0kg, 2.0kg-8.0kg, 6kg-20kg or 12kg-30kg, respectively. Preferably, the loading of the concentrated extract is in the range of 180g-220g, 300g-1000g, 1.2-2.5kg, 3.0-7.0kg, 9-16kg or 15kg-20kg, respectively.
Preferably, in industrial scale applications, preparative columns having a diameter of 1000mm to 1500mm are used.
In the high pressure preparative liquid chromatography, the length of the preparative column is not particularly limited. One skilled in the art can reasonably determine the appropriate preparative column length. For example, the length of the preparation column may be in the range of 20cm to 100 cm. In an exemplary embodiment, the preparation column is 50cm in length.
In the high pressure preparative liquid chromatography, preferably, petroleum ether and acetone are used as mobile phases. In some preferred embodiments, gradient elution may be used to further effect separation of the substances. For example, in the initial elution stage, petroleum ether and acetone in a volume ratio of 12:1 are used as elution solvents; in the intermediate elution stage, petroleum ether and acetone in a volume ratio of 6:1 are used as elution solvents; in the final elution stage, petroleum ether and acetone in a volume ratio of 1:1 were used as the elution solvents. The elution is generally carried out for 5 to 10 hours, more preferably
The flow rate of the mobile phase is selected according to different preparation diameters. Preferably, when a preparation column with the diameter of 200mm is adopted, the flow rate is 200-; when a preparation column with the diameter of 500mm is adopted, the flow rate is 800-1000 ml/min; when a preparation column with the diameter of 1000mm is adopted, the flow rate is 15-20L/min; or, when a preparation column with the diameter of 1200mm is adopted, the flow rate is 16-25L/min. More preferably, when a preparation column with a diameter of 200mm is used, the flow rate is 250-300 ml/min; when a preparation column with the diameter of 500mm is adopted, the flow rate is 850-950 ml/min; when a preparation column with the diameter of 1000mm is adopted, the flow rate is 16-17L/min; or when a preparation column with the diameter of 1200mm is adopted, the flow rate is 18-22L/min. The inventors found that when the above specific flow rate and diameter parameters of the preparative column are used, not only the purification efficiency is improved as much as possible and the total extraction time is shortened significantly, but also a higher extraction rate is obtained and the final quality of the product is ensured.
In some embodiments, the chromatographic packing in the preparative column is Sephadex LH-20 hydroxypropyl glucose gel, average particle size 20 microns, pore size
To
In high pressure preparative liquid chromatography, a UV detector may be used to detect the fractions. In some preferred embodiments, a detection wavelength of 230nm is employed.
In the analytical detection section, high performance liquid chromatography can also be used to detect the fractions. In some preferred embodiments, a chromatographic column using octadecylsilane bonded silica as a packing material is used. The column length may be 25cm, the inner diameter 4.6mm, and the particle size 5.0. mu.m. In the chromatography used for detection, acetonitrile was used as mobile phase a, and phosphate buffer (pH 4) was used as mobile phase B. Preferably, elution can be performed at a volume ratio of a: B of 85: 15. In some preferred embodiments, the flow rate of the eluent may be 1 ml/min.
Unless otherwise stated, in the process of the invention, in high pressure preparative liquid chromatography, fractions which do not meet the purity requirements are combined to recover the sample and the solvent. Adding the recovered sample and solvent to the concentrated extract, mixing well, and then performing high pressure preparative liquid chromatography.
In step (4), the crude cannabidiol is dissolved in a crystallization solvent. And crystallizing the solution at low temperature to obtain cannabidiol crystals. In the crystallization in the step (4), the crystallization solvent is used for repeated rinsing after the crystallization is finished, and the cannabidiol crystal which is high in purity and does not contain hallucinogenic or addictive component THC is obtained.
Preferably, the crystallization is carried out at a temperature below 20 ℃, more preferably at a temperature of-20 ℃ to 15 ℃, even more preferably at a temperature of-10 ℃ to 10 ℃. Most preferably at 4 ℃. + -. 1 ℃.
The crystallization solvent can be one or more of petroleum ether, n-hexane and ethanol. The amount of crystallization solvent is 5 to 15 times, preferably 8 to 12 times the weight of the crude cannabidiol. More preferably, the amount of crystallization solvent is 10 times the weight of the crude cannabidiol.
The crystallization is preferably carried out for 8 to 24h, more preferably 10-20 h. In some preferred embodiments, the crystallization process is carried out for 12 to 15 hours.
The inventors have found that when the above preferred range is adopted, a significantly more excellent crystallization effect is obtained. The obtained cannabidiol crystal not only has relatively complete appearance, but also has relatively narrow crystal size distribution, higher density and good particle fluidity, and is beneficial to long-term storage and transportation.
In step (4), preferably, a decoloring agent is added for decoloring. Decolorizing and filtering, and crystallizing the filtrate. One or more of activated carbon, silica gel and alumina can be used as a decoloring agent. The amount of decolorizer is 5% -20%, preferably 10% -15% of the weight of crude cannabidiol. The decoloring time is not particularly limited. The skilled person can reasonably determine the time of decolorization according to the actual needs and the state of the sample. In some embodiments, the decolorizing is performed for 10-30 min. Preferably, the decolorization is carried out for 20 min.
The cannabidiol crystals obtained in step (4) comprise at least 99.3% cannabidiol. In a further preferred embodiment, the cannabidiol crystals obtained in step (4) comprise at least 99.5% and even up to 99.8% cannabidiol.
In the process of the present invention, the organic solvent used in steps (1) to (4) may be recovered and reused, unless otherwise specified. Therefore, the investment cost of materials is reduced, the emission of organic solvents is reduced, the energy is saved, the environment is protected, and the total extraction rate and the purity of the product can be improved.
The inventors have found that the process of the present invention enables high purity cannabidiol crystals to be obtained from the floral leaf powder with a total extraction rate of 80% or more. In some preferred embodiments, the total extraction rate can be up to 85% or more, and even up to 90% or more. This is extremely advantageous in industrial scale applications. The inventor researches and tries various prior art schemes, the total extraction rate is not satisfactory, is usually about 70 percent and lower than 80 percent, and cannot meet the requirement of large-scale industrial production.
Furthermore, by the process of the present invention, cannabidiol crystals can be prepared using commercial grade solvents without the need to use more pure solvents (e.g., chromatographically pure grades). This further reduces the cost of the process of the invention significantly, reduces the strict requirements on the operators and equipment, simplifies the operating procedures, and at the same time still allows obtaining a higher extraction yield and high purity cannabidiol crystals.
Examples
The invention is further illustrated by the following non-limiting examples and comparative experiments. All parts, percentages, multiples, and ratios reported in the following examples are by weight unless otherwise stated. Moreover, all reagents used in the examples are commercially available and can be used directly without further treatment.
Materials and instruments
| Suppliers of goods | |
| Industrial hemp flower and leaf powder | Yunnan Muya agricultural science and technology Co Ltd |
| N-hexane, technical grade | Kunming Ming Jingmao Co Ltd |
| Absolute ethanol, technical grade | Kunming Ming Jingmao Co Ltd |
| Petroleum ether, technical grade | Kunming Ming Jingmao Co Ltd |
| Acetone, technical grade | Kunming Ming Jingmao Co Ltd |
| CBD and THC standards | Beijing Fenger' an science and technology Limited liability company |
A centrifuge: a DL-6000B type low-speed freezing centrifuge manufactured by shanghai incessant instruments and equipments ltd, and a LLW450 type horizontal screw centrifuge manufactured by seikagaku centrifuge ltd, zhanggang.
Industrial-grade high-pressure preparative liquid chromatography system: manufactured by Jiangsu Hanbang science and technology Limited, with the model numbers DAC200 and DAC1200, and the diameter of the preparation column is 200mm and 1200mm, respectively. The system mainly comprises a Cs-Prep industrial preparative chromatography separation and purification system and a DAC-HB dynamic axial compression column. The detector is an ultraviolet detector, and the detection wavelength is 230 nm. The column temperature was set to 30 ℃.
The prepared chromatographic column filler is Sephadex LH-20 hydroxypropyl glucose gel with the particle size of 20 mu m and the pore diameter
The analytical chromatographic column packing is octadecylsilane chemically bonded silica, the column length is 25cm, the inner diameter is 4.6mm, and the particle size is 5.0 μm. Acetonitrile was used as mobile phase a, and phosphate buffer (PH 4) was used as mobile phase B. Eluting at a volume ratio of A: B: 85:15 and a flow rate of 1 ml/min. The column temperature was 30 ℃ and the detection wavelength was 230 nm.
Example 1
Weighing 10kg of industrial hemp flower and leaf powder with particle size of 60 mesh and CBD content of 0.94%, and decarboxylating at 100 ℃ for 2 h.
Then, the decarboxylated powder was mixed with n-hexane at a weight ratio of 1:6 under heating to maintain a temperature of 60 ℃, and extraction was performed under stirring for 2 hours, recovering the CBD-containing n-hexane. The extraction step was repeated 2 more times. And (3) combining the recovered n-hexane, evaporating and concentrating to obtain 690g of extract with the CBD content of 13.4%.
Mixing the extract with anhydrous ethanol at a weight ratio of 1:10, standing at 4 deg.C for precipitation for 4 hr, and centrifuging with DL-6000B type low-speed freezing centrifuge at 1000rpm to remove precipitate. The absolute ethanol containing CBD is concentrated to obtain 580g of treated extract, and the content of CBD is 15.3%.
200g of the treated extract is weighed and mixed with a mixed solvent of petroleum ether and acetone (the volume ratio of the petroleum ether to the acetone is 12:1) according to the weight ratio of 1: 3. The mixture was filtered on a 0.45 micron nylon filter. The filtrate was injected into a high pressure preparative liquid chromatography system of model DAC200 and gradient eluted with petroleum ether and acetone as eluting solvents (12: 1 by volume ratio in the initial elution at 0-2 hours; 6:1 by volume ratio at 3-4 hours; 1:1 by volume ratio at 5-6 hours) at a flow rate of 300 ml/min. The CBD containing solvents were combined and the solvent was removed by evaporation to give 29.5g of crude CBD with a CBD content of 95.4%.
The crude CBD was mixed with n-hexane in a weight ratio of 1: 10. Activated carbon in an amount of 10% by weight of the crude CBD was added to the mixture under stirring, decolorized for 20min and filtered. The filtrate was left to crystallize at 4 ℃ for 12 h. Then, 27.3g of high-purity white CBD crystal with a CBD content of 99.5% was obtained by filtration.
The total extraction rate of CBD was calculated to be 83.8%.
Example 2
Weighing 10kg of industrial hemp flower and leaf powder with particle size of 60 mesh and CBD content of 0.94%, and decarboxylating at 100 ℃ for 2 h.
Then, the decarboxylated powder was mixed with 95% ethanol at a weight ratio of 1:6 under heating to maintain a temperature of 60 ℃, extraction was performed under stirring for 2 hours, and ethanol containing CBD was recovered. The extraction step was repeated 2 more times. The recovered ethanol is combined, evaporated and concentrated to obtain 1780g of extract with CBD content of 5.12%.
Mixing the extract with anhydrous ethanol at a weight ratio of 1:10, standing at 4 deg.C for precipitation for 4 hr, and centrifuging at 1000rpm with low-speed refrigerated centrifuge to remove precipitate. And (3) concentrating the absolute ethyl alcohol containing the CBD to obtain 760g of treated extract, wherein the content of the CBD is 11.6%.
200g of the treated extract is weighed and mixed with a mixed solvent of petroleum ether and acetone (the volume ratio of the petroleum ether to the acetone is 12:1) according to the weight ratio of 1: 3. The mixture was filtered on a 0.45 micron nylon filter. And (3) injecting the filtrate into a high-pressure preparative liquid chromatography system with the model number of DAC200, and performing gradient elution by using petroleum ether and acetone as elution solvents at the flow rate of 300 ml/min. The CBD containing solvents were combined and the solvent was removed by evaporation to give 22.7g of crude CBD with a CBD content of 92.6%.
The crude CBD was mixed with n-hexane in a weight ratio of 1: 10. Adding activated carbon into the mixture under stirring, decolorizing for 20min, and filtering. The filtrate was left to crystallize at 4 ℃ for 12 h. Then, filtration was carried out to obtain 19.8g of high-purity white CBD crystals having a CBD content of 99.2%.
The total extraction rate of CBD was calculated to be 79.4%.
Example 3
Weighing 10kg of industrial hemp flower and leaf powder with particle size of 60 mesh and CBD content of 0.94%, and decarboxylating at 100 ℃ for 2 h.
Then, the decarboxylated powder was mixed with n-hexane at a weight ratio of 1:6 under heating to maintain a temperature of 60 ℃, and extraction was performed under stirring for 2 hours, recovering the CBD-containing n-hexane. The extraction step was repeated 2 more times. And (3) combining the recovered n-hexane, evaporating and concentrating to obtain 690g of extract with the CBD content of 13.4%.
Mixing the extract with acetone at a weight ratio of 1:10, standing at 4 deg.C for precipitation for 4 hr, and centrifuging at 1000rpm with low-speed refrigerated centrifuge to remove precipitate. The acetone containing CBD was concentrated to give 405g of treated extract with CBD content of 22.8%.
200g of the treated extract is weighed and mixed with a mixed solvent of petroleum ether and acetone (the volume ratio of the petroleum ether to the acetone is 12:1) according to the weight ratio of 1: 3. The mixture was filtered on a 0.45 micron nylon filter. And (3) injecting the filtrate into a high-pressure preparative liquid chromatography system with the model number of DAC200, and performing gradient elution by using petroleum ether and acetone as elution solvents at the flow rate of 300 ml/min. The CBD containing solvents were combined and the solvent was removed by evaporation to give 45.4g of crude CBD. The crude CBD was analyzed by HPLC and the results are shown in figure 2. In the crude CBD, the CBD content was 96.3%.
The crude CBD was mixed with n-hexane in a weight ratio of 1: 10. Adding activated carbon into the mixture under stirring, decolorizing for 20min, and filtering. The filtrate was left to crystallize at 4 ℃ for 12 h. Then, filtration was carried out to obtain 42.1g of high-purity white CBD crystals. The product was analyzed by HPLC and the results are shown in fig. 3. The CBD content was 99.8%. No THC (< 0.05%) was detected.
The total extraction rate of CBD was calculated to be 90.51%.
Example 4
Weighing 10kg of industrial hemp flower and leaf powder with particle size of 60 mesh and CBD content of 0.94%, and decarboxylating at 100 ℃ for 2 h.
Then, the decarboxylated powder was mixed with n-hexane at a weight ratio of 1:6 under heating to maintain a temperature of 60 ℃, and extraction was performed under stirring for 2 hours, recovering the CBD-containing n-hexane. The extraction step was repeated 2 more times. And (3) combining the recovered n-hexane, evaporating and concentrating to obtain 690g of extract with the CBD content of 13.4%.
Mixing the extract with acetone at a weight ratio of 1:10, standing at 4 deg.C for precipitation for 4 hr, and centrifuging at 1000rpm with low-speed refrigerated centrifuge to remove precipitate. The acetone containing CBD was concentrated to give 405g of treated extract with CBD content of 22.8%.
250g of the treated extract is weighed and mixed with a mixed solvent of petroleum ether and acetone (the volume ratio of the petroleum ether to the acetone is 12:1) according to the weight ratio of 1: 3. The mixture was filtered on a 0.45 micron nylon filter. And (3) injecting the filtrate into a high-pressure preparative liquid chromatography system with the model number of DAC200, and performing gradient elution by using petroleum ether and acetone as elution solvents at the flow rate of 300 ml/min. The CBD containing solvents were combined and the solvent was removed by evaporation to give 51.0g of crude CBD with a CBD content of 93.6%.
The crude CBD was mixed with n-hexane in a weight ratio of 1: 10. Adding activated carbon into the mixture under stirring, decolorizing for 20min, and filtering. The filtrate was left to crystallize at 4 ℃ for 12 h. Then, 45.1g of high-purity white CBD crystals were obtained by filtration, the CBD content being 99.1%.
The total extraction rate of CBD was calculated to be 77.03%.
Example 5
Weighing 10kg of industrial hemp flower and leaf powder with particle size of 60 mesh and CBD content of 0.94%, and decarboxylating at 100 ℃ for 2 h.
Then, the decarboxylated powder was mixed with n-hexane at a weight ratio of 1:6 under heating to maintain a temperature of 60 ℃, and extraction was performed under stirring for 2 hours, recovering the CBD-containing n-hexane. The extraction step was repeated 2 more times. And (3) combining the recovered n-hexane, evaporating and concentrating to obtain 690g of extract with the CBD content of 13.4%.
Mixing the extract with acetone at a weight ratio of 1:10, standing at 4 deg.C for precipitation for 4 hr, and centrifuging at 1000rpm with low-speed refrigerated centrifuge to remove precipitate. The acetone containing CBD was concentrated to give 405g of treated extract with CBD content of 22.8%.
200g of the treated extract is weighed and mixed with a mixed solvent of petroleum ether and acetone (the volume ratio of the petroleum ether to the acetone is 12:1) according to the weight ratio of 1: 3. The mixture was filtered on a 0.45 micron nylon filter. And (3) injecting the filtrate into a high-pressure preparative liquid chromatography system with the model number of DAC200, and performing gradient elution by using petroleum ether and acetone as elution solvents at the flow rate of 400 ml/min. The CBD containing solvents were combined and the solvent was removed by evaporation to give 41.5g of crude CBD with a CBD content of 92.1%.
The crude CBD was mixed with n-hexane in a weight ratio of 1: 10. Adding activated carbon into the mixture under stirring, decolorizing for 20min, and filtering. The filtrate was left to crystallize at 4 ℃ for 12 h. Then, filtration was carried out to obtain 37.1g of high-purity white CBD crystals having a CBD content of 98.9%.
The total extraction rate of CBD was calculated to be 79.04%.
Example 6
Weighing 10kg of industrial hemp flower and leaf powder with particle size of 60 mesh and CBD content of 0.94%, and decarboxylating at 100 ℃ for 2 h.
Then, the decarboxylated powder was mixed with n-hexane at a weight ratio of 1:6 under heating to maintain a temperature of 60 ℃, and extraction was performed under stirring for 2 hours, recovering the CBD-containing n-hexane. The extraction step was repeated 2 more times. And (3) combining the recovered n-hexane, evaporating and concentrating to obtain 690g of extract with the CBD content of 13.4%.
Mixing the extract with dichloromethane at a weight ratio of 1:10, standing at 4 deg.C for precipitation for 4 hr, and centrifuging at 1000rpm with low-speed refrigerated centrifuge to remove precipitate. And (3) concentrating the absolute ethyl alcohol containing the CBD to obtain 672g of treated extract, wherein the content of the CBD is 13.5%.
200g of the treated extract is weighed and mixed with a mixed solvent of petroleum ether and acetone (the volume ratio of the petroleum ether to the acetone is 12:1) according to the weight ratio of 1: 3. The mixture was filtered on a 0.45 micron nylon filter. And (3) injecting the filtrate into a high-pressure preparative liquid chromatography system with the model number of DAC200, and performing gradient elution by using petroleum ether and acetone as elution solvents at the flow rate of 300 ml/min. The CBD containing solvents were combined and the solvent was removed by evaporation to give 26g of crude CBD with a CBD content of 93.3%.
The crude CBD was mixed with n-hexane in a weight ratio of 1: 10. Adding activated carbon into the mixture under stirring, decolorizing for 20min, and filtering. The filtrate was left to crystallize at 4 ℃ for 12 h. Then, filtration was carried out to obtain 23.2g of high-purity white CBD crystals having a CBD content of 95.8%.
The total extraction rate of CBD was calculated to be 79.44%.
Example 7-Industrial Scale application of reference example 1
Weighing 1.5 tons of industrial hemp flower and leaf powder with the grain size of 60 meshes and the CBD content of 0.94 percent, and decarboxylating at the high temperature of 100 ℃ for 2 hours. Then, the decarboxylated powder was mixed with n-hexane at a weight ratio of 1:6 under heating to maintain a temperature of 60 ℃, and extraction was performed under stirring for 2 hours, recovering the CBD-containing n-hexane. The extraction step was repeated 2 more times. And (3) combining the recovered n-hexane, evaporating and concentrating to obtain 99.3g of extract with the CBD content of 13.3%.
Mixing the extract with anhydrous ethanol at a weight ratio of 1:10, standing at 4 deg.C for precipitation for 4 hr, and centrifuging at 1000rpm in LLW450 horizontal screw centrifuge to remove precipitate. And (3) concentrating the absolute ethyl alcohol containing the CBD to obtain 82.9kg of treated extract, wherein the content of the CBD is 15.3%.
15kg of the treated extract was weighed and mixed with a mixed solvent of petroleum ether and acetone (the volume ratio of petroleum ether to acetone was 12:1) at a weight ratio of 1: 3. The mixture was filtered on a 0.45 micron nylon filter. And (3) injecting the filtrate into a high-pressure preparative liquid chromatography system with the model number of DAC1200, and performing gradient elution by using petroleum ether and acetone as elution solvents at the flow rate of 20L/min. The CBD containing solvents were combined and the solvent was removed by evaporation to give 2.16kg of crude CBD with a CBD content of 95.3%.
The crude CBD was mixed with n-hexane in a weight ratio of 1: 10. Adding activated carbon into the mixture under stirring, decolorizing for 20min, and filtering. The filtrate was left to crystallize at 4 ℃ for 12 h. Then, 1.95kg of high-purity white CBD crystals with the CBD content of 99.3 percent are obtained by filtration.
The total extraction rate of CBD was calculated to be 75.9%.
Example 8-Industrial Scale application of reference example 3
Weighing 1.5 tons of industrial hemp flower and leaf powder with the grain size of 60 meshes and the CBD content of 0.94 percent, and decarboxylating at the high temperature of 100 ℃ for 2 hours.
Then, the decarboxylated powder was mixed with n-hexane at a weight ratio of 1:6 under heating to maintain a temperature of 60 ℃, and extraction was performed under stirring for 2 hours, recovering the CBD-containing n-hexane. The extraction step was repeated 2 more times. And (3) combining the recovered n-hexane, evaporating and concentrating to obtain 99.1kg of extract with the CBD content of 13.5%.
Mixing the extract with acetone at a weight ratio of 1:10, standing at 4 deg.C for precipitation for 4 hr, and centrifuging at 1000rpm in a horizontal screw centrifuge of LLW450 type to remove precipitate. Acetone containing CBD is concentrated to obtain 58.2kg of treated extract, and the content of CBD is 22.8%.
15kg of the treated extract was weighed and mixed with a mixed solvent of petroleum ether and acetone (the volume ratio of petroleum ether to acetone was 12:1) at a weight ratio of 1: 3. The mixture was filtered on a 0.45 micron nylon filter. And (3) injecting the filtrate into a high-pressure preparative liquid chromatography system with the model number of DAC1200, and performing gradient elution by using petroleum ether and acetone as elution solvents at the flow rate of 20L/min. The CBD containing solvents were combined and the solvent was removed by evaporation to give 3.35kg of crude CBD with a CBD content of 96%.
The crude CBD was mixed with n-hexane in a weight ratio of 1: 10. Adding activated carbon into the mixture under stirring, decolorizing for 20min, and filtering. The filtrate was left to crystallize at 4 ℃ for 12 h. Then, 3.2kg of high-purity white CBD crystals with the CBD content of 99.6 percent are obtained by filtration.
The total extraction rate of CBD was calculated to be 87.7%.
Example 9 extraction before decarboxylation
The extraction step and the high temperature decarboxylation step of example 3 were exchanged in order with unchanged process conditions and material usage. Namely, 10kg of industrial hemp flower leaf powder is mixed with n-hexane for extraction, and then the extract is decarboxylated at high temperature for 2 hours to obtain 680g of decarboxylated extract, wherein the content of CBD is 13.6%. See example 3 for subsequent steps and specific operating parameters.
As a result, it was found that the total extraction rate remained substantially unchanged. However, the energy consumption of example 9 is significantly lower than that of example 3 in terms of industrial cost and production efficiency. When the method of first extraction and then decarboxylation is adopted, the raw material of the high-temperature decarboxylation step is less than 1kg of extract, but when the method of first decarboxylation and then extraction is adopted, the raw material of the high-temperature decarboxylation step is 10kg of industrial hemp flower leaf powder. And moreover, high-temperature decarboxylation can be carried out in the same device during concentration of the extraction solvent, extract extractum does not need to be separated, and possible unnecessary loss caused by separation and transfer of extractum is avoided. Therefore, in the method of decarboxylation after extraction, the energy consumption of the decarboxylation step is remarkably reduced, the production efficiency is remarkably improved, and the method is particularly favorable for industrial scale application.
In the above examples, in the crystallization step, repeated rinsing was performed using a crystallization solvent after completion of crystallization. The parameters and conditions employed refer to those of example 1, unless otherwise specified. Thus, the above-described embodiments of the present invention can be compared in general to investigate the effect of different parameters on the production of cannabidiol crystals.
Comparing example 1 with example 2, it can be seen that when ethanol is used as the extraction solvent in the extraction step, an extract having a low CBD content and a large volume is produced, and thus the extraction efficiency is low. Comparing example 3 with example 5, it can be seen that, when a mixed solvent of petroleum ether and acetone is used as an elution solvent, it should not exceed 350 ml/min. In preparative flow chromatography systems, the flow rate of the eluting solvent has a significant effect on the final extraction yield.
As can be seen from the results of example 1, example 3 and example 6, using acetone as a precipitation solvent in the standing precipitation step, significantly higher extraction rates were obtained compared to other solvents (e.g., absolute ethanol and dichloromethane). From the results of examples 7 and 8 using the industrial scale, it can be seen that using acetone as the precipitation solvent in the standing precipitation step still maintained a significantly higher extraction yield compared to other solvents (e.g. absolute ethanol). Moreover, when absolute ethanol was used as the precipitation solvent, the total extraction rate decreased from 83.80% to 75.90%, i.e., 7.9%, from laboratory scale (example 1) to industrial scale (example 7); whereas, when acetone was used as the precipitation solvent, the total extraction rate decreased from 90.51% to 87.70%, i.e. only 2.81%, on scale from laboratory (example 3) to industrial (example 8). Therefore, the acetone is used as the precipitation solvent, and the method is particularly beneficial to industrial large-scale production.
Comparing figure 3 with figure 1, it can be seen that the cannabidiol crystals obtained by the process of the invention are of comparable or even higher purity than the currently marketed standard.
The above results show that cannabidiol crystals of high purity can be obtained with a high extraction rate using the method of the present invention.
For the sake of brevity, only some numerical ranges are explicitly disclosed herein. However, any lower limit may be combined with any upper limit to form ranges not explicitly recited; and any lower limit may be combined with any other lower limit to form a range not explicitly recited, and similarly any upper limit may be combined with any other upper limit to form a range not explicitly recited. Also, although not explicitly recited, each point or individual value between endpoints of a range is encompassed within the range. Thus, each point or individual value can form a range not explicitly recited as its own lower or upper limit in combination with any other point or individual value or in combination with other lower or upper limits.
Appropriate changes and modifications to the embodiments described above will become apparent to those skilled in the art from the disclosure and teachings of the foregoing description. Therefore, the present invention is not limited to the specific embodiments disclosed and described above, and some modifications and variations of the present invention should fall within the scope of the claims of the present invention. Furthermore, although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.
Claims (6)
1. A process for the preparation of cannabidiol crystals, characterised in that the process comprises the steps of:
(1) decarboxylating and extracting a floral leaf powder of industrial hemp to obtain a decarboxylated extract, wherein the decarboxylation step is carried out at a temperature of 80 to 130 ℃;
(2) mixing the decarboxylated extract with a first solvent, standing at a temperature below 20 deg.C for precipitation, separating to remove the precipitate, and concentrating the solvent containing cannabidiol to obtain a concentrated extract;
(3) mixing the concentrated extract with a second solvent, filtering, subjecting the filtrate to high pressure preparative liquid chromatography, collecting a fraction containing cannabidiol, and removing the solvent from the fraction to obtain a cannabidiol crude product;
(4) mixing the cannabidiol crude product with a crystallization solvent, and crystallizing at a temperature lower than room temperature to obtain cannabidiol crystals;
wherein in step (1), the solvent used for extraction is n-hexane, petroleum ether, acetone or any combination thereof; in step (2), the first solvent is acetone; and in step (3), the second solvent is a mixed solution of petroleum ether and acetone, and the volume ratio of petroleum ether to acetone is in the range of 15:1 to 10: 1;
and wherein in the high pressure preparative liquid chromatography a preparative column diameter in the range of 200mm to 1500mm is employed; petroleum ether and acetone are used as mobile phases for gradient elution; in the initial elution stage, petroleum ether and acetone in a volume ratio of 12:1 are used as elution solvents; in the intermediate elution stage, petroleum ether and acetone in a volume ratio of 6:1 are used as elution solvents; in the final elution stage, petroleum ether and acetone in a volume ratio of 1:1 were used as the elution solvents.
2. The process according to claim 1, characterized in that in step (1) extraction is carried out before decarboxylation.
3. The method according to claim 1, wherein in step (1), the extraction step is carried out at a temperature of 40 to 65 ℃.
4. The method according to any one of claims 1 to 3, wherein the preparative column used in the high pressure preparative liquid chromatography has a diameter of 200mm and the flow rate of the mobile phase is in the range of 200 to 350 ml/min; or a preparative column having a diameter of 1200mm and a flow rate of the mobile phase in the range of 15 to 25L/min is used in the high pressure preparative liquid chromatography.
5. The method as claimed in any one of claims 1 to 3, wherein in the step (4), one or more of activated carbon, silica gel and alumina is/are used as a decoloring agent for decoloring.
6. A method according to any one of claims 1 to 3 wherein the cannabidiol crystals obtained in step (4) contain at least 99.3% cannabidiol.
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| CN110668923A (en) * | 2019-11-13 | 2020-01-10 | 贵州航天乌江机电设备有限责任公司 | Extraction and separation method of high-purity cannabidiol |
| CN111018675A (en) * | 2019-12-10 | 2020-04-17 | 云南罗瑞生物科技有限公司 | Method for efficiently and incrementally extracting cannabidiol |
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