Compositions and Methods to Separate Cannabinoids from Impurities by Crystallization

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application claims priority to United States Provisional Patent Application No. 63/056,314, filed July 24, 2020, and United States Provisional Patent Application No. 63/059,830, filed July 31, 2020, each of which is incorporated by reference in its entirety.

BACKGROUND

Industrial hemp biosynthetically produces a number of different cannabinoids. Cannabinoids can be isolated using flash chromatography, high-performance liquid chromatography, centrifugal partition chromatography, and crystallization in pentane. Each method requires hydrocarbon solvents, however, which are both expensive and limit the ability to obtain organic certification on finished consumer products. Separation methods that reduce the need for hydrocarbon solvents and allow organic certification remain desirable.

BRIEF DESCRIPTION

Cannabidiol can be crystallized in pentane to purify cannabidiol from hemp extracts. Pentane can detonate, however, which requires precautions that increase expense, and pentane is incompatible with organic certification. Various aspects of this disclosure relate to the discovery that selected cannabinoids can be crystallized in commercially-viable processes without pentane.

The cannabidiol of an industrial hemp distillate can at least partially crystallize in the relative absence of alkanes. The high viscosity of liquid impurities such as cannabichromene and tetrahydrocannabinol and the relative density of crystalline cannabidiol and liquid impurities nevertheless confound the separation of crystalline cannabidiol from impurities. High viscosity also inhibits crystallization because high viscosity inhibits the movement of liquid-phase cannabidiol toward a growing crystal. Alcohols such as ethanol can be added to a distillate to reduce viscosity and adjust relative density. Alcohols can also dissolve crystalline cannabidiol, however, which can confound the separation. Alternative liquids can therefore be either added to or substituted for an alcohol to reduce viscosity and/or reduce the dissolution of crystalline cannabidiol. Water and glycerol, for example, can both reduce viscosity and reduce the ability of a liquid phase to dissolve cannabidiol. Water and glycerol also reduce the ability of a water-miscible liquid to dissolve impurities, however, which can result in a water-immiscible liquid. When the density of a water- miscible liquid is either greater than or less than the densities of both crystalline cannabidiol and a water-immiscible liquid, then crystalline cannabidiol and the water-immiscible liquid can contact each other, and the relatively high viscosity of the water-immiscible liquid can confound separation. The density of a water-miscible liquid can be increased, for example, by increasing its water concentration, glycerol concentration, propylene glycol concentration, propane-1, 3-diol concentration, ionic strength, metal cation concentration, or anion concentration to allow for the separation of crystalline cannabidiol from a liquid phase. A liquid phase can therefore be separated from crystalline cannabidiol by adjusting density. Mixing a water-immiscible liquid in a water- miscible liquid, for example, can be used to produce a suspension of crystalline cannabidiol in a liquid phase. The temperature of a composition can also be increased to reduce viscosity and increase the ability of a liquid phase to dissolve impurities, but increasing temperature may also increase the ability of the liquid phase to dissolve crystalline cannabidiol. Decreasing temperature decreases the ability of a liquid phase to dissolve crystalline cannabidiol at the expense of increased viscosity and a decreased ability of the liquid phase to dissolve impurities. Accordingly, cannabidiol can be separated from impurities by crystallization upon optimizing one or more parameters as described in this disclosure.

The compositions and methods of this disclosure are generally applicable to cannabidiol, cannabigerol, and alkyl-chain variants of cannabidiol and cannabigerol in which the pentyl group of cannabidiol or cannabigerol is substituted with methyl, ethyl, propyl, butyl, hexyl, heptyl, or 2- phenyl ethyl.

BRIEF DESCRIPTION OF THE DRAWING

The Figure is a grayscale photograph of cannabidiol crystals obtained using methods disclosed in the following detailed description.

DETAILED DESCRIPTION

Various aspects of this patent document relate to a composition, comprising a cannabinoid, an impurity, a liquid phase, and a solid phase, in which: the cannabinoid has the molecular formula C _x H _y O2 ; the impurity has the molecular formula C _X H _Z O2 ; “x” is at least 17 and no greater than 24; “y” is at least 22 and no greater than 36; “z” is at least 22 and no greater than 34; the cannabinoid and the impurity each comprise an alkyl; the alkyl of the cannabinoid is identical to the alkyl of the impurity; the alkyl is either methyl, propyl, pentyl, heptyl, or 2 -phenyl ethyl; the cannabinoid is either (i) 2-[(lR,6R)-6-isopropenyl-3-methylcyclohex-2-en-l-yl]-5-alkyl benzene-l, 3-diol, and “z” equals “y” minus either 0, 2, or 4, or (ii) 2-[(2E)-3,7-dimethylocta-2,6-diene-l-yl]-5-alkylbenzene- 1, 3-diol, and “z” equals “y” minus either 2, 4, or 6; the impurity comprises a 1 chromene ring that either (i) comprises exactly 4 substituents that consist of a 2-methyl substituent; a 2-(4-methylpent- 3-en-l-yl) substituent; a 5 -hydroxy substituent; and a 7-alkyl substituent that is the alkyl of the impurity, in which “z” equals “y” minus either 0 or 2 or (ii) is the chromene of a benzo[c]chromene ring that comprises exactly 5 substituents that consist of a 1 -hydroxy substituent; a 3-alkyl substituent that is the alkyl of the impurity; two 6-methyl substituents; and a 9-methyl substituent, in which “z” equals “y” minus either 0, 2, 4, or 6; the composition comprises the cannabinoid and the impurity at a ratio of at least 3 : 1 and no greater than 333 : 1 by mass; the liquid phase consists of one or more liquids; the liquid phase has an average density of at least 770 and no greater than 1260 grams per liter; the liquid phase comprises greater than 50 percent of the impurity of the composition by mass; the liquid phase is in both physical and chemical communication with the solid phase such that the physical and chemical properties of the composition control the extent to which the cannabinoid partitions between the liquid phase and the solid phase; the solid phase consists of one or more solids; the solid phase comprises greater than 50 percent of the cannabinoid of the composition by mass; the solid phase comprises a crystal phase that consists of one or more crystals; the crystal phase comprises at least 90 percent of the cannabinoid of the solid phase by mass; the crystal phase comprises the cannabinoid at a concentration of at least 90 percent by mass; the composition comprises the liquid phase and the crystal phase at a ratio of at least 1:10 and no greater than 20:1 by mass; and the composition lacks molecules that comprise at least 5 carbon atoms and no greater than 16 carbon atoms at a concentration greater than 20 percent by mass.

“Comprising” and “comprise” refer to open sets. A composition that comprises a cannabinoid, an impurity, a liquid phase, and a solid phase can also comprise, for example, ethanol.

“Consist” refers to a closed set. A liquid phase that consists of one or more liquids cannot comprise, for example, a solid.

In some embodiments, the composition comprises the cannabinoid and the impurity at a ratio of at least 10:1 by mass.

In some embodiments, the liquid phase comprises at least 90 percent of the impurity of the composition by mass.

In some embodiments, the solid phase comprises at least 90 percent of the cannabinoid of the composition by mass.

In some embodiments, the crystal phase comprises at least 90 percent of the cannabinoid of the composition by mass.

In some embodiments, the composition comprises the liquid phase and the crystal phase at a ratio of no greater than 10: 1 by mass.

In some embodiments, the composition lacks molecules that comprise at least 5 carbon atoms and no greater than 16 carbon atoms at a concentration greater than 5 percent by mass; and the molecules that comprise at least 5 carbon atoms and no greater than 16 carbon atoms include, but are not limited to, n-pentane; n-hexane; n-heptane; n-octane; n-nonane; n-decane; n-undecane; n- dodecane; n-tridecane; n-tetradecane; n-pentadecane; n-hexadecane; 3,6-dimethyl-tridecane; 2,6- dimethyl-tetradecane; beta-caryophyllene; humulene; limonene; myrcene; ocimene; pinene; terpinolene; bisabolol; eucalyptol; guaiol; nerolidol; and linalool.

In some embodiments, the composition lacks n-pentane, n-hexane, n-heptane, n-octane, n-nonane, n-decane, n-undecane, n-dodecane, n-tridecane, n-tetradecane, n-pentadecane, n-hexadecane, 3,6- dimethyl-tridecane, 2,6-dimethyl-tetradecane, beta-caryophyllene, humulene, limonene, myrcene, ocimene, pinene, terpinolene, bisabolol, eucalyptol, guaiol, nerolidol, and linalool at a combined concentration greater than 5 percent by mass.

In some embodiments, the one or more liquids of the liquid phase comprise a water-miscible liquid that is miscible with water.

In some embodiments, the water-miscible liquid comprises water. In some specific embodiments, the water-miscible liquid comprises water at a concentration of at least 1 molar.

In some embodiments, the water-miscible liquid comprises an alcohol. In some specific embodiments, the water-miscible liquid comprises the alcohol at a concentration of at least 10 percent and no greater than 95 percent by mass.

In some embodiments, the alcohol is methanol, ethanol, or isopropanol. In some specific embodiments, the alcohol is ethanol.

In some embodiments, the water-miscible liquid comprises glycerol. In some specific embodiments, the water-miscible liquid comprises the glycerol at a concentration of at least 5 percent and no greater than 80 percent by mass.

In some embodiments, the water-miscible liquid comprises either one or both of propylene glycol and propane-1, 3-diol.

In some embodiments, the water-miscible liquid has an ionic strength of no greater than 200 millimolar.

In some embodiments, the water-miscible liquid has an ionic strength of at least 2 millimolar.

In some embodiments, the water-miscible liquid comprises a metal cation, and the metal cation is dissolved in the water-miscible liquid. In some specific embodiments, the metal cation is sodium cation. In some specific embodiments, the metal cation is potassium cation.

In some embodiments, the water-miscible liquid comprises the metal cation at a concentration of at least 100 micrograms per liter.

In some embodiments, the water-miscible liquid comprises an anion, and the anion is dissolved in the water-miscible liquid. In some specific embodiments, the anion is chloride, fluoride, bicarbonate, sulfate, or dihydrogen phosphate.

In some embodiments, the water-miscible liquid comprises the anion at a concentration of at least 100 micrograms per liter.

In some embodiments, the liquid phase comprises the water-miscible liquid at a concentration of at least 90 percent by mass.

In some embodiments, the one or more liquids of the liquid phase comprise a water-immiscible liquid that is not miscible with water.

In some embodiments, the water-miscible liquid has a density; the water-immiscible liquid has a density; and the density of the water-miscible liquid is greater than the density of the water- immiscible liquid.

In some embodiments, the water-miscible liquid has a density; the water-immiscible liquid has a density; and the difference between the density of the water-miscible liquid and the density of the water-immiscible liquid is no greater than plus or minus 200 grams per liter.

In some embodiments, the water-miscible liquid has a density; the water-immiscible liquid has a density; the solid phase has a density; and the density of the solid phase is greater than the density of the water-immiscible liquid.

In some embodiments, the water-immiscible liquid comprises 1, 2, 3, 4, 5, or each of (2R)-2- methyl-2-(4-methylpent-3-en-l-yl)-5-hydroxy-7-alkyl-2H-l-ben zopyran; (2S)-2-methyl-2-(4- methylpent-3-en- 1 -yl)-5-hydroxy-7-alkyl-2H- 1 -benzopyran; (6aR, 10aR)-6,6,9-trimethyl-3-alkyl- 6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-l-ol; 6,6,9-trimethyl-3-alkyl-6H-benzo[c]chromen-l- ol; (6aR,10aR)-6,6,9-trimethyl-3-alkyl-6a,7,10,10a-tetrahydro-6H -benzo[c]chromen-l-ol; and (6aS,10aR)-6,6,9-trimethyl-3-alkyl-6a,7,8,10a-tetrahydro-6H- benzo[c]chromen-l-ol. In some specific embodiments, the water-immiscible liquid comprises 1, 2, 3, 4, 5, or each of (2R)-2- methyl-2-(4-methylpent-3-en-l-yl)-5-hydroxy-7-pentyl-2H-l -benzopyran; (2S)-2-methyl-2-(4- methylpent-3-en- 1 -yl)-5-hydroxy-7-pentyl-2H- 1 -benzopyran; (6aR, 10aR)-6,6,9-trimethyl-3-pentyl- 6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-l-ol; 6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-l- ol; (6aR, 10aR)-6,6,9-trimethyl-3-pentyl-6a,7, 10, 10a-tetrahydro-6H-benzo[c]chromen-l-ol; and (6aS,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H -benzo[c]chromen-l-ol. In some specific embodiments, the water-immiscible liquid comprises 1, 2, 3, 4, 5, or each of (2R)-2- methyl-2-(4-methylpent-3-en-l-yl)-5-hydroxy-7-propyl-2H-l-be nzopyran; (2S)-2-methyl-2-(4- methylpent-3-en-l-yl)-5-hydroxy-7-propyl-2H-l-benzopyran; (6aR,10aR)-6,6,9-trimethyl-3- propyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-l-ol; 6,6,9-trimethyl-3-propyl-6H- benzo[c]chromen-l-ol; (6aR,10aR)-6,6,9-trimethyl-3-propyl-6a,7,10,10a-tetrahydro-6 H- benzo[c]chromen-l-ol; and (6aS, 10aR)-6,6,9-trimethyl-3-propyl-6a,7,8, 10a-tetrahydro-6H- benzo[c]chromen-l-ol.

In some embodiments, the water-immiscible liquid has a viscosity of at least 0.5 millipascal- seconds and no greater than 2 pascal-seconds.

In some embodiments, the solid phase has a density; and the density of the solid phase is at least 900 grams per cubic decimeter.

In preferred embodiments, the one or more crystals are thermodynamically stable relative to dissolution into the liquid phase.

In some embodiments, the cannabinoid is 2-[(lR,6R)-6-isopropenyl-3-methylcyclohex-2-en-l- yl]-5-alkylbenzene-l,3-diol.

In some embodiments, the cannabinoid is 2-[(2E)-3,7-dimethylocta-2,6-diene-l-yl]-5- alkylbenzene- 1 ,3 -diol .

In some embodiments, the impurity is (2R)-2-methyl-2-(4-methylpent-3-en-l-yl)-5-hydroxy-7- alkyl-2H- 1 -benzopyran or (2S)-2-methyl-2-(4-methylpent-3 -en- 1 -yl)-5-hydroxy-7-alkyl-2H- 1 - benzopyran.

In some embodiments, the impurity is (6aR,10aR)-6,6,9-trimethyl-3-alkyl-6a,7,8,10a-tetrahydro- 6H-benzo[c]chromen- 1 -ol .

In some embodiments, the impurity is (6aS,10aR)-6,6,9-trimethyl-3-alkyl-6a,7,8,10a-tetrahydro- 6H-benzo[c]chromen- 1 -ol .

In some specific embodiments, alkyl is propyl.

In some specific embodiments, alkyl is pentyl.

In some embodiments, the cannabinoid is 2-[(lR,6R)-6-isopropenyl-3-methylcyclohex-2-en-l- yl]-5-propylbenzene- 1 ,3 -diol .

In some embodiments, the cannabinoid is 2-[(lR,6R)-6-isopropenyl-3-methylcyclohex-2-en-l- yl] -5 -pentylbenzene- 1 , 3 -diol .

In some embodiments, the cannabinoid is 2-[(2E)-3,7-dimethylocta-2,6-diene-l-yl]-5- propylbenzene- 1 ,3 -diol .

In some embodiments, the cannabinoid is 2-[(2E)-3,7-dimethylocta-2,6-diene-l-yl]-5- pentylbenzene- 1 ,3 -diol .

In some embodiments, the impurity is (2R)-2-methyl-2-(4-methylpent-3-en-l-yl)-5-hydroxy-7- propyl-2H-l-benzopyran or (2S)-2-methyl-2-(4-methylpent-3-en-l-yl)-5-hydroxy-7-propyl- 2H-l- benzopyran.

In some embodiments, the impurity is (6aR,10aR)-6,6,9-trimethyl-3-propyl-6a,7,8,10a- tetrahydro-6H-benzo[c]chromen-l-ol.

In some embodiments, the impurity is (6aS,10aR)-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydro- 6H-benzo[c]chromen- 1 -ol .

In some embodiments, the impurity is (2R)-2-methyl-2-(4-methylpent-3-en-l-yl)-5-hydroxy-7- pentyl-2H-l -benzopyran or (2S)-2-methyl-2-(4-methylpent-3-en- 1 -yl)-5-hydroxy-7-pentyl-2H- 1 - benzopyran.

In some embodiments, the impurity is (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro- 6H-benzo[c]chromen- 1 -ol .

In some embodiments, the impurity is (6aS,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro- 6H-benzo[c]chromen- 1 -ol .

In some specific embodiments, “z” equals “y”.

In some specific embodiments, “z” equals “y” minus 2.

Various aspects of this disclosure relate to a method to purify a cannabinoid, comprising (i) providing a composition as described anywhere in the preceding description or in priority United States Patent Application No. 63/056,314, and (ii) separating the solid phase of the composition and the liquid phase of the composition to purify the cannabinoid.

Various aspects of this disclosure relate to a method to purify a cannabinoid, comprising (i) crystallizing a cannabinoid to produce a composition as described anywhere in the preceding description or in priority United States Patent Application No. 63/056,314, and (ii) separating the solid phase of the composition and the liquid phase of the composition to purify the cannabinoid.

In some embodiments, the separating is performed by filtering the composition.

In some embodiments, the separating is performed by centrifuging the composition.

In some embodiments, the separating is performed by decanting the composition.

In some embodiments, the separating is performed by stratifying the composition into layers and then mechanically separating a layer comprising a majority of the solid phase from a layer comprising a majority of the liquid phase.

Various aspects of this patent document relate to a method to produce cannabinoid crystals, comprising: (a) providing a precursor composition that comprises (i) a precursor, (ii) contaminant precursors, (iii) original lipids, and (iv) original organic matter, wherein: either (i) the precursor is cannabidiolic acid, and the contaminant precursors consist of tetrahydrocannabinolic acid and cannabichromenic acid, or (ii) the precursor is cannabidivarnic acid, and the contaminant precursors consist of tetrahydrocannabivarin acid and cannabichromevarin acid; the original lipids consist of one or more of n-nonane; n-decane; n-undecane; n-dodecane; n-tridecane; n-tetradecane; n- pentadecane; n-hexadecane; n-heptadecane; n-octadecane; n-nonadecane; n-icosane; n-heneicosane; n-docosane; n-tricosane; n-tetracosane; n-pentacosane; n-hexacosane; n-heptacosane; n-octacosane; n-nonacosane; n-triacontane; n-hentriacontane; n-dotriacontane; 3,6-dimethyl-tridecane; 2,6- dimethyl-tetradecane; 2,6-dimethyl-hexadecane; 3,6-dimethyl-heptadecane; 3,7-dimethyl- heptadecane; 3,6-dimethyl-octadecane; 3,7-dimethyl-octadecane; 3-methyl-heneicosane; 3-methyl- tricosane; 2-methyl-tetracosane; 3-methyl-pentacosane; 2-methyl-hexacosane; 3-methyl- heptacosane; and 3-methyl-triacontane; the original organic matter consists of plant-derived molecules and ions that do not vaporize at any temperature of less than 235 degrees Celsius at atmospheric pressure; and the precursor composition comprises the precursor at a concentration of at least 4 percent by mass; (b) heating the precursor composition to produce a decarboxyl ated composition that comprises (i) a cannabinoid, (ii) contaminants, (iii) lipids, and (iv) organic matter, wherein: the heating converts at least 90 percent of the precursor into (i) the cannabinoid and (ii) carbon dioxide by mole of the precursor; either (i) the precursor is cannabidiolic acid, and the cannabinoid is cannabidiol, or (ii) the precursor is cannabidivarnic acid, and the cannabinoid is cannabidivarin; the heating converts at least 90 percent of the contaminant precursors into (i) the contaminants and (ii) carbon dioxide by mole of the contaminant precursors; either (i) the contaminant precursors consist of tetrahydrocannabinolic acid and cannabichromenic acid, and the contaminants consist of tetrahydrocannabinol and cannabichromene, or (ii) the contaminant precursors consist of tetrahydrocannabivarin acid and cannabichromevarin acid, and the contaminants consist of tetrahydrocannabivarin and cannabichromevarin; the lipids consist of a portion of the original lipids that survive the heating; and the organic matter consists of a portion of the original organic matter that survives the heating; (c) combining a portion of the decarboxyl ated composition with ethanol to produce a dewaxing composition that comprises (i) ethanol, (ii) a portion of the cannabinoid of the decarboxyl ated composition, (iii) a portion of the contaminants of the decarboxylated composition, (iv) a portion of the lipids of the decarboxyl ated composition, and

(v) a portion of the organic matter of the decarboxylated composition, wherein: the portion of the decarboxylated composition comprises the cannabinoid at a concentration of at least 30 percent and no greater than 80 percent by mass; the portion of the decarboxylated composition comprises the cannabinoid and the contaminants at a ratio of at least 3 : 1 and no greater than 80: 1 by mass; the portion of the decarboxylated composition comprises the cannabinoid and the lipids at a concentration of at least 1 :2 and no greater than 40: 1 by mass; the portion of the decarboxylated composition comprises the cannabinoid and the organic matter at a concentration of at least 1 :2 and no greater than 40: 1 by mass; and the dewaxing composition comprises the ethanol at a concentration of at least 20 percent and no greater than 90 percent by mass; (d) cooling a portion of the dewaxing composition to produce a mixture that comprises (i) a portion of the ethanol of the dewaxing composition, (ii) a portion of the cannabinoid of the dewaxing composition, (iii) a portion of the contaminants of the dewaxing composition, (iv) a portion of the lipids of the dewaxing composition, and (v) a portion of the organic matter of the dewaxing composition, wherein: the mixture comprises a solid phase and a liquid phase; the cooling converts at least 65 percent of the portion of the lipids of the dewaxing composition into solid-phase lipids by mass such that the solid phase of the mixture comprises at least 65 percent of the lipids of the mixture by mass; the liquid phase comprises at least 90 percent of the ethanol of the mixture by mass; the liquid phase comprises at least 90 percent of the cannabinoid of the mixture by mass; the liquid phase comprises at least 90 percent of the contaminants of the mixture by mass; and the liquid phase comprises at least a portion of the organic matter of the mixture; (e) separating a portion of the liquid phase from the solid phase to produce a dewaxed composition that comprises (i) a portion of the ethanol of the liquid phase, (ii) a portion of the cannabinoid of the liquid phase, (iii) a portion of the contaminants of the liquid phase, and (iv) a portion of the organic matter of the liquid phase; (f) separating ethanol from a portion of the dewaxed composition to produce a concentrate composition that comprises (i) a portion of the cannabinoid of the dewaxed composition, (ii) a portion of the contaminants of the dewaxed composition, and (iii) a portion of the organic matter of the dewaxed composition, wherein the separating is performed by vaporizing ethanol from the portion of the dewaxed composition such that the concentrate composition lacks ethanol at a concentration greater than 20 percent by mass; (g) heating a portion of the concentrate composition to produce a vapor phase and residual organic matter, wherein: the portion of the concentrate composition comprises the cannabinoid and the contaminants at a combined concentration of at least 40 percent and no greater than 85 percent by mass; the vapor phase comprises (i) a portion of the cannabinoid of the concentrate composition and (ii) a portion of the contaminants of the concentrate composition; the residual organic matter comprises a portion of the organic matter of the concentrate composition; and the residual organic matter consists of one or both of a solid and a liquid; (h) separating a portion of the vapor phase from the residual organic matter to produce a distillate that comprises (i) a portion of the cannabinoid of the vapor phase, and (ii) a portion of the contaminants of the vapor phase; (i) condensing a portion of the distillate into a condensed phase that comprises (i) a portion of the cannabinoid of the distillate, and (ii) a portion of the contaminants of the distillate, wherein: the condensed phase comprises the cannabinoid at a concentration of at least 70 percent and no greater than 90 percent by mass; and the condensed phase comprises the contaminants at a concentration of at least 1 percent and no greater than 20 percent by mass; (j) combining a portion of the condensed phase and ethanol to produce a crystallization composition that comprises (i) ethanol, (ii) a portion of the cannabinoid of the condensed phase, and (iii) a portion of the contaminants of the condensed phase; (k) incubating a portion of the crystallization composition at a crystallization temperature to produce crystals and residual liquid, wherein: the cannabinoid has both a concentration and a solubility in the portion of the crystallization composition, and the crystallization temperature is a temperature at which the concentration is greater than the solubility; the crystals comprise a portion of the cannabinoid of the crystallization composition; and the residual liquid comprises a portion of the ethanol of the crystallization composition and a portion of the contaminants of the crystallization composition; (1) separating a portion of the crystals from the residual liquid to produce a product, wherein: the product comprises the cannabinoid at a concentration of at least 90 percent by mass; the product lacks the contaminants at a concentration of greater than 0.3 percent by mass; the product lacks the lipids at a concentration of greater than 1 percent by mass; the product lacks the organic matter at a concentration greater than 1 percent by mass; and the crystals are solids that have a melting point.

The term “portion” can include any amount greater than 0 percent, including 100 percent. The phrase “portion of the original lipids that survive the heating,” for example, refers to 100 percent of the original lipids when all of the original lipids survive the heating. The phrase “a portion of the lipids similarly refers to a percentage of the lipids that is greater than 0 percent, including 100 percent (and not, for example, a portion of species of lipids).

Various aspects of this patent document relate to a method to produce cannabinoid crystals from a decarboxyl ated cannabinoid extract, comprising: (i) combining (a) a starting composition comprising a decarboxylated cannabinoid extract and (b) a solubility -regulating composition to produce a heterogeneous composition, in which: the starting composition comprises ethanol, a cannabinoid, and a second molecule; the cannabinoid is cannabidiol, cannabidivarin, cannabigerol, or cannabigerovarin; the ethanol is a solvent of the starting composition; the cannabinoid is a solute that is dissolved in the ethanol of the starting composition; the second molecule is a solute that is dissolved in the ethanol of the starting composition; the solubility-regulating composition comprises water; the heterogeneous composition comprises an aqueous phase and a lipid phase; the aqueous phase of the heterogeneous composition comprises at least 95 percent of the water of the heterogeneous composition; the aqueous phase of the heterogeneous composition comprises at least 95 percent of the ethanol of the heterogeneous composition; the second molecule has a solubility in the aqueous phase that is less than 10 grams per liter; the lipid phase comprises greater than 65 percent of the second molecule of the heterogeneous composition; the cannabinoid has a solubility in the aqueous phase that is greater than 10 grams per liter; and the aqueous phase comprises greater than 65 percent of the cannabinoid of the heterogeneous composition; (ii) separating the aqueous phase and the lipid phase to separate the cannabinoid and the second molecule; and (iii) separating the cannabinoid from both (a) at least 95 percent of the water of the aqueous phase and (b) at least 95 percent of the ethanol of the aqueous phase to produce a product, in which: the product consists essentially of the molecules of the aqueous phase that are separated from (a) the at least 95 percent of the water of the aqueous phase and (b) the at least 95 percent of the ethanol of the aqueous phase; the product lacks the second molecule at a concentration greater than 0.3 percent by mass; the product comprises crystals; the crystals comprise the cannabinoid at a concentration greater than 50 percent by mass; and the crystals are solids that have a melting point.

Various aspects of this patent document relate to a method to produce cannabinoid crystals from a decarboxylated cannabinoid extract, comprising: (i) combining (a) a starting composition comprising a decarboxylated cannabinoid extract and (b) a solubility -regulating composition to produce a heterogeneous composition, in which: the starting composition comprises a cannabinoid and a second molecule; the cannabinoid is cannabidiol, cannabidivarin, cannabigerol, or cannabigerovarin; the solubility -regulating composition comprises water; the heterogeneous composition comprises ethanol and the water; the heterogeneous composition comprises an aqueous phase and a lipid phase; the aqueous phase of the heterogeneous composition comprises at least 95 percent of the water of the heterogeneous composition; the aqueous phase of the heterogeneous composition comprises at least 95 percent of the ethanol of the heterogeneous composition; the second molecule has a solubility in the aqueous phase that is less than 10 grams per liter; the lipid phase comprises greater than 65 percent of the second molecule of the heterogeneous composition; the cannabinoid has a solubility in the aqueous phase that is greater than 10 grams per liter; and the aqueous phase comprises greater than 65 percent of the cannabinoid of the heterogeneous composition; (ii) separating the aqueous phase and the lipid phase to separate the cannabinoid and the second molecule; and (iii) separating the cannabinoid from both (a) at least 95 percent of the water of the aqueous phase and (b) at least 95 percent of the ethanol of the aqueous phase to produce a product, in which: the product consists essentially of the molecules of the aqueous phase that are separated from (a) the at least 95 percent of the water of the aqueous phase and (b) the at least 95 percent of the ethanol of the aqueous phase; the product lacks the second molecule at a concentration greater than 0.3 percent by mass; the product comprises crystals; the crystals comprise the cannabinoid at a concentration greater than 50 percent by mass; and the crystals are solids that have a melting point.

In some embodiments, the method comprises heating a cannabinoid extract to decarboxylate the cannabinoid extract and produce the decarboxyl ated cannabinoid extract.

In some embodiments, the method comprises dissolving the decarboxyl ated cannabinoid extract in the ethanol to produce the starting composition.

In some embodiments, the second molecule is n-nonane; n-decane; n-undecane; n-dodecane; n- tridecane; n-tetradecane; n-pentadecane; n-hexadecane; n-heptadecane; n-octadecane; n- nonadecane; n-icosane; n-heneicosane; n-docosane; n-tricosane; n-tetracosane; n-pentacosane; n- hexacosane; n-heptacosane; n-octacosane; n-nonacosane; n-triacontane; n-hentriacontane; or n- dotriacontane.

In some embodiments, the second molecule is 3,6-dimethyl-tridecane; 2,6-dimethyl-tetradecane; 2,6-dimethyl-hexadecane; 3,6-dimethyl-heptadecane; 3,7-dimethyl-heptadecane; 3,6-dimethyl- octadecane; 3,7-dimethyl-octadecane; 3-methyl-heneicosane; 3-methyl-tricosane; 2-methyl- tetracosane; 3-methyl-pentacosane; 2-methyl-hexacosane; 3-methyl-heptacosane; or 3-methyl- triacontane.

In some embodiments, the second molecule is beta-caryophyllene or humulene.

In some embodiments, the second molecule is limonene, myrcene, ocimene, pinene, or terpinolene.

In some embodiments, the second molecule is bisabolol, eucalyptol, guaiol, nerolidol, or linalool.

In some very specific embodiments, the cannabinoid is cannabigerol, and the second molecule is beta-caryophyllene.

In some embodiments, separating the aqueous phase and the lipid phase to separate the cannabinoid and the second molecule comprises filtering the heterogeneous composition.

In some embodiments, separating the aqueous phase and the lipid phase to separate the cannabinoid and the second molecule comprises centrifuging the heterogeneous composition.

In some embodiments, separating the cannabinoid from both (a) the at least 95 percent of the water of the aqueous phase and (b) the at least 95 percent of the ethanol of the aqueous phase comprises combining the aqueous phase and a second solubility-regulating composition to (i) drive a portion of the cannabinoid of the aqueous phase out of the aqueous phase and (ii) produce a second heterogeneous composition; the second heterogeneous composition comprises a residual aqueous phase and a second lipid phase; the residual aqueous phase is a liquid; the residual aqueous phase comprises greater than 95 percent of the ethanol of the second heterogeneous composition; the residual aqueous phase comprises greater than 95 percent of the water of the second heterogeneous composition; the cannabinoid of the second heterogeneous composition has a solubility in the residual aqueous phase that is less than 10 grams per liter; the second lipid phase comprises greater than 80 percent of the cannabinoid of the second heterogeneous composition; the separation of the cannabinoid from both (a) the at least 95 percent of the water of the aqueous phase and (b) the at least 95 percent of the ethanol of the aqueous phase further comprises mechanically separating the residual aqueous phase of the second heterogeneous composition from the second lipid phase of the second heterogeneous composition; and the product consists essentially of the portion of the second lipid phase that is mechanically separated from the residual aqueous phase.

In some embodiments, the method is performed in compliance with the United States Organic Foods Production Act. In some embodiments, the method further comprises obtaining organic certification of the method under the United States Organic Foods Production Act.

The following exemplification sets forth specific embodiments that do not limit the preceding disclosure or any claim that matures from this patent document.

EXEMPLIFICATION

Example 1. Method to produce a composition of the disclosure from industrial hemp.

A precursor composition is provided, which consists of ground industrial hemp. The precursor composition comprises (i) a precursor, which consists of cannabidiolic acid, (ii) contaminant precursors, which consist of tetrahydrocannabinolic acid and cannabichromenic acid, (iii) original lipids, which consist of one or more of n-nonane; n-decane; n-undecane; n-dodecane; n-tridecane; n-tetradecane; n-pentadecane; n-hexadecane; n-heptadecane; n-octadecane; n-nonadecane; n- icosane; n-heneicosane; n-docosane; n-tricosane; n-tetracosane; n-pentacosane; n-hexacosane; n- heptacosane; n-octacosane; n-nonacosane; n-triacontane; n-hentriacontane; n-dotriacontane; 3,6- dimethyl-tridecane; 2,6-dimethyl-tetradecane; 2,6-dimethyl-hexadecane; 3,6-dimethyl-heptadecane; 3,7-dimethyl-heptadecane; 3,6-dimethyl-octadecane; 3,7-dimethyl-octadecane; 3-methyl- heneicosane; 3-methyl-tricosane; 2-methyl-tetracosane; 3-methyl-pentacosane; 2-methyl- hexacosane; 3-methyl-heptacosane; and 3-methyl-triacontane, and (iv) original organic matter, which consists of plant-derived molecules and ions that do not vaporize at any temperature of less than 235 degrees Celsius at atmospheric pressure. The precursor composition comprises the cannabidiolic acid at a concentration of at least 4 percent by mass.

The precursor composition is extracted and heated to produce a decarboxylated composition using the strategy set forth in U.S. Patent No. 10,669,248. The heating converts at least 90 percent of the cannabidiolic acid into (i) a cannabinoid, which is cannabidiol and (ii) carbon dioxide by mole of the cannabidiolic acid. The heating converts at least 90 percent of the tetrahydrocannabinolic acid into (i) a contaminant, which is tetrahydrocannabinol and (ii) carbon dioxide by mole of the tetrahydrocannabinolic acid. The heating converts at least 90 percent of the cannabichromenic acid into (i) a contaminant, which is cannabichromene and (ii) carbon dioxide by mole of the cannabichromenic acid.

The decarboxylated composition comprises (i) the cannabinoid, which is cannabidiol, (ii) the contaminants, which are tetrahydrocannabinol and cannabichromene, (iii) lipids, which consist of a portion of the original lipids that survive the heating, and (iv) organic matter, which consists of a portion of the original organic matter that survives the heating.

A portion of the decarboxylated composition is further processed, and the portion comprises (i) a portion of the cannabinoid of the decarboxylated composition, (ii) a portion of the contaminants of the decarboxylated composition, (iii) a portion of the lipids of the decarboxylated composition, and (iv) a portion of the organic matter of the decarboxylated composition. The term “portion” can include any amount greater than 0 percent, including 100 percent; and the term “portion” is used, for example, to account for transfer loss and for the optional separation of a composition into different batches for further processing. The portion of the decarboxylated composition comprises

(i) the cannabinoid at a concentration of at least 30 percent and no greater than 80 percent by mass;

(ii) the cannabinoid and the contaminants at a ratio of at least 3 : 1 and no greater than 80: 1 by mass; (iii) the cannabinoid and the lipids at a concentration of at least 1 :2 and no greater than 40: 1 by mass; and (iv) the cannabinoid and the organic matter at a concentration of at least 1 :2 and no greater than 40:1 by mass.

The portion of the decarboxylated composition is combined with ethanol to produce a dewaxing composition that comprises (i) the ethanol, (ii) the portion of the cannabinoid of the decarboxylated composition, (iii) the portion of the contaminants of the decarboxylated composition, (iv) the portion of the lipids of the decarboxylated composition, and (v) the portion of the organic matter of the decarboxylated composition such that the dewaxing composition comprises the ethanol at a concentration of at least 20 percent and no greater than 90 percent by mass.

A portion of the dewaxing composition is cooled to produce a mixture that comprises (i) a portion of the ethanol of the dewaxing composition, (ii) a portion of the cannabinoid of the dewaxing composition, (iii) a portion of the contaminants of the dewaxing composition, (iv) a portion of the lipids of the dewaxing composition, and (v) a portion of the organic matter of the dewaxing composition, wherein the mixture comprises a solid phase and a liquid phase. The cooling converts at least 65 percent of the portion of the lipids of the dewaxing composition into solid-phase lipids by mass such that the solid phase of the mixture comprises at least 65 percent of the lipids of the mixture by mass. The liquid phase comprises (i) at least 90 percent of the ethanol of the mixture by mass; (ii) at least 90 percent of the cannabinoid of the mixture by mass;

(iii) at least 90 percent of the contaminants of the mixture by mass; and (iv) at least a portion of the organic matter of the mixture.

A portion of the liquid phase is separated from the solid phase to produce a dewaxed composition that comprises (i) a portion of the ethanol of the liquid phase, (ii) a portion of the cannabinoid of the liquid phase, (iii) a portion of the contaminants of the liquid phase, and (iv) a portion of the organic matter of the liquid phase.

Ethanol of a portion of the dewaxed composition is separated from the rest of the portion of the dewaxed composition to produce a concentrate composition that comprises (i) a portion of the cannabinoid of the dewaxed composition, (ii) a portion of the contaminants of the dewaxed composition, and (iii) a portion of the organic matter of the dewaxed composition. The separating is performed by vaporizing ethanol from the portion of the dewaxed composition such that the concentrate composition lacks ethanol at a concentration greater than 20 percent by mass.

A portion of the concentrate composition is further processed. The portion of the concentrate composition comprises the cannabinoid and the contaminants at a combined concentration of at least 40 percent and no greater than 85 percent by mass.

The portion of the concentrate composition is heated to produce a vapor phase and residual organic matter. The vapor phase comprises (i) a portion of the cannabinoid of the concentrate composition and (ii) a portion of the contaminants of the concentrate composition. The residual organic matter comprises a portion of the organic matter of the concentrate composition. The residual organic matter consists of one or both of a solid and a liquid.

A portion of the vapor phase is separated from the residual organic matter to produce a distillate that comprises (i) a portion of the cannabinoid of the vapor phase, and (ii) a portion of the contaminants of the vapor phase.

A portion of the distillate is condensed into a condensed phase that comprises (i) a portion of the cannabinoid of the distillate, and (ii) a portion of the contaminants of the distillate. The condensed phase comprises the cannabinoid at a concentration of at least 70 percent and no greater than 90 percent by mass; and the condensed phase comprises the contaminants at a concentration of at least 1 percent and no greater than 20 percent by mass.

A portion of the condensed phase is combined with ethanol to produce a crystallization composition that comprises (i) ethanol, (ii) a portion of the cannabinoid of the condensed phase, and (iii) a portion of the contaminants of the condensed phase.

A portion of the crystallization composition is incubated at a crystallization temperature to produce crystals and residual liquid. The cannabinoid has both a concentration and a solubility in the portion of the crystallization composition, and the crystallization temperature is a temperature at which the concentration is greater than the solubility. The crystals comprise a portion of the cannabinoid of the crystallization composition. The residual liquid comprises a portion of the ethanol of the crystallization composition and a portion of the contaminants of the crystallization composition.

Example 2. A composition produced according to Example 1.

The method of Example 1 is performed to produce a crystallization composition comprising the cannabinoid (cannabidiol), an impurity (selected from the contaminants tetrahydrocannabinol and cannabichromene), a liquid phase (the residual liquid), and a solid phase (which comprises crystals of the cannabidiol). The cannabinoid has the molecular formula C _x H _{y (} ¾. The impurity has the molecular formula C _X H _Z O2. “x” is at least 17 and no greater than 24 (i.e., 21 for each of cannabidiol, tetrahydrocannabinol, and cannabichromene); “y” is at least 22 and no greater than 36 (i.e., 30 for cannabidiol); and “z” is at least 22 and no greater than 34 (i.e., 30 for both of tetrahydrocannabinol and cannabichromene).

The cannabinoid and the impurity each comprise an alkyl, and the alkyl of the cannabinoid is identical to the alkyl of the impurity. The alkyl is pentyl because the cannabinoid is cannabidiol and because the impurity is either tetrahydrocannabinol or cannabichromene.

The cannabinoid is 2-[(lR,6R)-6-isopropenyl-3-methylcyclohex-2-en-l-yl]-5-alkyl benzene-l,3- diol, and “z” equals “y” minus 0.

The impurity comprises a 1 chromene ring that either (i) comprises exactly 4 substituents that consist of a 2-methyl substituent; a 2-(4-methylpent-3-en-l-yl) substituent; a 5-hydroxy substituent; and a 7-alkyl substituent that is the alkyl of the impurity, wherein “z” equals “y” minus 0 (i.e., the impurity is cannabichromene) or (ii) is the chromene of a benzo[c]chromene ring that comprises exactly 5 substituents that consist of a 1 -hydroxy substituent; a 3 -alkyl substituent that is the alkyl of the impurity; two 6-methyl substituents; and a 9-methyl substituent, wherein “z” equals “y” minus 0 (i.e., the impurity is tetrahydrocannabinol).

The composition comprises the cannabinoid and the impurity at a ratio of at least 3 : 1 and no greater than 333:1 by mass.

The liquid phase consists of one or more liquids. The liquid phase has an average density of at least 770 and no greater than 1260 grams per liter. The liquid phase comprises greater than 50 percent of the impurity of the composition by mass.

The liquid phase is in both physical and chemical communication with the solid phase such that the physical and chemical properties of the composition control the extent to which the cannabinoid partitions between the liquid phase and the solid phase.

The solid phase consists of one or more solids. The solid phase comprises greater than 50 percent of the cannabinoid of the composition by mass. The solid phase comprises a crystal phase that consists of one or more crystals.

The crystal phase comprises at least 90 percent of the cannabinoid of the solid phase by mass, and the crystal phase comprises the cannabinoid at a concentration of at least 90 percent by mass.

The composition comprises the liquid phase and the crystal phase at a ratio of at least 1:10 and no greater than 20:1 by mass.

The composition lacks molecules that comprise at least 5 carbon atoms and no greater than 16 carbon atoms at a concentration greater than 20 percent by mass. Example 3. Implementation of the method of Example 1 to produce a composition of Example 2

The method of example 1 was performed on certified USDA organic industrial hemp. The hemp was extracted and decarboxylated using the strategy set forth in U.S. Patent No. 10,669,248 to produce a decarboxylated composition that was certified USDA organic.

The decarboxylated composition was heated to produce a vapor phase, and the vapor phase was separated from residual organic matter to produce a distillate that was condensed into a condensed phase that was certified USDA organic.

The condensed phase contained cannabidiol at a concentration of 79.06 percent by mass; tetrahydrocannabinol at a concentration of 1.55 percent by mass; cannabichromene at a concentration of 4.09 percent by mass; and cannabinol at a concentration of 0.35 percent by mass as determined by a third-party ISO/IEC 17025:2005 accredited cannabinoid testing laboratory.

Portions of the condensed phase were combined with 190 proof ethanol at ratios of 4: 1 to 9: 1 (condensed phase : 190 proof ethanol) at various temperatures in the absence or presence of nucleating cannabidiol crystals in an attempt to crystalize the cannabidiol, and these experiments failed. A portion of the condensed phase was therefore combined with 190 proof ethanol at a ratio of 1:4 (condensed phase : 190 proof ethanol) to produce a dewaxing composition, which was cooled to produce a liquid phase and a solid phase. The liquid phase was separated from the solid phase, and ethanol and water of the liquid phase were then separated from the liquid phase by vaporization. 190 proof ethanol was added back to portions of the liquid phase at ratios of 1 :6 to 1:20 (ethanol : liquid phase) at various temperatures to produce crystallization compositions. Each crystallization composition produced significant visible crystals as shown, for example, in the Figure. Following crystallization, the crystallization composition met the specification set forth in Example 2.

The order of the dewaxing and distillation steps are reversed in Example 3 relative to Example 1. While Example 3 was successful, Example 1 describes preferred methods because dewaxing prior to distilling generally increases purity.

Example 4. Obtaining purified cannabinoid from a crystallization composition.

A crystallization composition of any one of Examples 1-3 is provided. A portion of the crystals of the crystallization composition are separated from residual liquid to produce a product. The product comprises the cannabinoid (cannabidiol) at a concentration of at least 90 percent by mass. The product lacks the contaminants (tetrahydrocannabinol and cannabichromene) at a concentration of greater than 0.3 percent by mass. The product lacks the lipids at a concentration of greater than 1 percent by mass. The product lacks the organic matter at a concentration greater than 1 percent by mass. The crystals are solids that have a melting point.

Example 5. Obtaining purified cannabinoid from a crystallization composition. Residual liquid was separated from crystals of the crystallization composition of Example 3 according to the method of Example 4. Specifically, residual liquid was separated from crystals by decanting. The crystals were then analyzed by a third-party ISO/IEC 17025:2005 accredited cannabinoid testing laboratory and found to contain cannabidiol at a concentration of 93.29 percent by mass; tetrahydrocannabinol at a concentration of 0.38 percent by mass; cannabichromene at a concentration of 0.87 percent by mass; and cannabinol at a concentration of 0.10 percent by mass.

Residual liquid coated surfaces of the crystals following the decanting. The cannabidiol concentration would have been greater (and the tetrahydrocannabinol, cannabichromene, and cannabinol concentrations would have been lesser) if either (i) the residual liquid was separated from the crystals using a method superior to decanting or (ii) the crystals were washed, for example with water, following the decanting. The test results of this Example 5 therefore do not meet the specification of Example 4, but the skilled reader will instantly recognize that one could meet these specifications without any further experimentation, for example, by practicing a separation that is superior to decanting or by washing the crystals, for example, with water. The skilled reader will nevertheless recognize that the test results corroborate that the compositions disclosed in the detailed description that precedes this exemplification can be readily produced according to the methods set forth in this disclosure.