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WO2019145552A1 - Procédés de purification de cannabinoïdes par chromatographie liquide : liquide - Google Patents

Procédés de purification de cannabinoïdes par chromatographie liquide : liquide Download PDF

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Publication number
WO2019145552A1
WO2019145552A1 PCT/EP2019/052069 EP2019052069W WO2019145552A1 WO 2019145552 A1 WO2019145552 A1 WO 2019145552A1 EP 2019052069 W EP2019052069 W EP 2019052069W WO 2019145552 A1 WO2019145552 A1 WO 2019145552A1
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Prior art keywords
hours
cannabinoids
hexane
solvent mixture
thc
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PCT/EP2019/052069
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English (en)
Inventor
Xavier NADAL ROURA
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Phytoplant Research S.L
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Priority claimed from US15/882,516 external-priority patent/US10207198B2/en
Application filed by Phytoplant Research S.L filed Critical Phytoplant Research S.L
Priority to AU2019211188A priority Critical patent/AU2019211188A1/en
Priority to MX2020007960A priority patent/MX2020007960A/es
Priority to CA3089490A priority patent/CA3089490A1/fr
Priority to EP19702843.4A priority patent/EP3746419A1/fr
Priority to CN201980015943.2A priority patent/CN111788171A/zh
Publication of WO2019145552A1 publication Critical patent/WO2019145552A1/fr
Priority to IL276010A priority patent/IL276010A/en
Priority to CONC2020/0009747A priority patent/CO2020009747A2/es

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/004—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by obtaining phenols from plant material or from animal material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/02—Solvent extraction of solids
    • B01D11/0203—Solvent extraction of solids with a supercritical fluid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/02—Solvent extraction of solids
    • B01D11/0288—Applications, solvents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/04—Solvent extraction of solutions which are liquid
    • B01D11/0492—Applications, solvents used
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/10—Selective adsorption, e.g. chromatography characterised by constructional or operational features
    • B01D15/18—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to flow patterns
    • B01D15/1892—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to flow patterns the sorbent material moving as a whole, e.g. continuous annular chromatography, true moving beds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/18—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with unsaturation outside the aromatic ring
    • C07C39/19—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with unsaturation outside the aromatic ring containing carbon-to-carbon double bonds but no carbon-to-carbon triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/48—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/19—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups having unsaturation outside the aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0004—Crystallisation cooling by heat exchange
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to the isolation of cannabinoid compounds using unique biphasic solvent systems and liquid-liquid chromatography as centrifugation partitioning chromatography (CPC) or counter current chromatography (CCC).
  • CPC centrifugation partitioning chromatography
  • CCC counter current chromatography
  • Cannabis is a genus of flowering plants whose species are distinguished by plant phenotypes and secondary metabolite profiles.
  • Cannabis is a genus include: Cannabis sp. including Cannabis sativa L. and all subspecies, the putative species Cannabis indica Lam., Cannabis ruderalis Janisch, and hybrids and varieties thereof, as discussed further below.
  • Cannabis plants have been cultivated for a variety of uses including making fibers (hemp), medicinal use and recreational drug use. Cannabis is also commonly known as marijuana.
  • Cannabis has now been generally acknowledged as having substantial benefits for various medical uses.
  • cannabis is regularly used by a wide cross-section of society to treat a variety of maladies, ailments and symptoms including, but not limited to, nausea, pain relief (such as chronic pain, cancer related pain, or neuropathic pain), glaucoma, lack of appetite, mucous membrane inflammation, inflammatory diseases (such as Crohn's disease), neurodegenerative disease, epilepsy (that affects children and adults), seizures, diabetes, leprosy, fever, obesity, asthma, urinary tract infections, coughing, anorexia associated with weight loss in AIDS patients, graft-versus-host disease, glioma, perinatal asphyxia and post-traumatic stress disorder (PTSD) and autoimmune disease (such as multiple sclerosis).
  • nausea pain relief
  • pain relief such as chronic pain, cancer related pain, or neuropathic pain
  • glaucoma lack of appetite
  • mucous membrane inflammation such as Crohn's disease
  • inflammatory diseases such as Crohn's disease
  • Cannabinoids are compounds active on 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 L. are tetrahydracannabinolacid (THCA) or its decarboxylated product tetrahydracannabinol (THC) and cannabidiolic acid (CBDA) or its decarboxylated product cannabidiol (CBD). THC elicits psychoactive (calming) effects, analgesic effects, antioxidant effects and to increase appetite.
  • THCA tetrahydracannabinolacid
  • CBD cannabidiolic acid
  • CBD cannabidiolic acid
  • CBD cannabidiolic acid
  • THC is also associated with many negative or undesirable side effects including, but are not limited to, decreased short-term memory, dry mouth, impaired visual perception and motor skills, , red (i.e., blood shot) eyes, increased anxiety, occasional infarction, stroke, paranoia, acute psychosis, lowered mental aptitude, hallucinations, playful behavior, irrational panic attacks, irrational thoughts and various other cognitive and social problems.
  • CBD is increasingly becoming a popular cannabinoid for medicinal purposes because unlike THC, CBD is non-psychoactive at typical doses.
  • CBD was found to have neuroprotective effects and to have ameliorative effects in patients with epilepsy, schizophrenia and Parkinson's disease. Accordingly, patients and healthcare providers are exhibiting a preference for CBD because patients need to work, drive and function with clarity while undergoing treatment.
  • THC and THCA can also be purified by this method from THC-THCA rich or THC-THCA low Cannabis sativa L. plant and extracts.
  • Centrifugation partitioning chromatography CPC
  • counter current chromatography CCC
  • CPC and CCC are a liquid-liquid chromatography methods using a mostly two-phase solvent. It enables an almost loss-free separation of complex mixtures of substances from crude extracts.
  • CPC and CCC as compared to liquid chromatography (HPLC) are easier and also cheaper, because matrix effects and irreversible adsorption on solid phases do not occur.
  • Cannabinoids have been purified using CPC, but not using the solvent systems described in this patent application (see, e.g., Hazekamp, et al., "Preparative Isolation of Cannabinoids from Cannabis sativa by Centrifugal Partition Chromatography", Journal of Liquid Chromatography & Related Technologies, vol. 27, no. 15, 11 January 2004 (2004-01 -1 1 ), pages 2421 - 2439, XP055202081 , ISSN: 1082-6076, DOI: 10.1081/JLC-200028170; see also WO2016/135346). These systems have long run times, less sample load and only moderate yields.
  • the present disclosure solves these and other problems by providing a method for isolating and purifying cannabinoid compounds using a solvent system and centrifugation partition chromatography (CPC) or counter current chromatography (CCC).
  • CPC centrifugation partition chromatography
  • CCC counter current chromatography
  • ARMEN Quantum CPC rotor
  • GILSON CPC 1000 PRO
  • the present invention provides a method of purifying one or more cannabinoids from a plant material including a plant, a plant resin or a plant extract, the method consisting essentially of the following steps:
  • (b) for THC-type extracts adding to the solvent mixture a biphasic solvent system selected from the group consisting of hexane :ethanol: water, pentane:acetonitrile and hexane:acetonitrile, wherein the pentane:acetonitrile system and the hexane:acetonitrile system optionally include ethyl acetate and/or water as a modifier; for CBD-type extracts, adding to the extract a biphasic solvent system of hexane:ethanol:water; and for CBG-type extracts, adding to the extract a biphasic solvent system of hexane :ethanol:water; and
  • the biphasic solvent system is hexane :ethanol:water is at a ratio of (20:17:3) by volume.
  • the biphasic solvent system is pentane:ethyl acetate:acetonitrile:water at a ratio from (10:0:10:0) to (7:3:7:3) by volume.
  • the biphasic solvent system is hexane:ethyl acetate:acetonitrile:water at a ratio from (10:0:10:0) to (7:3:7:3) by volume.
  • the biphasic solvent system is hexane :ethanol: water at a ratio of (20:14:6) by volume.
  • the biphasic solvent system is hexane :ethanol: water at a ratio of at a ratio of (20:12:8) or (20:13:7) by volume.
  • an extract of chemotype I or II Cannabis sativa L. is used to purify THC, THCA, THCV, THCVA, CBN or CBV and fractionate the CBD-type and CBG-type cannabinoids.
  • an extract of chemotype II or III Cannabis sativa L. is used to purify CBD, CBDA, CBDVA or CBDV and fractionate the THC-type and CBG-type cannabinoids.
  • an extract of chemotype IV Cannabis sativa L. is used to purify CBG, CBGA, CBGVA or CBGV and fractionate the CBD- type and THC-type cannabinoids.
  • fractions of THC contaminated by CBC or the fractions of the THCV are fractions of THC contaminated by CBC or the fractions of the THCV
  • contaminated with CBN are re-purified using solid-liquid chromatography selected from the group consisting of gravity, Flash or preparative HPLC over C-8 or C-18 coated silica solid stationary phase, using a gradient of acetonitrile:water mobile liquid phase.
  • the liquid liquid chromatography is centrifugation partitioning chromatography (CPC) or is counter current chromatography (CCC).
  • step a) the solvent mixture is reduced to dryness or to about 50% or less of the original volume of the solvent mixture in step (a) thereby concentrating the one or more cannabinoids before the liquid:liquid chromatography.
  • the solvent mixture of step (a) is purified prior to step (b).
  • the one or more cannabinoids present in the plant material are decarboxylated by heating the plant material.
  • a dry extract product of the solvent mixture is dissolved in ethanol, chilled at a temperature from -20°C to 4°C, filtered to remove precipitated material and reduced to dryness before purification by liquid-liquid chromatography.
  • the method of CPC uses a rotor design Quantum CPC or CPC PRO. In another embodiment, the method of CPC uses a rotor design Quantum CPC or CPC PRO, wherein the total run time is 12-20 minutes, independent of rotor volume.
  • the CPC rotor has a rotor volume of 1 liter, a sample injection of 50 mL, a flow rate of a mobile phase (pentane or hexane phase) of the biphasic solvent system of 200 mL/min during the run, and a flow rate of a stationary phase (the ethanolic or acetonitrile phase) of the biphasic solvent system of 350 mL/min during the extrusion phase of the run.
  • a mobile phase pentane or hexane phase
  • a stationary phase the ethanolic or acetonitrile phase
  • the CBD, CBDA, CBDVA or CBDV is crystalized after the step of liquid liquid chromatography.
  • the CBG, CBGA, CBGVA or CBGV is crystalized after the step of liquid liquid chromatography.
  • the plant material is first incubated with a non-polar solvent selected from the group consisting of petroleum ether, pentane, hexane and heptane to form a solvent mixture which extracts the one or more cannabinoids from the plant material to form the solvent mixture.
  • a non-polar solvent selected from the group consisting of petroleum ether, pentane, hexane and heptane to form a solvent mixture which extracts the one or more cannabinoids from the plant material to form the solvent mixture.
  • the plant material is first incubated with a solvent selected from the group consisting of pentane, hexane, heptane, petroleum ethers, cyclohexane, dichloromethane, trichloromethane, tetrahydrofurane, diethyl ether, toluene, benzene, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane, propane, 1 ,1 ,1 ,2-Tetrafluoroethane (R134a) or, liquid, subcritical or supercritical CO2 or mixes thereof; filtered, decanted or centrifuged; reduced to dryness; and then incubated with a non-polar solvent selected from the group consisting of petroleum ether, pentane, hexane and heptane to form a solvent mixture which extracts the one or more cannabinoids from the plant material
  • step (a) the one or more cannabinoids present in the plant material and extracts are decarboxylated by heating the solvent mixture, wherein the solvent mixture is the original volume, a concentrated volume or a dry extract obtained from evaporation to dryness of the original volume of the solvent mixture.
  • fractions of THC contaminated by CBC or the fractions of the THCV contaminated with CBN are re-purified using solid-liquid chromatography selected from the group consisting of gravity, Flash or preparative HPLC over C-8 or C-18 coated silica solid stationary phase, using a gradient of acetonitrile:water mobile liquid phase.
  • the cannabinoid is selected from the group consisting of CBD, CBDA and CBDV. In another embodiment, the cannabinoid is selected from the group consisting of CBG, CBGA and CBGV. In another embodiment, the cannabinoid is selected from the group consisting of THC, THCA and THCV. [25] Other aspects of the present specification disclose methods of treating a disease or condition using purified cannabinoids and pharmaceutical compositions comprising one or more cannabinoid produced by the disclosed methods.
  • Non-limiting examples of a disease or condition include pain, schizophrenia, convulsion, inflammation, anxiety, depression, neurodegenerative disease, stroke, traumatic brain injury, cancer, migraines, arthritis, chronic pain, nausea and vomiting, anorexia, glaucoma, glioma, epilepsy, asthma, perinatal asphyxia, graft-versus-host disease, addiction, symptoms of dependency and withdrawal, multiple sclerosis, spinal cord injury, Tourette’s syndrome, dystonia, or tardive dyskinesia.
  • the present invention provides a method for isolating and purifying one or more cannabinoids from a plant extract using liquid:liquid chromatography.
  • a cannabinoid include tetrahydrocannabinol (THC), tetrahydrocannabidivarin (THCV), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidivarin (CBDV), cannabidiolic acid (CBDA), cannabigerovarin (CBGV), cannabigerol (CBG), and cannabigerol acid (CBGA)from a plant belonging to the genus Cannabis.
  • the disclosed method provides for purification of cannabinoids from a plant extract using a liquid :liquid chromatographic step.
  • An optional crystallization step(s) may be performed before or after the step of liquiddiquid chromatography. Alternatively, no crystallization step is used, only the liquid :liquid chromatographic step.
  • the liquiddiquid chromatography step includes countercurrent chromatography or centrifugal partition chromatography.
  • the chromatographic step is applied after each crystallization step described below (e.g. after step (c), (e), (h) or (i)).
  • the CPC/CCC chromatographic step is applied prior to the crystallization step described below (e.g. after step (b)).
  • Both CCC and CPC are liquid-liquid based chromatographic methods, where both the stationary phase and the mobile phase are liquids. By eliminating solid supports, permanent adsorption of the analyte onto the column is avoided, and a high recovery of the analyte can be achieved.
  • the instrument is also easily switched between normal-phase and reversed-phase modes of operation simply by changing the mobile and stationary phases. With liquid chromatography, operation is limited by the composition of the columns and media commercially available for the instrument. Nearly any pair of immiscible solutions can be used in liquid-liquid chromatography provided that the stationary phase can be successfully retained.
  • the mobile phase is organic and/or non-polar
  • the stationary phase is the aqueous and/or polar reagent.
  • the mobile organic phase may include pentane, petroleum ether, hexane, cyclohexane, or heptane.
  • the stationary phase may include ethanol, methanol, isopropanol, acetone, acetonitrile and/or water.
  • the mobile phase is pentane, hexane, cyclohexane, or heptane and the stationary phase is water and ethanol, methanol, or isopropanol.
  • the mobile phase is pentane or heptane
  • the stationary phase is acetone and/or acetonitrile with the possible use of water as a modifier.
  • CCC countercurrent chromatography
  • CPC centrifugal partition chromatography
  • the two-phase system includes hexane :ethanol:water used at ratios of (20:19:1 ) to (20:8:12).
  • ratios of (20:14:6) for isolation of CBD-type cannabinoids CBD-type cannabinoids (CBD, CBDA, CBDVA and CBDV).
  • One embodiment uses ratios of (20:17:3) for isolation of THC-type cannabinoids (THC, THCA, THCVA and THCV).
  • THC-type cannabinoids THC-type cannabinoids
  • One embodiment uses a gradient reverse phase run with ethanol and water mix as mobile phase increasing the concentration of ethanol gradually from the ratio (20:12:8) to (20:18:2), with substitutions of pentane, heptane and/or cyclohexane with hexane and methanol or isopropanol instead of ethanol, with the organic phase of pentane or hexane as mobile phase or the two-phase system.
  • the two phase system is pentane:acetonitrile or hexane:acetonitrile with or without ethyl acetate or water as a modifier for the isolation of THC-type cannabinoids.
  • the ratio of pentane:acetonitrile is from 10:10 to 7:3, e.g., pentane:ethyl acetate:acetonitrile:water (10:0:10:0) to pentane:ethyl acetate:acetonitrile:water (7:3:7:3) by volume.
  • the ratio of hexane:acetonitrile is from 10:10 to 7:3, e.g., hexane:ethyl acetate:acetonitrile:water (10:0:10:0) to hexane:ethyl acetate:acetonitrile:water (7:3:7:3) by volume.
  • Preferred solvent ratios for THC-type cannabinoids are pentane:ethyl acetate: acetonitrile:water at (19:1 :19:1 ) by volume or (9:1 :9:1 ) by volume. These two systems can also be used for CBD and CBG-type extracts.
  • the ratio of pentane:ethyl acetate:acetonitrile:water is preferably (8:2:8:2) by volume and for CBG-type extracts the ratio of pentane:ethyl acetate:acetonitrile: water is (7:3:7:3) by volume.
  • Another embodiment of the present methods includes a two-phase system having hexane :ethanol:water at ratios 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 ).
  • the ratio of hexane to ethanol may be range from about 1 :20 to about 20:1 , e.g., about 1 :20, about 1 :10, about 3:20, about 4:20, 5:20, about 6:20, about 7:20, about 8:20, about 9:20, about 10:20, about 1 1 :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 20:1 1 , 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 .
  • the ratio of ethanol to water may range from about 20:1 to about 1 :20, e.g., about 1 :20, about 1 :10, about 3:20, about 4:20, 5:20, about 6:20, about 7:20, about 8:20, about 9:20, about 10:20, about 1 1 :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 .
  • the ratio of hexane :ethanol:water is (20:19:1 ) to (20:8:12), and with substitutions of pentane, heptane and/or cyclohexane with hexane and methanol and/or isopropanol instead of ethanol, with the organic phase of pentane or hexane as mobile phase or the two-phases system.
  • the ratios of the two-phase system hexane :ethanol: water are (20:13:7) for isolation of CBG-type cannabinoids, (20:14:6) for isolation of CBD-type cannabinoids and (20:17:3) to isolate THC-type cannabinoids or using a gradient reverse phase run with ethanol and water mix as mobile phase increasing the concentration of ethanol gradually from the ratio (20:12:8) to (20:18:2).
  • Another embodiment is the method of the invention, wherein the two-phase system, hexane :ethanol:water is used, and substitutions of pentane, heptane and/or cyclohexane with hexane and methanol and/or isopropanol instead of ethanol, with the organic phase of pentane or hexane as mobile phase in the chromatographic techniques of CPC and CCC for isolating and/or purifying the cannabinoids that are present in extracts made with pentane, hexane, heptane, petroleum ethers, cyclohexane, dichloromethane, trichloromethane, tetrahydrofurane, diethyl ether, toluene, benzene, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane, propane, refrigerant gases (e.
  • an embodiment of the method of the invention includes before or after each crystallization step (e.g., after step (c), (e), (h) or (i) as shown below) a countercurrent chromatography (CCC) or a centrifugal partition chromatography (CPC) are carried out to isolate and purify the cannabinoids: tetrahydrocannabinol (THC), tetrahydrocannabidivarin (THCV), tetrahydrocannabinolic acid (THCA), tetrahydrocannabidivarinic acid (THCVA), cannabidiol (CBD), cannabidivarin (CBDV), cannabidiolic acid (CBDA), cannabidivarinic acid (CBDVA), cannabinol (CBN), cannabivarin (CBV), cannabigerovarin (CBGV), cannabigerol (CBG), cannabigerovarinic acid (CBGVA) and
  • 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 which extracts the 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 the one or more cannabinoids; c) incubating the reduced first solvent mixture in a manner that crystalizes the one or more cannabinoids; d) incubating the one or more crystalized cannabinoids with a second nonpolar solvent to form a second solvent mixture; and e) incubating the second solvent mixture in a manner that crystalizes the one or more cannabinoids, thereby resulting in the purification of one or more cannabinoids.
  • the disclosed methods further provide that the one or more crystalized cannabinoids of step (c) may be purified prior to step (d), using, e.g. , filtration that results in a collection of a mother liquor.
  • the mother liquor may be collected and incubated in a manner that crystalizes the one or more cannabinoids.
  • Step (a) may be repeated one or more times.
  • Steps (d) and (e) may be repeated one or more times until the purity of the one or more cannabinoids is 95% or more.
  • 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 which extracts the one or more cannabinoids from a plant material; b) filtering the first solvent mixture; 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 the one or more cannabinoids; d) incubating the reduced first solvent mixture in a manner that crystalizes the one or more cannabinoids; e) purifying the one or more crystalized cannabinoids in step (d) using filtration that results in a collection of a mother liquor; f) incubating the one or more crystalized 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 crystalized cannabinoids; g) incubating
  • the disclosed methods may further comprise: i) purifying the one or more crystalized cannabinoids using filtration that results in a collection of a mother liquor; and j) incubating the mother liquor in a manner that crystalizes the one or more cannabinoids.
  • Step (a) may 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 the one or more cannabinoids is 95% or more.
  • 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 which extracts the one or more cannabinoids from a plant material; b) filtering the first solvent mixture; c) reducing by evaporation, the volume of the first non-polar solvent in the filtrate obtained in step (b); d) incubating the reduced first solvent mixture in a manner that crystalizes the one or more cannabinoids; e) removing the first non-polar solvent by vacuum filtering; f) further reducing the amount of first non-polar solvent from the filtrate of (e) by evaporation; g) incubating the one or more crystalized cannabinoids with a second nonpolar solvent to form a second solvent mixture, wherein the second solvent mixture dissolves at least 50% of the one or more crystalized cannabinoids; h) incubating the second solvent mixture in a manner that crystalize
  • aspects of the present specification disclose, in part, incubating the plant material with a first non-polar solvent to form a first solvent mixture which extracts the 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 liquid non-polar solvent comprising lower C5-C12, or Cs-Cs straight chain, or branched chain alkanes.
  • Non-limiting examples of the non-polar solvent include pentane, hexane, petroleum ether (60-80°C bp), cyclohexane, heptane, chloroform, benzene, toluene, or diethyl ether.
  • the non-polar solvent used in any one of or all of the present extraction steps is hexane.
  • at least one of the extraction and/or purification steps for extraction of CBG and/or CBGA is performed with hexane.
  • the non-polar solvent used in any one of or all of the present extraction steps is pentane or petroleum ether (40-60°C bp).
  • one or more of the extraction and/or purification steps for extraction/purification of CBD is performed with pentane or petroleum ether (40-60°C bp).
  • the non-polar solvent used in any one of or all of the present extraction steps is heptane.
  • one or more of the extraction and/or purification steps for extraction/purification of THCA is performed with heptane.
  • extraction of the one or more cannabinoids from a plant material is a function of temperature, time and number of extraction steps.
  • incubating the plant material with a non-polar solvent occurs for a time period of, e.g., 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.
  • incubating the plant material with a non-polar solvent occurs for a time period of, e.g., at most 5 hours, for at most 4.75 hours, for at most 4.5 hours, for at most 4.25 hours, for at most 4.0 hours, for at most 3.75 hours, for at most 3.5 hours, for at most 3.25 hours, for at most 3.0 hours, for at most 2.75 hours, for at most 2.5 hours, for at most 2.25 hours, for at most 2.0 hours, for at most 1.75 hours, for at most 1 .5 hours, for at most 1 .25 hours, for at most 1 .25 hours, for at most 1 .0 hours, for at most 45 minutes, for at most 30 minutes, or for at most 15 minutes.
  • incubating the plant material with a non-polar solvent occurs for a time period of, e.g. , 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.
  • a time period of, e.g. , 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
  • incubating the plant material with a non-polar solvent occurs at a temperature of, e.g., 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, 28°C or higher, 32°C or higher, 36°C or higher, 40°C or higher, 44°C or higher, 48°C or higher, 52°C or higher, 56°C or higher or 60°C or higher.
  • incubating the plant material with a non-polar solvent occurs at a temperature of, e.g., 0°C or lower, 4°C or lower, 8°C or lower, 12°C or lower, 16°C or lower, 20°C or lower, 24°C or lower, 28°C or lower, 32°C or lower, 36°C or lower, 40°C or lower, 44°C or lower, 48°C or lower, 52°C or lower, 56°C or lower or 60°C or lower.
  • incubating the plant material with a non-polar solvent occurs at a temperature of, e.g., 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 0°C to about 32°C, about 0°C to about 36°C, about 0°C to about 40°C, about 0°C to about 44°C, about 0°C to about 48°C, about 0°C to about 52°C, about 0°C to about 56°C, about 0°C to about 60°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°
  • aspects of the present specification disclose, in part, purifying the solvent mixture.
  • the solvent mixture is purified by filtration.
  • aspects of the present specification disclose, in part, reducing the volume of the solvent mixture in a manner that concentrates the one or more cannabinoids, by at least 50% of the original volume to dryness.
  • the volume of the first solvent mixture is reduced by evaporation.
  • the volume of the first solvent mixture is reduced by, e.g., 60% or less, 50% or less, 45% or less, 40% 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 the one or more cannabinoids from a plant material.
  • the volume of the first solvent mixture is reduced by, e.g., 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 0.5% to about 30%, about 0.5% to about 35%, about 0.5% to about 40%, about 0.5% to about 45%, about 0.5% to about 50%, about 1 % to about 15%, about 1 % to about 20%, about 1 % to about 25%, about 1 % to about 30%, about 1 % to about 35%, about 1 % to about 40%, about 1 % to about 45%, about 1 % to about 50%, about 1 % to
  • aspects of the present specification disclose, in part, incubating the reduced solvent mixture in a manner that crystalizes one or more cannabinoids.
  • crystallization of the one or more cannabinoids in the reduced first solvent mixture is a function of temperature and time.
  • the reduced first solvent mixture is incubated at a temperature of, e.g., -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.
  • the reduced first solvent mixture is incubated at a temperature of, e.g. , -70°C or lower, -60°C or lower, -50°C or lower, -40°C or lower, -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 lower or 28°C or lower.
  • the reduced first solvent mixture is incubated at a temperature of, e.g., 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 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
  • the reduced first solvent mixture is incubated for a time period of, e.g., 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.
  • a time period of, e.g., 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
  • the reduced first solvent mixture is incubated for a time period of, e.g., 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 less, 16 hours or less, 18 hours or less, 20 hours or less, 22 hours or less, 24 hours or less, 28 hours or less, 32 hours or less, 36 hours or less, 40 hours or less, 44 hours or less, 48 hours or less, 52 hours or less, 56 hours or less, 60 hours or less, 64 hours or less, 68 hours or less, 72 hours or less, 76 hours or less, 80 hours or less, 84 hours or less, 88 hours or less, 92 hours or less or 96 hours or less.
  • a time period e.g., 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
  • the reduced first solvent mixture is incubated for a time period of, e.g., 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, about 4 hours to about 72 hours, about 4 hours to about 84 hours, about 4 hours to about 96 hours, about 6 hours to about 12 hours, about 6 hours to about 24 hours, about 6 hours to about 36 hours, about 6 hours, about 6 hours to about 36
  • aspects of the present specification disclose, in part, purifying the one or more cannabinoids which are crystalized after incubation in the reduced solvent mixture.
  • purification of the one or more crystalized cannabinoids is performed using filtration that results in a collection of a mother liquor.
  • aspects of the present specification disclose, in part, incubating the one or more crystalized cannabinoids with a second non-polar solvent to form a second solvent mixture. Incubation of the one or more crystalized cannabinoids with a second non-polar solvent to form a second solvent mixture at least partially dissolves the one or more crystalized cannabinoids.
  • incubation of the one or more crystalized cannabinoids with a second non-polar solvent to form a second solvent mixture dissolves, e.g., 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 the one or more crystalized cannabinoids.
  • incubation of the one or more crystalized cannabinoids with a second nonpolar solvent to form a second solvent mixture dissolves, e.g., 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 the one or more crystalized cannabinoids.
  • incubation of the one or more crystalized cannabinoids with a second non-polar solvent to form a second solvent mixture dissolves, e.g., 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%.
  • aspects of the present specification disclose, in part, purifying the one or more crystalized cannabinoids obtained from a second solvent mixture, as described above for the solvent mixture.
  • the one or more crystalized cannabinoids is purified using filtration that results in a collection of a mother liquor.
  • the disclosed methods may further comprise, incubating the mother liquor in a manner that crystalizes the one or more cannabinoids.
  • the one or more cannabinoids can be crystalized using the same temperature and time conditions used to crystalizes the one or more cannabinoids from the reduced solvent mixture described above.
  • the result of the disclosed methods is a substantially pure preparation of one or more cannabinoids.
  • a “substantially pure" preparation of a cannabinoid or a cannabinoid acid is defined as a preparation having 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 area normalisation of an HPLC profile or by a quantification percent of purity respect a certified commercial standard.
  • the disclosed methods result in the purification of CBGA having 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 normalisation of an HPLC profile or by a quantification percent of purity respect a certified commercial standard.
  • the disclosed methods result in the purification of CBG having 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 normalisation of an HPLC profile or by a quantification percent of purity respect a certified commercial standard.
  • the disclosed methods result in the purification of CBD having 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 normalisation of an HPLC profile or by a quantification percent of purity respect a certified commercial standard.
  • the term “crude cannabinoid”, “raw cannabinoid” or “product enriched in a given cannabinoid” encompasses preparations having 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.
  • the cannabinoids purified by the disclosed methods are not particularly limited and include cannibigerol-type (CBG-type) cannabinoids; cannaibichromene-type cannabinoids (CBC-type); cannabidiol-type cannabinoids (CBD-type); tetrahydracannabinol-type cannabinoids (THC-type); cannabinol-type cannabinoids (CBN-type); and derivatives thereof.
  • the cannabinoid derivatives may not themselves be cannabinoids. However, their chemistry is recognized as being derived from cannabigerol, cannabinol, or cannabidiol.
  • cannabinoids of interest include the following and their corresponding acids: CBG (Cannabigerol), CBC (Cannabichromene), CBL (Cannabicyclol), CBV (Cannabivarin), THCV (Tetrahydrocannabivarin), CBDV (Cannabidivarin), CBCV (Cannabichromevarin), CBGV (Cannabigerovarin), CBGM (Cannabigerol Monomethyl Ether), THC (tetrahydrocannabinol), CBT (Cannabicitran-type), Iso-THC (Iso-Tetrahydrocannabinol-type) and CBE (Cannabielsoin-type).
  • cannabinoids are present in the form carboxylic acid known as acidic cannabinoids or“cannabinoid acids”.
  • acidic cannabinoids or“cannabinoid acids”.
  • free phenolic forms of the cannabinoids are also known as neutral cannabinoids.
  • the disclosed methods may be used to extract/purify cannabinoids or cannabinoid acids from any plant material known to contain such cannabinoids or cannabinoid acids.
  • the source for the cannabinoids is not limited, but can include plant material.
  • plant material encompasses a plant or plant part (e.g. bark, wood, leaves, stems, roots, flowers, fruits, seeds, berries or parts thereof) as well as exudates, resins, and plant extracts, and includes material falling within the definition of "botanical raw material” in the Guidance for Industry Botanical Drug Products Draft Guidance, August 2000, US Department of Health and Human Services, Food and Drug Administration Centre for Drug Evaluation and Research.
  • the disclosed methods may be used to extract/purify cannabinoids or cannabinoid acids from any plant material known to contain such cannabinoids or cannabinoid acids. Most typically, but not necessarily, the "plant material" will be derived from one or more cannabis plants. Plants from which cannabinoids may be isolated include: Cannabis sp. including Cannabis sativa L. and all subspecies, the putative species Cannabis indica Lam., Cannabis ruderalis Janisch, and hybrids and varieties thereof, as discussed further below. The Cannabis sativa L.
  • the disclosed methods use material from the plant Cannabis sativa L. variety belonging to chemotype IV, having CBGA/CBG as main cannabinoids. In another embodiment, the disclosed methods use material from the plant Cannabis sativa L. variety belonging to chemotype III, having CBDA/CBD as main cannabinoids. In another embodiment, the disclosed methods use material from the plant Cannabis sativa L. variety belonging to chemotype II, having THCA-CBDA/THC-CBD as main cannabinoids. In yet another embodiment, the disclosed methods use material from the plant Cannabis sativa L. variety belonging to chemotype I, having THCA/THC as the main cannabinoids.
  • annabis plant(s) encompasses wild type Cannabis sativa and also variants thereof, including cannabis chemovars (varieties characterised by virtue of chemical composition) which naturally contain different amounts of the individual cannabinoids, also Cannabis sativa L. subspecies indica including the variants var. indica and var. kafiristanica, Cannabis indica and also plants which are the result of genetic crosses, self-crosses or hybrids thereof.
  • the term “cannabis plant material” is to be interpreted accordingly as encompassing plant material derived from one or more cannabis plants. For the avoidance of doubt, it is hereby stated that “cannabis plant material” includes herbal cannabis and dried cannabis biomass.
  • Decarboxylated cannabis plant material refers to cannabis plant material which has been subject to a decarboxylation step in order to convert cannabinoid acids to the corresponding free cannabinoids.
  • Resin as used herein includes resins produced from any of the plant types discussed above, and in one embodiment, includes products of the stalked resin glands of Cannabis sp., including the putative species Cannabis indica, the species Cannabis sativa and Cannabis ruderalis, and hybrids or varietals thereof. These stalked resin glands may be from female, unfertilized or fertilized plants or from dioecious or monoecious varieties of Cannabis.
  • the method of the invention makes it possible to isolate the cannabinoids of interest (e.g., CBG, CBGA, CBGVA, CBD, CBDA, CBDVA, THC, THCA or THCVA) by crystallization with a non-polar solvent (e.g., hexane, pentane, heptane or petroleum ethers), from the plant, resin or the extracts obtained from the plant, wherein the crystallization is before or after a liquid liquid chromatography step.
  • a non-polar solvent e.g., hexane, pentane, heptane or petroleum ethers
  • the extract of the resin or plant is first obtained by extracting with pentane, hexane, heptane, petroleum ethers, cyclohexane, dichloromethane, trichloromethane, tetrahydrofurane, diethyl ether, toluene, benzene, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane, propane, refrigerant gases (e.g.: 1 ,1 ,1 ,2-Tetrafluoroethane (R134a)) or, liquid, subcritical or supercritical CO2 or mixes of these solvents.
  • refrigerant gases e.g.: 1 ,1 ,1 ,2-Tetrafluoroethane (R134a)
  • the disclosed method obtains the cannabinoids of interest (e.g., CBG, CBGA, CBGVA, CBD, CBDA, CBDVA, THC, THCA or THCVA) with a purity of 60% to 96%, which will be called “raw” with a high yield and further with a purity of 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%, 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%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%,
  • this“raw” composition in a non-polar solvent (e.g., hexane, pentane, heptane or petroleum ethers), it is possible to obtain a purity 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%, of e.g., CBG, CBGA, CBGVA, CBD, CBDA, CBDVA, THC, THCA or THCVA.
  • a non-polar solvent e.g., hexane, pentane, heptane or petroleum ethers
  • 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 of pentane, hexane, heptane, cyclohexane, petroleum ethers, dichloromethane, trichloromethane, tethrahydrofurane, toluene, benzene, diethyl ether, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane, propane, refrigerant gases (e.g.: 1 ,1 ,1 ,2-Tetrafluoroethane (R134a)) and liquid, subcritical or supercritical CO2 or mixes of these solvents.
  • refrigerant gases e.g.: 1 ,1 ,1 ,2-Tetrafluoroethane (R134a)
  • an acidified extraction solvent to prepare the initial extract may optionally be used to ensure the extraction of high levels of cannabinoid acids.
  • the primary purpose of this acidification is to prevent/minimise ionisation of the cannabinoid acid, which could otherwise adversely affect the purification process.
  • the method uses acidified non-polar solvents, of the types described above. Acidification may be achieved by the addition of a small volume of acid to the solvent. Generally, it is sufficient to add a relatively weak acid, such as acetic acid. For any given purification process the optimal amount and type of acid used may 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, tethrahydrofurane, 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 mixes of these solvents
  • This is the extraction solvent of choice for preparing an initial extract from the starting plant material in the preparation of cannabinoid acids.
  • the plant material may be subjected to a decarboxylation step.
  • the purpose of the decarboxylation step is to convert cannabinoid acids present in the plant material to the corresponding free cannabinoids.
  • Decarboxylation may be carried out by heating the plant material to a defined temperature for a suitable length of time. Decarboxylation of cannabinoid acids is a function of time and temperature, thus at higher temperatures a shorter period of time will be taken for complete decarboxylation of a given amount of cannabinoid acid.
  • appropriate conditions for decarboxylation consideration must, however, be given to minimizing thermal degradation of the desirable, pharmacological cannabinoids into undesirable degradation products, particularly thermal degradation of D 9 THC to cannabinol (CBN).
  • cannabinoids e.g., CBG, CBGA, CBGV, CBD, CBDA, CBDV, THC, THCA or THCV are isolated and purified, and in which prior to performing step (a), the plant material, resin or extracts from the plant are decarboxylated for at least about 1 hour, 1.1 hours, 1 .2 hour, 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 around 60°C, 65°C, 70°C, 75°C, 80°C, 85°C,
  • the decarboxylation is performed 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, 1 10°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.
  • the decarboxylation is performed 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.
  • the decarboxylation is performed 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 to 130°C, or 120°C to 130°C.
  • Another embodiment is the method, wherein cannabigerol (CBG), cannabidiol (CBD), cannabidivarin (CBDV), tetrahydrocannabinol (THC), tetrahydrocannabidivarin (THCV), cannabinol (CBN), cannabivarin (CBV) and/or cannabigerovarin (CBGV) are isolated and purified, and in which prior to performing step (a), the plant material or resin of said plant are decarboxylated at least at 120 °C for 2 hours.
  • CBG cannabigerol
  • CBD cannabidiol
  • CBDDV cannabidivarin
  • THC tetrahydrocannabinol
  • THCV tetrahydrocannabidivarin
  • CBN cannabinol
  • CBV cannabivarin
  • CBGV cannabigerovarin
  • step (a) is repeated at least once. In one embodiment, step (a) is repeated 2 times or 3 times. Another embodiment is the method, wherein time in step (a) is at least about 60 minutes.
  • step (i) is repeated at least once. In one embodiment, step (i) is repeated 2 times or 3 times.
  • the present methods obtain a substantially pure cannabinoid product.
  • a “substantially pure" preparation of a cannabinoid or a cannabinoid acid is defined as a preparation having a chromatographic purity (of the desired cannabinoid or cannabinoid acid) of 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 area normalisation of an HPLC profile or by quantification by HPLC with a certified commercial standard.
  • the present methods obtain a composition which includes a substantially pure cannabinoid or cannabinoid acid in liquid or solid form.
  • the final product may be applied while in its crystalline form or may be further dissolved or formulated into a liquid, powder or compressed tablet.
  • the present methods obtain a crystalline cannabinoid in powder form.
  • the present methods obtain a cannabinoid solution.
  • the product obtained herein may be incorporated or formulated into products suitable for pharmaceutical purposes, recreational ingestion (e.g., food supplements, nutriceuticals), or as recreational inhalants (e.g., cigarettes and/or oils or liquids for electronic cigarettes/vape/hookah products, or incense).
  • recreational ingestion e.g., food supplements, nutriceuticals
  • recreational inhalants e.g., cigarettes and/or oils or liquids for electronic cigarettes/vape/hookah products, or incense.
  • the present methods in one embodiment produce a product which may be included in a pharmaceutical product, medicinal preparation, or medicament (hereinafter“pharmaceuticals”).
  • pharmaceutical products may be formulated as liquids, tablets, capsules, microcapsules, nanocapsules, trans-dermal patches, gels, foams, oils, aerosols, nanoparticulates, powders, creams, emulsions, micellar systems, films, sprays, ovules, infusions, teas, decoctions, suppositories, etc.
  • Products obtained by the present methods may be included in a pharmaceutical composition including a compound of the present product or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprises CBGA, CBG, CBGV, CBDA, CBD, CBDV, THCA, THC, THCV or any combination thereof.
  • excipient is used herein to describe any ingredient other than the compound of the invention.
  • the choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and
  • Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include both solid and liquid formulations.
  • Solid formulations include tablets, capsules (containing particulates, liquids, microcapsules, or powders), lozenges (including liquid-filled lozenges), chews, multi- and nano-particulates, gels, solid solutions, liposomal preparations, microencapsulated preparations, creams, films, ovules, suppositories and sprays.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed 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 more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic patents, 11 (6), 981 -986, by Liang and Chen (2001 ).
  • the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
  • tablets In addition to the drug, tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl- substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight % or from 5 weight % to 20 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, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. [87] 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.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight % to 10 weight %, from 0.5 weight % to 3 weight % of the tablet.
  • ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • Consumable oral films are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a filmforming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscositymodifying agent and a solvent. Some components of the formulation may perform more than one function.
  • the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
  • Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freezedrying or vacuuming.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations for the purposes of the invention are described in U.S. Pat. No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in "Pharmaceutical Technology On-line", 25(2), 1-14, by Verma et al (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • the 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 which may contain excipients such as salts, carbohydrates and buffering agents (in one embodiment, to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compound of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound.
  • examples of such formulations include drug-coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.
  • the compounds obtained by the present methods may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, cosmetics, oils, eye drops, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions.
  • Liposomes may also be used.
  • Typical carriers include 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).
  • Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g., Powderject. TM., Bioject.TM., etc.) injection.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include 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, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11 172, WO 94/02518 and WO 98/55148.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid pharmaceutical compositions can contain suitable pharmaceutically acceptable excipients.
  • the pharmaceutical compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Pharmaceutical compositions in pharmaceutically acceptable solvents can be nebulized by use of inert gases. Nebulized solutions can be inhaled directly from the nebulizing device or the nebulizing device can be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder pharmaceutical compositions can be administered, e.g., orally or nasally, from devices that deliver the formulation in an appropriate manner.
  • the pharmaceutical composition described herein may be combined with the administration of another drug or active ingredient.
  • the present products may be used to alleviate, minimize or prevent not only a disease or condition, but a side effect of another treatment regime.
  • the purified cannabinoids obtained by the present methods may be included in compositions such as oils (both for topical administration as massage oil, or to be burned or aeresolized), incense, cosmetics, bath oils, perfumes, makeup, food seasonings, toothpastes, ingestible solids (e.g., as a powder included in or on foods) or liquids (e.g., teas), etc.
  • oils both for topical administration as massage oil, or to be burned or aeresolized
  • incense cosmetics
  • bath oils perfumes
  • perfumes makeup
  • food seasonings e.g., toothpastes
  • ingestible solids e.g., as a powder included in or on foods
  • liquids e.g., teas
  • a product produced by the present methods may be included in a“vape” product containing propylene glycol, glycerine, vegetable glycerine, aqueous glycerine, and optionally flavorings.
  • the“vape” product may also include other drugs, such as nicotine.
  • the pharmaceutical products described herein may be administered to treat or reduce the symptoms of a disease or condition.
  • the present products may be administered to treat pain, Schizophrenia, convulsion, inflammation, anxiety or panic, depression (including unipolar or bipolar mood disorder and syndromal depression etc.), as a neuroprotective (i.e., for treatment of neurodegenerative disease, stroke, traumatic brain injury), cancer, graft-versus-host disease, migraines, arthritis, chronic pain (including neuropathic pain), nausea and vomiting, anorexia, glaucoma, glioma, epilepsy (that affects children and adults), asthma, perinatal asphyxia, addiction (and symptoms of dependency and withdrawal), movement disorders evidencing spasticity (in multiple sclerosis and spinal cord injury), Tourette’s syndrome, dystonia, and tardive dyskinesia.
  • treatment methods reduce, decrease, suppress, limit, control or inhibit the presence of one or more symptoms associated with a condition; reduce, decrease, suppress, limit, control or inhibit side-effects of another pharmaceutical treatment; reduce, decrease, suppress, limit, control or inhibit the symptoms of addiction.
  • treatment methods include administration of an amount of the present product sufficient to increase, induce, enhance, augment, promote or stimulate an immune response against the condition; or decrease, reduce, inhibit, suppress, prevent, control, or limit the spread of the condition within a subject or patient, or between subjects or patients.
  • treatment methods include administration of an amount of the present products sufficient to protect an individual from a pathology related to the condition, or reduce, decrease, limit, control or inhibit susceptibility to a pathology related to the condition.
  • the present invention includes reagents for the purification of cannabinoids.
  • reagents include hexane (for CBG and CBGA), pentane and petroleum ether 40-60°C bp (for CBD), heptane and petroleum ether 60-80°C bp (for THCA) for the crystallization of the cannabinoid, and optionally reagents for the liquid chromatography such as ethanol, methanol, or isopropyl, or heptane, acetone, and acetonitrile.
  • a method of purifying one or more cannabinoids from a plant material comprising a) incubating the plant material with a first non-polar solvent to form a first solvent mixture which extracts the 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 the one or more cannabinoids; c) incubating the reduced first solvent mixture at a temperature range of between about -70°C to about 40°C in a manner that crystalizes the one or more cannabinoids; d) incubating the one or more crystalized 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 crystalized cannabinoids; and e) incubating the second solvent mixture at a temperature range of between about -70°C to about 40°C in a manner that crystalizes
  • the Cannabis s ativa L. varietal comprises a Chemotype I varietal, Chemotype II varietal, a Chemotype III varietal or a Chemotype IV varietal.
  • the Cannabis s ativa L. varietal comprises a Carma varietal, a AIDA varietal, a SARA varietal, a PILAR varietal, a Futura 75 varietal, MONIEK varietal, or a 60.2/1/9 experimental varietal.
  • step (a) the plant material is treated to decarboxylate one or more cannabinoids present in the plant material.
  • step (a) comprises pentane, hexane, heptane, cyclohexane, petroleum ether, dicloromethane, tricloromethane, tethrahydrofurane, diethyl ether, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane, propane, refrigeration gas 1 ,1 ,1 ,2-Tetrafluoroethane (R134a), liquid CO2, subcritical CO2 and supercritical CO2.
  • the first non-polar solvent of step (a) comprises pentane, hexane, heptane, cyclohexane, petroleum ether, dicloromethane, tricloromethane, tethrahydrofurane, diethyl ether, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, but
  • the one or more cannabinoids comprise tetrahydrocannabinol (THC), tetrahydrocannabidivarin (THCV), tetrahydrocannabinolic acid (THCA), tetrahydrocannabidivarinic acid (THCVA), cannabinol (CBN), cannabivarin (CBV), cannabidiol (CBD), cannabidivarin (CBDV), cannabidiolic acid (CBDA), cannabidivarinic acid (CBDVA), cannabigerol (CBG), canabigerovarin (CBGV), canabigerovarinic acid (CBGV) or cannabigerolic acid (CBGA).
  • THC tetrahydrocannabinol
  • THCV tetrahydrocannabidivarin
  • THCA tetrahydrocannabinolic acid
  • THCVA tetrahydrocannabidivarinic acid
  • step (a) the first solvent mixture is incubated at about 10 minutes to about 1500 minutes.
  • step (a) the first solvent mixture is incubated at about 30 minutes to about 120 minutes.
  • step (a) is repeated at least once.
  • step (a) is repeated three times.
  • step (b) the volume of the first solvent mixture is reduced to about 1 % to about 50% of the original volume of the first solvent mixture in step (a).
  • step (b) the volume of the first solvent mixture is reduced to about 0.1 % to about 15% of the original volume of the first solvent mixture in step (a).
  • 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).
  • step (b) the volume of the first solvent mixture is reduced by evaporation.
  • step (c) the reduced first solvent mixture is incubated at a temperature range of between about -20°C to about 30°C.
  • step (c) the reduced first solvent mixture is incubated at a temperature range of between about 0°C to about 25°C.
  • step (c) the reduced first solvent mixture is incubated at a temperature range of between about 4°C to about 8°C
  • step (c) the reduced first solvent mixture is incubated for a time period of at least 30 minutes, at least 1 hour or at least 2 hours.
  • step (c) the reduced first solvent mixture is incubated for a time period of between 1 hour and 96 hours.
  • step (c) the reduced first solvent mixture is incubated for a time period of between 2 hour and 72 hours.
  • step (c) the reduced first solvent mixture is incubated for a time period of between 4 hour and 48 hours.
  • step (c) the reduced first solvent mixture is incubated for a time period of between 6 hour and 24 hours.
  • step (c) the reduced first solvent mixture is incubated for a time period of between 12 hour and 24 hours.
  • step (c) further comprises seeding the reduced solvent mixture with a cannabinoid.
  • the cannabinoid used to seed the reduced solvent mixture comprises a purified cannabinoid, a partially purified cannabinoid or crude extract comprising a cannabinoid.
  • step (d) comprises pentane, hexane, heptane, petroleum ethers, cyclohexane, dichloromethane, trichloromethane, tetrahydrofurane, diethyl ether, toluene, benzene, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane, propane, refrigerant gases (e.g.: 1 ,1 ,1 ,2-Tetrafluoroethane (R134a)) or, liquid, subcritical or supercritical C02 or mixes of these solvents.
  • refrigerant gases e.g.: 1 ,1 ,1 ,2-Tetrafluoroethane (R134a)
  • step (d) the second solvent mixture dissolves at least 75% of the one or more crystalized cannabinoids.
  • step (d) the second solvent mixture dissolves at least 85% of the one or more crystalized cannabinoids.
  • step (d) the second solvent mixture dissolves at least 95% of the one or more crystalized cannabinoids.
  • step (d) the second solvent mixture is incubated at a temperature range of between about 30°C to about 60°C.
  • step (d) the second solvent mixture is incubated at a temperature range of between about 40°C to about 50°C.
  • step (d) the second solvent mixture is incubated for a time period of at least 6 minutes.
  • step (d) the second solvent mixture is incubated for a time period of between 0.25 hour and 4 hours.
  • step (e) the second solvent mixture is incubated at a temperature range of between about -20°C to about 30°C.
  • step (e) the second solvent mixture is incubated at a temperature range of between about 0°C to about 25°C.
  • step (e) the second solvent mixture is incubated at a temperature range of between about 4°C to about 8°C
  • step (e) the second solvent mixture is incubated for a time period of at least 6 minutes, at least 1 hour, at least 2 hours, at least 3 hours or at least 4 hours.
  • step (e) the second solvent mixture is incubated for a time period of between 0.1 hour and 96 hours.
  • step (e) the second solvent mixture is incubated for a time period of between 2 hour and 72 hours.
  • step (e) the second solvent mixture is incubated for a time period of between 4 hour and 48 hours.
  • step (e) the second solvent mixture is incubated for a time period of between 6 hour and 24 hours.
  • step (e) the second solvent mixture is incubated for a time period of between 12 hour and 24 hours.
  • step (c) The method according to any one of embodiments 1 -47, wherein the one or more crystalized cannabinoids of step (c) is purified prior to step (d).
  • the method according to embodiment 49 further comprising incubating the mother liquor at a temperature range of between about -70°C to about 40°C in a manner that crystalizes the one or more cannabinoids.
  • the method according to embodiment 50 further comprising f) purifying the one or more crystalized cannabinoids using filtration that results in a collection of a mother liquor; and g) incubating the mother liquor at a temperature range of between about -70°C to about 40°C in a manner that crystalizes the one or more cannabinoids.
  • steps (f) and (g) are repeated at least once.
  • steps (f) and (g) are repeated 2 times.
  • steps (f) and (g) are repeated 3 times.
  • steps (d) and (e) are repeated at least once.
  • steps (d) and (e) are repeated 2 times.
  • steps (d) and (e) are repeated 3 times.
  • step (a) is purified prior to step (b).
  • step (e) is filtered.
  • liquidliquid chromatography is counter current chromatography (CCC) or centrifugal partition chromatography (CPC).
  • CCC counter current chromatography
  • CPC centrifugal partition chromatography
  • the mobile organic phase includes pentane, hexane, cyclohexane, or heptane.
  • the stationary phase includes ethanol, methanol, isopropanol, acetone, acetonitrile and/or water.
  • the mobile phase is pentane, hexane, cyclohexane, or heptane and the stationary phase is water and ethanol, methanol, or isopropanol.
  • the two-phase system is hexane :ethanol:water at ratios of (20:19:1 ) to (20:8:12) and wherein hexane may be substituted by pentane, heptane and/or cyclohexane and wherein ethanol may be substituted by methanol and/or isopropanol instead of ethanol, with the organic phase of pentane or hexane as mobile phase or the two-phase system.
  • the ratios of the two-phase system, hexane:ethanol: water are (20:13:7) for CBG-type cannabinoids (20:14:6) for CBD-type cannabinoids and (20:17:3) for THC-type cannabinoids or using a gradient reverse phase run with ethanol and water mix as mobile phase increasing the concentration of ethanol gradually from the ratio (20:12:8) to (20:18:2).
  • the mobile phase is pentane, hexane or heptane with or without ethyl acetate as a modifier
  • the stationary phase is acetone and/or acetonitrile with or without water as a modifier.
  • the two phase system is pentane:acetonitrile or hexane:acetonitrile with or without ethyl acetate or water as a modifier, at ratios of (10:0:10:0) to (7:3:7:3).
  • the ratio of pentane:acetonitrile is from 10:10 (e.g., pentane:ethyl acetate:acetonitrile:water (10:0:10:0)) to 7:3:7:3 pentane:ethyl acetate:acetonitrile:water by volume.
  • the ratio of hexane:acetonitrile is from 10:10 (e.g., hexane:ethyl acetate:acetonitrile:water (10:0:10:0)) to 7:3:7:3 hexane:ethyl acetate:acetonitrile:water by volume.
  • Preferred solvent ratios for THC-type cannabinoids are pentane:ethyl acetate: acetonitrile:water at 19:1 :19:1 by volume or 9:1 :9:1 by volume.
  • a pharmaceutical composition comprising a purified cannabinoid produced by the method according to any one of embodiments 1-66.
  • composition of embodiment 68 further comprising a pharmaceutically acceptable excipient or carrier.
  • a method of treating a disease or condition comprising administering the cannabinoid produced by the method according to any one of embodiments 1-66 to a subject in need thereof.
  • the method of treating a disease or condition of embodiment 70 wherein the disease or condition is pain, schizophrenia, convulsion, inflammation, anxiety, depression, neurodegenerative disease, stroke, traumatic brain injury, cancer, migraines, arthritis, chronic pain, nausea and vomiting, anorexia, glaucoma, epilepsy, asthma, addiction, symptoms of dependency and withdrawal, multiple sclerosis, spinal cord injury, Tourette’s syndrome, dystonia, or tardive dyskinesia.
  • a method of purifying a cannabinoid from a plant material comprising: a) incubating the plant material with a first non-polar solvent to form a first solvent mixture which extracts the one or more cannabinoids from a plant material; b) filtering the first solvent mixture; 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 the one or more cannabinoids; d) incubating the reduced first solvent mixture at a temperature range of between about -70°C to about 40°C in a manner that crystalizes the one or more cannabinoids; e) purifying the one or more crystalized cannabinoids in step (d) using filtration that results in a collection of a mother liquor; f) incubating the one or more crystalized 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
  • step (e) and/or step (h) is incubated at a temperature range of between about -70°C to about 40°C in a manner that crystalizes the one or more cannabinoids.
  • the method according to embodiment 73 further comprising i) purifying the one or more crystalized cannabinoids using filtration that results in a collection of a mother liquor; and j) incubating the mother liquor at a temperature range of between about -70°C to about 40°C in a manner that crystalizes the one or more cannabinoids.
  • steps (i) and (j) are repeated at least once.
  • steps (i) and (j) are repeated 2 times.
  • steps (i) and (j) are repeated 3 times.
  • steps (f) and (g) are repeated at least once.
  • steps (f) and (g) are repeated 2 times.
  • steps (f) and (g) are repeated 3 times.
  • steps (f), (g) and (h) are repeated at least once.
  • steps (f), (g) and (h) are repeated 2 times.
  • steps (f), (g) and (h) are repeated 3 times.
  • the plaint material is derived from Cannabis s ativa L, Cannabis indica Cannabis ruderalis, hybrids thereof or varietals thereof.
  • the Cannabis s ativa L. varietal comprises a Carma varietal, a AIDA varietal, a SARA varietal, a PILAR varietal, a Futura 75, MONIEK varietal or a 60.2/1/9 experimental varietal.
  • step (a) the plant material is treated to decarboxylate one or more cannabinoids present in the plant material.
  • the first non-polar solvent of step (a) comprises pentane, hexane, heptane, cyclohexane, petroleum ether, dicloromethane, tricloromethane, tethrahydrofurane, diethyl ether, benzene, toluene, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane, propane, refrigeration gas 1 ,1 ,1 ,2-Tetrafluoroethane (R134a), liquid CO2, subcritical CO2 and supercritical CO2.
  • the first non-polar solvent of step (a) comprises pentane, hexane, heptane, cyclohexane, petroleum ether, dicloromethane, tricloromethane, tethrahydrofurane, diethyl ether, benzene, toluene, ethanol, methanol
  • the one or more cannabinoids comprise tetrahydrocannabinol (THC), tetrahydrocannabidivarin (THCV), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidivarin (CBDV), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerovarin (CBGV) or cannabigerolic acid (CBGA).
  • THC tetrahydrocannabinol
  • THCV tetrahydrocannabidivarin
  • THCA cannabidiol
  • CBDDV cannabidivarin
  • CBDA cannabidiolic acid
  • CBD cannabigerol
  • CBDGV cannabigerovarin
  • CBGA cannabigerolic acid
  • step (a) the first solvent mixture is incubated at least 5 minutes.
  • step (a) the first solvent mixture is incubated at about 10 minutes to about 1500 minutes.
  • step (a) the first solvent mixture is incubated at about 30 minutes to about 120 minutes.
  • step (a) is repeated at least once.
  • step (a) is repeated twice.
  • step (a) is repeated 3 times.
  • step (c) the volume of the first solvent mixture is reduced to about 5% to about 50% of the original volume of the first solvent mixture in step (a).
  • 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).
  • 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).
  • step (c) the volume of the first solvent mixture is reduced by evaporation.
  • step (d) the reduced first solvent mixture is incubated at a temperature range of between about -20°C to about 30°C.
  • step (d) the reduced first solvent mixture is incubated at a temperature range of between about 0°C to about 25°C.
  • step (d) the reduced first solvent mixture is incubated at a temperature range of between about 4°C to about 8°C
  • step (d) the reduced first solvent mixture is incubated for a time period of at least 30 minutes, at least 1 hour or at least 2 hours.
  • step (d) the reduced first solvent mixture is incubated for a time period of between 1 hour and 96 hours.
  • step (d) the reduced first solvent mixture is incubated for a time period of between 2 hour and 72 hours.
  • step (d) the reduced first solvent mixture is incubated for a time period of between 4 hour and 48 hours.
  • step (d) the reduced first solvent mixture is incubated for a time period of between 6 hour and 24 hours.
  • step (d) the reduced first solvent mixture is incubated for a time period of between 12 hour and 24 hours.
  • step (d) further comprises seeding the reduced solvent mixture with a cannabinoid.
  • the cannabinoid used to seed the reduced solvent mixture comprises a purified cannabinoid, a partially purified cannabinoid or crude extract comprising a cannabinoid.
  • the second non-polar solvent of step (f) comprises pentane, hexane, heptane, cyclohexane, petroleum ether, dichloromethane, trichloromethane, tethrahydrofurane, diethyl ether, benzene, toluene, ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, butane, propane, refrigeration gas 1 ,1 ,1 ,2-Tetrafluoroethane (R134a), liquid CO2, subcritical CO2 and supercritical CO2.
  • the second non-polar solvent of step (f) comprises pentane, hexane, heptane, cyclohexane, petroleum ether, dichloromethane, trichloromethane, tethrahydrofurane, diethyl ether, benzene, toluene, ethanol,
  • step (f) the second solvent mixture dissolves at least 75% of the one or more crystalized cannabinoids.
  • step (f) the second solvent mixture dissolves at least 85% of the one or more crystalized cannabinoids.
  • step (f) the second solvent mixture dissolves at least 95% of the one or more crystalized cannabinoids.
  • step (f) the second solvent mixture is incubated at a temperature range of between about 30°C to about 60°C.
  • step (f) the second solvent mixture is incubated at a temperature range of between about 40°C to about 50°C.
  • step (f) the second solvent mixture is incubated for a time period of at least 6 minutes.
  • step (f) the second solvent mixture is incubated for a time period of between 0.1 hour and 4 hours.
  • step (g) the second solvent mixture is incubated at a temperature range of between about -20°C to about 30°C.
  • step (g) the second solvent mixture is incubated at a temperature range of between about 0°C to about 25°C.
  • step (g) the second solvent mixture is incubated at a temperature range of between about 4°C to about 8°C
  • step (g) the second solvent mixture is incubated for a time period of at least 6 minutes, at least 1 hour, at least 2 hours, at least 3 hours or at least 4 hours.
  • step (g) the second solvent mixture is incubated for a time period of between 0.1 hour and 96 hours.
  • step (g) the second solvent mixture is incubated for a time period of between 2 hour and 72 hours.
  • step (g) the second solvent mixture is incubated for a time period of between 4 hour and 48 hours.
  • step (g) the second solvent mixture is incubated for a time period of between 6 hour and 24 hours.
  • step (g) the second solvent mixture is incubated for a time period of between 12 hour and 24 hours.
  • step (d) is at most about 4°C for CBGA/CBG purification and step (d) is at most -20°C for CBD purification.
  • step (d) is at most -20°C for CBD purification.
  • the method according to any one of embodiments 72-130 further comprising performing liquid liquid chromatography after one or more of steps (c), (e) or (h).
  • liquidliquid chromatography is counter current chromatography (CCC) or centrifugal partition chromatography (CPC).
  • the stationary phase includes ethanol, methanol, isopropanol, acetone, acetonitrile and/or water.
  • the method according to any one of embodiments 72-136 further comprising performing counter current chromatography (CCC) or centrifugal partition chromatography (CPC) after the steps (e) or (h) to isolate, purify or repurify the cannabinoids tetrahydrocannabinol (THC), tetrahydrocannabidivarin (THCV), tetrahydrocannabinolic acid (THCA), tetrahydrocannabidivarinic acid (THCVA), cannabinol (CBN), cannabivarin (CBV) cannabidiol (CBD), cannabidivarin (CBDV), cannabidiolic acid (CBDA), cannabidivarinic acid (CBDVA), cannabigerol (CBG), cannabigerovarin (CBGV), cannabigerovarinic acid (CBGVA) and cannabigerolic acid (CBGA).
  • CCCC counter current chromatography
  • the chromatography also uses a two phase system pentane:acetonitrile or hexane:acetonitrile with or without ethyl acetate or water as a modifier, at ratios of (10:0:10:0) to (7:3:7:3).
  • the ratio of pentane:acetonitrile is from 10:10 (e.g., pentane:ethyl acetate:acetonitrile:water (10:0: 10:0)) to 7:3:7:3 pentane:ethyl acetate:acetonitrile:water by volume.
  • the ratio of hexane:acetonitrile is from 10:10 (e.g., hexane:ethyl acetate:acetonitrile:water (10:0:10:0)) to 7:3:7:3 hexane:ethyl acetate:acetonitrile:water by volume.
  • Preferred solvent ratios for THC-type cannabinoids are pentane:ethyl acetate: acetonitrile:water at 19:1 :19:1 by volume or 9:1 :9:1 by volume.
  • CBD cannabigerol
  • CBD cannabigerovarin
  • CBD cannabidiol
  • CBD cannabidivarin
  • CBDV cannabivarin
  • CBV cannabinol
  • THCV tetrahydrocannabidivarin
  • THC tetrahydrocannabinol
  • CBD cannabigerol
  • CBD cannabigerovarin
  • CBD cannabidiol
  • CBD cannabidivarin
  • CBDV cannabivarin
  • CBV cannabinol
  • THCV tetrahydrocannabidivarin
  • THC tetrahydrocannabinol
  • a purified cannabinoid produced by the method according to any one of embodiments 72-141 is provided.
  • a pharmaceutical composition comprising a purified cannabinoid produced by the method according to any one of embodiments 72-141.
  • the pharmaceutical composition of embodiment 143 further comprising a pharmaceutically acceptable excipient or carrier.
  • a method of treating a disease or condition comprising administering the cannabinoid produced by the method according to any one of embodiments 72-141 to a subject in need thereof.
  • the method of treating a disease or condition of embodiment 145 wherein the disease or condition is pain, schizophrenia, convulsion, inflammation, anxiety, depression, neurodegenerative disease, stroke, traumatic brain injury, cancer, migraines, arthritis, chronic pain, nausea and vomiting, anorexia, glaucoma, epilepsy, asthma, addiction, symptoms of dependency and withdrawal, multiple sclerosis, spinal cord injury, Tourette’s syndrome, dystonia, or tardive dyskinesia.
  • the method according to any one of embodiments 1-150, wherein the one or more cannabinoids purified is CBGA, CBG, CBGV, CBDA, CBD, CBDV, THCA, THC, THCV or any combination thereof.
  • the method according to embodiments 151 wherein the CBGA has 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 area normalisation of an HPLC profile or by a quantification percent of purity respect a certified commercial standard.
  • CBD, CBDA or CBDV has 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 area normalisation of an HPLC profile or by a quantification percent of purity respect a certified commercial standard.
  • THC, THCA, or THCV has 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 area normalisation of an HPLC profile or by a quantification percent of purity respect a certified commercial standard.
  • composition of embodiment 156, wherein the purified cannabinoid is CBGA or CBGV having 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 area normalisation of an HPLC profile or by a quantification percent of purity respect a certified commercial standard.
  • composition of embodiment 156, wherein the purified cannabinoid is CBG having 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 area normalisation of an HPLC profile or by a quantification percent of purity respect a certified commercial standard.
  • composition of embodiment 156, wherein the purified cannabinoid is THC, THCA or THCV having 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 area normalisation of an HPLC profile or by a quantification percent of purity respect a certified commercial standard.
  • composition of embodiment 156, wherein the purified cannabinoid is CBD, CBDA, or CBDV having 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 area normalisation of an HPLC profile or by a quantification percent of purity respect a certified commercial standard.
  • the use of solvent per run is from 2 L of hexane and 1.4 L of Ethanolic phase.
  • the total solvent used is from 3.4 L per run.
  • the purity of the evaporated fractions was > 95% after recrystallization in petroleum ether (40-60 °C bp) the CBD or after wash or recrystallization in petroleum ether (40-60 °C bp) or hexane from the CBDV.
  • the fraction from minute 32 to 45 contains 0.1 g of a mixture of CBG/CBGV.
  • the purity of the evaporated fractions was > 95% after dryness of the CBGV and after recrystallization in hexane for the CBG.
  • CBGV was easily recrystallized in hexane in order to obtain higher purity.
  • the fraction from minute 35 to 38 contains 0.2g of a mixture of THCA/THC.
  • the purity of the evaporated fractions was > 95% after dryness.
  • THCA can be recrystallized in heptane in order to increase the purity at higher percentages.
  • the use of solvent per run is from 1.250 L of hexane and 0.875 L of Ethanolic phase.
  • the total solvent used is from 2.125 L per run.
  • the fraction from minute 27 to 32 contains 0.1 g of a mixture of THC/THCV.
  • the fraction from minute 40 to 48 contains 0.035 g of CBV.
  • the purity of the evaporated fractions was > 95% after dryness.
  • 0.5 g of the extract was dissolved with hexane at a volume of 5 mL and then used as a sample for injection in the LabPrep CCC (AECS) in the coil of 155 mL and 0.8 mm I.D.
  • AECS LabPrep CCC
  • the complete run last 102 minutes, with 2 phases: run with pumping mobile phase that last 90 minutes and an extrusion phase of 12 minutes.
  • the use of solvent per run is from 0.720 L of hexane and 0.180 L of acetonitrile phase.
  • the total solvent used is from 0.9 L per run.
  • the fraction from minute 59 to 64 contains 0.01 g of a mixture of THC/THCV + CBCV.
  • the fraction from minute 39 to 45 contains 0.04 g of THC + CBC.
  • the purity of the evaporated fractions that contain one cannabinoid was > 95% after dryness.
  • 0.5 g of the extract was dissolved with hexane at a volume of 5 mL and then used as a sample for injection in the LabPrep CCC (AECS) in the coil of 155 mL and 0.8 mm I.D.
  • AECS LabPrep CCC
  • the complete run last 72 minutes, with 2 phases: run with pumping mobile phase that last 60 minutes and an extrusion phase of 12 minutes.
  • the use of solvent per run is from 0.480 L of hexane:ethyl acetate and 0.180 L of acetonitrile : water phase.
  • the total solvent used is from 0.660 L per run.
  • the fraction from minute 38 to 46 contains 0.01 g of a mixture of THC/THCV.
  • the purity of the evaporated fractions that contain one cannabinoid was > 95% after dryness.
  • the flow rate of the mobile phase (hexane: ethyl acetate phase) is 200 mL/min during the run, and changed to 350 mL/min in the extrusion and change of the stationary phase (acetonitrile:water phase).
  • the complete run last 21 minutes, with 2 phases: run with pumping mobile phase that is from 17 minutes and an extrusion phase of 4 minutes.
  • the use of solvent per run is from 3.4 L of hexane:ethyl acetate phase and 1.4 L of acetonitrile:water phase.
  • the total solvent used is from 4.8 L per run.
  • the purity of the evaporated fractions was > 95% after dryness of the THC and > 90% of the THCV.
  • the 14g of extract was purified by 3 runs of CPC obtaining 1.2g of THCV fraction.
  • the starting material is cannabis extract (whatever solvent is used in the production of the extract) and if it is decarboxylated or not, even if it is "winterized” (solved in ethanol, chilled at 4°C or -20°C and filtered from the precipitated material) or not.
  • the open-ended transitional term“comprising” (and equivalent open-ended transitional phrases thereof like including, containing and having) encompasses all the expressly recited elements, limitations, steps and/or features alone or in combination with unrecited subject matter; the named elements, limitations and/or features are essential, but other unnamed elements, limitations and/or features may be added and still form a construct within the scope of the claim.
  • the meaning of the open-ended transitional phrase “comprising” is being defined as encompassing all the specifically recited elements, limitations, steps and/or features as well as any optional, additional unspecified ones.
  • the meaning of the closed-ended transitional phrase“consisting of is being defined as only including those elements, limitations, steps and/or features specifically recited in the claim whereas the meaning of the closed-ended transitional phrase“consisting essentially of is being defined as only including those elements, limitations, steps and/or features specifically recited in the claim and those elements, limitations, steps and/or features that do not materially affect the basic and novel characteristic(s) of the claimed subject matter.
  • the open-ended transitional phrase“comprising” (and equivalent open-ended transitional phrases thereof) includes within its meaning, as a limiting case, claimed subject matter specified by the closed-ended transitional phrases“consisting of or“consisting essentially of.”
  • embodiments described herein or so claimed with the phrase“comprising” are expressly or inherently unambiguously described, enabled and supported herein for the phrases“consisting essentially of and “consisting of.”
  • All patents, patent publications, and other publications referenced and identified in the present 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 might be used in connection with the present invention.

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Abstract

La présente invention concerne des procédés de purification d'un ou de plusieurs cannabinoïdes à partir d'un matériau végétal à l'aide de systèmes de solvants biphasiques uniques et d'une chromatographie liquide-liquide comme la chromatographie de séparation par centrifugation (CPC) ou la chromatographie à contre-courant (CCC). La présente invention concerne également des cannabinoïdes purifiés tels que CBG, CBGA, CBGV, CBD, CBDA, CBDV, THC, THCA et THCV, des compositions comprenant un ou plusieurs de ces cannabinoïdes produits par le procédé selon l'invention, et des méthodes de traitement d'une maladie ou d'un état pathologique utilisant de tels cannabinoïdes purifiés et compositions.
PCT/EP2019/052069 2018-01-29 2019-01-29 Procédés de purification de cannabinoïdes par chromatographie liquide : liquide WO2019145552A1 (fr)

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CA3089490A CA3089490A1 (fr) 2018-01-29 2019-01-29 Procedes de purification de cannabinoides par chromatographie liquide : liquide
EP19702843.4A EP3746419A1 (fr) 2018-01-29 2019-01-29 Procédés de purification de cannabinoïdes par chromatographie liquide : liquide
CN201980015943.2A CN111788171A (zh) 2018-01-29 2019-01-29 使用液：液色谱法纯化大麻素的方法
IL276010A IL276010A (en) 2018-01-29 2020-07-13 Methods for purifying cannabinoids using liquid:liquid chromatography
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US11986505B2 (en) 2021-10-26 2024-05-21 Ecofibre USA Inc. Methods of treating endometriosis and other noncancer gynecological disorders with hemp extract
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CN110590511A (zh) * 2019-09-11 2019-12-20 上海同田生物技术股份有限公司 一种同时分离次大麻二酚和大麻萜酚的方法
WO2021047491A1 (fr) * 2019-09-11 2021-03-18 上海同田生物技术有限公司 Procédé de séparation simultanée de cannabidivarine et de cannabigérol
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US11986505B2 (en) 2021-10-26 2024-05-21 Ecofibre USA Inc. Methods of treating endometriosis and other noncancer gynecological disorders with hemp extract
US12102657B2 (en) 2021-10-26 2024-10-01 Ecofibre USA Inc. Systems and methods for producing hemp extracts and compositions
US12011451B2 (en) 2022-10-26 2024-06-18 Ecofibre USA Inc. Stabilized compositions comprising cannabidiol
US12097211B2 (en) 2022-10-26 2024-09-24 Ecofibre USA Inc. Methods of treating estrogen sensitive diseases with cannabis extract
FR3146813A1 (fr) * 2023-03-24 2024-09-27 Gilson Purification Procédés de séparation et de purification d'un composé organique contenu dans une matière d'origine naturelle
EP4442344A1 (fr) 2023-03-24 2024-10-09 Gilson Purification Procédés de séparation et de purification d'un composé organique contenu dans une matière d'origine naturelle

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