COMPOSITIONS COMPRISING 2-[(1R,6R)-6-ISOPROPENYL-3-METHYLCYCLOHEX-2-EN-1-YL]-3-HYDROXY-5-PENTYLPHENOLATE

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is the United States national stage under 35 U.S.C. § 371 of International Application No. PCT/US19/065197, filed Dec. 9, 2019, which claims priority to U.S. patent application Ser. No. 16/683,055, which granted as U.S. Pat. No. 10,864,459, and to U.S. patent application Ser. No. 16/680,365, which granted as U.S. Pat. No. 10,610,805; this patent application claims priority to the preceding applications and the following provisional patent applications: U.S. 62/777,608, filed Dec. 10, 2018; U.S. 62/780,181, filed Dec. 14, 2018; U.S. 62/787,724, filed Jan. 2, 2019; U.S. 62/803,412, filed Feb. 8, 2019; US 62/812,852, filed Mar. 1, 2019; US 62/818,695, filed Mar. 14, 2019; U.S. 62/821,971, filed Mar. 21, 2019; U.S. 62/832,009, filed Apr. 10, 2019; U.S. 62/839,569, filed Apr. 26, 2019; U.S. 62/860,218, filed Jun. 11, 2019; U.S. 62/925,203, filed Oct. 23, 2019; and U.S. 62/933,742, filed November 11, 2019; and the contents of each application identified in this paragraph is incorporated by reference in its entirety.

BACKGROUND

The Cannabis plant generally produces cannabinoids that are carboxylic acids. These carboxylic acids display only nominal pharmacological and psychoactive activity. The carboxylic acids can be converted into decarboxylated cannabinoids that display robust pharmacological and psychoactive effects, for example, by combusting Cannabis.

Decarboxylated cannabinoids are also produced industrially by heating cannabinoid carboxylic acids under vacuum. Decarboxylated cannabinoids are sparingly soluble in water, and attempts have been made to improve solubility, for example, by emulsification to produce beverages suitable for human consumption. Thermostable emulsions frequently display unfavorable characteristics including undesirable taste. Improved methods of solubilizing cannabinoids are desirable to produce beverages comprising cannabinoids.

BRIEF DESCRIPTION

Various aspects of the disclosure relate to a composition, comprising 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate and 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol (“1R,6R CBD”) at a molar ratio of 1:10 to 10,000:1.

In some embodiments, a composition is a liquid. In some embodiments, a composition has a pH, and the pH of the composition is 7 to 13. In some specific embodiments, the pH of the composition is 8 to 10. In some very specific embodiments, the pH of the composition is 8.5 to 9.5. In some specific embodiments, the pH of the composition is 9.0 to 11.0.

In some specific embodiments, a composition comprises 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate and 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol at a molar ratio of 1:1 to 100:1. In some specific embodiments, a composition comprises 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate and 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol at a molar ratio of 100:1 to 10,000:1

In some embodiments, a composition comprises water. In some specific embodiments, a composition comprises water at a concentration by weight of 50% to 99.99%. In some very specific embodiments, a composition comprises water at a concentration by weight of 80% to 99.99%.

In some embodiments, a composition comprises ethanol. In some specific embodiments, a composition comprises ethanol at a concentration by weight of 50 parts per million to 2%. In some specific embodiments, a composition comprises ethanol at a concentration by weight of 1% to 20%. In some specific embodiments, a composition comprises ethanol at a concentration by weight of 10% to 95%.

In some specific embodiments, a composition comprises 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate at a concentration of 1 milligram per liter to 100 milligrams per liter. In some specific embodiments, a composition comprises 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5- pentylphenolate at a concentration of 50 milligrams per liter to 5 grams per liter. In some specific embodiments, a composition comprises 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate at a concentration of 2 grams per liter to 200 grams per liter.

In some embodiments, a composition comprises one or more of sodium ion (Na⁺), potassium ion (K⁺), calcium ion (Ca²⁺), magnesium ion (Mg²⁺), chloride ion (Cl⁻), sulfate (SO₄²⁻), bicarbonate (HCO₃⁻), carbonate (CO₃²⁻), hydrogen phosphate (HPO₄²⁻), hydrogen pyrophosphate (HP₂O₇³⁻), hydrogen triphosphate (HP₃O₁₀⁴⁻), and triphosphate (P₃O₁₀⁵⁻).

In some embodiments, a composition comprises one or more of caffeine, thiamine, niacin, nicotinamide, riboflavin, pantothenate, sucrose, fructose, glucose, acesulfame, saccharin, stevioside, rebaudioside A, sucralose, tagatose, erythritol, maltitol, xylitol, mannitol, isomalt, and a mogroside.

In some embodiments, a composition comprises a solid phase, the solid phase comprises a salt, and the salt comprises 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate. In specific embodiments, a salt comprises a cation selected from sodium, potassium, calcium, zinc, magnesium manganese, iron(II), iron(III), copper, thiamine, choline, citicoline, lysine, and arginine.

DETAILED DESCRIPTION

Various aspects of the disclosure relate to 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate and compositions comprising 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate.

2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate

In some embodiments, a composition comprises a salt of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate. The salt can be, for example, a sodium, potassium, calcium, zinc, magnesium, manganese, iron(II), iron(III), copper, choline, citicoline, thiamine, lysine, or arginine salt.

In some embodiments, a composition comprises 1R,6R CBD.

In some embodiments, a composition comprises water, ethanol, or both water and ethanol.

In some embodiments, a composition comprises sodium ion at a concentration of at least 10 parts per billion (“ppb”) by weight. A composition can optionally comprise sodium ion at a concentration of 10 ppb to 10% by weight.

In some embodiments, a composition comprises potassium ion at a concentration of at least 10 ppb by weight. A composition can optionally comprise potassium ion at a concentration of 10 ppb to 10% by weight.

Exemplification

The examples disclose specific embodiments that do not limit this disclosure or any patent claim that matures from this disclosure.

Example 1. Determining pH stability of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate in Water

1 gram of 1R,6R CBD was dissolved in 6.6 milliliters of 0.5 molar potassium hydroxide (0.5 M KOH) in ethanol to produce 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate. The solution was then diluted with 100 millimolar sodium carbonate (100 mM Na₂CO₃) in water to a final volume of 50 milliliters and a 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5- pentylphenolate concentration of approximately 20 grams per liter. 0.5 milliliters of the 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate solution was added to each of 25 test tubes containing 9.5 milliliters of 0.1 molar carbonate/bicarbonate (CO₃²⁻/HCO₃⁻) buffer according to Table 1. Each test tube contained approximately 10 milligrams of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate at a concentration of approximately 1 gram per liter, approximately 0.66% ethanol by weight, trace potassium ion, and variable sodium ion, carbonate ion, and bicarbonate ion. pH's were confirmed by multiple different measurements.

TABLE 1
Aqueous compositions comprising 2-[(1R,6R)-
6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-
hydroxy-5-pentylphenolate at variable pH

			0.1M	0.1M
	Sample	pH	Na2CO3*	NaHCO3

	1	9.1	0.06 mL	8.94 mL
	2	9.2	0.20 mL	8.80 mL
	3	9.3	0.36 mL	8.64 mL
	4	9.4	0.56 mL	8.44 mL
	5	9.5	0.80 mL	8.20 mL
	6	9.6	1.08 mL	7.92 mL
	7	9.7	1.41 mL	7.59 mL
	8	9.8	1.78 mL	7.22 mL
	9	9.9	2.21 mL	6.79 mL
	10	10.0	2.67 mL	6.33 mL
	11	10.3	4.25 mL	4.75 mL
	12	10.3	4.25 mL	4.75 mL
	13	10.3	4.25 mL	4.75 mL
	14	10.4	4.79 mL	4.21 mL
	15	10.4	4.79 mL	4.21 mL
	16	10.4	4.79 mL	4.21 mL
	17	10.5	5.32 mL	3.68 mL
	18	10.5	5.32 mL	3.68 mL
	19	10.5	5.32 mL	3.68 mL
	20	11.0	7.42 mL	1.58 mL
	21	11.0	7.42 mL	1.58 mL
	22	11.0	7.42 mL	1.58 mL
	23	11.5	8.44 mL	0.56 mL
	24	11.5	8.44 mL	0.56 mL
	25	11.5	8.44 mL	0.56 mL

The amount of Na₂CO₃ in Table 1 does not include the ˜0.5 mL of 0.1 M Na₂CO₃ that was added with the 0.5 mL of 20 gram-per-liter solution of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate.

It was expected that 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate would form 1R,6R CBD at pH's below a threshold pH as evidenced by an expected color change from purple (indicative of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate) to yellow-brown (indicative of 1R,6R CBD). No color change occurred at pH's of 9.1 and above. This finding suggested that either the pK_a of 1R,6R CBD is less than 9.1, at least in dilute aqueous solutions, or that it may be possible to kinetically trap 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate in an aqueous solution at a pH below the pK_a of 1R,6R CBD.

Example 2. Determining the approximate pK_a of IR, 6R CBD 0.5 milliliters of the 20 gram-per-liter solution of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate described in Example 1 was diluted with 9.5 milliliters of distilled water comprising varying concentrations of sodium bicarbonate, and color was monitored as shown in Table 2. pH's were confirmed by multiple different measurements.

TABLE 2
Samples used to determine an approximate pKa for 1R,6R CBD

		NaHCO3 concentration
Sample	pH	in millimolar	color

26	8.0	1000	faint purple
27	8.3	500	light purple
28	8.6	250	purple
29	8.9	125	purple
30	9.2	62	purple

A color change was visually apparent at a pH of 8.0, and a subtle color change was visually apparent at pH of 8.3. These findings suggest that the pK_a of 1R,6R CBD was between 8.0 and 8.5 under the test conditions. This result is surprising given that previously reported pK_a's for 1R,6R CBD range from 9.13 to 9.64 and because the chemically-related molecule resorcinol has a pK_a of 9.15. Further, even though sample 26, which had a pH of 8.0, displayed a color change indicative of conversion from 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate to 1R,6R CBD, no lipid phase formed, which suggests that the interconversion between 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate and 1R,6R CBD in aqueous solution can kinetically trap 1R,6R CBD in the aqueous phase and inhibit the production of a lipid phase. These findings suggest that 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate, the conjugate base of 1R,6R CBD, is suitable for use in beverages for human consumption.

Example 3. Confirming Commercial Viability of Beverages Comprising 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate

20 milliliters of water was removed from a 1 liter bottle of ESSENTIA® OVERACHIEVING H₂O®. ESSENTIA® OVERACHIEVING H₂O® contains purified water, sodium bicarbonate, dipotassium phosphate, magnesium sulfate, and calcium chloride, and its pH was determined to be about 9.5. The 20 milliliters of removed water was replaced with 20 milliliters of the 20 gram-per-liter solution of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate, which is described in Example 1, and the bottle was hermetically sealed using the screw cap top of the bottle to produce a hermetically-sealed container comprising approximately 400 milligrams of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate. The pH of the liquid was measured and determined to be about 10. The liquid was purple and transparent. 5 milliliters of water was removed from a 500 milliliter bottle of DASANI® purified water.

DANSANI® purified water contains purified water, magnesium sulfate, potassium chloride, and sodium chloride, and its pH was determined to be about 7.0. The 5 milliliters of removed water was replaced with 5 milliliters of the 20 gram-per-liter solution of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate, which is described in Example 1, and the bottle was hermetically sealed using the screw cap top of the bottle to produce a hermetically-sealed container comprising approximately 100 milligrams of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate. The pH of the liquid was measured and determined to be about 9.5. The liquid was transparent and purple.

0.5 milliliters of water was removed from a 500 milliliter bottle of DASANI® purified water. DANSANI® purified water contains purified water, magnesium sulfate, potassium chloride, and sodium chloride, and its pH was determined to be about 7.0. The 0.5 milliliters of removed water was replaced with 0.5 milliliters of the 20 gram-per-liter solution of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5- pentylphenolate, which is described in Example 1, and the bottle was hermetically sealed using the screw cap top of the bottle to produce hermetically-sealed container comprising approximately 10 milligrams of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate. The pH of the liquid was measured and determined to be about 8.5. The liquid was transparent and lacked discernable color.

The preceding experiments confirm that 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-3-hydroxy-5-pentylphenolate is suitable for use in beverages.