cannabinoid purification methods

专利摘要:
METHODS OF PURIFICATION OF CANNABINOIDS, THEIR COMPOSITIONS AND KITS. This descriptive report describes methods of purification of one or more cannabinoids from a plant material, purified cannabinoids and pharmaceutical compositions comprising one or more cannabinoids produced by the disclosed method, methods and uses for the treatment of a disease or health condition that it employs such purified cannabinoids and pharmaceutical compositions.
公开号:BR112017015536B1
申请号:R112017015536-2
申请日:2016-01-22
公开日:2021-05-18
发明作者:Xavier Nadal Roura
申请人:Phytoplant Research S.L；
IPC主号:

专利说明:

[001] This application claims the benefit of the priority and filing date of the US Provisional Patent Application. 62/106,644, filed January 22, 2015, the contents of which are incorporated herein in their entirety by reference. TECHNICAL STATUS
[002] The present invention relates to the isolation of cannabinoid compounds. BACKGROUND OF THE INVENTION
[003] Cannabis is a genus of flowering plants whose species are distinguished by plant phenotypes and secondary metabolite profiles. At least three species are recognized, Cannabis sativa, C. indica and C. ruderalis. Cannabis plants have been cultivated for a variety of uses, including fiber making (hemp), medicinal use and recreational drug use. Cannabis is also commonly known as marijuana or marijuana.
[004] It is now widely recognized that Cannabis has substantial benefits for various medicinal uses. For example, Cannabis is regularly used by a wide part of society to treat a variety of ailments, illnesses and symptoms including but not limited to nausea, pain relief (such as chronic pain, cancer-related pain or neuropathic pain) , glaucoma, poor appetite, inflammation of the mucous membranes, inflammatory diseases (such as Crohn's disease), neurodegenerative diseases, epilepsy, seizures, diabetes, leprosy, fever, obesity, asthma, urinary tract infections, cough, anorexia associated with loss of weight in patients with AIDS, post-traumatic stress disorder (PTSD) and autoimmune disease (such as multiple sclerosis).
[005] One of the most common ways to use cannabis for medicinal use in many countries is through smoking. Medical cannabis smoking, although it has been proven to be beneficial in certain indications, has disadvantages. For example, the amounts of active ingredients may vary depending on differences present in plant varieties, as well as changes in growing conditions, which result in intravarietal variations. As a result, it can be difficult to keep tabs on the proper dosage of medicinal cannabis due to variations in the active ingredients. Another disadvantage of medical marijuana smoke is the negative impact of some of the constituents of cannabis smoke. In addition to the desired cannabinoids, the smoke from plant matter comprises carcinogenic substances. Furthermore, the constant use of cannabis through smoking has been associated with accelerated pulmonary deterioration.
[006] Cannabinoids are active compounds at cannabinoid receptors in humans and are responsible for eliciting many of the pharmacological effects of cannabis. Cannabinoids of plant origin, also known as phytocannabinoids, are abundant in cannabis. Two known cannabinoids, which are present in relatively high concentrations in Cannabis sativa, are tetrahydrocannabinolic acid (THCA) or its decarboxylated product tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) or its decarboxylated product, cannabidiol (CBD). THC elicits psychoactive (soothing) effects, analgesic effects, antioxidant effects and increases appetite. However, THC is also associated with many negative or undesirable side effects, including, but not limited to, short-term memory impairment, dry mouth, impaired visual perception and motor skills, erectile dysfunction, lower fertility, redness in the eyes ( (ie, red eyes), increased anxiety, occasionally heart attack, stroke, paranoia, acute psychosis, reduced mental fitness, hallucinations, bizarre behavior, irrational panic attacks, irrational thoughts, and various other cognitive and social problems. On the other hand, CBD is increasingly becoming a popular cannabinoid for medicinal purposes because, unlike THC, CBD is not psychoactive at low doses. In addition, CBD has been found to have neuroprotective and ameliorative effects in patients with schizophrenia and Parkinson's disease. Consequently, patients and healthcare providers have a preference for CBD, as patients need to work, drive and perform their duties clearly while undergoing treatment.
[007] Efforts have been made to reduce the amount of THC in Cannabis and cannabinoid products without significantly reducing the therapeutic effects of other non-psychoactive cannabinoids. One way is to selectively breed Cannabis strains with an increased CBD:THC ratio. However, such Cannabis varieties still need to be administered through smoking, exposing the patient to their associated disadvantages and detrimental health effects. Another way to selectively control or eliminate THC would be to use a series of fractionation columns. Several chromatographic techniques were used to purify the cannabinoid compounds from the Cannabis sativa plant. For example, flash chromatography on silica gel, C8 or C18; preparative HPLC on silica gel columns, C8 or C18; and chromatography with supercritical CO2 on silica gel. However, these chromatographic processes are time-consuming and expensive.
Consequently, what is needed is a simple and less expensive process that selectively purifies and concentrates medicinally beneficial cannabinoids from THC, thereby reducing the THC content by a percentage of the cannabinoid mixture. Furthermore, it is also desirable to develop medicinal formulations which comprise higher levels of beneficial cannabinoids which, at the same time, have a lowered THC content.
The present disclosure solves these and other problems by providing a method for isolating and purifying cannabinoid compounds that does not use chromatographic steps. By this procedure, it is possible to obtain high yields of cannabinoid compounds with a purity of 95% or more. ABSTRACT
[0010] Aspects of this descriptive report disclose methods of purifying one or more cannabinoids from plant material. The disclosed methods comprise a) incubating the plant material with a first non-polar solvent to form a first solvent mixture which extracts one or more cannabinoids from a plant material; b) reducing the volume of the first solvent mixture to about 50% or less of the original volume of the first solvent mixture in step (a) in a manner that concentrates one or more cannabinoids; c) incubating the first reduced solvent mixture in a manner that crystallizes one or more cannabinoids; d) incubating one or more crystallized cannabinoids with a second non-polar solvent to form a second solvent mixture; and e) incubating the second solvent mixture in a manner that crystallizes one or more cannabinoids, thus resulting in purification of one or more cannabinoids. The disclosed methods further allow one or more crystallized cannabinoids from step (c) to be purified prior to step (d), using, for example, filtration that results in a collection of a mother liquor. The mother liquor can be collected, reduced by evaporation and incubated in a way that crystallizes one or more cannabinoids.
[0011] Other aspects of this specification disclose methods of purifying one or more cannabinoids from plant material. The disclosed methods comprise a) incubating the plant material with a first non-polar solvent to form a first solvent mixture which extracts one or more cannabinoids from a plant material; b) filtering the first mixture of solvents; c) reducing the volume of the first solvent mixture to about 50% or less of the original volume of the first solvent mixture in step (a) in a manner that concentrates one or more cannabinoids; d) incubating the first reduced solvent mixture in a manner that crystallizes one or more cannabinoids; e) purify one or more cannabinoids crystallized in step (d) using filtration that results in a collection of a mother liquor; f) incubating one or more crystallized cannabinoids with a second non-polar solvent to form a second solvent mixture; g) incubating the second solvent mixture in a manner that crystallizes one or more cannabinoids; and h) purifying one or more crystallized cannabinoids from step (g) using filtration that results in a collection of a mother liquor, thus resulting in the purification of one or more cannabinoids. The disclosed methods may further comprise i) purifying one or more crystallized cannabinoids using filtration which results in a collection of a mother liquor; and j) incubating the mother liquor in a way that crystallizes one or more cannabinoids. Steps (i) and (j), steps (f) and (g) and steps (f), (g) and (h) may be repeated one or more times.
[0012] Other aspects of this specification disclose purified cannabinoids and pharmaceutical compositions comprising one or more cannabinoids produced by the disclosed methods.
[0013] Other aspects of this specification disclose methods of treating a disease or medical condition using purified cannabinoids and pharmaceutical compositions comprising one or more cannabinoids produced by the disclosed methods. Non-limiting examples of a disease or medical condition include pain, schizophrenia, seizure, inflammation, anxiety, depression, neurodegenerative disease, stroke, traumatic brain injury, cancer, migraines, arthritis, chronic pain, nausea and vomiting, anorexia, glaucoma, epilepsy, asthma, addiction, addiction and withdrawal symptoms, multiple sclerosis, spinal cord injury, Tourette syndrome, dystonia or tardive dyskinesia. BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 shows a HPLC chromatogram at 270 nm of CBGA obtained in Example 4 with purity above 95% with peak area normalized.
[0015] FIG. 2 shows the CBGA x-ray crystallography diffraction pattern obtained in Example 4.
[0016] FIG. 3 shows a HPLC chromatogram at 210 nm of CBG obtained in Example 13 with a purity of 99.06 ± 0.38 quantified with a certified commercial standard.
[0017] FIG. 4 shows the CBGA x-ray crystallography diffraction pattern obtained in Example 13.
[0018] FIG. 5 shows a HPLC chromatogram, at 210 nm, of CBD obtained in Example 17 with a purity of 97.16 ± 0.15 quantified with a certified commercial standard.
[0019] FIG. 6 shows the CBGD x-ray crystallography diffraction pattern obtained in Example 17. DETAILED DESCRIPTION
The present invention provides a method for isolating and purifying one or more cannabinoids. Non-limiting examples of a cannabinoid include cannabigerol (CBG), cannabigerolic acid (CBGA) or cannabidiol (CBD) from a plant belonging to the genus Cannabis.
[0021] In one embodiment, a method of purifying one or more cannabinoids from a plant material comprises a) incubating the plant material with a first non-polar solvent to form a first solvent mixture that extracts one or more cannabinoids from of a plant material; b) reducing the volume of the first solvent mixture to about 50% or less of the original volume of the first solvent mixture in step (a) in a manner that concentrates one or more cannabinoids; c) incubating the first reduced solvent mixture in a manner that crystallizes one or more cannabinoids; d) incubating one or more crystallized cannabinoids with a second non-polar solvent to form a second solvent mixture; and e) incubating the second solvent mixture in a manner that crystallizes one or more cannabinoids, thus resulting in purification of one or more cannabinoids. The disclosed methods further allow one or more crystallized cannabinoids from step (c) to be purified prior to step (d), using, for example, filtration that results in a collection of a mother liquor. The mother liquor can be collected and incubated in a way that crystallizes one or more cannabinoids. Step (a) can be repeated one or more times. Steps (d) and (e) may be repeated one or more times until the purity of one or more cannabinoids is 95% or more.
[0022] In one embodiment, the method of purifying one or more cannabinoids from plant material comprises a) incubating the plant material with a first non-polar solvent to form a first solvent mixture that extracts one or more cannabinoids from the a plant material; b) filtering the first mixture of solvents; c) reducing the volume of the first solvent mixture to about 50% or less of the original volume of the first solvent mixture in step (a) in a manner that concentrates one or more cannabinoids; d) incubating the first reduced solvent mixture in a manner that crystallizes one or more cannabinoids; e) purifying one or more cannabinoids crystallized in step (d) using filtration that results in a collection of a mother liquor; f) incubating one or more crystallized cannabinoids with a second non-polar solvent to form a second solvent mixture, wherein the second solvent mixture dissolves at least 50% of the one or more crystallized cannabinoids; g) incubating the second solvent mixture in a manner that crystallizes one or more cannabinoids; and h) purifying one or more crystallized cannabinoids from step (g) using filtration that results in a collection of a mother liquor, thus resulting in the purification of one or more cannabinoids. The disclosed methods may further comprise i) purifying one or more crystallized cannabinoids using filtration which results in a collection of a mother liquor; and j) incubating the mother liquor in a way that crystallizes one or more cannabinoids. Step (a) can be repeated one or more times. Steps (i) and (j), steps (f) and (g) and steps (f), (g) and (h) may be repeated one or more times until the purity of one or more cannabinoids is 95% or more.
[0023] In one embodiment, a method of purifying one or more cannabinoids from plant material comprises a) incubating the plant material with a first non-polar solvent to form a first solvent mixture that extracts one or more cannabinoids from the a plant material; b) filtering the first mixture of solvents; c) reducing, by evaporation, the volume of the first non-polar solvent in the filtrate obtained in step (b); d) incubating the first reduced solvent mixture in a manner that crystallizes one or more cannabinoids; e) removing the first non-polar solvent by vacuum filtration; f) further reducing the amount of non-polar solvent from the filtrate of (e) by evaporation; g) incubating one or more crystallized cannabinoids with a second non-polar solvent to form a second solvent mixture, wherein the second solvent mixture dissolves at least 50% of the one or more crystallized cannabinoids; i) removing the second non-polar solvent by vacuum filtration and reserving the obtained crystals; and j) adding non-polar solvent per gram of cannabinoid sufficient to dissolve the crystals obtained in step (i) and recrystallize.
[0024] Aspects of this specification disclose, in part, incubating plant material with a first non-polar solvent to form a first solvent mixture that extracts one or more cannabinoids from a plant material; the extract obtained from a plant can be obtained by maceration in a non-polar solvent. A non-polar solvent, as used herein, includes a non-polar liquid solvent comprising C5-C12 or C5-C8 straight chain or branched chain lower alkanes. Non-limiting examples of the non-polar solvent include pentane, hexane, petroleum ether (eg 60-80°C), cyclohexane, heptane, chloroform, benzene, toluene or diethyl ether. In one embodiment, the non-polar solvent used in any or all of the extraction steps present is hexane. In one aspect of this embodiment, at least one of the extraction and/or purification steps for CBG and/or CBGA extraction is performed with hexane. In another embodiment, the non-polar solvent used in any or all of the extraction steps present is pentane or petroleum ether (eg 40-60°C). In one aspect of this embodiment, one or more of the extraction and/or purification steps for CBD extraction/purification is carried out with pentane or petroleum ether (eg 4060°C).
[0025] In addition to the particular non-polar solvent, the extraction of one or more cannabinoids from a plant material is a function of temperature, time and the number of extraction steps. In aspects of this embodiment, incubation of the plant material with a first non-polar solvent occurs for a time period of, for example, at least 5 minutes, at least 10 minutes, at least 15 minutes, for at least 30 minutes, for at least at least 45 minutes, for at least 1 hour, for at least 1.25 hours, for at least 1.5 hours, for at least 1.75 hours, for at least 2 hours, for at least 2.25 hours, for at least at least 2.5 hours, for at least 2.75 hours, for at least 3.0 hours, for at least 3.25 hours, for at least 4.5 hours, for at least 4.75 hours, or for at least 5.0 hours. In other aspects of this embodiment, the incubation of the plant material with a first non-polar solvent takes place for a time period of, for example, a maximum of 5 hours, for a maximum of 4.75 hours, for a maximum of 4, 5 hours for a maximum of 4.25 hours for a maximum of 4.0 hours for a maximum of 3.75 hours for a maximum of 3.5 hours for a maximum of 3.25 hours for a maximum of 3.0 hours for a maximum of 2.75 hours for a maximum of 2.5 hours for a maximum of 2.25 hours for a maximum of 2.0 hours for maximum 1.75 hours for maximum 1.5 hours for maximum 1.25 hours for maximum 1.25 hours for maximum 1 hour for maximum , 45 minutes, for a maximum of 30 minutes, or for a maximum of 15 minutes. In still other aspects of this embodiment, incubation of the plant material with a first non-polar solvent occurs for a time period of, for example, about 15 minutes to about 5 hours, about 30 minutes to about 5 hours, about 45 minutes to about 5 hours, about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3.5 hours, about 1 hour to about 3, 0 hours, about 1 hour to about 2.25 hours, about 1 hour to about 2 hours, about 1 hour to about 1.75 hours, about 1 hour to about 1.5 hours, about 30 minutes to about 1.5 hours, about 30 minutes to about 1.25 hours, about 30 minutes to about 1 hour, about 45 minutes to about 1.75 hours, about 45 minutes to about 1.5 hours, about 45 minutes to about 1.25 hours, or about 45 minutes to about 1 hour.
[0026] In aspects of this embodiment, the incubation of plant material with a first non-polar solvent occurs at a temperature of, for example, 0°C or higher, 4°C or higher, 8°C or higher, 12°C or higher, 16°C or higher, 20°C or higher, or 24°C or higher. In other aspects of this embodiment, incubation of the plant material with a first non-polar solvent occurs at a temperature of, for example, 0°C or less, 4°C or less, 8°C or less, 12°C or less, 16°C or less, 20°C or less, or 24°C or less. In other aspects of this embodiment, incubation of the plant material with a first non-polar solvent occurs at a temperature of, for example, about 0°C to about 4°C, about 0°C to about 8°C, about 0°C to about 12°C, about 0°C to about 16°C, about 0°C to about 20°C, about 0°C to about 24°C, about 0°C to about 28°C, about 4°C to about 8°C, about 4°C to about 12°C about 4°C to about 16°C, about 4°C at about 20°C, about 4°C to about 24°C, about 4°C to about 28°C, about 8°C to about 12°C, about 8°C to about about 16°C, about 8°C to about 20°C, about 8°C to about 24°C, about 8°C to about 28°C, about 12°C to about 16 °C, about 12°C to about 20°C, about 12°C to about 24°C, about 12°C to about 28°C, about 16°C to about 20°C about 16°C to about 24°C, about 16°C to about 28°C, about 20°C to about 24°C, about 20°C to about 28°C or about from 24°C to about 28°C.
[0027] Aspects of this descriptive report disclose, in part, the purification of the first mixture of solvents. In one aspect of this embodiment, the first mixture of solvents is purified by filtration.
[0028] Aspects of this specification disclose, in part, reducing the volume of the first mixture of solvents in a manner that concentrates one or more cannabinoids. In aspects of this embodiment, the volume of the first mixture of solvents is reduced by evaporation In aspects of this embodiment, the volume of the first mixture of solvents is reduced, for example, 60% or less, 50% or less, 45% or less, % or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2 % or less, or 1% or less of the original volume of the first solvent mixture used to extract one or more cannabinoids from a plant material. In aspects of this embodiment, the volume of the first mixture of solvents is reduced from, for example, about 0.1% to about 5%, about 0.1% to about 10%, about 0.1% to about 15%, about 0.1% to about 20%, about 0.1% to about 25%, about 0.1% to about 30%, about 0.1% to about 35%, about 0.1% to about 40%, about 0.1% to about 45%, about 0.1% to about 50%, about 0.5% to about 5% , about 0.5% to about 10%, about 0.5% to about 15%, about 0.5% to about 20%, about 0.5% to about 25%, about from 0.5% to about 30%, about 0.5% to about 35%, about 0.5% to about 40%, about 0.5% to about 45%, about 1% to about 15%, about 1% to about 25%, about 1% to about 35%, about 1% to about 45%, about 1% to about 55%, about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50 about 25% to about 35 %, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 25% to about 55%, about 25% to about 60 %, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 30% to about 55 %, about 30% to about 60%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 35% to about 55 %, about 35% to about 60%, about 40% to about 45%, about 40% to about 50%, about 40% to about 55%, about 40% to about 60 %, about 45% to about 50%, about 45% to about 55%, about 45% to about 60%, about 50% to about 55%, about 50% to about 60 % or about 55% to about 60%.
[0029] Aspects of this specification disclose, in part, the incubation of the reduced volume of the first solvent mixture in a manner that crystallizes one or more cannabinoids. Generally, crystallization of one or more cannabinoids in the first reduced solvent mixture is a function of temperature and time. In aspects of this embodiment, the first reduced solvent mixture is incubated at a temperature of, for example, -70°C or higher, -60°C or higher, -50°C or higher, -40°C or higher, - 30°C or higher, -20°C or higher, or 0°C or higher, 4°C or higher, 8°C or higher, 12°C or higher, 16°C or higher, 20°C or higher, 24 °C or higher or 28°C or higher. In other aspects of this embodiment, the reduced first solvent mixture is incubated at a temperature of, for example, -70°C or less, -60°C or less, -50°C or less, -40°C or less, -30°C or lower, -20°C or lower, or 0°C or higher, 4°C or lower, 8°C or lower, 12°C or lower, 16°C or lower, 20°C or lower, 24°C or less or 28°C or less. In yet other aspects of this embodiment, the reduced first solvent mixture is incubated at a temperature of, for example, about -70°C to about 40°C, -70°C to about 30°C, -70° C to about 20°C, -70°C to about 10°C, -70°C to about 0°C, -20°C to about 40°C, -20°C to about 30° C, -20°C to about 20°C, -20°C to about 10°C, -20°C to about 0°C, about 0°C to about 5°C, about 0 °C to about 10°C, about 0°C to about 15°C, about 0°C to about 20°C, about 0°C to about 25°C, about 0°C at about 4°C, about 0°C to about 8°C, about 0°C to about 12°C, about 0°C to about 16°C, about 0°C to about about 20°C, about 0°C to about 24°C, about 0°C to about 28°C, about 4°C to about 8°C, about 4°C to about 12 °C about 4°C to about 16°C, about 4°C to about 20°C, about 4°C to about 24°C, about 4°C to about 28°C, about 8°C to about 12°C, about 8°C to about 16°C, About 8°C to about 20°C, about 8°C to about 24°C, about 8°C to about 28°C, about 12°C to about 16°C, about 12°C to about 20°C, about 12°C to about 24°C, about 12°C to about 28°C, about 16°C to about 20°C, about 16°C to about 24°C, about 16° C to about 28°C, about 20°C to about 24°C, about 20°C to about 28°C, or about 24°C to about 28°C.
[0030] In aspects of this embodiment, the first reduced solvent mixture is incubated for a time period of, for example, 1 hour or more, 2 hours or more, 3 hours or more, 4 hours or more, 5 hours or more , 6 hours or more, 7 hours or more, 8 hours or more, 9 hours or more, 10 hours or more, 12 hours or more, 14 hours or more, 16 hours or more, 18 hours or more, 20 hours or more , 22 hours or more, 24 hours or more, 28 hours or more, 32 hours or more, 36 hours or more, 40 hours or more, 44 hours or more, 48 hours or more, 52 hours or more, 56 hours or more , 60 hours or more , 64 hours or more , 68 hours or more , 72 hours or more , 76 hours or more , 80 hours or more , 84 hours or more , 88 hours or more , 92 hours or more , or 96 hours or more . In other aspects of this embodiment, the first reduced solvent mixture is incubated for a time period of, for example, 1 hour or less, 2 hours or less, 3 hours or less, 4 hours or less, 5 hours or less, 6 hours or less, 7 hours or less, 8 hours or less, 9 hours or less, 10 hours or less, 12 hours or less, 14 hours or other aspects of this embodiment, the first reduced solvent mixture is incubated for a period of time from, for example, about 1 hour to about 12 hours, about 1 hour to about 24 hours, about 1 hour to about 36 hours, about 1 hour to about 48 hours, about 1 hour to about 60 hours, about 1 hour to about 72 hours, about 1 hour to about 84 hours, about 1 hour to about 96 hours, about 2 hours to about 12 hours, about 2 hours to about 24 hours, about 2 hours to about 36 hours, about 2 hours to about 48 hours, about 2 hours to about 60 hours, about 2 hours to about 72 hours, about 2 hours to about 84 hours, about 2 hours to about 96 hours, about 4 hours to about 12 hours, about 4 hours to about 24 hours, about 4 hours to about 36 hours, about 4 hours to about 48 hours, about 4 hours to about 60 hours, 72 4 12 6 48 6 84 8 24 8 60 8 96 12 48 12 84 16 36 16 72 16 36 24 72 about 4 hours to about about 84 hours, about about 6 hours to about 24 hours, about about 6 hours to about 60 hours, about about 6 hours to about about 96 hours, about about 8 hours to about 36 hours, about about 8 hours to about 72 hours, about about 8 hours to about 24 hours, about about 12 hours to about about 60 hours, about about 12 hours to about 96 hours, about about 16 hours to about 48 hours, about about 16 hours to about about 84 hours, about about from 24 hours to about 48 hours s, about 24 hours to about hours, about 4 hours to about 96 hours, hours, about 6 hours to about 36 hours, hours, about 6 hours to hours to about 72 hours, hours, about 6 hours to about 12 hours, hours, about 8 hours to about 48 hours, hours, about 8 hours to about 84 hours, hours, about 12 hours to about 36 hours, hours, about 12 hours to about 72 hours, hours, about 12 hours to about 24 hours, hours, about 16 hours to about 60 hours , hours, about 16 hours to about 96 hours, hours, about 24 hours to about 60 hours, hours, about 24 hours to about 84 hours, about 24 hours to about 96 hours , about 36 hours to about 48 hours, about 36 hours to about 60 hours, about 36 hours to about 72 hours, about 36 hours to about 84 hours, about 36 hours to about 96 hours , about 48 hours to about 60 hours , about 48 hours to about 72 hours, about 48 hours to about 84 hours, about 48 hours to about 96 hours, or about 72 hours to about 96 hours.
[0031] Aspects of this specification disclose, in part, the purification of one or more crystallized cannabinoids after incubation in the first reduced solvent mixture. In one aspect of this embodiment, purification of one or more crystallized cannabinoids is accomplished using filtration that results in a collection of a mother liquor.
[0032] Aspects of this specification disclose, in part, the incubation of one or more crystallized cannabinoids with a second non-polar solvent to form a second solvent mixture. Incubation of one or more crystallized cannabinoids with a second non-polar solvent to form a second solvent mixture at least partially dissolves one or more crystallized cannabinoids. In aspects of this embodiment, incubating one or more crystallized cannabinoids with a second non-polar solvent to form a second solvent mixture dissolves, for example, at least 50%, at least 55%, at least 60%, at least 65% , at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95% of one or more crystallized cannabinoids. In other aspects of this embodiment, incubating one or more crystallized cannabinoids with a second non-polar solvent to form a second solvent mixture dissolves, for example, at most 50%, at most 55%, at most 60%, at most 65 % at most 70%, at most 75%, at most 80%, at most 85%, at most 90% or at most 95% of one or more crystallized cannabinoids. In yet other aspects of this embodiment, incubating one or more crystallized cannabinoids with a second non-polar solvent to form a second solvent mixture dissolves, for example, about 50% to about 95%, about 55% to about 95%, about 60% to about 95%, about 65% to about 95%, about 70% to about 95%, about 75% to about 95%, about 80% to about 95%, about 85% to about 95%, about 90% to about 95%, about 50% to 100%, about 55% to 100%, about 60% to 100%, about 65 % to 100%, about 70% to 100%, about 75% to 100%, about 80% to 100%, about 85% to 100%, about 90% to 100% or about 95% to 100%.
[0033] Generally, the dissolution of one or more cannabinoids in the second solvent mixture is a function of temperature and time. In aspects of this embodiment, the second mixture of solvents is incubated at a temperature of, for example, 20°C or higher, 25°C or higher, 30°C or higher, 35°C or higher, 40°C or higher, 45°C or higher, 50°C or higher, 55°C or higher, or 60°C or higher. In other aspects of this embodiment, the second mixture of solvents is incubated at a temperature of, for example, 20°C or higher, 25°C or higher, 30°C or higher, 35°C or higher, 40°C or higher , 45°C or higher, 50°C or higher, 55°C or higher, or 60°C or higher. In other aspects of this embodiment, the second mixture of solvents is incubated at a temperature of, for example, about 20°C to about 25°C, about 20°C to about 30°C, about 20°C at about 35°C, about 20°C to about 40°C, about 20°C to about 45°C, about 20°C to about 50°C, about 20°C to about about 55°C, about 20°C to about 60°C, about 25°C to about 30°C, about 25°C to about 35°C, about 25°C to about 40 °C, about 25°C to about 45°C, about 25°C to about 50°C, about 25°C to about 55°C, about 25°C to about 60°C about 30°C to about 35°C, about 30°C to about 40°C, about 30°C to about 45°C, about 30°C to about 50°C, about about 30°C to about 55°C, about 30°C to about 60°C, about 35°C to about 40°C, about 35°C to about 45°C, about 35 °C to about 50°C, about 35°C to about 55°C, about 35°C to about 60°C, about 40°C to about 45°C, about 40°C at about 50°C, about 40°C ace about 55°C, about 40°C to about 60°C, about 45°C to about 50°C, about 45°C to about 55°C, about 45°C to about 60°C, about 50°C to about 55°C, about 50°C to about 60°C, or about 55°C to about 60°C.
[0034] In aspects of this embodiment, the second solvent mixture is incubated for a time period of, for example, at least 5 minutes, at least 10 minutes, at least 15 minutes, for at least 30 minutes, for at least 45 minutes for at least 1 hour for at least 1.25 hours for at least 1.5 hours for at least 1.75 hours for at least 2 hours for at least 2.25 hours for at least 2 .5 hours, for at least 2.75 hours, for at least 3.0 hours, for at least 3.25 hours, for at least 4.5 hours, for at least 4.75 hours, or for at least 5, 0 hours. In other aspects of this embodiment, the second mixture of solvents is incubated for a time period of, for example, a maximum of 5 hours, for a maximum of 4.75 hours, for a maximum of 4.5 hours, for, maximum 4.25 hours, maximum 4.0 hours, maximum 3.75 hours, maximum 3.5 hours, maximum 3.25 hours, maximum , 3.0 hours, for a maximum of 2.75 hours, for a maximum of 2.5 hours, for a maximum of 2.25 hours, for a maximum of 2.0 hours, for a maximum of 1 .75 hours, for a maximum of 1.5 hours, for a maximum of 1.25 hours, for a maximum of 1.0 hour, for a maximum of 45 minutes, for a maximum of 30 minutes, or for a maximum of 15 minutes. In yet other aspects of this embodiment, the second mixture of solvents is incubated for a time period of, for example, about 15 minutes to about 5 hours, about 30 minutes to about 5 hours, about 45 minutes to about about 5 hours, about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3.5 hours, about 1 hour to about 3.0 hours, about 1 hour to about 2.25 hours, about 1 hour to about 2 hours, about 1 hour to about 1.75 hours, about 1 hour to about 1.5 hours, about 30 minutes to about 1.5 hours, about 30 minutes to about 1.25 hours, about 30 minutes to about 1 hour, about 45 minutes to about 1.75 hours, about 45 minutes to about 1.5 hours, about 45 minutes to about 1.25 hours, or about 45 minutes to about 1 hour.
[0035] Aspects of this specification disclose, in part, the incubation of the second mixture of solvents in a manner that crystallizes one or more cannabinoids. Generally, the crystallization of one or more cannabinoids in the second solvent mixture is a function of temperature and time. In aspects of this embodiment, the second mixture of solvents is incubated at a temperature of, for example, -70°C or higher, -60°C or higher, -50°C or higher, -40°C or higher, -30 °C or higher, -20°C or higher, or 0°C or higher, 4°C or higher, 8°C or higher, 12°C or higher, 16°C or higher, 20°C or higher, 24° C or higher or 28°C or higher. In other aspects of this embodiment, the second solvent mixture is incubated at a temperature of, for example, -70°C or less, -60°C or less, -50°C or less, -40°C or less, - 30°C or lower, -20°C or lower, or 0°C or higher, 4°C or lower, 8°C or lower, 12°C or lower, 16°C or lower, 20°C or lower, 24 °C or below or 28 °C or below. In still other aspects of this embodiment, the second mixture of solvents is incubated at a temperature of, for example, about -70°C to about 40°C, -70°C to about 30°C, -70°C at about 20°C, -70°C to about 10°C, -70°C to about 0°C, -20°C to about 40°C, -20°C to about 30°C , -20°C to about 20°C, -20°C to about 10°C, -20°C to about 0°C, about 0°C to about 5°C, about 0° C to about 10°C, about 0°C to about 15°C, about 0°C to about 20°C, about 0°C to about 25°C, about 0°C to about 4°C, about 0°C to about 8°C, about 0°C to about 12°C, about 0°C to about 16°C, about 0°C to about 20°C, about 0°C to about 24°C, about 0°C to about 28°C, about 4°C to about 8°C, about 4°C to about 12°C C about 4°C to about 16°C, about 4°C to about 20°C, about 4°C to about 24°C, about 4°C to about 28°C, about about 8°C to about 12°C, about 8°C to about 16°C, about 8°C to about 20°C, about 8°C to about 24°C, about 8°C to about 28°C, about 12°C to about 16°C, about 12°C to about 20°C, about 12°C C to about 24°C, about 12°C to about 28°C, about 16°C to about 20°C, about 16°C to about 24°C, about 16°C to about 28°C, about 20°C to about 24°C, about 20°C to about 28°C, or about 24°C to about 28°C.
[0036] In aspects of this embodiment, the second mixture of solvents is incubated for a time period of, for example, 1 hour or more, 2 hours or more, 3 hours or more, 4 hours or more, 5 hours or more, 6 hours or more, 7 hours or more, 8 hours or more, 9 hours or more, 10 hours or more, 12 hours or more, 14 hours or more, 16 hours or more, 18 hours or more, 20 hours or more, 22 hours or more, 24 hours or more, 28 hours or more, 32 hours or more, 36 hours or more, 40 hours or more, 44 hours or more, 48 hours or more, 52 hours or more, 56 hours or more, 60 hours or more, 64 hours or more, 68 hours or more, 72 hours or more, 76 hours or more, 80 hours or more, 84 hours or more, 88 hours or more, 92 hours or more, or 96 hours or more. In other aspects of this embodiment, the second solvent mixture is incubated for a time period of, for example, 1 hour or less, 2 hours or less, 3 hours or less, 4 aspects of this embodiment, the second solvent mixture is incubated for a period of time of, for example, about about about about about about about about about about about about about about about about about about about about about about about about about about 1 hour to 24 hours, 1 hour to 60 hours, 1 hour to 96 hours, 2 hours to 36 hours, 2 hours to 72 hours, 2 hours to 12 hours, 4 hours to 48 hours, 4 hours to 84 hours, 6 hours to 24 hours, 6 hours to 60 hours, 6 hours to 96 hours, 8 hours to 36 hours, 8 hours to about about about about about about about about about about about about about about about about about about about about about about about about about about 12 hours, 1 hour to 48 hours, 1 hour to 84 hours, 2 hours to 24 hours, 2 hours to 60 hours, 2 hours to 96 hours, 4 hours to 36 hours, 4 hours to 72 hours, 4 hours to 12 hours, 6 hours to 48 hours, 6 hours to 84 hours, 8 hours to 24 hours, 8 hours to 60 hours, about about about about about about about about about about about about about about about about about about about about about about about about about 1 hour to 36 hours, 1 hour to 72 hours, 1 hour to 12 hours, 2 hours to 48 hours, 2 hours to 84 hours, 4 hours to 24 hours, 4 hours to 60 hours, 4 hours to 96 hours, 6 hours to 36 hours, 6 hours to 72 hours, 6 hours to 12 hours, 8 hours to 48 hours, 8 hours to about 72 hours, about 8 hours to about 84 hours, about 8 hours to about 96 hours, about 12 hours to about 24 hours, about 12 hours to about 36 hours, about 12 hours to about 48 hours, about 12 hours to about 60 hours, about 12 hours to about 72 hours, about 12 hours to about 84 hours, about 12 hours to about 96 hours, about 16 hours to about 24 hours, about 16 hours to about 36 hours, about 16 hours to about 48 hours, about 16 hours to about 60 hours, about 16 hours to about 72 hours, about 16 hours to about 84 hours, about 16 hours to about 96 hours, about 24 hours to about 36 hours, about 24 hours to about 48 hours, about 24 hours to about 60 hours, about 24 hours to about 72 hours, about 24 hours to about 84 hours, about 24 hours to about 96 hours, about 36 hours to about 48 hours, about 36 hours to about 60 hours, about 36 hours to about 72 hours, about 36 hours to about 84 hours, about 36 hours to about 96 hours, about 48 hours to about 60 hours, about 48 hours to about 72 hours, about 48 hours to about 84 hours, about 48 hours to about 96 hours, or about 72 hours to about 96 hours.
[0037] Aspects of this specification disclose, in part, the purification of one or more crystallized cannabinoids obtained from the second mixture of solvents. In one aspect of this embodiment, one or more crystallized cannabinoids is purified using filtration which results in a collection of a mother liquor.
[0038] The disclosed methods may further comprise incubating the mother liquor in a way that crystallizes one or more cannabinoids. One or more cannabinoids can be crystallized using the same temperature and time conditions as used to crystallize one or more cannabinoids from the reduced first solvent mixture and/or the second solvent or solvent mixture.
[0039] The result of the disclosed methods is a substantially pure preparation of one or more cannabinoids. A "substantially pure" preparation of a cannabinoid or cannabinoid acid is defined as a preparation with a chromatographic purity (of the desired cannabinoid or cannabinoid acid) of 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater, as determined by normalizing the area of a HPLC profile or by a percentage of relative purity quantification a certified commercial standard.
[0040] In one aspect of this embodiment, the disclosed methods result in the purification of CBGA with a purity that is 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater, as determined by area normalization of a HPLC profile or by a percent purity quantification for a certified commercial standard. In one aspect of this embodiment, the disclosed methods result in the purification of CBG to a purity that is 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater, as determined by area normalization of a HPLC profile or by a percent purity quantification for a certified commercial standard. In one aspect of this embodiment, the disclosed methods result in the purification of CBD to a purity that is 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater, as determined by area normalization of a HPLC profile or by a percent purity quantification for a certified commercial standard.
[0041] The disclosed methods can obtain substantially pure preparations of one or more cannabinoids without the use of chromatographic techniques. In other words, the disclosed methods do not use chromatographic techniques to purify one or more cannabinoids. Thus, in one embodiment, the disclosed methods result in a substantially pure preparation of one or more cannabinoids without the use of chromatographic techniques. In one aspect of this embodiment, the disclosed methods result in a substantially pure preparation of CBGA without the use of chromatographic techniques. In another aspect of this embodiment, the disclosed methods result in a substantially pure preparation of CBG without the use of chromatographic techniques. In yet another aspect of this embodiment, the disclosed methods result in a substantially pure preparation of CBD without the use of chromatographic techniques.
[0042] The term "raw cannabinoid", "raw cannabinoid" or "product enriched in a particular cannabinoid" encompasses preparations of at least 60%, at least 65%, at least 70%, at least 75%, at least 80% , at least 85%, or at least 90% chromatographic purity for the desired cannabinoid. Such a product will generally contain a greater proportion of impurities, non-target materials and other cannabinoids than a “substantially pure” preparation. CANNABINOIDS
Cannabinoids purified by the disclosed methods are not particularly limited and comprise canibigerol-type (CBG-type) cannabinoids; cannabichromene type cannabinoids (CBC type); cannabidiol-type cannabinoids (CBD-type); cannabinoids of the tetrahydrocannabinol type (of the THC type); cannabinol-type cannabinoids (CBN-type); and its derivatives. Cannabinoid derivatives may not themselves be cannabinoids. However, its chemistry is recognized as being derived from cannabigerol, cannabinol or cannabidiol. For example, cannabinoids of interest comprise the following and their corresponding acids: CBG (Cannabigerol), CBC (Cannabichromene), CBL (Canabicyclol), CBV (Cannabicycline), THCV (Tetrahydrocannabivarin), CBDV (Cannabidivarin), CBCV (Canabicromevarine), CBGV (Cannabigerovarin), CBGM (Cannabigerol Monomethyl Ether), THC (Tetrahydrocannabinol), CBT (Cannabicitran type), Iso-THC (Iso-Tetrahydrocannabinol type) and CSE (Cannabielsoin type). In fresh cannabis plant material, most cannabinoids are present in the form of carboxylic acid known as acidic cannabinoids or “cannabinoid acids”. The free phenolic forms of cannabinoids are also known as neutral cannabinoids.
[0044] The disclosed methods can be used to extract/purify cannabinoids or cannabinoid acids from any plant material known to contain such cannabinoids or cannabinoid acids. The source of cannabinoids is not limited but may comprise plant material. The term "plant material" encompasses a plant or plant part (eg, bark, wood, leaves, stems, roots, flowers, fruits, seeds, berries or parts thereof), as well as exudates, resins and plant extracts, and includes material that meets the definition of “botanical raw material” in the Guidance for Industry Botanical Drug Products Draft Guidance of August 2000, US Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research”, in English).
The disclosed methods can be used to extract/purify cannabinoids or cannabinoid acids from any plant material known to contain such cannabinoids or cannabinoid acids. More typically, but not necessarily, the “plant material” will be derived from one or more Cannabis plants. Plants from which cannabinoids can be isolated include: Cannabis sp. including Cannabis sativa L. and all subspecies, the putative species Cannabis indica Lam., Cannabis ruderalis Janisch, and their hybrids and varieties, as discussed further below. The Cannabis sativa L. plant can be of the Carma variety or any other variety of chemotype IV, whose main cannabinoid is CBG or CBGA (Meijer EP, Hammond KM. The inheritance of chemical phenotype in Cannabis sativa L. (II): Cannabigerol predominant plants. Euphytica. 2005. 145: 189-198.) or any variety belonging to chemotype II or III (from Meijer EP, Bagatta M, Carboni A, Crucitti P, Moliterni VM, Ranalli P, Mandolino G. The inheritance of chemical phenotype in Cannabis sativa L. Genetics. 2003. Jan;163(1):335-46.)
[0046] In one embodiment, the methods disclosed use material from the plant Cannabis sativa L., a variety belonging to chemotype IV, having CBGA/CBG as the main cannabinoids. In another modality, the methods disclosed use material from the Cannabis sativa L. plant, a variety belonging to chemotype III, having CBGA/CBD as the main cannabinoids. In yet another modality, the methods disclosed use plant material Cannabis sativa L., a variety belonging to chemotype II, having THCA-CBDA/THCCBD as the main cannabinoids.
[0047] The term "Cannabis plant(s)" encompasses wild-type Cannabis sativa and also its variants, including Cannabis chemovars (varieties characterized by virtue of chemical composition) that naturally contain different amounts of the individual cannabinoids, also Cannabis sativa L. subspecies indica including variants var. indicates and var. kafiristanica, Cannabis indica and also plants that are the result of their genetic crosses, self-crosses or hybrids. The term “Cannabis plant material” should therefore be interpreted as comprehensive plant material derived from one or more Cannabis plants. For the avoidance of doubt, it is stated here that “Cannabis plant material” comprises herbal Cannabis and Cannabis biomass that has been dried.
[0048] Decarboxylated Cannabis Plant Material" refers to Cannabis plant material that has undergone a decarboxylation step to convert cannabinoid acids into the corresponding free cannabinoids. RESINS
"Resin", as used herein, comprises resins produced from any of the types of plants discussed above and, in one embodiment, includes products from the pedunculated resin glands of Cannabis sp., including the putative species Cannabis indica, the species Cannabis sativa and Cannabis ruderalis, and their hybrids or their varieties These pedunculated resinous glands can be from female plants, unfertilized or fertilized or from dioecious or monoecious varieties of Cannabis.
[0050] The method of the invention makes it possible to isolate the cannabinoids of interest (for example, CBG, CBGA or CBD) directly by crystallization with a non-polar solvent (for example, hexane or pentane), from the plant, resin or from extracts obtained from the plant, whether the extract obtained with pentane, hexane, heptane, petroleum ethers, cyclohexane, dichloromethane, trichloromethane, tetrahydrofuran, diethyl ether, toluene, benzene, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane , propane, refrigerant gases (eg 1,1,1,2-Tetrafluoroethane (R134a)), either with liquid, subcritical or supercritical CO2 or mixtures of these solvents. In this modality, the disclosed method obtains the cannabioids of interest (for example, CBG, CBGA or CBD) with a purity of 60% to 85%, which will be called "crude" with high yield and, additionally, with a purity of fur at least 60%, at least 61%, at least 62%, at least 63%, at least 64% at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least at least 70%, at least 71%, at least 72%, at least 73%, at least 74% at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84% or at least 85% (yield varies between 50%-90% depending on the type of vegetable raw material or the type of extract). With the subsequent recrystallizations of this "raw" composition in a non-polar solvent (eg hexane), it is possible to obtain a purity greater than 90%, achieving a purity of 95% of CBG, CBGA and CBD without using chromatographic techniques and , additionally, in which the purity is greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94% or greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, of CBG, CBGA and CBD without using chromatographic techniques.
[0051] The non-polar solvent used to obtain an extract is not particularly limited, the method of the invention offers good results with extracts obtained with any one of pentane, hexane, heptane, cyclohexane, petroleum ethers, dichloromethane, trichloromethane, tetrahydrofuran, toluene , benzene, diethyl ether, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane, propane, refrigerant gases (eg 1,1,1,2-Tetrafluoroethane (R134a)) and liquid, subcritical or supercritical CO2. or mixtures of these solvents. ISOLATION OF CANNABINOID ACIDS
In embodiments where the method is to be used for the isolation of cannabinoid acids, an acidified extraction solvent to prepare the starting extract can optionally be used to ensure extraction of high levels of cannabinoid acids. The main purpose of this acidification is to avoid/minimize cannabinoid acid ionization, which otherwise could negatively affect the purification process. In one embodiment, the method uses acidified non-polar solvents of the types described above. Acidification can be achieved by adding a small volume of acid to the solvent. It is usually sufficient to add a relatively weak acid such as acetic acid. For any given purification process, the optimal amount and type of acid used can be determined empirically. An example of an acidified solvent is 0.1% acetic acid in hexane. Other solvents include pentane, hexane, heptane, cyclohexane, petroleum ethers, dichloromethane, trichloromethane, tetrahydrofuran, diethyl ether, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane, propane, refrigerant gas 1,1,1, 2- Tetrafluoroethane (R134a), liquid CO2, subcritical CO2 or supercritical CO2 or mixtures of these solvents. This is the extraction solvent chosen to prepare an initial extract from the starting plant material in the preparation of cannabinoid acids. ISOLATION OF CANNABIGEROL, CANNABIDIOL OR TETRAHYDROCANABINOL - PREVIOUS DECARBOXYLATION
[0053] In embodiments of the method where it is desired to purify free cannabinoids instead of cannabinoid acids, the plant material can be subjected to a decarboxylation step. The purpose of the decarboxylation step is to convert the cannabinoid acids present in the plant material into the corresponding free cannabinoids. Decarboxylation can be carried out by heating the plant material to a defined temperature for a suitable period of time. The decarboxylation of cannabinoid acids is a function of time and temperature, therefore, at higher temperatures, it will take a shorter period of time for complete decarboxylation of a given amount of cannabinoid acid. However, when selecting the appropriate conditions for decarboxylation, consideration should be given to minimizing the thermal degradation of desirable pharmacological cannabinoids into undesirable degradation products, particularly the thermal degradation of Δ9 THC to cannabinol (CBN).
[0054] Thus, in another modality of the present methods, cannabigerol (CBG), cannabidiol (CBD) cannabidivarin (CBDV), tetrahydrocannabinol (THC) or tetrahydrocannabidivarin (THCV) are isolated and purified, and in which, before performing the step (a), the plant material, resin or plant extracts are decarboxylated for at least about 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, 2 hours, 2.1 hours, 2.2 hours, 2.3 hours, 2.4 hours, 2.5 hours, 2, 6 hours, 2.7 hours, 2.8 hours, 2.9 hours, 3 hours, 3.1 hours, 3.2 hours, 3.3 hours, 3.4 hours, 3.5 hours, 4 hours, 4 .5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours at about 60°C, 65°C, 70°C, 75°C, 80 °C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 111°C, 112°C, 113°C, 114°C, 115°C, 116°C , 117°C, 118°C, 119°C, 120°C, 121°C, 122°C, 123°C, 124°C, 125°C, 126°C, 127°C, 128°C, 129 °C or 130°C, 135°C, 140°C, 145°C, 150°C, 155°C, 160°C, 165°C, 170°C, 175 °C or 180 °C. In one embodiment, decarboxylation is carried out for at least 2 hours at a temperature of 120°C. In one embodiment, decarboxylation is carried out for at least 1 hour at a temperature of 150°C.
[0055] In one embodiment, the decarboxylation is carried out at a temperature of at least 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100 °C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C, 145°C, 150°C, 155°C, 160°C , 165°C, 170°C, 175°C, or 180°C. In one embodiment, the decarboxylation is carried out at a temperature of at most 175°C, 170°C, 165°C, 160°C, 155°C, 150°C, 145°C, 140°C, 135°C, 130°C, 125°C, 120°C, 115°C, 110°C, 100°C, 95°C, 90°C, 85°C, 80°C, 75°C, 70°C, 65° C, or 60°C. In one embodiment, decarboxylation is carried out at a temperature ranging from 60°C to 180°C, ranging from 70°C to 175°C, 75°C to 170°C, 80°C to 165°C, 85 °C to 160°C, 90°C to 155°C, 95°C to 150°C, 100°C to 145°C, 105°C to 140°C, 110°C to 135°C, 115°C at 130°C, or 120°C to 130°C.
[0056] In one embodiment, decarboxylation is carried out for a period ranging from at least about 1 hour to 10 hours. In one aspect, the decarboxylation is carried out over a period of approximately at least 1 hour, at least 1.1 hours, at least 1.2 hours, at least 1.3 hours, at least 1.4 hours, at least 1, 5 hours, at least 1.6 hours, at least 1.7 hours, at least 1.75 hours, at least 1.8 hours at least 1.9 hours, at least 2.0 hours, at least 2.1 hours , at least 2.2 hours, at least 2.25 hours, at least 2.3 hours, at least 2.4 hours, at least 2.5 hours, at least 2.75 hours, at least 3.0 hours at least 3.25 hours at least 3.5 hours at least 3.75 hours at least 4.0 hours at least 4.25 hours at least 4.5 hours at least 4.75 hours , at least 5.0 hours, at least 5.5 hours, at least 6.0 hours, at least 6.5 hours, at least 7.0 hours, at least 8.0 hours, at least 8.5 hours, at least 9.0 hours, at least 9.5 hours, or at least 10 hours. In one aspect, decarboxylation is carried out for a maximum of 5 hours, for a maximum of 10 hours, a maximum of 9.5 hours, a maximum of 9.0 hours, a maximum of 8.5 hours, a maximum of 8.0 hours 7.5 hours maximum 7.0 hours maximum 6.5 hours maximum 6.0 hours maximum 5.5 hours maximum 5.0 hours maximum 4 .75 hours, maximum 4.5 hours, maximum 4.25 hours, maximum 4.0 hours, maximum 3.75 hours, maximum 3.5 hours, maximum 3.25 hours, in maximum 3.0 hours, maximum 2.75 hours, maximum 2.5 hours, maximum 2.25 hours, or maximum 2.0 hours.
[0057] Following the disclosed methods, in order to increase the purity of the cannabinoid compound to values greater than 98%, a chromatography can be performed. Conventional chromatography techniques such as Flash, preparative HPLC and even liquid-liquid chromatographic techniques such as countercurrent chromatography (CCC) or centrifugal partition chromatography (CPC) can be used.
[0058] In another embodiment, the disclosed method provides a chromatographic step that is performed before each crystallization step. In one embodiment, a chromatographic step can be added to the present methods. In one embodiment, the chromatographic technique can include column chromatography (such as FLASH or HPLC chromatography) and liquid:liquid chromatography (such as countercurrent chromatography and centrifugal partition chromatography). In one embodiment, countercurrent chromatography (CCC) or centrifugal partition chromatography (CPC) steps are optional and may be included after one or more of the other steps. In one aspect of the chromatographic modality, the chromatographic step is applied after each crystallization step (for example, after step (c), (e), (h) or (i)).
[0059] Both CCC and CPC are liquid-based chromatographic methods, in which both the stationary phase and the mobile phase are liquid. By eliminating solid supports, permanent adsorption of the analyte to the column is avoided and high analyte recovery can be achieved. Easily switch between instrument operating modes between normal phase and reversed phase by simply swapping mobile and stationary phases. With liquid chromatography, operation is limited by the composition of commercially available columns and media for the instrument. Almost any pair of immiscible solutions can be used in liquid-liquid chromatography as long as the stationary phase can be successfully retained. In one embodiment, the mobile phase is organic and/or non-polar and the stationary phase is the aqueous and/or polar reactant.
[0060] Solvent costs for liquid:liquid chromatography are also generally lower than for high performance liquid chromatography (HPLC) and the acquisition and disposal cost of solid adsorbents is eliminated. Another advantage is that the experiments carried out in the laboratory can be scaled to industrial volumes. When performing a GC or HPLC with large volumes, resolution is lost due to problems with surface-volume relationships and flow dynamics; this is avoided when both phases are liquid.
[0061] In one embodiment, the mobile organic phase may include hexane, cyclohexane or heptane. In one embodiment, the stationary phase can include ethanol, methanol, isopropanol, acetone, acetonitrile and/or water. In one embodiment, the mobile phase is hexane, cyclohexane or heptane and the stationary phase is water and ethanol, methanol or isopropanol. In one embodiment, the mobile phase is heptane and the stationary phase is acetone and acetonitrile.
[0062] In countercurrent chromatography (CCC) and in centrifugal partition chromatography (CPC), a two-phase system is used. In one embodiment of the methods just cited, the two-phase system includes Hexane:Ethanol:Water used in ratios of (20:19:1) to (20:8:12), in one embodiment, ratios of (20 :13:7) for the isolation of CBG type cannabinoids, use ratios of (20:14:6) for the isolation of CBD and CBDV, use ratios of (20:17:3) for the isolation of THC and THCV or a reversed phase gradient run is used with a mixture of ethanol and water as the mobile phase, progressively increasing the ethanol concentration from the ratio of (20:12:8) to (20:18:2 ), with the replacement of heptane and/or cyclohexane by hexane and methanol or isopropanol instead of ethanol, with the organic phase of hexane as mobile phase or two-phase system.
[0063] Another embodiment of the present methods comprises a two-phase system with Hexane:Ethanol:Water in proportions ranging from 20:20:1 to 20:1:20 and from 20:1:5 to 20:1:10 and from 1:20:10 to 30:20:1. For example, the ratio of hexane to ethanol can range from about 1:20 to about 20:1, for example, about 1:20, about 1:10, about 3:20, about 4:20 , about 5:20, about 6:20, about 7:20, about 8:20, about 9:20, about 10:20, about 11:20, about 12:20, about about 1:20 pm, about 2:20 pm, about 3:20 pm, about 4:20 pm, about 5:20 pm, about 6:20 pm, about 7:20 pm, about 8:20 pm, about 20 :19, about 20:18, about 20:17, about 20:16, about 20:15, about 20:14, about 20:13, about 20:12, about 20:11 , about 20:10, about 20:9, about 20:8, about 20:7, about 20:6, about 20:5, about 20:4, about 20:3, about of 20:2, or about 20:1. Likewise, the ratio of ethanol to water can range from about 20:1 to about 1:20, for example, about 1:20, about 1:10, about 3:20, about 4: 20, about 5:20, about 6:20, about 7:20, about 8:20, about 9:20, about 10:20, about 11:20, about 12:20, about 13:20, about 14:20, about 15:20, about 16:20, about 17:20, about 18:20, about 19:20, about 20:20, about 20:19, about 20:18, about 20:17, about 20:16, about 20:15, about 20:14, about 20:13, about 20:12, about 20: 11, about 20:10, about 20:9, about 20:8, about 20:7, about 20:6, about 20:5, about 20:4, about 20:3, about 20:2, or about 20:1.
[0064] In one aspect, the ratio of Hexane:Ethanol:Water is (20:19:1) to (20:8:12), and with the replacement of heptane and/or cyclohexane by hexane and methanol and /or isopropanol instead of ethanol, with the organic phase of hexane as the mobile phase or two-phase system. In particular, the ratios of the Hexane:Ethanol:Water two-phase system are (20:13:7) for the isolation of CBG type cannabinoids, (20:14:6) for the isolation of CBD type cannabinoids, and (20 :17:3) to isolate THC-type cannabinoids or using a reversed-phase gradient run with a mixture of ethanol and water as the mobile phase, gradually increasing the ethanol concentration in the ratio (20:12: 8) to (20:18:2).
[0065] Another modality is the method of the invention, in which the two-phase system, Hexane:Ethanol:Water is used and replacement of heptane and/or cyclohexane by hexane and methanol and/or isopropanol instead of ethanol, with the hexane organic phase as mobile phase in CPC and CCC chromatographic techniques to isolate and/or purify cannabinoids that are present in extracts made with pentane, hexane, heptane, petroleum ethers, cyclohexane, dichloromethane, trichloromethane, tetrahydrofuran, diethyl ether, toluene, benzene, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane, propane, refrigerant gases (for example: 1,1,1,2-Tetrafluoroethane (R134a)), or liquid, subcritical or supercritical CO2 or mixtures of these solvents from any variety and chemotype of Cannabis sativa L plant.
[0066] Consequently, an embodiment of the method of the invention comprises before each crystallization step (for example, after step (c), (e), (h) or (i)) a countercurrent chromatography (CCC) or a Centrifugal partition chromatography (CPC) are performed to isolate and purify the cannabinoids: tetrahydrocannabinol (THC), tetrahydrocannabidivarin (THCV), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidivarin (CBDV) and cannabidiolic acid (CBDA).
[0067] Another modality is the method, in which cannabigerol (CBG), cannabidiol (CBD), cannabidivarin (CBDV), tetrahydrocannabinol (THC) or tetrahydrocannabidivarin (THCV) are isolated and purified, and in which, before carrying out the step (a), the plant material or resin of said plant is decarboxylated at at least 120°C for 2 hours.
[0068] Another modality is the method, in which step (a) is repeated at least once. In one modality, step (a) is repeated 2 times or 3 times. Another modality is the method, in which step (a) is at least about 60 minutes.
[0069] Another modality is the method, in which step (i) is repeated at least once. In one modality, step (i) is repeated 2 times or 3 times.
[0070] Another embodiment is the method of the invention, wherein the temperature in steps (d) and (g) is at least about -30°C. In one aspect, the temperature ranges from -30°C to 30°C, -25°C to 30°C, -20°C to 30°C, -10°C to 30°C, -5°C to 30 °C, 0°C to 30°C, 5°C to 30°C, 10°C to 30°C, -30°C to 25°C, -25°C to 25°C, -20°C to 25°C, -10°C to 25°C, -5°C to 25°C, 0°C to 25°C, 5°C to 25°C, 10°C to 25°C, -30°C at 20°C, -25°C to 20°C, -20°C to 20°C, -10°C to 20°C, -5°C to 20°C, 0°C to 20°C, 5 °C to 20 °C, 10 °C to 20 °C. In one aspect, temperatures range from about -20°C to about 6°C. In one embodiment, the temperature is at least -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, -4°C, 0°C, 4 °C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C , 17°C, 18°C, 19°C, 20°C, 25°C, or 30°C. In one aspect, the temperature is at most -10°C, -5°C, -4°C, 0°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9 °C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 25°C , or 30°C.
[0071] Another embodiment is the method, wherein the time in step (d) is from at least about 0.5 hours to at least about 108 hours. In one aspect, the time in step (d) can range from about 1 hour to about 108 hours, from about 2 hours to about 108 hours, from about 3 hours to about 108 hours, from about 5 hours to about 108 hours, from about 6 hours to about 108 hours, from about 8 hours to about 108 hours, from about 10 hours to about 108 hours, from about 12 hours to about 108 hours , from about 18 hours to about 108 hours, from about 24 hours to about 108 hours, from about 36 hours to about 108 hours, from about 48 hours to about 108 hours, from about 72 hours to about 108 hours, from about 84 to about 108 hours, from about 96 hours to about 108 hours, from about 1 hour to about 96 hours, from about 2 hours to about 96 hours, from about 3 hours to about 96 hours, about 5 hours to about 96 hours, about 6 hours to about 96 hours, about 8 hours to about 96 hours, about 10 hours to about 96 hours, from about 12 hours to about 96 hours, from about 18 hours to about 96 hours, from about 24 hours to About 96 hours, from about 36 hours to about 96 hours, from about 48 hours to about 96 hours, from about 72 hours to about 96 hours, from about 84 to about 96 hours, from 1 hour to about 72 hours, from about 2 hours to about 72 hours, from about 3 hours to about 72 hours, from about 5 hours to about 72 hours, about 6 hours to about 72 hours, about 8 hours to about 72 hours, about 10 hours to about 72 hours, about 12 hours to about 72 hours, about 18 hours to about 72 hours, about 24 hours to about 72 hours, about 36 hours to about 72 hours, about 48 hours to about 72 hours, 1 hour to about 48 hours, from about 2 hours to about 48 hours, from about 3 hours to about 48 hours, from about 5 hours to about 48 hours, from about 6 hours to about 48 hours, from about 8 hours to about 48 hours, from about 10 hours to about 48 hours, from about 12 hours to about 48 hours, from about 18 hours to about 48 hours, from about 24 hours to about 48 hours, from about 36 hours to about 48 hours, 1 hour to about 36 hours, about 2 hours to about 36 hours, about 3 hours to about 36 hours, about 5 hours to about 36 hours, about 6 hours to about 36 hours, from about 8 hours to about 36 hours, from about 10 hours to about 36 hours, from about 12 hours to about 36 hours, from about 18 hours to about 36 hours, from about 24 hours to about 36 hours, 1 hour to about 24 hours, about 2 hours to about 24 hours, about 3 hours to about 24 hours, about 5 hours to about 24 hours, about 6 hours to about 24 hours, about 8 hours to about 24 hours, about 10 hours to about 24 hours, about 12 hours to about 24 hours, about 18 hours to about 24 hours, from about 1 hour to about 12 hours, from approx. 2 hours to about 12 hours, about 3 hours to about 12 hours, about 4 hours to about 12 hours, about 5 hours to about 12 hours, about 6 hours to about 12 hours, about 8 hours to about 12 hours, or about 9 hours to about 12 hours. In one aspect, the time in step (d) ranges from 1 hour to 96 hours, 1 hour to 72 hours, 1 hour to 48 hours, 1 hour to 24 hours, or 1 hour to 12 hours.
[0072] Another embodiment is the method of the invention, wherein the time in step (g) is at least about 0.5 hour to 108 hours. In one aspect, the time in step (g) can range from about 1 hour to about 108 hours, from about 2 hours to about 108 hours, from about 3 hours to about 108 hours, from about 5 hours to about 108 hours, from about 6 hours to about 108 hours, from about 8 hours to about 108 hours, from about 10 hours to about 108 hours, from about 12 hours to about 108 hours , from about 18 hours to about 108 hours, from about 24 hours to about 108 hours, from about 36 hours to about 108 hours, from about 48 hours to about 108 hours, from about 72 hours to about 108 hours, from about 84 to about 108 hours, from about 96 hours to about 108 hours, from about 1 hour to about 96 hours, from about 2 hours to about 96 hours, from about 3 hours to about 96 hours, about 5 hours to about 96 hours, about 6 hours to about 96 hours, about 8 hours to about 96 hours, about 10 hours to about 96 hours, from about 12 hours to about 9 6 hours, from about 18 hours to about 96 hours, from about 24 hours to about 96 hours, from about 36 hours to about 96 hours, from about 48 hours to about 96 hours, from about 72 hours to about 96 hours, from about 84 to about 96 hours, from 1 hour to about 72 hours, from about 2 hours to about 72 hours, from about 3 hours to about 72 hours, from about 5 hours to about 72 hours, about 6 hours to about 72 hours, about 8 hours to about 72 hours, about 10 hours to about 72 hours, about 12 hours to about 72 hours, from about 18 hours to about 72 hours, from about 24 hours to about 72 hours, from about 36 hours to about 72 hours, from about 48 hours to about 72 hours, from 1 hour to about 48 hours, from about 2 hours to about 48 hours, from about 3 hours to about 48 hours, from about 5 hours to about 48 hours, from about 6 hours to about 48 hours , from about 8 hours to about 48 hours, from about 10 hours to about 48 hours, from about 12 hours to about 48 hours, from about 18 hours to about 48 hours, from about 24 hours to about 48 hours, from about 36 hours to about 48 hours, 1 hour to about 36 hours, from about 2 hours to about 36 hours, from about 3 hours to about 36 hours, from about 5 hours to about 36 hours, from about 6 hours to about 36 hours, from about 8 hours to about 36 hours, from about 10 hours to about 36 hours, from about 12 hours to about 36 hours, from about 18 hours to about 36 hours, from about 24 hours to about 36 hours, 1 hour to about 24 hours, from about 2 hours to about 24 hours, from about 3 hours to about 24 hours, from about 5 hours to about 24 hours, from about 6 hours to about 24 hours, from about 8 hours to about 24 hours, from about 10 hours to about 24 hours, from about 12 hours to about 24 hours, from about 18 hours to about 24 hours, from about 1 hour to about 12 hours, from about 2 hours to about 12 hours, about 3 hours to about 12 hours, about 4 hours to about 12 hours, about 5 hours to about 12 hours, about 6 hours to about 12 hours, from about 8 hours to about 12 hours, or from about 9 hours to about 12 hours. In one aspect, the time in step (g) ranges from 1 hour to 96 hours, 1 hour to 72 hours, 1 hour to 48 hours, 1 hour to 24 hours, or 1 hour to 12 hours. CHARACTERIZATION OF THE RESULTING PRODUCT
[0073] In one embodiment, the present methods obtain a substantially pure cannabinoid product. A "substantially pure" preparation of a cannabinoid or cannabinoid acid is defined as a preparation with a chromatographic purity (of the desired cannabinoid or cannabinoid acid) greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99% and greater than 99.5%, as determined by normalizing the area of a HPLC profile or by quantification by HPLC with a certified commercial standard.
[0074] CBG and CBD purities are expressed as quantification by HPLC with a certified commercial standard from THCPharm GmBH shown in FIG. 3 and 5. The purity of CBGA is expressed as % of the normalized HPLC peak area shown in FIG. 1.
[0075] The HPLC conditions used to test the purity of the cannabinoid were as follows: Column: Mediterranean Sea, C18, particle size 3 µm, 250 mm x 4.6 mm; Mobile phase: Water and Methanol with ammonium formate; Det.: DAD, 210nm (CBG and CBD) and 270nm (CBGA); Inj.: 10 µL; Oven: 34°C.
[0076] X-ray crystallography diffraction patterns also investigated and shown in FIG. 2, 4 and 6. PRODUCTS OBTAINED BY THE METHODS
The present methods obtain a composition comprising a substantially pure cannabinoid or cannabinoid acid in liquid or solid form. For example, the final product can be applied in its crystalline form or it can be additionally dissolved or formulated in a liquid, powder or tablet. In one embodiment, the present methods obtain a crystalline cannabinoid in powder form. In another embodiment, the present methods provide a cannabinoid solution.
[0078] The product obtained here can be incorporated or formulated into products suitable for pharmaceutical purposes, recreational ingestion (e.g., food supplements, nutraceuticals), or as recreational inhalers (e.g., cigarettes and/or oils or liquids for electronic cigarettes/ vape/waterpipe products, or incense).
[0079] Working with cannabis and cannabinoid plants may, of course, require a government license or approval in some territories, but it can generally be obtained for medicinal purposes. That said, the present methods do not preclude the use of the product as a non-medicinal product, with the appropriate government approvals. PHARMACEUTICAL PRODUCT
[0080] The present methods in an embodiment produce a product, which can be included in a pharmaceutical, medicinal preparation or medicine (hereinafter "pharmaceuticals"). Such pharmaceutical products can be formulated as liquids, tablets, capsules, microcapsules, transcutaneous adhesives, gels, foams, oils, aerosols, powders, creams, films, sprays, eggs, infusions, teas, decoctions, etc.
[0081] Products obtained by the present methods may be included in a pharmaceutical composition which includes a compound of the present product or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient. In one aspect of this embodiment, a pharmaceutical composition comprises CBGA, CBG, CBD or any combination thereof. In a preferred aspect of this embodiment, a pharmaceutical composition comprises CBD.
[0082] The term "excipient" is used herein to describe any ingredient other than the compound of the invention. The choice of excipient will depend, to a large extent, on factors such as the particular mode of administration, the effect of the excipient on solubility and the pharmaceutical compositions suitable for the release of the compounds of the present invention and the methods for their preparation will be readily evident for the technical experts on the subject. Such compositions and methods for their preparation can be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).
The compounds of the invention can be administered orally. Oral administration can involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration can be employed, whereby the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include both solid and liquid formulations.
[0084] Solid formulations include tablets, capsules (containing particulates, liquids, microcapsules or powders), pellets (including liquid-filled pellets), chewables, microparticulates and nanoparticulates, gels, solid solutions, liposomal preparations, microencapsulated preparations, creams , films, eggs and sprays.
[0085] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or plus emulsifying agents and/or suspending agents. Liquid formulations can also be prepared by reconstituting a solid, for example, from a sachet.
The compounds of the invention can also be used in rapidly disintegrating, rapidly disintegrating dosage forms such as those described in Expert Opinion in Therapeutic patents, 11 (6), 981-986, by Liang and Chen (2001) .
For tablet dosage forms, depending on the dose, the drug may constitute from 1% by weight to 80% by weight of the dosage form, more typically from 5% by weight to 60% by weight of the dosage form.
[0088] In addition to the drug, tablets usually contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropylcellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1% by weight to 25% by weight or from 5% by weight to 20% by weight of the dosage form.
Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose.
Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate .
[0091] Tablets may also optionally comprise surface active agents such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2% by weight to 5% by weight of the tablet, and glidants may comprise from 0.2% by weight to 1% by weight of the tablet.
Tablets generally also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate and sodium lauryl sulfate. Lubricants generally comprise from 0.25% by weight to 10% by weight, from 0.5% by weight to 3% by weight of the tablet.
[0093] Other possible ingredients include antioxidants, dyes, flavoring agents, preservatives and taste masking agents.
Exemplary tablets contain up to about 80% drug, from about 10% by weight to about 90% by weight binder, from about 0% by weight to about 85% by weight weight of diluent, from about 2% by weight to about 10% by weight of disintegrant, and from about 0.25% by weight to about 10% by weight of lubricant.
[0095] Tablet blends can be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet granulated, dry or melted, melted and frozen, or extruded prior to tableting. The final formulation can comprise one or more layers and can be coated or uncoated; it can even be encapsulated.
[0096] Tablet formulation is discussed in "Pharmaceutical Dosage Forms: Tablets", Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
[0097] Oral disintegrating films are typically water-soluble or water-swellable thin, flexible film dosage forms that can be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a polymer forming film, a binder, a solvent, a wetting agent, a plasticizer, a stabilizer or agent, a viscosity-modifying agent, and a solvent. Some components of the formulation may have more than one function. The film-forming polymer can be selected from natural polysaccharides, proteins or synthetic hydrocolloids and is typically present in a range of 0.01 to 99% by weight, more typically in the range of 30 to 80% by weight. Other possible ingredients include antioxidants, dyes, flavors and flavor enhancers, preservatives, saliva stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, defoamers, surfactants and taste masking agents. Films according to the invention are typically prepared by evaporative drying of thin aqueous films coated onto a removable backing or backing paper. This can be done in an oven or drying tunnel, typically a combined coating drier, or by freeze drying or applying a vacuum.
[0098] Solid formulations for oral administration can be formulated to be immediate release and/or modified. Modified release formulations comprise delayed, sustained, pulsed, controlled, targeted and programmed release.
[0099] Modified release formulations suitable for the purposes of the invention are described in U.S. Pat. USA No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are found in “Pharmaceutical Technology On-line”, 25(2), 1-14, by Verma et al (2001).” Usage of chewing gum to obtain controlled release is described in WO 00/35298.
The compounds of the invention can also be administered directly into the bloodstream, muscle or an internal organ. Products obtained by the present methods can also be administered parenterally (for example, by subcutaneous, intravenous, intraarterial, intrathecal, intraventricular, intracranial, intramuscular or intraperitoneal injection). Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffering agents (in one embodiment, to a pH between 3 and 9), but, for some applications, may be more appropriately formulated as a non-adherent solution. sterile aqueous or as a dry form to be used in conjunction with a suitable vehicle, such as sterile, pyrogen-free water.
[00101] Formulations for parenteral administration may be formulated to be immediate release and/or modified. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. Thus, the compound of the invention can be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot that provides modified release of the active compound. Examples of such formulations include drug-coated stents and poly(D,L-lactic-coglycolic) acid (PGLA) microspheres.
The compounds obtained by the present methods can also be administered topically to the skin or mucosa, i.e., dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, cosmetics, oils, eye drops, dressings, foams, films, skin adhesives, wafers , implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical vehicles comprise alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated -- see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
[00103] Other means of topical administration include release by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needleless injection (eg, Powderject.TM., Bioject.TM., etc.).
[00104] Formulations for topical administration may be formulated to be immediate release and/or modified. Modified release formulations comprise delayed, sustained, pulsed, controlled, targeted and programmed release.
The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, vaginal suppository or enema. Cocoa butter is a traditional suppository base, but several alternatives can be used as appropriate.
[00106] Formulations for rectal/vaginal administration may be formulated to be immediate release and/or modified. Modified release formulations comprise delayed, sustained, pulsed, controlled, targeted and programmed release.
[00107] The compounds of the invention can be combined with soluble macromolecular entities, such as cyclodextrin and its suitable derivatives or polymers containing polyethylene glycol, in order to improve its solubility, dissolution rate, taste masking, bioavailability and/or stability for use in any of the modes of administration discussed above.
[00108] Drug-cyclodextrin complexes, for example, are generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrin can be used as an auxiliary additive, that is, as a carrier, diluent or solubilizer. The most commonly used for these purposes are the alpha-, beta- and gamma-cyclodextrins, examples of which can be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
[00109] Pharmaceutical compositions for inhalation or insufflation comprise solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid pharmaceutical compositions can comprise suitable pharmaceutically acceptable excipients. In some embodiments, pharmaceutical compositions are administered via the oral or nasal airway for local or systemic effect. Pharmaceutical compositions in pharmaceutically acceptable solvents can be nebulized using inert gases. Nebulized solutions can be inhaled directly from the nebulizer device or the nebulizer device can be connected to a face mask or an intermittent positive pressure respirator. Solution, suspension, or powder pharmaceutical compositions can be administered, for example, orally or nasally, from devices that deliver the formulation in an appropriate manner.
[00110] The pharmaceutical composition described herein can be combined with the administration of another drug or active ingredient. Thus, the present products can be used to alleviate, minimize or prevent not only a disease or medical condition, but a side effect of another treatment regimen. RECREATIONAL PRODUCTS
[00111] In one embodiment, purified cannabinoids obtained by the present methods can be included in compositions such as oils (either for topical administration as massage oil, or to be burned or aerosolized), incense, cosmetics, bath oils, perfumes, make-up, food spices, toothpaste, ingestible solids (eg as a powder included in or on foods) or liquids (eg teas), etc.
[00112] For example, a product produced by the present methods can be included in a "vape" product containing propylene glycol, glycerin, vegetable glycerin, aqueous glycerin and, optionally, flavors. In one aspect, the "vape" product may also include other drugs, such as nicotine. METHODS OF TREATMENT OF A MEDICAL CONDITION
[00113] The pharmaceuticals described herein can be administered to treat or reduce the symptoms of a disease or medical condition. In one embodiment, the present products can be administered to treat pain, schizophrenia, seizure, inflammation, anxiety or panic, depression (including unipolar or bipolar mood disorder and syndromic depression, etc.), as a neuroprotective (i.e., for the treatment of neurodegenerative disease, stroke, traumatic brain injury), cancer, migraines, arthritis, chronic pain (including neuropathic pain), nausea and vomiting, anorexia, glaucoma, epilepsy, asthma, addiction (and addiction and withdrawal symptoms ), movement disorders that show spasticity (in multiple sclerosis and spinal cord injury), Tourette's syndrome, dystonia and tardive dyskinesia.
[00114] In particular embodiments of methods, the methods of treatment reduce, decrease, suppress, limit, control or inhibit the presence of one or more symptoms associated with a medical condition; reduce, decrease, suppress, limit, control or inhibit the side effects of other pharmaceutical treatment; reduce, decrease, suppress, limit, control or inhibit the symptoms of addiction. In additional particular embodiments of methods, the methods of treatment include administering an amount of the present product sufficient to increase, induce, enhance, amplify, promote or stimulate an immune response against the medical condition; or decrease, reduce, inhibit, suppress, prevent, control or limit the spread of the medical condition in an individual or patient, or between individuals or patients. In additional particular embodiments of methods, the methods of treatment include administering an amount of the present products sufficient to protect an individual from a condition related to the medical condition, or to reduce, lessen, limit, control or inhibit susceptibility to a condition related to the medical condition. medical condition. REAGENTS FOR PERFORMING THE CURRENT METHOD
[00115] In yet another embodiment, the present invention comprises reagents for the purification of cannabinoids. Such reagents include hexane (for CBG and CBGA), pentane and petroleum ether 40-60°C eg (for CBD), heptane and petroleum ether 60-80°C eg for cannabinoid crystallization, and optionally reagents for liquid chromatography such as ethanol, methanol or isopropyl alcohol or heptane, acetone and acetonitrile. Kit
[00116] Yet another embodiment of the present invention includes a kit for the purification of cannabinoids, including the non-polar organic solvent, any necessary filtration devices (such as a vacuum filtration mechanism including bottle-filters). top filters”) and syringe filters) and any reagents, columns, or cartridges required for optional chromatography.
[00117] Aspects of the present modality can also be described as follows: 1. Method of purifying one or more cannabinoids from a plant material, characterized in that the method comprises a) incubating the plant material with a first solvent non-polar to form a first solvent mixture that extracts one or more cannabinoids from a plant material; b) reducing the volume of the first solvent mixture to about 50% or less of the original volume of the first solvent mixture in step (a) in a manner that concentrates one or more cannabinoids; c) incubating the first reduced solvent mixture at a temperature range between about -70°C and about 40°C in a manner that crystallizes one or more cannabinoids; d) incubating one or more crystallized cannabinoids with a second non-polar solvent to form a second solvent mixture, wherein the second solvent mixture dissolves at least 50% of the one or more crystallized cannabinoids; and e) incubating the second mixture of solvents at a temperature range between about -70°C and about 40°C in a manner that crystallizes one or more cannabinoids, thus resulting in the purification of one or more cannabinoids. 2. Method, according to modality 1, characterized in that the plant material is a plant extract or plant resin. 3. Method, according to modality 1 or modality 2, characterized by the fact that the plant material is derived from the Cannabis genera. 4. Method, according to any one of modalities 1 to 3, characterized by the fact that the plant material is derived from a Cannabis sativa, Cannabis indica, Cannabis ruderalis, their hybrids or their varieties. 5. Method, according to modality 4, characterized in that the Cannabis sativa variety comprises a Chemotype II variety, a Chemotype IIl variety or a Chemotype IV variety. 6. Method, according to modality 4, characterized in that the Cannabis sativa variety comprises a Carma variety, an AIDA variety, a SARA variety, a PILAR variety, a Futura 75 variety or an experimental 60.2/1/1/ 9. 7. Method, according to any one of the modalities 1 to 6, characterized in that, before step (a), the plant material is treated to decarboxylate one or more cannabinoids present in the plant material. 8. Method according to any one of modalities 1 to 7, characterized in that the first non-polar solvent of step (a) comprises pentane, hexane, heptane, cyclohexane, petroleum ether, dichloromethane, trichloromethane, tetrahydrofuran, diethyl ether, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane, propane, refrigerant gas 1,1,1,2- Tetrafluoroethane (R134a), liquid CO2, subcritical CO2 and supercritical CO2. 9. Method, according to any one of modalities 1 to 8, characterized in that one or more cannabinoids comprise tetrahydrocannabinol (THC), tetrahydrocannabidivarin (THCV), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidivarin (CBDV ), cannabidiolic acid (CBDA), cannabigerol (CBG) or cannabidiolic acid (CBGA). 10. Method, according to any one of the modalities 1 to 9, characterized in that, in step (a), the first solvent mixture is incubated for at least 5 minutes. 11. Method, according to modality 10, characterized by the fact that, in step (a), the first mixture of solvents is incubated for between about 10 minutes and about 1500 minutes. 12. Method, according to modality 11, characterized by the fact that, in step (a), the first mixture of solvents is incubated for between about 30 minutes and about 120 minutes. 13. Method according to any one of the modalities 1 to 12, characterized in that step (a) is repeated at least once. 14. Method, according to modality 13, characterized by the fact that step (a) is repeated three times. 15. Method according to any one of modalities 1 to 14, characterized in that, in step (b), the volume of the first mixture of solvents is reduced to about 1% to about 50% of the original volume of the first mixture of solvents in step (a). 16. Method according to modality 15, characterized in that, in step (b), the volume of the first solvent mixture is reduced to about 0.1% to about 1.5% of the original volume of the first mixture of solvents in step (a). 17. Method according to modality 15, characterized in that, in step (b), the volume of the first solvent mixture is reduced to about 16% to about 50% of the original volume of the first solvent mixture in step (a). 18. Method according to any one of the modalities 1 to 17, characterized in that, in step (b), the first mixture of solvents is reduced by evaporation. 19. Method according to any one of modalities 1 to 18, characterized in that, in step (c), the first reduced solvent mixture is incubated at a temperature range between about -20°C and about 30°C. 20. Method according to any one of modalities 1 to 18, characterized in that, in step (c), the first reduced solvent mixture is incubated at a temperature range between about 0°C and about 25 °C. 21. Method according to embodiment 20, characterized in that, in step (c), the first reduced solvent mixture is incubated at a temperature range between about 4°C and about 8°C. 22. Method according to any one of modalities 1 to 21, characterized in that, in step (c), the first reduced solvent mixture is incubated for a period of time of at least 30 minutes, at least 1 hour or at least 2 hours. 23. Method according to modality 22, characterized in that, in step (c), the first reduced solvent mixture is incubated for a period of time between 1 hour and 96 hours. 24. Method according to modality 23, characterized in that, in step (c), the first reduced solvent mixture is incubated for a period of time between 2 hours and 72 hours. 25. Method according to modality 24, characterized in that, in step (c), the first reduced solvent mixture is incubated for a period of time between 4 hours and 48 hours. 26. Method according to modality 25, characterized in that, in step (c), the first reduced solvent mixture is incubated for a period of time between 6 hours and 24 hours. 27. Method according to modality 26, characterized in that, in step (c), the first reduced solvent mixture is incubated for a period of time between 12 hours and 24 hours. 28. Method according to any one of embodiments 1 to 27, characterized in that step (c) further comprises seeding the reduced solvent mixture with a cannabinoid. 29. Method according to embodiment 28, characterized in that the cannabinoid used to seed the reduced solvent mixture comprises a purified cannabinoid, a partially purified cannabinoid, or crude extract comprising a cannabinoid. 30. Method according to any one of embodiments 1 to 29, characterized in that the second non-polar solvent of step (d) comprises pentane, hexane, heptane, petroleum ethers, cyclohexane, dichloromethane, trichloromethane, tetrahydrofuran, diethyl ether, toluene, benzene, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane, propane, refrigerant gas (eg: 1,1,1,2-Tetrafluoroethane (R134a)), or liquid CO2, subcritical or supercritical or mixtures of these solvents. 31. Method according to any one of embodiments 1 to 30, characterized in that, in step (d), the second mixture of solvents dissolves at least 75% of one or more crystallized cannabinoids. 32. Method according to embodiment 31, characterized in that, in step (d), the second solvent mixture dissolves at least 85% of one or more crystallized cannabinoids. 33. Method according to embodiment 32, characterized in that, in step (d), the second solvent mixture dissolves at least 95% of one or more crystallized cannabinoids. 34. Method according to any one of modalities 1 to 33, characterized in that, in step (d), the second solvent mixture is incubated at a temperature range between about 30°C and about 60 °C. 35. Method according to embodiment 34, characterized in that, in step (d), the second solvent mixture is incubated at a temperature range between about 40°C and about 50°C. 36. Method according to any one of the modalities 1 to 35, characterized in that, in step (d), the second mixture of solvents is incubated for a period of time of at least 30 minutes. 37. Method according to modality 36, characterized in that, in step (d), the second mixture of solvents is incubated for a period of time between 1 hour and 4 hours. 38. Method according to any one of modalities 1 to 37, characterized in that, in step (e), the second solvent mixture is incubated at a temperature range between about -20°C and about 30°C. 39. Method according to any one of modalities 1 to 38, characterized in that, in step (e), the second solvent mixture is incubated at a temperature range between about 0°C and about 25 °C. 40. Method according to modality 39, characterized in that, in step (e), the second mixture of solvents is incubated at a temperature range between about 4°C and about 8°C. 41. Method according to any one of the modalities from 1 to 40, characterized in that, in step (e), the second mixture of solvents is incubated for a period of time of at least 30 minutes, at least 1 hour , at least 2 hours, at least 3 hours, or at least 4 hours. 42. Method according to modality 41, characterized in that, in step (e), the second mixture of solvents is incubated for a period of time between 1 hour and 96 hours. 43. Method according to modality 42, characterized in that, in step (e), the second mixture of solvents is incubated for a period of time between 2 hours and 72 hours. 44. Method according to modality 43, characterized in that, in step (e), the second mixture of solvents is incubated for a period of time between 4 hours and 48 hours. 45. Method according to modality 46, characterized in that, in step (e), the second mixture of solvents is incubated for a period of time between 6 hours and 24 hours. 46. Method according to modality 45, characterized in that, in step (e), the second mixture of solvents is incubated for a period of time between 12 hours and 24 hours. 47. Method according to any one of embodiments 1 to 46, characterized in that one or more crystallized cannabinoids from step (c) is purified before step (d). 48. Method, according to modality 47, characterized by the fact that purification is carried out using filtration that results in a collection of a mother liquor. 49. Method according to embodiment 48, characterized in that it further comprises incubating the mother liquor at a temperature range between about -70°C and about 40°C in a manner that crystallizes a or more cannabinoids. 50. Method according to modality 49, characterized in that it further comprises f) purifying one or more crystallized cannabinoids using filtration that results in a collection of a mother liquor; and g) incubating the mother liquor at a temperature range between about -70°C and about 40°C in a manner that crystallizes one or more cannabinoids. 51. Method according to any one of the modalities 1 to 50, characterized in that steps (f) and (g) are repeated at least once. 52. Method, according to modality 51, characterized by the fact that steps (f) and (g) are repeated 2 times. 53. Method, according to modality 52, characterized by the fact that steps (f) and (g) are repeated 3 times. 54. Method according to any one of modalities 1 to 53, characterized in that steps (d) and (e) are repeated at least once. 55. Method, according to modality 49, characterized by the fact that steps (d) and (e) are repeated 2 times. 56. Method, according to modality 50, characterized by the fact that steps (d) and (e) are repeated 3 times. 57. Method according to any one of embodiments 1 to 56, characterized in that the first mixture of solvents from step (a) is purified before step (b). 58. Method according to modality 57, characterized in that purification is carried out using filtration. 59. Method according to any one of embodiments 1 to 58, characterized in that one or more crystallized cannabinoids from step (e) is filtered. 60. Method according to any one of the modalities 1 to 59, characterized in that it further comprises performing liquid:liquid chromatography after one or more of steps (b) or (d). 61. Method, according to modality 60, characterized in that the liquid:liquid chromatography is countercurrent chromatography (CCC) or centrifugal partition chromatography (CPC). 62. Method according to modality 61, characterized in that the mobile organic phase comprises hexane, cyclohexane or heptane. 63. Method, according to modality 61, characterized in that the stationary phase comprises ethanol, methanol, isopropanol, acetone, acetonitrile and/or water. 64. Method, according to modality 61, characterized in that the mobile phase is hexane, cyclohexane or heptane and the stationary phase is water and ethanol, methanol or isopropanol. 65. Method according to modality 61, characterized in that the mobile phase is heptane, and the stationary phase is acetone and acetonitrile. 66. Purified cannabinoid characterized in that it is produced by the method, according to any one of the modalities 1 to 65. 67. Pharmaceutical composition, characterized in that it comprises a purified cannabinoid produced by the method, according to any of the modalities 1 to 65. 68. Pharmaceutical composition of modality 67, characterized in that it additionally comprises a pharmaceutically acceptable excipient or carrier. 69. Method of treating a disease or medical condition, characterized in that it comprises administering the cannabinoid produced by the method, according to any one of the modalities 1 to 65, to an individual in need of it. 70. Method of treatment of a disease or medical condition of modality 69, characterized in that the disease or medical condition is pain, schizophrenia, seizure, inflammation, anxiety, depression, neurodegenerative disease, stroke, traumatic brain injury, cancer, migraines , arthritis, chronic pain, nausea and vomiting, anorexia, glaucoma, epilepsy, asthma, addiction, addiction and withdrawal symptoms, multiple sclerosis, spinal cord injury, Tourette syndrome, dystonia or tardive dyskinesia. 71. Method of purifying a cannabinoid from a plant material, characterized in that the method comprises: a) incubating the plant material with a first non-polar solvent to form a first solvent mixture that extracts one or more cannabinoids to from a plant material; b) filtering the first mixture of solvents; c) reducing the volume of the first solvent mixture to about 50% or less of the original volume of the first solvent mixture in step (a) in a manner that concentrates one or more cannabinoids; d) incubating the first reduced solvent mixture in a manner that crystallizes one or more cannabinoids; e) purify one or more cannabinoids crystallized in step (d) using filtration that results in a collection of a mother liquor; f) incubating one or more crystallized cannabinoids with a second non-polar solvent to form a second solvent mixture, wherein the second solvent mixture dissolves at least 50% of the one or more crystallized cannabinoids; g) incubating the second solvent mixture at a temperature range between about -70°C and about 40°C in a manner that crystallizes one or more cannabinoids; and h) purifying one or more crystallized cannabinoids from step (g) using filtration that results in a collection of a mother liquor, thus resulting in the purification of one or more cannabinoids. 72. Method according to modality 71, characterized in that the mother liquor of step (e) and/or step (h) is incubated at a temperature range between about -70°C and about 40°C in a manner that crystallizes one or more cannabinoids. 73. Methods, according to modality 72, characterized in that it further comprises i) purifying one or more crystallized cannabinoids using filtration that results in a collection of a mother liquor; and j) incubating the mother liquor at a temperature range between about -70°C and about 40°C in a manner that crystallizes one or more cannabinoids. 74. Method according to modality 73, characterized in that steps (i) and (j) are repeated at least once. 75. Method, according to modality 74, characterized by the fact that steps (i) and (j) are repeated 2 times. 76. Method, according to modality 75, characterized by the fact that steps (i) and (j) are repeated 3 times. 77. Method according to any one of the modalities 71 to 76, characterized in that steps (f) and (g) are repeated at least once. 78. Method, according to modality 77, characterized by the fact that steps (f) and (g) are repeated 2 times. 79. Method, according to modality 78, characterized by the fact that steps (f) and (g) are repeated 3 times. 80. Method according to any one of the modalities 71 to 79, characterized in that steps (f), (g) and (h) are repeated at least once. 81. Method, according to modality 80, characterized by the fact that steps (f), (g) and (h) are repeated 2 times. 82. Method, according to modality 81, characterized by the fact that steps (f), (g) and (h) are repeated 3 times. 83. Method, according to any one of the modalities 72 to 83, characterized in that the plant material is a plant extract or a plant resin. 84. Method, according to any one of the modalities 71 to 83, characterized by the fact that the plant material is derived from the Cannabis genera. 85. Method, according to any one of the modalities 71 to 84, characterized by the fact that the plant material is derived from a Cannabis sativa, Cannabis indica, Cannabis ruderalis, their hybrids or their varieties. 86. Method, according to modality 86, characterized in that the variety of Cannabis sativa comprises a variety of Chemotype II, a variety of Chemotype IIl or a variety of Chemotype IV. 87. Method, according to modality 86, characterized in that the Cannabis sativa variety comprises a Carma variety, an AIDA variety, a SARA variety, a PILAR variety, a Futura 75 variety or an experimental 60.2/1/1/ 9. 88. Method according to any one of embodiments 71 to 87, characterized in that, prior to step (a), the plant material is treated to decarboxylate one or more cannabinoids present in the plant material. 89. Method according to any one of the modalities 71 to 88, characterized in that the first non-polar solvent of step (a) comprises pentane, hexane, heptane, cyclohexane, petroleum ether, dichloromethane, trichloromethane, tetrahydrofuran, diethyl ether, benzene, toluene, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane, propane, refrigerant gas 1,1,1,2- Tetrafluoroethane (R134a), liquid CO2, subcritical CO2 and supercritical CO2. 90. Method according to any one of the modalities 71 to 89, characterized in that one or more cannabinoids comprise tetrahydrocannabinol (THC), tetrahydrocannabidivarin (THCV), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidivarin (CBDV ), cannabidiolic acid (CBDA), cannabigerol (CBG) or cannabidiolic acid (CBGA). 91. Method, according to any one of the modalities from 71 to 90, characterized by the fact that, in step (a), the first solvent mixture is incubated for at least 5 minutes. 92. Method according to modality 91, characterized by the fact that, in step (a), the first mixture of solvents is incubated for between about 10 minutes and about 1500 minutes. 93. Method, according to modality 92, characterized in that, in step (a), the first mixture of solvents is incubated for between about 30 minutes and about 120 minutes. 94. Method according to any one of the modalities 71 to 93, characterized in that step (a) is repeated at least once. 95. Method, according to modality 94, characterized by the fact that step (a) is repeated twice. 96. Method, according to modality 95, characterized by the fact that step (a) is repeated 3 times. 97. Method according to any one of the modalities 71 to 96, characterized in that, in step (c), the volume of the first solvent mixture is reduced to about 5% to about 50% of the original volume of the first mixture of solvents in step (a). 98. Method according to modality 97, characterized in that, in step (c), the volume of the first solvent mixture is reduced to about 1% to about 15% of the original volume of the first solvent mixture in step (a). 99. Method according to modality 97, characterized in that, in step (c), the volume of the first solvent mixture is reduced to about 15% to about 50% of the original volume of the first solvent mixture in step (a). 100. Method according to any one of the modalities 71 to 99, characterized in that, in step (c), the volume of the first solvent mixture is reduced by evaporation. 101. Method according to any one of the modalities 71 to 100, characterized in that, in step (d), the first reduced solvent mixture is incubated at a temperature range between about -20°C and about of 30°C. 102. Method according to embodiment 101, characterized in that, in step (d), the first reduced solvent mixture is incubated at a temperature range between about 0°C and about 25°C. 103. Method according to embodiment 102, characterized in that, in step (d), the first reduced solvent mixture is incubated at a temperature range between about 4°C and about 8°C. 105. Method according to any one of the modalities 71 to 103, characterized in that, in step (d), the first reduced solvent mixture is incubated for a period of time of at least 30 minutes, at least 1 hour or at least 2 hours. 106. Method according to embodiment 104, characterized in that, in step (d), the first reduced solvent mixture is incubated for a period of time between 1 hour and 96 hours. 107. Method according to modality 104, characterized in that, in step (d), the first reduced solvent mixture is incubated for a period of time between 2 hours and 72 hours. 108. Method according to embodiment 106, characterized in that, in step (d), the first reduced solvent mixture is incubated for a period of time between 4 hours and 48 hours. 109. Method according to embodiment 107, characterized in that, in step (d), the first reduced solvent mixture is incubated for a period of time between 6 hours and 24 hours. 110. Method according to embodiment 108, characterized in that, in step (d), the first reduced solvent mixture is incubated for a period of time between 12 hours and 24 hours. 111. Method according to any one of embodiments 71 to 109, characterized in that step (d) further comprises seeding the reduced solvent mixture with a cannabinoid. 112. Method according to embodiment 110, characterized in that the cannabinoid used to seed the reduced solvent mixture comprises a purified cannabinoid, a partially purified cannabinoid, or crude extract comprising a cannabinoid. 113. Method according to any one of embodiments 71 to 111, characterized in that the first non-polar solvent of step (f) comprises pentane, hexane, heptane, cyclohexane, petroleum ether, dichloromethane, trichloromethane, tetrahydrofuran, diethyl ether, benzene, toluene, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane, propane, refrigerant gas 1,1,1,2- Tetrafluoroethane (R134a), liquid CO2, subcritical CO2 and supercritical CO2. 114. Method according to any one of embodiments 71 to 112, characterized in that, in step (f), the second mixture of solvents dissolves at least 75% of one or more crystallized cannabinoids. 115. Method according to embodiment 113, characterized in that, in step (f), the second solvent mixture dissolves at least 85% of one or more crystallized cannabinoids. 116. Method according to embodiment 114, characterized in that, in step (f), the second solvent mixture dissolves at least 95% of one or more crystallized cannabinoids. 117. Method according to any one of the modalities 71 to 115, characterized in that, in step (f), the second mixture of solvents is incubated at a temperature range between about 30°C and about 60 °C. 118. Method according to embodiment 116, characterized in that, in step (f), the second mixture of solvents is incubated at a temperature range between about 40°C and about 50°C. 119. Method according to any one of embodiments 71 to 117, characterized in that, in step (f), the second mixture of solvents is incubated for a time period of at least 30 minutes. 120. Method according to modality 118, characterized in that, in step (f), the second mixture of solvents is incubated for a period of time between 1 hour and 4 hours. 121. Method according to any one of the modalities 71 to 119, characterized in that, in step (g), the second mixture of solvents is incubated at a temperature range between about -20°C and about 30°C. 122. Method according to modality 120, characterized in that, in step (g), the second mixture of solvents is incubated at a temperature range between 0°C and about 25°C. 123. Method, according to modality 121, characterized in that, in step (a), the second mixture of solvents is incubated at a temperature range between 4°C and about 8°C. 124. Method according to any one of the modalities 71 to 122, characterized in that, in step (g), the second mixture of solvents is incubated for a period of time of at least 30 minutes, at least 1 hour , at least 2 hours, at least 3 hours, or at least 4 hours. 125. Method according to modality 123, characterized in that, in step (g), the second mixture of solvents is incubated for a period of time between 1 hour and 96 hours. 126. Method according to modality 124, characterized in that, in step (g), the second mixture of solvents is incubated for a period of time between 2 hours and 72 hours. 127. Method according to modality 125, characterized in that, in step (g), the second mixture of solvents is incubated for a period of time between 4 hours and 48 hours. 128. Method according to modality 126, characterized in that, in step (g), the second mixture of solvents is incubated for a period of time between 6 hours and 24 hours. 129. Method according to modality 127, characterized in that, in step (g), the second mixture of solvents is incubated for a period of time between 12 hours and 24 hours. 130. Method, according to any one of the modalities 71 to 128, characterized by the fact that the temperature in steps (d) and (g) is at most about 4°C for the purification of CBGA/CBG and that of step (d) is at most -20°C for the purification of CBD. 131. Method according to any one of the modalities of 71 to 129, characterized in that it further comprises performing liquid:liquid chromatography after one or more of steps (c), (e) or (h). 132. Method, according to modality 130, characterized in that the liquid:liquid chromatography is countercurrent chromatography (CCC) or centrifugal partition chromatography (CPC). 133. Method, according to modality 130, characterized in that the mobile organic phase comprises hexane, cyclohexane, or heptane. 134. Method according to any one of modalities 130-131, characterized in that the stationary phase comprises ethanol, methanol, isopropanol, acetone, acetonitrile and/or water. 135. Method according to modality 130 or modality 131, characterized in that the mobile phase is hexane, cyclohexane, or heptane and the stationary phase is water and ethanol, methanol, or isopropanol. 136. Method according to modality 130 or modality 131, characterized in that the mobile phase is heptane, and the stationary phase is acetone and acetonitrile. 137. Method, according to any one of the modalities 71 to 135, characterized in that it additionally comprises performing countercurrent chromatography (CCC) or dentifuge partition chromatography (CPC) after steps (e) or (h) to isolate, purify or repurify the cannabinoids tetrahydrocannabinol (THC), tetrahydrocannabidivarin (THCV), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidiol (CBDV), cannabidiolic acid (CBDA), cannabigerol (CBG) and cannabigerolic acid (CBGA) . 138. Method according to any one of the modalities 130 to 136, characterized in that the chromatography uses a two-phase system, Hexane:Ethanol:Water in the proportions of (20:19:1) to (20:8 :12) and in which hexane can be replaced by heptane and/or cyclohexane and in which ethanol can be replaced by methanol and/or isopropanol instead of ethanol, with the organic phase of hexane as the mobile phase or the two system phases. 139. Method according to any one of the modalities 130 to 137, characterized by the fact that the proportions of the two-phase system, Hexane: Ethanol: Water are (20:13:7) for the isolation of CBG-type cannabinoids , (20:14:6) for the isolation of CBD-type cannabinoids and (20:17:3) for THC-type cannabinoids or the use of a reversed-phase gradient run with a mixture of ethanol and water as mobile phase , gradually increasing the ethanol concentration from the ratio of (20:12:8) to (20:18:2). 140. Method, according to any one of the modalities 71 to 138, characterized in that cannabigerol (CBG), cannabidiol (CBD), cannabidivarin (CBD), tetrahydrocannabidivarin (THCV) or tetrahydrocannabinol (THC) are isolated and purified and , prior to step (a), the plant material, resin or extracts of said plant are decarboxylated at at least about 120°C for at least 1 hour. 141. Method, according to any one of modality 71 to 138, characterized in that cannabigerol (CBG), cannabidiol (CBD), cannabidivarin (CBD), tetrahydrocannabidivarin (THCV) or tetrahydrocannabinol (THC) is isolated and purified and , prior to step (a), the plant, plant material, plant extract, or resin is decarboxylated by hydrodistillation (steam distillation) at at least 90°C for 2 hours. 142. Purified cannabinoid characterized in that it is produced by the method, according to any one of the modalities 71 to 140. 143. Pharmaceutical composition, characterized in that it comprises a purified cannabinoid produced by the method, according to any of the modes 71 to 140. 144. Pharmaceutical composition of embodiment 142, characterized in that it additionally comprises a pharmaceutically acceptable excipient or carrier. 145. Method of treating a disease or medical condition, characterized in that it comprises administering the cannabinoid produced by the method, according to any one of the modalities 71 to 140, to an individual in need of it. 146. Method of treatment of a disease or medical condition of modality 144, characterized in that the disease or medical condition is pain, schizophrenia, seizure, inflammation, anxiety, depression, neurodegenerative disease, stroke, traumatic brain injury, cancer, migraines , arthritis, chronic pain, nausea and vomiting, anorexia, glaucoma, epilepsy, asthma, addiction, addiction and withdrawal symptoms, multiple sclerosis, spinal cord injury, Tourette syndrome, dystonia or tardive dyskinesia. 147. Method according to either embodiment 7 or 88, characterized in that the plant material is heated to between 100°C and 160°C to decarboxylate one or more cannabinoids present in the plant material. 148. Method, according to modality 146, characterized in that the plant material is heated between 120°C and 150°C to decarboxylate one or more cannabinoids present in the plant material. 149. Method, according to modalities 146 or 147, characterized in that the plant material is heated for a period of at least 30 minutes. 150. Method, according to modality 148, characterized in that the plant material is heated for a period of 1 hour to 3 hours. 151. Method, according to any one of the modalities 1 to 149, characterized by the fact that one or more cannabinoids is CBGA, CBG, CBD, or any combination thereof. 152. Method, according to modality 151, characterized by the fact that CBGA has a purity of 90% or higher, 91% or higher, 92% or higher, 93% or higher, 94% or higher, 95% or higher , 96% or greater, 97% or greater, 98% or greater, or 99% or greater, as determined by normalizing the area of a HPLC profile or by a percent purity quantification against a certified commercial standard. 153. Method, according to modality 150, characterized by the fact that CBG has a purity of 90% or higher, 91% or higher, 92% or higher, 93% or higher, 94% or higher, 95% or higher , 96% or greater, 97% or greater, 98% or greater, or 99% or greater, as determined by normalizing the area of a HPLC profile or by a percent purity quantification against a certified commercial standard. 154. Method, according to modality 150, characterized by the fact that CBD has a purity of 90% or higher, 91% or higher, 92% or higher, 93% or higher, 94% or higher, 95% or higher , 96% or greater, 97% or greater, 98% or greater, or 99% or greater, as determined by normalizing the area of a HPLC profile or by a percent purity quantification against a certified commercial standard. 155. Pharmaceutical composition of any of the modalities 67, 68, 142 or 143, characterized by the fact that the purified cannabinoid is CBGA, CBG, CBD or any combination thereof. 156. Method, according to modality 154, characterized in that the purified cannabinoid is CBGA with a purity of 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater, as determined by normalizing the area of a HPLC profile or by a percent purity quantification with respect to a commercial standard certificate. 157. Method, according to modality 154, characterized in that the purified cannabinoid is CBG with a purity of 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater, as determined by normalizing the area of a HPLC profile or by a percent purity quantification with respect to a commercial standard certificate. 158. Method, according to modality 154, characterized in that the purified cannabinoid is CBD with a purity of 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater, as determined by normalizing the area of a HPLC profile or by a percent purity quantification with respect to a commercial standard certificate. 159. Method according to any one of modalities 1 to 153, characterized in that a substantially pure preparation of one or more cannabinoids is achieved without the use of a chromatographic technique. 160. Method, according to modality 158, characterized in that a substantially pure preparation of CBGA is achieved without the use of a chromatographic technique. 161. Method, according to modality 158, characterized in that a substantially pure preparation of CBG is achieved without the use of a chromatographic technique. 162. Method, according to modality 158, characterized in that a substantially pure preparation of CBD is achieved without the use of a chromatographic technique. EXAMPLES
[00118] The following non-limiting examples are provided for illustrative purposes only, in order to facilitate a more complete understanding of the representative modalities now contemplated. These examples are not to be construed to limit any of the embodiments disclosed in this specification, including those relating to the compounds, pharmaceutical compositions, or methods and uses disclosed herein. Example 1 Isolation of CBGA from plant material
[00119] The maceration of 150 g of plant material of Cannabis sativa L. of the Carma variety is made, with predominant CBGA, in 750 mL of hexane for one hour. This procedure is repeated three times. The plant material is filtered and the hexane is evaporated to a volume of about 100 ml. The extract is then incubated at about 4°C for about 24 hours in order to crystallize the CBGA-“raw” material. The "raw" CBGA-material is vacuum filtered and the collected mother liquor is evaporated to a volume of about 30 ml to about 50 ml, is incubated at about 4°C for about 48 hours in order to crystallize the “raw” CBGA-material and then it is vacuum filtered. The amount of CBGA-“raw” material obtained in this two-step process depends on the concentration of CBGA in the starting plant material.
[00120] The "raw" CBGA obtained is recrystallized with 5 ml of hexane per gram of CBGA, two or three more times to obtain CBGA with a purity greater than 90% and about 95%.
[00121] Subsequently, the crude or recrystallized CBGA is purified by countercurrent chromatography, using the two-phase system, Hexane:Ethanol:Water (20:14:6) or (20:12:8) with the hexane organic phase as mobile phase. The CBGA is eluted at a K of 3.2-3.5 (20:14:6) or a K of 1-1.5 (20:12:8), assuming a charge of 0.5 g to 1 g of recrystallized CBGA per 100 ml of CCC coil. Generally, a CBGA with a purity greater than 98% is obtained. Example 2 Isolation of CBGA from plant material
[00122] This experiment was repeated 3 times, the data shown is the average of the three experiments. 150 g of plant material of Cannabis sativa L. of the Carma variety was maceration, with predominant CBGA, in 1 L of hexane for one hour. This procedure is repeated two more times with 0.75 L of hexane. The plant material was filtered and the hexane was evaporated to a volume of 65 ml and then incubated at 4°C for 18 hours in order to crystallize the CBGA-“raw” material. About 1.54 g of CBGA-“raw” material were obtained. The CBGA - "raw" material was vacuum filtered and the mother liquor collected, evaporated to a volume of about 35 mL and incubated at 4°C for 24 hours in order to crystallize the CBGA - "raw" material. About 0.22 g of CBGA-"raw" material were obtained. The total amount of CBGA- "raw" material obtained in this three-step process was 1.76 g, representing a yield of 1.75% by weight of the initial plant material used.
[00123] 1.7 g of CBGA-“raw” material were then recrystallized with 9 ml of hexane (ratio of about 5 ml of hexane per gram of CBGA). The CBGA mixture was heated to 50°C and then incubated at 4°C for 2 hours to crystallize CBGA. About 1.42 g of CBGA were obtained from the first recrystallization; a yield of 83.5% from the initial “raw” CBGA-material. A second recrystallization was performed in two of the three experiments with 1.49 g of CBGA and 15 mL of hexane (ratio of about 10 mL of hexane per gram of CBGA). The CBGA mixture was heated to 50°C and then incubated at 4°C for 2 hours to crystallize CBGA. About 1.43 g of CBGA with a purity of 95% or greater was obtained, with a yield of 95.9% of the first amount of the CBG recrystallization. A third recrystallization was performed in one of the three experiments with 1.45 g of CBGA and 15 mL of hexane (ratio of about 10 mL of hexane per gram of CBGA). The CBGA mixture was heated to 50°C and then incubated at 4°C for 2 hours to crystallize CBGA. Approximately 1.36 g of CBGA with a purity of 95% or more were obtained. The third recrystallization yield was 93.7% and represents an 80% yield from the initial "raw" CBGA-material. The total amount of CBGA with a purity of 95% or more obtained was 1.43 g, representing a yield of 84.1% from the CBGA-used "raw" material and 1.43% by weight of the starting plant material used. With a recrystallization, CBGA with a purity greater than 95% was obtained. Example 3 Isolation of CBGA from plant material
[00124] This experiment was repeated 3 times, the data shown is the average of the three experiments. 95.2 g of plant material of Cannabis sativa L. of the AIDA variety (CVPO file number: 20160167 of 14-1-16) was maceration with predominant CBGA in 1 L of hexane for one hour. This procedure is repeated two more times with 0.75 L of hexane. The plant material was filtered and the hexane was evaporated to a volume of 80 ml and then incubated at 4°C for 18 hours in order to crystallize the CBGA-“raw” material. About 1.8 g of CBGA-“raw” material were obtained. The CBGA-"raw" material was vacuum filtered and the mother liquor collected, evaporated to a volume of 40 mL and incubated at 4°C for 24 hours in order to crystallize the CBGA-"raw" material. About 0.4 g of CBGA-“raw” material were obtained. The total amount of CBGA-“raw” material obtained in this two-step process was 2.2 g, representing a yield of 2.3% by weight of the starting plant material used.
[00125] 1.75 g of CBGA-“raw” material was then recrystallized with 9 ml of hexane (ratio of about 10 ml of hexane per gram of CBGA). The CBGA mixture was heated to 50°C and then incubated at 4°C for 2 hours to crystallize CBGA. About 1.51 g of CBGA with 97% purity was obtained. The same recrystallization process was carried out with 0.4 g of "raw" CBGA obtained from the mother liquor using 4 mL of hexane. Approximately 0.35 g of CBGA with a purity of 99% was obtained. The total amount of CBGA with a purity of 95% or more obtained was 1.86 g, representing a yield of 86.5% from the CBGA-used "raw" material and 1.95% by weight of the starting plant material used. With a single recrystallization, CBGA with a purity greater than 95% was obtained. Example 4 Isolation of CBGA from plant material
[00126] A maceration of 2.8 kg of plant material of Cannabis sativa L. of the AIDA variety (CVPO file number: 20160167 of 14-1-16) was made with predominant CBGA in 25 L of hexane for a period of time. hour. This procedure was repeated two more times. The plant material was filtered and the hexane was evaporated to a volume of 3 L and then incubated at 23°C in order to crystallize the CBGA-“raw” material. About 26.5 g of CBGA-“raw” material were obtained. The CBGA- "crude" material was vacuum filtered and the mother liquor collected, evaporated to a volume of 2 L and then incubated at 7°C for 24 hours in order to crystallize the CBGA-"crude" material . About 8.8 g of CBGA-“raw” material were obtained. The total amount of CBGA-"raw" material obtained in this three-step process was 37.4 g, representing a yield of 1.3% by weight of the starting plant material used.
[00127] 35.3 g of CBGA-“raw” material were then recrystallized with 1 L of hexane (ratio of about 28 mL of hexane per gram of CBGA). The CBGA mixture was heated at 50°C for 1 hour and then vacuum filtered to obtain 18.7 g of "washed" CBGA material. The collected mother liquors were evaporated and then incubated at room temperature (23°C) for 2 hours in order to crystallize CBGA. About 6.5 g of CBGA were obtained. CBGA was vacuum filtered and the mother liquor collected, evaporated and incubated at 5°C for 2 hours in order to crystallize CBGA. Approximately 3.7 g of CBGA were obtained. The total amount of CBGA with a purity of 95% or more obtained was 28.9 g, representing a yield of 81.9% from the used CBGA-“raw” material and 1% by weight of the starting plant material used. With a recrystallization at room temperature, CBGA with a purity greater than 95% was obtained (see FIG. 1 and FIG. 2). Example 5 Isolation of CBGA from extracts
[00128] It was made the maceration of 10 g of extract of Cannabis sativa L. of the Carma variety, with predominant CBGA, in 50 mL of hexane for one hour (3x). The part of the extract not dissolved in hexane was filtered or decanted, the hexane, evaporated to a volume of 50 mL and then incubated at 4°C for 24 hours in order to crystallize the CBGA-“raw” material. The CBGA-"raw" material was vacuum filtered and the mother liquor collected, evaporated to a volume of 25 mL, incubated at 4°C for 24 hours in order to crystallize the CBGA-"raw" material. About 0.4 g of CBGA-“raw” material were obtained.
[00129] The obtained CBGA-material "raw" was recrystallized with 5 ml of hexane per gram of CBGA, two or three more times to obtain CBGA with a purity greater than 90% and about 95%.
[00130] Subsequently, the recrystallized CBGA was purified. To obtain a purity greater than 98%, the recrystallized CBGA was purified by countercurrent chromatography (CCC), using the two-phase system, Hexane:Ethanol:Water (10:7:3) with the organic phase of hexane as mobile phase. CBGA was eluted at a K of 3.2-3.5, assuming a charge of 0.5 g to 1 g of recrystallized CBGA per 100 mL of CCC coil. Example 6 Isolation of CBGA ethanol from extracts
[00131] The maceration of 50.3 g of plant material was made and dried of the Carma variety with 500 ml of ethanol for 1 hour (3x) and the ethanol was evaporated to obtain about 4.7 g of solid extract , representing a yield of 9.4%, according to the method disclosed in WO2009043836 or EP2044935, except without the decarboxylation step. 4.7 g of plant material of Cannabis sativa L. of the Carma variety was maceration, with predominant CBGA, in 50 mL of hexane for one hour. The part of the extract not dissolved in hexane was filtered or decanted, the hexane, evaporated to a volume of 40 mL and then incubated at 7°C for 18 hours in order to crystallize the CBGA-“raw” material. About 491 mg of CBGA-"raw" material were obtained. The CBGA-"raw" material was vacuum filtered and the mother liquor collected, evaporated to a volume of 20 mL and then incubated at 4°C for 5 hours in order to crystallize the CBGA-"raw" material. About 300 mg of CBGA-“raw” material were obtained. The "raw" CBGA material was vacuum filtered and the mother liquor collected, evaporated to a volume of 10 mL and then incubated at 7°C for 18 hours in order to crystallize the CBGA. Approximately 79 mg of CBGA were obtained. The total amount of CBGA obtained was 870 mg, representing a yield of 18.5% from the initial extract used and 1.7% by weight of the initial plant material used. The 870 mg of CBGA obtained was recrystallized with 5 ml of hexane per gram of CBGA two or three more times to obtain CBGA with a purity of greater than 90% and about 95%. Example 7 Isolation of CBGA ethanol from extracts
[00132] The maceration of 51.0 g of dry plant material of the AIDA variety (CVPO file number: 20160167 of 14-1-16) was extracted by maceration with 500 mL of ethanol for 1 hour (3x) and the ethanol was evaporated to obtain about 9.2 g of solid extract, representing a yield of 18%, according to the method disclosed in WO2009043836 or EP2044935, except without the decarboxylation step. The maceration of 9.2 g of Cannabis sativa L. extract of the AIDA variety, with predominant CBGA, was carried out in 50 mL of hexane for one hour. The part of the extract not dissolved in hexane was filtered or decanted, the hexane, evaporated to a volume of 40 mL and then incubated at 7°C for 18 hours in order to crystallize the CBGA-“raw” material. About 1251 mg of CBGA-“raw” material were obtained. The "raw" CBGA material was vacuum filtered and the mother liquor collected, evaporated to a volume of 20 mL and then incubated at 7°C for 18 hours in order to crystallize the CBGA. Approximately 1070 mg of CBGA were obtained. The CBGA was vacuum filtered and the mother liquor collected, evaporated to a volume of 10 mL and then incubated at 7°C for 7 hours in order to crystallize the CBGA. Approximately 70 mg of CBGA was obtained. The total amount of CBGA obtained was 2391 mg, representing a yield of 25.9% from the initial extract used and 4.7% by weight of the initial plant material used. The 2391 mg of "crude" CBGA obtained were recrystallized with 5 ml of hexane per gram of CBGA two or three more times to obtain CBGA with a purity of greater than 90% and about 95%. Example 8 Isolation of CBGA acetone from extracts
[00133] The maceration of 100.3 g of dried plant material of the Carma variety were extracted by maceration with 1000 mL of acetone for 1 hour (3x) and the acetone was evaporated to obtain about 11 g of solid extract, representing a 11% yield, according to the method disclosed in WO2009043836 or EP2044935, except without the decarboxylation step. The maceration of 7.7 g of Cannabis sativa L. extract of the Carma variety was made, with predominant CBGA, in 25 mL of hexane for one hour, repeating with 10 mL of hexane. The part of the extract not dissolved in hexane was decanted, the hexane, evaporated to a volume of 25 mL and then incubated at 7°C for 18 hours in order to crystallize the CBGA-“raw” material. About 634 mg of CBGA-"raw" material were obtained. The CBGA- "raw" material was vacuum filtered and the mother liquor collected, evaporated to a volume of 10 mL and then incubated at 7°C for 18 hours in order to crystallize the CBGA. Approximately 121 mg of CBGA were obtained. The CBGA was vacuum filtered and the mother liquor collected, evaporated to a volume of 10 mL and then incubated at 7°C for 7 hours in order to crystallize the CBGA. Approximately 9 mg of CBGA was obtained. The total amount of CBGA obtained was 764 mg, representing a yield of 9.9% from the initial extract used and 1.1% by weight of the initial plant material used. The 870 mg of CBGA obtained was recrystallized with 5 ml of acetone per gram of CBGA two or three more times to obtain CBGA with a purity of greater than 90% and about 95%. Example 9 Isolation of CBGA acetone from extracts
[00134] The maceration of 100.2 g of dry plant material of the AIDA variety (CVPO file number: 20160167 of 14-1-16) was extracted by maceration with 1000 mL of acetone for 1 hour (3x) and the acetone was evaporated, obtaining approximately 16.6 g of solid extract, representing a yield of 16.6%, according to the method disclosed in WO2009043836 or EP2044935, except without the decarboxylation step. 9.8 g of Cannabis sativa L. extract of the AIDA variety was maceration, with predominant CBGA, in 25 mL of hexane for one hour, repeating with 10 mL of hexane. The part of the extract not dissolved in hexane was decanted, the hexane, evaporated to a volume of 35 mL and then incubated at 7°C for 18 hours in order to crystallize the CBGA-“raw” material. About 283 mg of CBGA-"raw" material were obtained. The "raw" CBGA material was vacuum filtered and the mother liquor collected, evaporated to a volume of 20 mL and then incubated at 7°C for 18 hours in order to crystallize the CBGA. Approximately 1172 mg of CBGA were obtained. CBGA was vacuum filtered and the mother liquor collected, evaporated to a volume of 10 mL and then incubated at 7°C for 18 hours in order to crystallize the CBGA. Approximately 236 mg of CBGA were obtained. The total amount of CBGA obtained was 1691 mg, representing a yield of 17.2% from the initial extract used and 2.8% by weight of the initial plant material used. The 1691 mg of CBGA obtained was recrystallized with 5 ml of hexane per gram of CBGA two or three more times to obtain CBGA with a purity of greater than 90% and about 95%. Example 10 Isolation of CBG from plant material
[00135] To decarboxylate CBGA into CBG, 150 g of Cannabis sativa L. of the Carma variety, with predominant CBGA, were decarboxylated by heating at 120°C for two hours. There was a subsequent maceration in 750 ml of hexane for one hour (3x). The plant material was filtered, hexane, evaporated to a volume of 100 ml and then incubated at 4°C for 24 hours in order to crystallize the CBG-"crude" material. The "raw" CBG-material was vacuum filtered and the mother liquor collected, evaporated to a volume of 30 mL to 50 mL and then incubated at 4°C for 24 hours in order to crystallize the CBG. The amount of CBG obtained in this two-step process depends on the concentration of CBG in the starting plant material. The CBG obtained was recrystallized with 5 ml of hexane per gram of CBG two or three more times to obtain CBG with a purity between 95% and 98%.
[00136] To obtain a purity greater than 98%, the recrystallized CBG was purified by countercurrent chromatography (CCC), using the two-phase system, Hexane:Ethanol:Water (120:14:6) or (10:13:7) with the organic hexane phase as the mobile phase. CBG was eluted at a K of 2 or 1, respectively, assuming a charge of 0.5 g to 1 g of recrystallized CBG per 100 mL of CCC coil. Example 11 Isolation of CBG from plant material
[00137] This experiment was repeated 3 times, the data shown is the average of the three experiments. To decarboxylate CBGA to CBG, 150 g of Cannabis sativa L. of the Carma variety, with predominant CBGA, were decarboxylated by heating at 150°C for 1 hour. 100.5 g of decarboxylated plant material was macerated in 1 L of hexane for one hour. This procedure is repeated two more times with 0.75 L of hexane. The plant material was filtered and the hexane was evaporated to a volume of 50 ml and then incubated at 4°C for 72 hours in order to crystallize the CBG-“raw” material. About 2.24 g of CBG-"raw" material were obtained. The "raw" CBG-material was vacuum filtered and the mother liquor collected, evaporated to a volume of 30 mL and then incubated at -18°C for 24 hours in order to crystallize the CBG. Approximately 0.26 g of CBG was obtained. The total amount of CBG obtained in this two-step process was 2.5 g, representing a yield of 2.48% by weight of the initial decarboxylated plant material used.
[00138] 2.1 g of CBG-“raw” material obtained were then recrystallized with 12.5 ml of hexane (ratio of about 6 ml of hexane per gram of CBG). The CBG mixture was heated to 40°C until all of the CBG-“raw” material was dissolved and then incubated at 4°C for 12 hours to crystallize CBG. About 1.79 g of CBG were obtained from the first recrystallization; an 85% yield from the initial “raw” CBG-material. A second recrystallization was carried out with 1.77 g of CBG and 13.5 ml of hexane (ratio of about 8 ml of hexane per gram of CBG). The CBG mixture was heated to 40°C until all of the CBG had dissolved and then incubated at 4°C for 12 hours to crystallize CBG. About 1.57 g of CBG with a purity of 95% or more were obtained. The yield of the second recrystallization was 86.7% from the material from the first CBGA recrystallization, or 74.8% from the CBG-initial “raw” material. A third recrystallization was performed in two of the three experiments with 1.59 g of CBG and 12.5 mL of hexane (ratio of about 8 mL of hexane per gram of CBG). The CBG mixture was heated to 40°C and then incubated at 4°C for 12 hours to crystallize CBG. About 1.38 g of CBG with a purity of 95% or more were obtained. The third recrystallization yield was 86.9% and represented a 66.2% yield from the initial "raw" CBG-material. The total amount of CBG with a purity of 95% or more obtained was 1.43 g to 1.57 g, representing a yield of 66.2% to 74.8% from the initial "raw" CBG-material and 1 .4% to 1.5% by weight of the starting decarboxylated plant material used. Example 12 Isolation of CBG from plant material
[00139] This experiment was repeated 3 times, the data shown is the average of the three experiments. To decarboxylate CBGA to CBG, 150 g of Cannabis sativa L. of the AIDA variety (CVPO file number: 20160167 of 14-1-16), with predominant CBGA, were decarboxylated by heating at 150°C for 1 hour. 100.4 g of decarboxylated plant material was macerated in 1 L of hexane for one hour. This procedure is repeated two more times with 0.75 L of hexane. The extract is then incubated at 4°C for 72 hours in order to crystallize the CBG-crude material. About 4.8 g of CBG-“raw” material were obtained. The "raw" CBG-material was vacuum filtered and the mother liquor collected, evaporated to a volume of 30 mL and then incubated at 4°C for 72 hours in order to crystallize the CBG. About 0.1 g of CBG was obtained. The total amount of CBG obtained in this two-step process was 4.9 g, representing a yield of 4.88% by weight of the initial decarboxylated plant material used.
[00140] 4.77 g of CBG-"raw" material were then recrystallized with 20 mL of hexane (ratio of about 4.2 mL of hexane per gram of CBG). The CBG mixture was heated to 40°C until all of the CBG had dissolved and then incubated at 4°C for 12 hours to crystallize CBG. About 4.3 g of CBG were obtained from the first recrystallization; a 90.2% yield from the initial "raw" CBG-material. A second recrystallization was carried out with 4.3 g of CBG and 20 ml of hexane (ratio of about 4.6 ml of hexane per gram of CBG). The CBG mixture was heated to 40°C until all of the CBG had dissolved and then incubated at 4°C for 12 hours to crystallize CBG. About 4.12 g of CBG were obtained. The yield of the second recrystallization was 89.5% from the material from the first CBG recrystallization, or 86.4% from the CBG-initial "raw" material. A second recrystallization was carried out with 4.1 g of CBG and 20 ml of hexane (ratio of about 4.9 ml of hexane per gram of CBG). The CBG mixture was heated to 40°C until all of the CBG had dissolved and then incubated at 4°C for 12 hours to crystallize CBG. About 3.85 g of CBG with a purity of >95% were obtained. The third recrystallization yield was 93.9% and represented an 80.7% yield from the initial "raw" CBG-material. The total amount of CBG with a purity of 95% or more obtained was 3.85 g, representing a yield of 80.7% from the initial "raw" CBG-material and 3.84% by weight of the decarboxylated plant material initial used. Example 13 Isolation of CBG from plant material
[00141] To decarboxylate CBGA to CBG, 4 kg of Cannabis sativa L. of the AIDA variety (CVPO file number: 20160167 of 14-1-16), with predominant CBGA, were decarboxylated by heating at 150°C for 1 hour. 3.65 kg of decarboxylated plant material was macerated in 25 L of hexane for one hour. This procedure is repeated two more times with 20 L of hexane. The plant material was filtered and the hexane was evaporated to a volume of 2 L and then incubated at 7°C for 15 hours in order to crystallize the CBG-“raw” material. About 75.3 g of CBG-“raw” material were obtained. The "raw" CBG-material was vacuum filtered and the mother liquor collected, evaporated to a volume of 1.5 L and then incubated at 7°C for 24 hours in order to crystallize the CBG. About 29.2 g of CBG were obtained. The total amount of CBG obtained in this two-step process was 4.9 g, representing a yield of 4.88% of the initial plant material. The CBG was vacuum filtered a second time and the mother liquor collected, evaporated to a volume of 1 L and then incubated at 7°C for 12 hours to crystallize the CBG. About 5.9 g of CBG were obtained. The CBG was vacuum filtered a third time and the mother liquor collected, evaporated to a volume of 0.6 L and then incubated at 7°C for 24 hours in order to crystallize the CBG. About 10.6 g of CBG were obtained. The total amount of CBG obtained in this four-step process was 121 g, representing a yield of 3% from the starting plant material used.
[00142] 110.2 g of CBG-"raw" material were then recrystallized with 335 mL of hexane (ratio of about 3 mL of hexane per gram of CBG). The CBG mixture was heated to 40°C until all of the CBG had dissolved and then incubated at 7°C for 72 hours to crystallize CBG. About 87.6 g of CBG were obtained from the first recrystallization; a 79.5% yield from initial "raw" CBG-material. A second recrystallization was carried out with 77.1 g of CBG and 225 ml of hexane (ratio of about 3 ml of hexane per gram of CBG). The CBG mixture was heated to 40°C until all of the CBG had dissolved and then incubated at 7°C for 2 hours to crystallize CBG. About 61.8 g of CBG were obtained. CBG was vacuum filtered and the collected mother liquor was evaporated and then incubated at 7°C for 70 hours in order to crystallize CBG. About 11.6 g of CBG were obtained. The second recrystallization yield was 95.2% from the material from the first CBG recrystallization.
[00143] An additional recrystallization was carried out with the 9.4 g of CBG remaining from the first recrystallization plus the 11.6 g of CBG from the second recrystallization with 210 mL of hexane (ratio of about 10 mL of hexane per gram of CBG ). The CBG mixture was heated to 40°C until all of the CBG had dissolved and then incubated at 7°C for 24 hours to crystallize CBG. About 19.3 g of CBG were obtained. The third recrystallization yield was 91.9% and represented 80.7%. The sum of the results of the second recrystallization indicated that 81.1 g of CBG were obtained and represent a 92.6% yield or a 73.6% yield from the initial "raw" CBG-material.
[00144] A third recrystallization was performed with 80.8 g of CBG and 500 mL of hexane (ratio of about 6.2 mL of hexane per gram of CBG). The CBG mixture was heated to 40°C until all of the CBG had dissolved and then incubated at room temperature (23°C) for 12 hours to crystallize CBG. About 67.2 g of CBG with a purity of 99% or more were obtained. CBG was vacuum filtered and the collected mother liquor was evaporated and then incubated at 7°C for 2 hours in order to crystallize CBG. About 7.9 g of CBG with a purity of >95% were obtained. The total amount of CBG with a purity of 95% or more obtained in the third recrystallization was 75.1 g with a yield of 92.6% and represents a yield of 68.2% from the initial "raw" CBG-material.
[00145] The 10.5 g of CBG obtained in the last crystallization were treated and processed separately, and initially recrystallized with 100 mL of hexane (ratio of about 10 mL of hexane per gram of CBG). The CBG mixture was incubated at 7°C for 24 hours to crystallize CBG. About 7.24 g of CBG were obtained. The yield of the first recrystallization was 69% from the initial “raw” CBG-material. A second recrystallization was carried out with 7.12 g of CBG and 60 ml of hexane (ratio of about 8.4 ml of hexane per gram of CBG). The CBG mixture was heated to 40°C until the CBG was dissolved and then incubated at 4°C for 5 hours to crystallize CBG. About 6.55 g of CBG were obtained. The yield of the second recrystallization was 92% from the material from the first CBG recrystallization, or 62.4% of the CBG-starting "raw" material. A third recrystallization was carried out with 6.55 g of CBG and 60 ml of hexane (ratio of about 9.2 ml of hexane per gram of CBG). The CBG mixture was heated to 40°C until the CBG was dissolved and then incubated at 4°C for 5 hours to crystallize CBG. About 5.99 g of CBG with a purity of 95% or more were obtained. The third recrystallization yield was 91.5% and represented a 57% yield from the initial "raw" CBG-material. The total amount of CBG with a purity of 95% or more obtained was 80.8 g, representing a yield of 66.8% from the CBG-starting "raw" material and 2.2% by weight of the starting decarboxylated plant material used . (See FIG. 3 and FIG. 4). Example 14 Isolation of CBG from extracts
[00146] To decarboxylate CBGA to CBG, 150 g of Cannabis sativa L. of the Carma variety, with predominant CBGA, were decarboxylated by heating at 120°C for two hours. The decarboxylated plant material was extracted by maceration with 750 ml of acetone for 1 hour (3x) and the acetone was evaporated to obtain about 12 g of solid extract, according to the method disclosed in WO2009043836 or EP2044935, except without the decarboxylation step. A subsequent maceration of 10 g of Cannabis sativa L. extract of the Carma variety, with predominant CBG, was carried out in 50 mL of hexane for one hour (3x). The part of the extract not dissolved in hexane was filtered or decanted, and the hexane, evaporated to a volume of 50 mL and then incubated at 4°C for 24 hours in order to crystallize the CBGA-“raw” material. The “crude” CBG-material was vacuum filtered and the mother liquor collected, evaporated to a volume of 25 mL and then incubated at 4°C for 48 hours in order to crystallize the “crude” CBG-material. The amount of CBG-“raw” material obtained in this two-step process depends on the concentration of CBG in the starting extract.
The "raw" CBG-material was then recrystallized with 5 mL of hexane per gram of CBG two or three more times to obtain CBG with a purity of 95% or more.
[00148] To obtain a purity greater than 98%, the recrystallized CBG was purified by countercurrent chromatography (CCC), using the two-phase system, Hexane:Ethanol:Water (20:14:6), with the organic hexane phase as the mobile phase. The CBG is eluted at a K of 2-2.5 (20:14:6) or a K of 1-1.5 (20:13:7), assuming a charge of 0.5 g to 1 g of recrystallized CBG per 100 mL of CCC coil. Example 15 Isolation of CBG from Butane Resin Extracts
[00149] 1 kg of Cannabis sativa L. of the Carma variety, with predominant CBGA, was sieved with a 150 μm sieve, obtaining 87 g of resin. To decarboxylate CBGA to CBG, 87 g of Cannabis sativa L. of the Carma variety, with predominant CBGA, were decarboxylated by heating at 120°C for two hours. 75 g of the decarboxylated resin was extracted by cold extraction using butane as solvent with 200 g of butane for 20 minutes to 45 minutes (4x). About 11 g of solid resin extract were obtained. A subsequent maceration of 10 g of the butane extract of Cannabis sativa L. of the Carma variety, with predominant CBG, was carried out in 50 mL of hexane for one hour. The resin extract was dissolved and the solution was left at 4°C for 12 hours in order to crystallize the CBGA-"crude" material. About 4.5 mg of CBGA-“raw” material were obtained. The collected mother liquor was used to purify other cannabinoids with countercurrent chromatography (CCC). The amount of CBG- "raw" material represents a yield of 45% from the used extract and 6% by weight of the decarboxylated resin used.
[00150] 4.5 g of CBG-"raw" material were then recrystallized with 50 mL of hexane (ratio of about 10 mL of hexane per gram of CBG). The CBG mixture was heated to 40°C until the CBG was dissolved and then incubated at 4°C for 12 hours to crystallize CBG. The recrystallization step was performed twice. About 3.1 g of CBG with a purity of 95% or more were obtained. The yield of CBG with a purity of 95% or more was 31% from the starting "raw" CBG-material and 4.1% by weight of the starting decarboxylated resin used.
[00151] To obtain the THC and CBD from the collected mother liquors with a purity greater than 95%, the mother liquors were evaporated and the dry residue, purified by means of countercurrent chromatography (CCC), using the two-phase system, Hexane:Ethanol:Water (10:7:3), with the organic hexane phase as the mobile phase if CBD was the main target compound. THC was eluted at a K of 0.5 and CBD was eluted at a K of 1-1.5, assuming a charge of 1 g to 2 g of dry mother liquor per 100 mL of coil. of CCC. If TCH was the main target compound, the two-phase system used was Hexane:Ethanol”Water (20:17:3), with the organic phase of hexane as the mobile phase. THC was eluted at a K of 1 and CBD was eluted at a K of 2-2.5, assuming a charge of 1 g to 2 g of dry mother liquor per 100 mL of CCC coil. . Example 16 Isolation of CBD from plant material
[00152] This experiment was repeated 2 times, the data shown is the average of the two experiments. To decarboxylate CBDA to CBD, 465 g of Cannabis sativa L. of the SARA variety (CVPO file number: 20150098 of 15-1-15), with predominant CBDA, were decarboxylated by heating at 150°C for 1 hour. 203.6 g of decarboxylated plant material were macerated in 2 L of petroleum ether (40-60°C pe) for one hour. This maceration procedure was repeated twice with 1.5 L of petroleum ether (40-60°C pe). The plant material was filtered and the petroleum ether was evaporated to a volume of 120 ml and then incubated at -18°C for 1 to 2 hours in order to precipitate insoluble material. The solution was vacuum filtered, seeded with 0.1 g of CBD and incubated at -18°C for 14 hours to crystallize CBD-"crude" material. About 16.3 g of "raw" CBD-material were obtained. The CBD - "raw" material was vacuum filtered and the mother liquor collected, evaporated to a volume of 70 mL and then incubated at -18°C for 20 hours in order to crystallize the CBD. About 1.4 g of CBD were obtained. The CBD was vacuum filtered and the mother liquor collected, evaporated to a volume of 50 mL and then incubated at -18°C for 48 hours in order to crystallize the CBD. About 1.05 g of CBD were obtained. CBD was vacuum filtered. The total amount of CBD obtained in this three-step process was 18.7 g, representing a yield of 9.2% by weight of the initial decarboxylated plant material used.
[00153] In an experiment, the CBD of each crystallization step was processed independently. The 15 g of CBD obtained in the first crystallization were recrystallized with 22.5 ml of petroleum ether (40-60°C pe), proportion of about 1.5 ml of petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until all of the CBD had dissolved and then incubated at room temperature (23°C) for 12 hours to crystallize CBD. About 2.8 g of CBD were obtained. CBD was vacuum filtered and the collected mother liquor was evaporated and then incubated at 7°C for 2 hours to crystallize CBD. About 10.5 g of CBD were obtained. The CBD was vacuum filtered and the collected mother liquor was evaporated and then incubated at -18°C for 24 hours in order to crystallize the CBD. About 0.5 g of CBD were obtained. The yield of CBD recrystallized at room temperature (23°C) was 18.7%, whereas the yield of CBD recrystallized at 7°C is 70%.
[00154] A second recrystallization was carried out with 8.3 g of CBD obtained at 7°C after washing with cold petroleum ether with 8.5 mL of petroleum ether (40-60°C pe), ratio of about 1 mL of petroleum ether per gram of CBD. CBD was heated to 40°C until all of the CBD had dissolved and then incubated at room temperature (23°C) for 12 hours to crystallize CBD. About 4.6 g of CBD were obtained. The CBD material was vacuum filtered and the mother liquor collected, evaporated and then incubated at 7°C for 2 hours to crystallize the CBD. About 1.0 g of CBD were obtained. The yield of the second recrystallization at room temperature (23°C) was 55.4%, and the yield of the recrystallization at 7°C is 12.7%. Together, both represent a return of 58.1%.
[00155] A third recrystallization was carried out with 4.6 g of CBD and 5 ml of petroleum ether (40-60°C pe), ratio of about 1 ml of petroleum ether per gram of CBD. CBD was heated to 40°C until all of the CBD had dissolved and then incubated at room temperature (23°C) for 12 hours to crystallize CBD. About 3.6 g of CBD were obtained. After filtering the CBD, the collected mother liquors were evaporated and then incubated at 7°C for 2 hours in order to crystallize the CBD. About 0.7 g of CBD were obtained.
[00156] 2.4 g of CBD obtained in the second crystallization were recrystallized with 2.5 ml of petroleum ether (40-60°C pe), proportion of about 1 ml of petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until all of the CBD had dissolved and then incubated at 4°C for 12 hours to crystallize CBD. About 1.3 g of CBD were obtained. After filtering the CBD, the collected mother liquors were evaporated and then incubated at 7°C for 2 hours in order to crystallize the CBD material. About 0.6 g of CBD were obtained. The yield of the first recrystallization at room temperature (23°C) was 54.2%, and the yield of the recrystallization at 7°C is 25%.
[00157] 0.8 g of CBD obtained in the third crystallization were recrystallized with 1 ml of petroleum ether (40-60°C pe), proportion of about 1.25 ml of petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until all of the "crude" CBD was dissolved and then incubated at room temperature (23°C) for 12 hours to crystallize CBD. About 0.5 g of CBD were obtained. After filtering the CBD, the collected mother liquors were evaporated and then incubated at 7°C for 2 hours in order to crystallize the CBD. About 0.2 g of CBD were obtained. The yield of the first recrystallization at room temperature (23°C) was 54.2%, and the yield of the recrystallization at 7°C is 25%. The yield of the first recrystallization at room temperature (23°C) is 62.5%, and the yield of the recrystallization at 7°C is 25%.
[00158] The CBD recrystallized at room temperature (23°C) from all 3 crystallization steps plus the CBD obtained at 7°C from the first and second crystallization steps were pooled (9.1 g) and this amount of CBD was recrystallized for a second time with 10 ml of petroleum ether (40-60°C pe), proportion of about 1 ml of petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until all of the CBD had dissolved and then incubated at room temperature (23°C) for 12 hours to crystallize CBD. About 7.0 g of CBD were obtained. After filtering the CBD, the collected mother liquors were evaporated and then incubated at 7°C for 2 hours in order to crystallize the CBD. About 1.4 g of CBD were obtained. The yield of the first recrystallization at room temperature (23°C) was 54.2%, and the yield of the recrystallization at 7°C is 25%. The yield of the first recrystallization at room temperature (23°C) is 62.5%, and the yield of the recrystallization at 7°C is 25%.
[00159] The CBD recrystallized at 7°C from the third crystallization plus the CBD obtained at 7°C from the first and second crystallization steps were pooled (9.1 g) and this amount of CBD was recrystallized for a second time with 10 ml petroleum ether (40-60°C pe), ratio of about 1 ml petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until all of the CBD had dissolved and then incubated at room temperature (23°C) for 12 hours to crystallize CBD. About 2.8 g of CBD were obtained. After filtering the CBD, the collected mother liquors were evaporated and then incubated at 7°C for 2 hours in order to crystallize the CBD. About 0.5 g of CBD were obtained.
[00160] A third and final recrystallization was performed with the CBD obtained at room temperature (23°C) from the two second recrystallizations (9.3 g) and this amount of CBD was recrystallized with 10 mL of petroleum ether (4060°C pe), ratio of about 1 mL petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until all of the CBD had dissolved and then incubated at room temperature (23°C) for 5 hours to crystallize CBD. About 7.3 g of CBD with a purity of 98.3% were obtained. After filtering the CBD, the collected mother liquors were evaporated and then incubated at 7°C for 2 hours in order to crystallize the CBD. About 1.4 g of CBD were obtained. The yield of the third recrystallization at room temperature (23°C) was 78.5%, and the yield of the recrystallization at 7°C was 15%. The total amount of CBD with a purity of 95% or more was 7.3 g with a yield of 78.5%, representing a 40.5% yield from the initial "raw" CBD-material and a yield of 3 .6% by weight of the starting decarboxylated plant material used.
[00161] In the second experiment, 17.6 g of CBD- "raw" material were recrystallized with 13.5 mL of petroleum ether (40-60°C pe), proportion of about 0.75 mL of petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until all of the CBD had dissolved and then incubated at room temperature (23°C) for 7 hours to crystallize CBD. About 8.5 g of CBD were obtained. After filtering the CBD, the collected mother liquors were evaporated and then incubated at 7°C for 2 hours in order to crystallize the CBD. About 6.5 g of CBD were obtained. The yield of the first recrystallization at room temperature (23°C) is 48.3%, and the yield of the recrystallization at 7°C is 36.9%.
[00162] A second recrystallization was carried out with 6.56 g of CBD obtained at 7°C and 4.8 ml of petroleum ether (40-60°C pe), proportion of about 0.75 ml of petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until all of the CBD had dissolved and then incubated at room temperature (23°C) for 48 hours to crystallize CBD. About 4.1 g of CBD were obtained. After filtering the CBD, the collected mother liquors were evaporated and then incubated at 7°C for 2 hours in order to crystallize the CBD material. About 1.3 g of CBD were obtained. The yield of the first recrystallization at room temperature (23°C) was 63%, and the yield of the recrystallization at 7°C is 20%. With the 8.5 g and 4.1 g of CBD from the recrystallizations at room temperature (23°C), a second recrystallization was carried out with 9.75 mL of petroleum ether (40-60°C pe), ratio of about 1.5 mL of petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at room temperature (23°C) for 3 hours to crystallize CBD. About 9.4 g of CBD were obtained. After filtering the CBD, the collected mother liquors were evaporated and then incubated at 7°C for 3 hours in order to crystallize the CBD. About 2.1 g of CBD were obtained. The yield of the second recrystallization at room temperature (23°C) is 74.6%, and the yield of the recrystallization at 7°C is 16.7%. Together, both represent a yield of 91.3%. The amount of the second recrystallization at room temperature (23°C) was 9.4 g yielding 53.4% of the initial "crude" CBD-material.
A third recrystallization was carried out with 12.6 g of CBD and 19 ml of petroleum ether (40-60°C pe), ratio of about 1.5 ml of petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at 7°C for 2 hours to crystallize CBD material. About 11.7 g of CBD with a purity of 97.5% were obtained. The total amount of CBD with a purity of 95% or more obtained was 11.7 g with a yield of 93.6% and represents 61.5% yield from the initial "raw" CBD-material and a yield of 5. 7% by weight of the starting decarboxylated plant material used. Example 17 Isolation of CBD from plant material
[00164] To decarboxylate CBDA to CBD, 1 kg of Cannabis sativa L. of the SARA variety (CVPO file number: 20150098 of 15-1-15), with predominant CBDA, were decarboxylated by heating at 150°C for 1 hour. 880 g of decarboxylated plant material was macerated in 10 L of petroleum ether (40-60°C pe) for one hour. This procedure was repeated twice with 7.5 L of petroleum ether (40-60°C pe). The plant material was filtered and the petroleum ether was evaporated to a volume of 850 ml and incubated at -18°C for 1 to 2 hours in order to precipitate insoluble material. The solution was vacuum filtered, seeded with 0.1 g of CBD and incubated at -18°C for 16 hours to crystallize CBD-"crude" material. About 24 g of "raw" CBD-material were obtained. The "crude" CBD-material was vacuum filtered and the mother liquor collected, evaporated to a volume of 450 mL and then incubated at -18°C for 16 hours in order to crystallize the "crude" CBD-material . About 13.2 g of CBD- "raw" material were obtained. The "raw" CBD-material was vacuum filtered and the mother liquor collected, evaporated to a volume of 210 mL and then incubated at -18°C for 24 hours in order to crystallize CBD. About 12.3 g of CBD were obtained. The CBD was vacuum filtered and the mother liquor collected, evaporated to a volume of 110 mL and then incubated at -18°C for 96 hours in order to crystallize the CBD. About 10.8 g of CBD were obtained. CBD was vacuum filtered. The total amount of CBD obtained in this four-step process was 60.3 g, representing a yield of 6.8% by weight of the initial decarboxylated plant material used.
[00165] 44.7 g of the "crude" CBD-material were then washed with 100 ml of cold (-18°C) petroleum ether (40-60°C) and filtered to obtain 34.4 g of CBD - “washed” material. 100 ml of the wash was evaporated to a volume of 20 ml and incubated at -18 °C in order to crystallize the CBD. About 4.4 g of CBD were obtained. 34.4 g of CBD-"washed" material were recrystallized with 35 mL of petroleum ether (40-60 °C pe), ratio of about 1 mL petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at room temperature (23°C) for 14 hours to crystallize CBD. About 11 g of CBD were obtained. The CBD was vacuum filtered and the collected mother liquor was evaporated and then incubated at 7°C for 12 hours in order to crystallize the CBD. About 16.3 g of CBD were obtained. The CBD was vacuum filtered and the collected mother liquor was evaporated and then incubated at -18°C for 72 hours in order to crystallize the CBD. About 3.1 g of CBD were obtained.
[00166] A second recrystallization was carried out with 16.3 g of the CBD obtained in the first recrystallization at 7°C by dissolving with 10 mL of petroleum ether (40-60°C pe), proportion of about 0.6 mL of petroleum ether per gram of CBD. CBD was heated to 40°C until all of the CBD had dissolved and then incubated at room temperature (23°C) for 3 hours to crystallize CBD. About 11.6 g of CBD were obtained. The CBD material was vacuum filtered and the collected mother liquor was evaporated and then incubated at 7°C for 2 hours in order to crystallize the CBD. About 3.3 g of CBD were obtained. The CBD material was vacuum filtered and the collected mother liquor was evaporated and then incubated at -18°C for 48 hours in order to crystallize the CBD. About 0.7 g of CBD were obtained.
[00167] A first recrystallization was carried out with 6.7 g of CBD-"crude" material obtained with 5 mL of petroleum ether (40-60°C pe), proportion of about 0.75 mL of petroleum ether per gram of CBD. CBD was heated to 40°C until all of the CBD had dissolved and then incubated at room temperature (23°C) for 4 hours to crystallize CBD. About 1.9 g of CBD were obtained. The CBD material was vacuum filtered and the collected mother liquor was evaporated and then incubated at 7°C for 2 hours in order to crystallize the CBD. About 3.1 g of CBD were obtained. The CBD material was vacuum filtered and the collected mother liquor was evaporated and then incubated at -18°C for 48 hours in order to crystallize the CBD. About 0.8 g of CBD were obtained.
[00168] A first recrystallization was carried out with 6.6 g of "crude" CBD-material obtained with 4.7 ml of petroleum ether (40-60°C pe), proportion of about 0.7 ml of ether of oil per gram of CBD. CBD was heated to 40°C until CBD was dissolved and then incubated at room temperature (23°C) for 14 hours to crystallize CBD. About 1.2 g of CBD were obtained. The CBD was vacuum filtered and the mother liquor collected, mixed with 1.5 mL of petroleum ether (40-60°C pe) and then incubated at 7°C for 2 hours in order to crystallize the CBD . About 3.5 g of CBD were obtained. The CBD material was vacuum filtered and the collected mother liquor was evaporated and then incubated at -18°C for 36 hours in order to crystallize the CBD. About 0.65 g of CBD was obtained.
[00169] The last 2.3 g of CBD-material "raw" were combined with the 4.4 g of CBD from the wash and the 3.3 g and 3.1 g of CBD obtained in the first recrystallizations at 7°C. 12.8 g of this pooled CBD were recrystallized with 6.4 mL of petroleum ether (40-60°C pe), proportion of about 0.5 mL of petroleum ether per gram of CBD. CBD was heated to 40°C until CBD was dissolved and then incubated at room temperature (23°C) for 2.5 hours to crystallize CBD. About 4.4 g of CBD were obtained. The collected mother liquor was decanted into a new container and left at room temperature (23°C) for 1.5 hours in order to crystallize CBD. About 3.9 g of CBD were obtained. The total CBD at room temperature (23°C) after 4 hours was 8.3 g. The CBD material was vacuum filtered and the collected mother liquor was evaporated and then incubated at 7°C for 2 hours in order to crystallize the CBD. About 0.9 g of CBD were obtained.
[00170] A second recrystallization was carried out with 24.4 g of the CBD obtained in the first recrystallization at room temperature (23°C) and 15.6 mL of petroleum ether (40-60°C pe), proportion of about 0 .65 mL of petroleum ether per gram of CBD. CBD was heated to 40°C until CBD was dissolved and then incubated at room temperature (23°C) for 36 hours to crystallize CBD. About 21.8 g of CBD were obtained. The CBD material was vacuum filtered and the collected mother liquor was evaporated and then incubated at 7°C for 3 hours in order to crystallize the CBD. About 1.1 g of CBD were obtained. The CBD material was vacuum filtered and the collected mother liquor was evaporated and then incubated at -18°C for 6 hours in order to crystallize the CBD. About 0.8 g of CBD were obtained. The recrystallization yield at room temperature (23°C) is 89.3%, and the recrystallization yield at 7°C is 4.5%. Together, both represent a yield of 93.8%.
[00171] The remainder of the CBD obtained from the first recrystallizations at 7°C (3.5 g + 1.1 g) and the second recrystallization (2.6 g) was pooled to obtain 7.2 g of CBD that were recrystallized for the second time with 5 ml petroleum ether (40-60°C pe), the proportion was 0.7 ml petroleum ether per gram of CBD. CBD was heated to 40°C until CBD was dissolved and then incubated at room temperature (23°C) for 3 hours to crystallize CBD. About 5.6 g of CBD were obtained. The CBD material was vacuum filtered and the mother liquor collected, evaporated and then incubated at 7°C for 12 hours in order to crystallize the CBD. About 1.1 g of CBD were obtained. The recrystallization yield at room temperature (23°C) is 77.8%, and the recrystallization yield at 7°C is 15.3%. Together, both represent a yield of 93.1%. The total amount of the second recrystallization at room temperature (23°C) was 27.4 g with a yield of 45% of the initial "raw" CBD-material.
[00172] A third recrystallization was carried out with 27.4 g of CBD obtained in the second recrystallization at 23°C and 8.3 g and 1.2 g of the remaining CBD obtained in the first recrystallizations at 23°C. 36.1 g of this amount of pooled CBD was recrystallized with 27 ml of petroleum ether (40-60°C pe), ratio of about 0.75 ml of petroleum ether per gram of CBD. CBD was heated to 40°C until CBD was dissolved and then incubated at room temperature (23°C) for 12 hours to crystallize CBD. About 31.9 g of CBG with a purity of 95% or more were obtained. The CBD material was vacuum filtered and the collected mother liquor was evaporated and then incubated at 7°C for 2 hours in order to crystallize the CBD. About 3.1 g of CBD with a purity of 92.5% were obtained. The total amount of CBD with a purity of 95% or more obtained in the third recrystallization was 31.9 g with a yield of 88.4% and represents 52.9% yield from the CBD-initial "raw" material and a yield of 3.6% by weight of the starting decarboxylated plant material used. (See FIG. 5 and FIG. 6). Example 18 Isolation of CBD from plant material
[00173] To decarboxylate CBDA to CBD, 1.5 kg of Cannabis sativa L. of the PILAR variety (CVPO file number: 20160115 of 14-1-16), with predominant CBDA, were decarboxylated by heating at 150°C for 1 hour. 1.28 kg of decarboxylated plant material was macerated in 10 L of petroleum ether (40-60°C pe) for one hour. This procedure was repeated twice with 7.5 L of petroleum ether (40-60°C pe). The plant material was filtered and the petroleum ether was evaporated to a volume of 300 ml and then incubated at -18°C for 1 to 2 hours in order to precipitate insoluble material. The solution was vacuum filtered, seeded with 1 g of CBD and incubated at -18°C for 48 hours to crystallize CBD-"crude" material. About 22.3 g of "raw" CBD-material were obtained. The CBD - "raw" material was vacuum filtered and the mother liquor collected, evaporated to a volume of 150 mL and then incubated at -18°C for 48 hours in order to crystallize the CBD. About 3.8 g of CBD were obtained. CBD was vacuum filtered. The total amount of CBD obtained in this two-step process was 26.2 g, representing a yield of 2% by weight of the initial decarboxylated plant material used.
[00174] 22.2 g of CBD-"crude" material were recrystallized with 33 ml of petroleum ether (40-60°C pe), ratio of about 1.5 ml of petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at 7°C for 48 hours to crystallize CBD. About 163 g of CBD were obtained. 3.8 g of CBD-"crude" material were recrystallized with 5.7 ml of petroleum ether (40-60°C pe), ratio of about 1.5 ml petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at 7°C for 5 hours to crystallize CBD. About 2.3 g of CBD were obtained. The yield of the first recrystallization was 71.5% from the initial “raw” CBG-material.
A second recrystallization was carried out with 15 g of CBD and 22.5 ml of petroleum ether (40-60°C pe), ratio of about 1.5 ml of petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at room temperature (23°C) for 48 hours to crystallize CBD. About 8.3 g of CBD were obtained. The CBD was vacuum filtered and the collected mother liquor was evaporated and then incubated at 7°C for 2 hours in order to crystallize the CBD. About 4.9 g of CBD were obtained. The yield of the first recrystallization at room temperature (23°C) was 37%, and the yield of the recrystallization at 7°C was 21.8%. Together, both represent a yield of 58.8%.
[00176] With the 2.3 g of CBD from the first recrystallization at 7°C and the 4.9 g obtained in the second recrystallization at 7°C, another recrystallization was performed with 10.5 mL of petroleum ether (40- 60°C pe), ratio of about 1.5 ml petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at room temperature (23°C) for 18 hours to crystallize CBD. About 4 g of CBD were obtained. The CBD was vacuum filtered and the collected mother liquor was evaporated and then incubated at 7°C for 18 hours in order to crystallize the CBD. About 2.6 g of CBD were obtained. The recrystallization yield at room temperature (23°C) is 56.3%, and the recrystallization yield at 7°C is 36.6%. Together, both represent a yield of 92.9%. The total amount of the second recrystallization at room temperature (23°C) was 12.3 g yielding 47.3% of the initial "raw" CBD-material.
A third recrystallization was carried out with 12.1 g of CBD and 12 ml of petroleum ether (40-60°C pe), ratio of about 1 ml of petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at room temperature (23°C) for 18 hours to crystallize CBD. About 9.8 g of CBD with a purity of 95.1% were obtained. The CBD was vacuum filtered and the collected mother liquor was evaporated and then incubated at 7°C for 2 hours in order to crystallize the CBD. About 1.9 g of CBD with a purity of 95.1% were obtained. The total amount of CBD with a purity of 95% or more obtained in the third recrystallization was 11.7 g, representing a 45% yield from the used CBD-initial "raw" material and 0.9% by weight of the material starting decarboxylated vegetable used. Example 19 Isolation of CBD from ethanol extracts
[00178] To decarboxylate CBDA to CBD, 150 g of Cannabis sativa L. of the Futura 75 variety, with predominant CBDA/CBD, were decarboxylated by heating at 150°C for 1 hour. 100.1 g of the decarboxylated plant material were extracted by maceration with 750 ml of ethanol for 1 hour (3x) and the ethanol was evaporated, obtaining about 5.8 g of solid extract, according to the method disclosed in WO2009043836 or EP2044935, except without the decarboxylation step. A subsequent maceration of 1.8 g of Cannabis sativa L. extract of the Futura 75 variety, with predominant CBD, was carried out in 20 mL of petroleum ether (40-60°C pe) for one hour. The part of the extract not dissolved in petroleum ether was filtered, the petroleum ether, evaporated to a volume of 15 mL and then incubated at -18°C for 24 hours in order to crystallize the "crude" CBD-material . About 34 g of "raw" CBD-material were obtained. The "crude" CBD-material was vacuum filtered and the mother liquor collected, evaporated to a volume of 7 mL and then incubated at -18°C for 48 hours in order to crystallize the "crude" CBD-material . About 48 mg of CBD-“raw” material were obtained. The total amount of "raw" CBD-material obtained in this two-step process was 159 mg, representing a yield of 8.8% from the initial ethanolic extraction used and 0.46% by weight of the initial decarboxylated plant material used.
[00179] The 159 mg of CBD-"crude" material was then recrystallized with 1.5 mL of petroleum ether (4060°C) bp per gram of CBD two or three more times at room temperature (23°C) to obtain CBD with a purity above 95%. Example 20 Isolation of CBD from ethanol extracts
[00180] To decarboxylate CBDA to CBD, 150 g of Cannabis sativa L. of the PILAR variety (CVPO file number: 20160115 of 14-1-16), with predominant CBDA/CBD, were decarboxylated by heating at 150°C for 1 hour. 50.3 g of the decarboxylated plant material were extracted by maceration with 500 ml of ethanol for 1 hour (3x) and the ethanol was evaporated, obtaining approximately 4.9 g of solid extract, representing a yield of 9.8%. according to the method disclosed in WO2009043836 or EP2044935. A subsequent maceration of 4.9 g of the extract of Cannabis sativa L. of the PILAR variety, with predominant CBD, was carried out in 35 mL of petroleum ether (40-60°C pe) for one hour. The part of the extract not dissolved in petroleum ether was filtered, the petroleum ether, evaporated to a volume of 15 mL and then cooled to -18°C, seeded with 25 mg of CBD and then incubated at -18 °C for 24 hours in order to crystallize the "crude" CBD-material. About 1040 mg of CBD-“raw” material were obtained. The "crude" CBD-material was vacuum filtered and the mother liquor collected, evaporated to a volume of 8 mL and then incubated at -18°C for 12 hours in order to crystallize the "crude" CBD-material . About 152 mg of CBD-“raw” material were obtained. The collected mother liquors were evaporated down to a volume of 4 mL and then incubated at -18°C for 24 hours in order to crystallize the "raw" CBD-material. About 45 mg of CBD-“raw” material were obtained. The total amount of "raw" CBD-material obtained in this three-step process was 1237 mg, representing a yield of 25.2% from the initial ethanolic extraction used and 2.46% by weight of the initial decarboxylated plant material used.
[00181] The 1.2 g of CBD-"crude" material was then recrystallized with 1.5 mL of petroleum ether (4060°C) bp per gram of CBD two or three more times at room temperature (23°C) C) in order to obtain CBD with a purity above 95%. Example 21 Isolation of CBD from acetone extracts
[00182] To decarboxylate CBDA in CBD, 101.3 g of Cannabis sativa L. of the experimental variety 60.2/1/9, with predominant CBDA/CBD, were decarboxylated by hydrodistillation process remaining at 100°C for 2 hours. The plant material was dried by heating at 50°C for 12 hours. 88.6 g of the decarboxylated plant material were extracted by maceration with 750 ml of acetone for 1 hour (3x) and the acetone was evaporated to obtain about 12.6 g of solid extract, according to the method disclosed in WO2009043836 or EP2044935, except that the decarboxylation step has been modified. A subsequent maceration of 5 g of Cannabis sativa L. extract of the experimental variety 600.2/1/9, with predominant CBD, was carried out in 50 mL of petroleum ether (40-60°C pe) for one hour under agitation. The part of the extract not dissolved in petroleum ether was filtered, the petroleum ether, evaporated to a volume of 30 mL and then cooled to -18°C, seeded with 50 mg of CBD and then incubated at -18 °C for 36 hours in order to crystallize the "crude" CBD-material. After a wash with cold petroleum ether (40-60°C pe) about 219 mg of CBD-"crude" material were obtained. The "crude" CBD-material was vacuum filtered and the mother liquor collected, evaporated to a volume of 20 mL and then incubated at -18°C for 72 hours in order to crystallize the "crude" CBD-material . After a wash with cold petroleum ether (40-60°C pe) about 493 mg of CBD-"crude" material were obtained. The "crude" CBD-material was vacuum filtered and the mother liquor collected, evaporated to a volume of 20 mL and then incubated at -18°C for 24 hours in order to crystallize the "crude" CBD-material . After a wash with cold petroleum ether (40-60°C pe) about 209 mg of CBD-"crude" material were obtained. The total amount of "raw" CBD-material obtained in this three-step process was 921 mg, representing a yield of 18.4% from the extraction into initial acetone used and 2.6% by weight of the initial decarboxylated plant material used.
[00183] The 921 mg of CBD-"crude" material was then recrystallized with 1 mL of petroleum ether (40-60°C) bp per gram of CBD two or three more times to obtain CBD with a purity above 95%. Example 22 Isolation of CBD from acetone extracts
[00184] To decarboxylate CBDA to CBD, 100 g of Cannabis sativa L. of the SARA variety (CVPO file number: 20150098 from 15-1-15), with predominant CBDA/CBD, were decarboxylated in the hydrodistillation process remaining at 100° C for 2.5 hours. The plant material was dried by heating at 50°C for 12 hours. 88.8 g of the decarboxylated plant material were extracted by maceration with 750 ml of acetone for 1 hour (3x) and then evaporating the acetone to obtain 15 g of solid extract, according to the method disclosed in WO2009043836 or EP2044935, except that the decarboxylation step has been modified. A subsequent maceration of 7.9 g of Cannabis sativa L. extract of the SARA variety, with predominant CBD, was carried out in 50 mL of petroleum ether (40-60°C pe) for one hour under agitation. The part of the extract not dissolved in petroleum ether was filtered, the petroleum ether, evaporated to a volume of 30 mL, cooled to -18°C, seeded with 50 mg of CBD and then incubated at -18°C for 24 hours in order to crystallize the “raw” CBD-material. After a wash with cold petroleum ether (40-60°C pe) about 727 mg of CBD-"crude" material were obtained. The "crude" CBD-material was vacuum filtered and the mother liquor collected, evaporated to a volume of 15 mL and then incubated at -18°C for 24 hours in order to crystallize the "crude" CBD-material . After a wash with cold petroleum ether (40-60°C pe) about 149 mg of CBD-"crude" material were obtained. The total amount of CBD-"raw" material obtained in this three-step process was 1.4 g, representing a yield of 17.7% from the initial used acetone extraction and 3% by weight of the initial decarboxylated plant material used.
The 1.4 g of CBD-"crude" material was then recrystallized with 3 ml of petroleum ether (40-60°C pe), ratio of 2 ml of petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at 7°C for 12 hours to crystallize CBD. After a wash with cold petroleum ether (40-60°C pe) about 1.13 mg of CBD were obtained. The yield of the first recrystallization was 80.7% from the initial "raw" CBD-material.
[00186] A second recrystallization was carried out with 1.13 g of CBD and 2 mL plus 1 mL of petroleum ether wash (40-60°C pe), ratio of about 2.6 mL of petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at 7°C for 12 hours to crystallize CBD. The mother liquor was decanted and the crystalline mass of CBD was recrystallized for the third time with 1.5 mL of petroleum ether (40-60°C pe), ratio of about 1-1.5 mL of petroleum ether per gram of CBD. The solution was incubated at room temperature (23°C) for 12 hours to crystallize CBD. About 0.8 g of CBD with a purity of 95% or more was obtained. After filtration, the mother liquors were evaporated and then incubated at 7°C for 12 hours in order to crystallize the CBD. About 0.2 g of CBD with a purity of 90% or more was obtained. The recrystallization yield at room temperature (23°C) is 57.1%, and the recrystallization yield at 7°C is 14.3% from the initial "washed" CBD material. Together, both represent a yield of 71.4%. The total amount of CBD with a purity of 95% or more obtained in the third recrystallization was 0.8 g, representing a yield of 57.1% from the "raw" CBD-material and a yield of 10.1% at from the extraction in initial acetone and 1.7% by weight of the initial decarboxylated plant material used. Example 23 Isolation of CBD from acetone extracts
[00187] 100 g of dried plant material from Cannabis sativa L. of the SARA variety (CVPO file number: 20150098 of 15-1-15), with predominant CBDA, were extracted by maceration with 750 mL of acetone for 1 hour (3x) and the acetone was evaporated to obtain about 18.1 g of solid extract, according to the method disclosed in WO2009043836 or EP2044935, except without the decarboxylation step. To decarboxylate CBDA to CBD, 10 g of acetone extract was decarboxylated by heating at 150 °C for 2 hours, resulting in 6.7 g of decarboxylated extract. The 6.7 g was subsequently macerated in 50 ml of petroleum ether (40-60°C pe) for one hour under stirring. The part of the extract not dissolved in petroleum ether was filtered, the petroleum ether, evaporated to a volume of 20 mL, cooled to -18°C, seeded with 50 mg of CBD and then incubated at -18°C for 48 hours in order to crystallize the “raw” CBD-material. About 1.6 g of CBD- "raw" material were obtained. The "crude" CBD-material was vacuum filtered and the mother liquor collected, evaporated to a volume of 15 mL and then incubated at -18°C for 78 hours in order to crystallize the "crude" CBD-material . About 0.1 g of "raw" CBD-material was obtained. The collected mother liquors were evaporated to a volume of 4 mL and then incubated at -18°C for 24 hours in order to crystallize the CBD-“raw” material. About 45 mg of CBD- "raw" material were obtained. The total amount of CBD- "raw" material obtained in this three-step process was 2.1 g, representing a yield of 21% from the extraction into initial used acetone and 2.1% by weight of the initial used plant material.
[00188] The 1.5 g of CBD-"crude" material was then recrystallized with 3 ml of petroleum ether (40-60°C pe), ratio of about 2 ml of petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at 7°C for 12 hours to crystallize CBD. About 1.3 g of CBD were obtained. The yield of the first recrystallization was 86.7% from the initial "raw" CBD-material.
[00189] A second recrystallization was carried out with 1.3 g of CBD and 3 ml petroleum ether (40-60°C pe), ratio of about 2.3 ml petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at 7°C for 12 hours to crystallize CBD. About 1.14 g of CBD with a purity of 90% or more were obtained. The yield of the second recrystallization was 87.7% and 76% from the CBD-initial “raw” material. The mother liquor from both recrystallizations was evaporated to 3 ml and left at 7°C for 48 hours to crystallize CBD. About 0.3 g of CBD was obtained.
[00190] The CBD from the second and third stages of crystallization, the CBD recovered from the mother liquor and the CBD from the recrystallization of the two recrystallizations were pooled (1.9 g) and recrystallized with 4 mL of petroleum ether (40- 60°C pe), ratio of about 2 ml petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at 7°C for 12 hours to crystallize CBD. About 1.6 g of CBD were obtained. The recrystallization yield can be considered 84.2% from the first recrystallization and 76.2% from the initial “raw” CBD-material.
[00191] 1.6 g and recrystallized with 3 ml of petroleum ether (40-60°C pe), proportion of about 2 ml of petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at 7°C for 12 hours to crystallize CBD. About 1.4 g of CBD with a purity of 90% or more were obtained. The yield of the second recrystallization was 87.5% and 66.7% from the initial "raw" CBD-material.
[00192] 1.4 g of CBD were recrystallized for a third time with 3 ml of petroleum ether (40-60°C pe), proportion of about 1.5 ml of petroleum ether per gram of CBD. The solution was incubated at room temperature (23°C) for 12 hours to crystallize CBD. About 1 g of CBD with a purity of 95% or more was obtained. After filtration, the mother liquors were evaporated and then incubated at 7°C for 12 hours in order to crystallize the CBD. About 0.3 g of CBD with a purity of 90% or more was obtained. The yield of the third recrystallization at room temperature (23°C) is 71.4%, and the yield of the recrystallization at 7°C is 21.4%, and 47.6% and 14.3%, respectively, from the initial “raw” CBD-material. The total amount of CBD with a purity of 95% or more obtained in the third recrystallization was 1 g with a yield of 47.6% from the initial "raw" CBD-material, a yield of 10% from the extraction in starting acetone used, 15% from the extraction with the starting decarboxylated acetone used, and 1% by weight of the starting plant material used. Example 24 Isolation of CBD from acetone extracts
[00193] This experiment has been repeated twice and the results shown are the averages of both. 100.7 g of the plant material which was dried from Cannabis sativa L. of the experimental variety 60.2/1/9, with predominant CBDA, were extracted by maceration with 750 ml of acetone for 1 hour (3x) and the acetone was evaporated in order to obtain about 15.3 g of solid extract, according to the method disclosed in WO2009043836 or EP2044935, except without the decarboxylation step. To decarboxylate CBDA to CBD, 5 g of acetone extract was decarboxylated by heating at 150 °C for 1 hour, resulting in 3.8 g of decarboxylated extract. The 3.8 g of the decarboxylated acetone extract was subsequently macerated in 40 ml of petroleum ether (40-60°C pe) for one hour under stirring. The part of the extract not dissolved in petroleum ether was filtered, the petroleum ether, evaporated to a volume of 20 mL, cooled to -18°C, seeded with 50 mg of CBD and then incubated at -18°C for 18 hours in order to crystallize the "raw" CBD-material. About 0.95 g of CBD-“raw” material was obtained. The "crude" CBD-material was vacuum filtered and the mother liquor collected, evaporated to a volume of 20 mL and then incubated at -18°C for 72 hours in order to crystallize the "crude" CBD-material . About 0.25 g of CBD-“raw” material was obtained. The collected mother liquors were evaporated to a volume of 10 mL and then incubated at -18°C for 78 hours in order to crystallize the "raw" CBD-material. About 0.18 g of "raw" CBD-material was obtained. The total amount of "raw" CBD-material obtained in this three-step process was 1.4 g, representing a yield of 28% from the initial used acetone extraction, 36.8% from the decarboxylated extraction used, and a yield 4.3% by weight of the starting plant material used.
[00194] The 1.3 g of CBD-"crude" material was then recrystallized with 2.6 mL of petroleum ether (40-60°C pe), ratio of about 2 mL of petroleum ether per gram of CBD . The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at 7°C for 12 hours to crystallize CBD. The mother liquor was decanted and the crystalline mass of CBD was recrystallized for the second time with 2 ml petroleum ether (40-60°C pe), proportion of about 1.5-2 ml petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at room temperature (23°C) for 1 hour to crystallize CBD. About 0.6 g of CBD with a purity of 95% or more was obtained. After filtration, the mother liquors were evaporated and then incubated at 7°C for 12 hours in order to crystallize the CBD. About 0.3 g of CBD with a purity of 90% or more was obtained. The third recrystallization yield at room temperature (23°C) was 46.1%, and the 7°C recrystallization yield is 23.1% from the CBD-initial "raw" material. The total amount of CBD with a purity of 95% or more obtained in the second recrystallization was 0.6 g with a yield of 46.1% from the initial "raw" CBD-material, 12% from the acetone extraction starting material used, 15.8% from extraction in decarboxylated acetone used, and 1.8% by weight of starting plant material used. Example 25 Isolation of CBD from acetone extracts
[00195] 100.2 g of the plant material that was dried from Cannabis sativa L. of the PILAR variety (CVPO file number: 20160115 of 14-1-16), with predominant CBDA, were extracted by maceration with 750 mL of acetone for 1 hour (3x) and the acetone was evaporated to obtain about 11.8 g of solid extract, according to the method disclosed in WO2009043836 or EP2044935, except without the decarboxylation step. To decarboxylate CBDA to CBD, 5 g of acetone extract was decarboxylated by heating at 150 °C for 1 hour, resulting in 2.8 g of decarboxylated extract. The 2.8 g of the decarboxylated acetone extract was subsequently maceration in 25 ml of petroleum ether (40-60°C pe) for one hour under stirring. The part of the extract not dissolved in petroleum ether was filtered, the petroleum ether, evaporated to a volume of 15 mL, cooled to -18°C, seeded with 25 mg of CBD and then incubated at -18°C for 18 hours in order to crystallize the "raw" CBD-material. About 0.3 g of "raw" CBD-material was obtained. The "crude" CBD-material was vacuum filtered and the mother liquor collected, evaporated to a volume of 10 mL and then incubated at -18°C for 72 hours in order to crystallize the "crude" CBD-material . About 0.13 g of "raw" CBD-material were obtained. The collected mother liquors were evaporated down to a volume of 4 mL and then incubated at -18°C for 78 hours in order to crystallize the "raw" CBD-material. About 0.14 g of "raw" CBD-material was obtained. The total amount of "raw" CBD obtained in this three-step process was 0.58 g, representing a 20.7% yield from the decarboxylated extraction used.
[00196] 0.58 g of CBD-"crude" material was then recrystallized with 1.5 ml of petroleum ether (40-60°C pe), ratio of about 3 ml petroleum ether per gram of CBD. The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at 7°C for 12 hours to crystallize CBD. The mother liquor was then decanted and the crystalline mass of CBD was recrystallized for the second time with 1 mL of petroleum ether (40-60°C pe), proportion of about 2 mL of petroleum ether per gram of CBD . The CBD mixture was heated to 40°C until the CBD was dissolved and then incubated at room temperature (23°C) for 12 hours to crystallize CBD. About 0.36 g of CBD with a purity of 95% or more was obtained. After filtration, the mother liquors were evaporated and then incubated at 7°C for 12 hours in order to crystallize the CBD. About 0.05 g of CBD with a purity of 90% or more was obtained. The yield of the second recrystallization at room temperature (23°C) is 46.1%, and the yield of the recrystallization at 7°C is 23.1% from the initial "raw" CBD-material. The total amount of CBD with a purity of 95% or more obtained in the second recrystallization was 0.6 g with a yield of 62.1% from the initial "raw" CBD-material and a yield of 12.9% at from the initial decarboxylated acetone extraction used.
[00197] Finally, it should be understood that, although the aspects of this descriptive report are highlighted when referring to specific modalities, a technical expert on the subject will readily appreciate that these disclosed modalities are only illustrative of the principles of the subject disclosed herein. Therefore, it is to be understood that the disclosed subject matter is in no way limited to a particular compound, composition, article, apparatus, methodology, protocol and/or reagent, etc., described herein, unless expressly indicated as such. In addition, those skilled in the art will recognize that certain changes, modifications, permutations, alterations, additions, subtractions and sub-combinations thereof may be made in accordance with the teachings presented herein, without departing from the spirit of this descriptive report. Accordingly, it is intended that the following appended claims and claims set forth below be interpreted to include all such changes, modifications, permutations, alterations, additions, subtractions and sub-combinations thereof, in accordance with their true spirit and scope.
Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Obviously, variations in these described embodiments will become apparent to those skilled in the art after reading the foregoing description. The inventor expects experienced skilled artisans to employ such variations as appropriate, and the inventors intend that the present invention be practiced other than as specifically described herein. Accordingly, this invention includes all modifications and equivalents to the subject matter of the appended claims, as permitted by applicable law. Furthermore, any combination of the above-described embodiments in all their possible variations is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by the context.
[00199] The groupings of alternative embodiments, elements or steps of the present invention are not to be construed as limitations. One may refer to and claim each group member individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included or excluded from a group for reasons of convenience and/or patentability. When any such inclusion or exclusion occurs, the descriptive report is deemed to contain the group as modified, thus fulfilling the written description of all Markush groups used in the appended claims.
[00200] Unless otherwise indicated, all numbers expressing a characteristic, item, quantity, parameter, property, term, and so forth used in this specification and claims shall be understood to be modified in all cases by the term "about in". As used herein, the term "about" means that the characteristic, item, quantity, parameter, property or term so qualified covers a range of plus or minus ten percent above and below the value of the characteristic, item, quantity, parameter , property or stated term. Consequently, unless otherwise indicated, the numerical parameters set forth in the specification and in the appended claims are approximations which may vary. For example, as mass spectrometry instruments can vary slightly in determining the mass of a given analyte, the term "about" in the context of an ion's mass or an ion's mass/charge ratio refers to +/- 0.50 atomic mass units. At the very least, and not in an attempt to limit the application of the equivalents doctrine to the scope of the claims, each numerical indication should at least be interpreted in light of the number of significant figures reported and applying common rounding techniques.
[00201] The use of the terms "may" or "could" in reference to a modality or aspect of a modality also carries with it the alternative meaning of "cannot" or "could not". As such, if this descriptive report discloses that a modality or an aspect of a modality can or could be included as part of the inventive subject, then the negative limitation or exclusion condition is also explicitly meant, meaning that a modality or an aspect of an embodiment cannot or could not be included as part of the inventive subject matter. Similarly, the use of the term "optionally" in reference to an embodiment or aspect of an embodiment means that such an embodiment or aspect of an embodiment could be included as part of the inventive subject matter or could not be included as part of the inventive subject matter. Whether or not such negative limitation or exclusion clause applies will be based on whether or not the negative limitation or exclusion condition is addressed in the claimed subject matter.
[00202] Although the numerical ranges and values establishing the broad scope of the invention are approximations, the numerical ranges and values set forth in the specific examples are reported as accurately as possible. Any numerical range or value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective test measures. The indication of numerical ranges and values here is merely intended to serve as a shorthand method of referring individually to each separate numerical value that falls within the range. Unless otherwise indicated herein, each individual value of a numerical range is incorporated into this specification as if it were individually indicated herein.
[00203] The terms "a", "an", "the", "a" and similar references used in the context of describing the present invention (especially in the context of the claims below) are to be interpreted as covering both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Also, ordinal indicators - such as "first", "second", "third", etc. - for identified elements are used to distinguish between elements and do not indicate or imply a mandatory or limited number of such elements and do not indicate a certain position or order of such elements, unless specifically indicated. All methods described herein may be performed in any suitable order, unless otherwise stated herein or otherwise clearly contradicted by the context. The use of any and all examples, or exemplary language (e.g., "as") provided herein is only intended to further elucidate the present invention and does not represent a limitation on the scope of the invention otherwise claimed. No linguistic expression in this specification shall be interpreted as indicating any unclaimed element essential to the practice of the invention.
[00204] When used in claims, either as filed or added by amendment, the independent transition term "which comprises" (and the equivalent independent transition phrases such as "including"/"which includes", "containing"/"which contains” and “having”/“having”/“with”) encompasses all elements, limitations, steps and/or characteristics expressly cited alone or in combination with a disliked subject; the named elements, limitations and/or characteristics are essential, but other unnamed elements, limitations and/or characteristics may be added and still form a construct within the scope of the claim. The specific embodiments described herein may be further limited in claims that use the closed transitional phrases "consisting of"/"consisting of" or "consisting essentially of"/"consisting essentially of" instead of or as a modification to "understanding"/"understanding". When used in the claims, whether as filed or added by amendment, the closed transition phrase “consisting of”/”consisting of” excludes any element, limitation, step or feature not expressly cited in the claims. Thus, the meaning of the open expression transition phrase "comprising"/"comprising" is defined to encompass all specifically recited elements, limitations, steps and/or characteristics, as well as any additional and unspecified options. The meaning of the closed transition phrase "consisting of"/"consisting of" is defined as including only the elements, limitations, steps and/or characteristics specifically cited in the claim, while the meaning of the closed transition phrase "consisting essentially of" /"consisting essentially of" is defined as including only those elements, limitations, steps and/or characteristics specifically cited in the claim and those elements, limitations, steps and/or characteristics that do not materially affect the basic characteristic(s) (s) and innovator(s) of the claimed subject matter. Thus, the open expression transitional phrase "comprising"/"understanding" (and its equivalent independent transitional phrases) includes, within its meaning, as a limiting case , the intended subject specified by the closed transition phrases "consisting of"/"consisting of" or "consisting essentially of"/ "consisting essentially of". The embodiments described or claimed herein with the phrase "comprising"/"comprising" are expressly or inherently unambiguously described, enabled and supported here for the phrases "consisting essentially of"/"consisting essentially of" and "consisting of"/" that consists of".
[00205] All patents, patent publications and other publications referenced and identified in this specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that could be used in connection with the present invention. These publications are provided for your dissemination only prior to the submission date of this application. Nothing in this regard should be construed as an admission that inventors are not entitled to advance such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation of the content of these documents are based on the information available to applicants and do not constitute an admission as to the accuracy of the dates or content of these documents.
[00206] Finally, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which is defined solely by the claims. Consequently, the present invention is not limited to that precisely as shown and described.

权利要求:
Claims (12)
[0001]
1. Method of purification of one or more cannabinoids from a plant material, CHARACTERIZED by the fact that the method consists essentially of the following steps: a) Incubate the plant material with a non-polar solvent selected from a group consisting of petroleum ether (40 to 60°C), pentane or hexane, to form a first solvent mixture which extracts one or more cannabinoids from a plant material; b) reduce the volume of the first solvent mixture to 50% or less of the original volume of the first solvent mixture in step (a) thereby concentrating one or more cannabinoids; c) incubate the first reduced solvent mixture at a temperature range between -70°C and 40°C to crystallize one or more cannabinoids; d) incubating one or more crystallized cannabinoids with the non-polar solvent, wherein the non-polar solvent is the same non-polar solvent used in step (a), to form a second solvent mixture, in which it dissolves at least 50% of a or more crystallized cannabinoids; and e) incubating the second mixture of solvents at a temperature range between -70°C and 40°C to crystallize one or more cannabinoids, thus resulting in the purification of one or more cannabinoids.
[0002]
2. Method according to claim 1, characterized by the fact that the one or more crystallized cannabinoids from step (c) are recovered before step (d).
[0003]
3. Method according to claim 2, CHARACTERIZED by the fact that the recovery is carried out using filtration that results in the collection of a crystalline product and a mother liquor.
[0004]
4. Method according to claim 3, characterized by the fact that it further comprises incubating the mother liquor at a temperature range between -70°C and 40°C to crystallize one or more cannabinoids.
[0005]
5. Method according to any one of claims 1 to 4, characterized by the fact that steps (d) and (e) or steps (b) and (c) are repeated at least once.
[0006]
6. Method of purification of a cannabinoid from a plant material, CHARACTERIZED by the fact that the method consists essentially of the following steps: a) incubating the plant material with a solvent selected from a group consisting of pentane, hexane, heptane, cyclohexane , petroleum ether, dichloromethane, trichloromethane, tetrahydrofuran, diethyl ether, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane, propane, refrigerant gas 1,1,1,2-tetrafluoroethane (R134a), liquid CO2, subcritical CO2 or supercritical CO2 or mixtures of these solvents to form a crude extract of one or more cannabinoids from a plant material; b) filter, decant or centrifuge the crude extract; c) reduce the crude extract volume to 50% or less of the original crude extract volume in step (a), thus concentrating one or more cannabinoids in the crude extract; d) incubating the crude extract with a non-polar solvent selected from a group consisting of petroleum ether (40 to 60°C), pentane or hexane to form a first solvent mixture that extracts one or more cannabinoids from the crude extract; e) filtering, decanting or centrifuging the first mixture of solvents; f) incubate the first solvent mixture at a temperature range between -70°C and 40°C to crystallize one or more cannabinoids; g) collecting one or more cannabinoids crystallized in step (d) using filtration which results in the collection of a crystalline product and a mother liquor; h) incubating one or more crystallized cannabinoids with the non-polar solvent, wherein the non-polar solvent is the same non-polar solvent from step (d) to form a second solvent mixture, wherein the second solvent mixture dissolves at least 50 % of one or more crystallized cannabinoids; i) incubate the second solvent mixture at a temperature range between -70°C and 40°C to crystallize one or more cannabinoids; and j) collecting one or more crystallized cannabinoids from step (i) using filtration which results in a collection of a crystallized product and a mother liquor, thus resulting in the purification of one or more cannabinoids.
[0007]
7. Method according to claim 6, CHARACTERIZED by the fact that the mother liquor from step (g) and/or step (j) is incubated at a temperature range between -70°C and 40°C to crystallize one or more cannabinoids.
[0008]
8. Method according to claim 6 or 7, CHARACTERIZED by the fact that steps (h) and (i) are repeated at least once.
[0009]
9. Method according to claim 6 or 7, CHARACTERIZED by the fact that steps (h), (i) and (j) are repeated at least once.
[0010]
10. Method according to any one of claims 1 to 9, CHARACTERIZED by the fact that before purification, one or more cannabinoids present in the plant material are decarboxylated by heating.
[0011]
11. Method according to any one of claims 6 to 10, CHARACTERIZED by the fact that it further comprises performing liquid:liquid chromatography after one or more of steps (c), (g) or (j).
[0012]
12. Method according to any one of claims 1 to 5, CHARACTERIZED by the fact that it additionally comprises performing liquid:liquid chromatography after one or more of steps (c) or (e).

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EP3247371B1|2020-04-01|

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ES2801005T3|2021-01-07|

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CO2017008437A2|2018-01-05|

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CL2017001873A1|2018-04-13|

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PT3247371T|2020-07-02|

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CN107567435B|2019-08-09|

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JP6342587B2|2018-06-13|

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CA2977421A1|2016-07-28|

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DK3247371T3|2020-06-15|

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CN107567435A|2018-01-09|

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IL253576A|2018-11-29|

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BR122019001241B1|2021-05-04|

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AU2016210070A1|2017-09-07|

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US9765000B2|2017-09-19|

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EP3556376A1|2019-10-23|

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PE20171108A1|2017-08-07|

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EP3247371A1|2017-11-29|

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SI3247371T1|2020-08-31|

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JP2018504407A|2018-02-15|

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法律状态:
2019-10-08| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2020-10-06| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-10-20| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-02-17| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-05-18| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 22/01/2016, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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