WO2023275864A1

WO2023275864A1 - A process for the preparation of aqueous cannabinoid compositions

Info

Publication number: WO2023275864A1
Application number: PCT/IL2022/050683
Authority: WO
Inventors: Miron Hazani
Original assignee: Roxx Labs Ltd.
Priority date: 2021-06-27
Filing date: 2022-06-26
Publication date: 2023-01-05

Abstract

The present disclosure generally relates to processes for the preparation of aqueous compositions comprising a cannabinoid acid or a salt thereof.

Description

A PROCESS FOR THE PREPARATION OF AQUEOUS CANNABINOID COMPOSITIONS

TECHNICAU FIEUD

[0001] The present disclosure generally relates to processes for the preparation of aqueous compositions comprising a cannabinoid acid or a salt thereof.

BACKGROUND

[0002] Cannabinoids are a diverse class of chemical compounds that act as ligands to the cannabinoid receptors. The clinical usefulness of the cannabinoids, including D⁹- tetrahydrocannabinol (Δ⁹-THC), to provide analgesia, help alleviate nausea and emesis, as well as stimulate appetite has been well-recognized. Cannabinoids offer a variety of pharmacological benefits, including, but not limited to, anti-spasmodic, anti inflammatory, anti-convulsant, anti-oxidant, neuroprotective, reducing pain, anti cancer, and immunomodulatory effects.

[0003] The principle cannabinoids present in herbal cannabis are cannabinoid acids Δ⁹-tetrahydrocannabinolic acid (Δ⁹-THCA) and cannabidiolic acid (CBDA) with small amounts of the respective neutral (decarboxylated) cannabinoids - tetrahydrocannabinol and cannabidiol (CBD). In addition, cannabis may contain lower levels of other minor cannabinoids. The relative levels of THCA, CBDA, THC and CBD in the plant material typically depend on the plant species, with specific species being engineered to contain high level of the THC derivatives (THC and THCA)

[0004] Tetrahydrocannabinolic acid (THCA) is a non-psychoactive natural precursor of tetrahydrocannabinol (THC). THCA is found in variable quantities in fresh, undried cannabis, but is progressively decarboxylated to THC with drying, and especially under intense heating such as when cannabis is smoked or cooked into cannabis edibles.

[0005] THC is highly insoluble in water and is typically used in oily compositions. THCA is more soluble in water. However, typical THC compositions are provided as viscous suspensions and/or in organic solvents, such as vegetable glycerin (VG) or propylene glycol (PG). [0006] US 7,524.881 is directed to isolation and purification of THC. It disclosed the extraction of cannabis plant material with heptane, basic extraction of the organic phase with sodium hydroxide at a pH of 12.7-13.2, further extraction of the resultant basic aqueous phase with isopropyl ether, acidification, and treatments with florisil and charcoal to form THC solution, which is then concentrated and purified.

[0007] Hazekamp et al. (Preparative Isolation of Cannabinoids from Cannabis sativa by Centrifugal Partition Chromatography, Journal of Liquid Chromatography & Related Technologies 27(15):2421-2439 · December 2004) discloses a method is presented for the preparative isolation of seven major cannabinoids from Cannabis sativa plant material. Hazekamp discloses the use of a two solvent system, to obtain purified samples of the cannabinoids; (-)-Δ⁹-(trans)- tetrahydrocannabinol (Δ⁹-THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), (-)-Δ⁹-(trans)- tetrahydrocannabinolic acid- A (THCA), cannabigerolic acid (CBGA) and cannabidiolic acid (CBDA).

[0008] Stepanov I and Naomi F ("Bringing attention to e-cigarette pH as an important element for research and regulation", Tobacco Control 24(4), p. 413-414) discusses pH effects on nicotine in electronic cigarettes.

[0009] US 2014/166028 discloses a method for the administration of nicotine, THC, tobacco, cannabidiol or a base alkaloid. The method includes administering in the oral or nasal cavity an absorption conditioning unit having at least two agents selected from the group consisting of (a) a buffer agent, (b) a capturing agent, (c) a penetration agent, and (d) a thermal agent, to the mammal, and then administering by inhalation a bioactive agent selected from the group consisting of nicotine, THC, cannabidiol and a base alkaloid. The absorption conditioning unit may be in a dosage form not containing a drug. The absorption conditioning unit may create a pH in the oral cavity or nasal cavity of 7.8-10 for a period of ten minutes or more after administration, the dosage form not containing an acid and not containing a drug.

[0010] US 2014/209109 discloses a pharmaceutical composition and administration apparatus including a portable powered vaporizer with a mouthpiece, smokeless vaporizing element, and a removable chamber. The chamber contains a composition comprising tetrahydrocannabinol (THC), cannabidiol (CBD), FCC grade ethanol, flavoring, pharmaceutical grade nicotine, USP grade aqueous glycerin,

USP/EP grade propylene glycol, and USP grade vegetable glycerin.

[0011] WO 2016/019353 discloses a pharmaceutical formulation of cannabis compounds suitable for pulmonary delivery to a patient, comprising: a volatile liquid, wherein the volatile liquid comprises a mixture of: a cannabis oil extract having a known amount of a medicinal cannabis compound; and an aerosol precursor. The volatile liquid may be in an inhalable form, in an aerosol form and/or in vapor form.

[0012] WO 2020/194297 relates to the field of aerosol generation devices, and to electronic cigarettes configured to generation of aerosols from aqueous formulations of nicotine or cannabis products.

[0013] PCT/IL2021/050311 relates to aqueous compositions comprising a cannabinoid acid or a salt thereof, processes for the preparation thereof and uses thereof for inhalation.

[0014] There is an unmet need for improved procedure for the preparation of cannabinoid compositions comprising cannabinoid acids and/or salts thereof.

SUMMARY

[0015] The following embodiments and aspects thereof are described and illustrated in conjunction with compositions and methods which are meant to be exemplary and illustrative, not limiting in scope. In various embodiments, one or more of the above-described problems have been reduced or eliminated, while other embodiments are directed to other advantages or improvements.

[0016] The present invention provides improved processes for the preparation of aqueous solutions of cannabinoids which are suitable and useful for inhalation by a subject. These aqueous solutions are prepared by first contacting cannabis plant material with a non-aqueous solvent, to form a non-aqueous extract composition comprising cannabinoids, including cannabinoid acid(s); optionally removing the non- aqueous solvent to provide a dry extract; and then extracting the formed extract with an aqueous base. Advantageously, the basic aqueous extraction is performed with appropriated amounts of aqueous base so as to result in a liquid aqueous composition (e.g. a solution), which contains effective amounts of the desired cannabinoid acid(s) in the deprotonated salt form. [0017] Preferably, the formed aqueous liquid has a pH higher than 9 or higher than 10, and the cannabinoid acid basic salt(s) is stable therein. Furthermore, the cannabinoid salts can be generated in the liquid composition, which is substantially devoid of organic solvents. The present process is reproducible and easy to carry out. Moreover, the present process can easily result in high concentrations of up to 10% w/w cannabinoid acids in the formed aqueous composition.

[0018] Thus, according to some embodiments, there is provided a process for the preparation of an aqueous cannabinoid composition, the process comprising:

(a) contacting cannabis plant material with a non-aqueous solvent, to provide a non-aqueous extract comprising at least one cannabinoid acid and insoluble plant material;

(b) optionally removing the non-aqueous solvent to provide a dry extract;

(c) contacting the extract of step (a) or (b) with an appropriate amount of an aqueous base, wherein the amount is appropriate for forming an aqueous cannabinoid solution comprising the at least one cannabinoid acid in a deprotonated form at a concentration in the range of 1% to 15% w/w.

[0019] According to some embodiments, the non-aqueous solvent of step (a) is a non-toxic solvent.

[0020] According to some embodiments, the non-aqueous solvent of step (a) is selected from the group consisting of supercritical CO₂, liquid CO₂, an alcohol, an ester, a ketone, an ether, an alkane, a haloalkane and combinations thereof.

[0021] According to some embodiments, the non-aqueous solvent is selected from the group consisting of supercritical CO₂, liquid CO₂, ethanol, n-propanol isopropanol, ethyl acetate, acetone, diethyl ether, tetrahydrofuran, methyl tert-butyl ether, pentane, hexane, heptane, dichloromethane, chloroform and combinations thereof.

[0022] According to some embodiments, the non-aqueous solvent is selected from the group consisting of ethanol, acetone, hexane and combinations thereof.

[0023] According to some embodiments, the aqueous base of step (c) comprises a metal hydroxide, a metal carbonate or a combination thereof. [0024] According to some embodiments, the aqueous base of step (c) comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate or a combination thereof.

[0025] According to some embodiments, the aqueous base comprises a hydroxide anion at a concentration in the range of 0.01M to 0.5M.

[0026] According to some embodiments, the aqueous base has a pH in the range of 12 to 13.5.

[0027] According to some embodiments, the aqueous cannabinoid solution of step (c) comprises the at least one cannabinoid acid in a deprotonated form at a concentration in the range of 4% to 6% w/w.

[0028] According to some embodiments, the aqueous cannabinoid composition has a pH in the range of 9.5 to 11.5.

[0029] According to some embodiments, step (c) further comprises adding concentrated base to the aqueous cannabinoid solution thereby adjusting the pH of the aqueous cannabinoid solution to be in the range of 10 to 11.5.

[0030] According to some embodiments, the aqueous cannabinoid composition is substantially devoid of organic solvents.

[0031] According to some embodiments, the process comprises step (b) of removing the non-aqueous solvent to provide a dry extract.

[0032] According to some embodiments, removing the non-aqueous solvent to provide a dry extract is performed by evaporating the non-aqueous solvent at ambient temperature, boiling the non-aqueous solvent at ambient temperature, boiling or evaporating the non-aqueous solvent at elevated temperature, freeze-drying the non- aqueous solvent, performing rotary evaporation, applying of high vacuum or by a combination thereof.

[0033] According to some embodiments, the dry extract comprises no more than 1% organic solvents w/w.

[0034] According to some embodiments, step (c) further comprises removing residual organic solvents from the aqueous cannabinoid solution. [0035] According to some embodiments, step (c) further comprises isolating the aqueous cannabinoid solution from residual insoluble plant material.

[0036] According to some embodiments, isolating the aqueous cannabinoid solution from residual insoluble plant material is performed by filtration, centrifugation or both.

[0037] According to some embodiments, step (b) further comprises measuring the amount of the at least one cannabinoid acid in the dry extract, wherein step (c) further comprises determining the appropriate amount of an aqueous base based on the measured amount of the at least one cannabinoid acid.

[0038] According to some embodiments, step (c) comprises: adding the aqueous base to the extract of step (a) or (b) gradually, while measuring the amount of at least one of: the at least one cannabinoid acid and the deprotonated cannabinoid acid, and ceasing the addition of aqueous base based on the measured amount.

[0039] According to some embodiments, wherein step (c) comprises: adding the aqueous base to the extract of step (a) or (b) gradually, while measuring the amount of at least one of deprotonated cannabinoid acid, and ceasing the addition of aqueous base, upon the measured amount of deprotonated cannabinoid acid being equal or higher than a predetermined value, which indicates that the concentration of the deprotonated cannabinoid acid in the aqueous cannabinoid solution is in the range of 1% to 15% w/w.

[0040] According to some embodiments, wherein step (c) comprises: adding the aqueous base to the extract of step (a) or (b) gradually, while measuring the amount of at least one of cannabinoid acid, and ceasing the addition of aqueous base, upon the measured amount of deprotonated cannabinoid acid being equal or lower than a predetermined value. [0041] According to some embodiments, step (a) further comprises isolating the non-aqueous extract from the insoluble plant material.

[0042] According to some embodiments, isolating the non-aqueous extract from the insoluble plant material is performed by filtration, centrifugation or both. [0043] According to some embodiments, step (a) comprises grinding raw cannabis plant material and contacting the ground cannabis plant material with a non-aqueous solvent, to provide a non-aqueous extract comprising at least one cannabinoid acid and insoluble plant material.

[0044] According to some embodiments, the contacting of the cannabis plant material with the non-aqueous solvent in step (a) entails soaking the cannabis plant material in the non-aqueous solvent of at least 15 minutes.

[0045] According to some embodiments, the soaking is performed for of at least 60 minutes.

[0046] According to some embodiments, the process further comprises the steps of: (d) adding an acid to the composition produced in step (c) to a pH in the range of 1-5, thereby precipitating the at least one cannabinoid acid or salt thereof and forming an acidic aqueous solution;

(e) separating the precipitated at least one cannabinoid acid or salt thereof from the acidic aqueous solution; and (f) dissolving the precipitated at least one cannabinoid acid or salt thereof in a second aqueous base, thereby forming a purified aqueous cannabinoid solution comprising the at least one cannabinoid acid in a deprotonated form at a concentration in the range of 1% to 15% w/w.

[0047] According to some embodiments, the acid of step (d) is a mineral acid. [0048] According to some embodiments, the pH of the acidic aqueous solution of step (d) is in the range of 3.5 to 4.5.

[0049] According to some embodiments, the second aqueous base of step (f) comprises a hydroxide anion at a concentration in the range of 0. 01M to 0.5M. [0050] According to some embodiments, the cannabis plant material comprises a

THCA-enriched cannabis species.

[0051] According to some embodiments, the at least one cannabinoid acid comprises tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) or a combination thereof.

[0052] According to some embodiments, the at least one cannabinoid acid comprises THCA.

[0053] According to some embodiments, there is provided an aqueous cannabinoid composition prepared by a process as disclosed herein

[0054] According to some embodiments, the aqueous cannabinoid composition comprises at least 90% w/w water.

[0055] According to some embodiments, the aqueous cannabinoid composition is for use in the administration of the cannabinoid via inhalation.

Certain embodiments of the present disclosure may include some, all, or none of the above advantages. One or more technical advantages may be readily apparent to those skilled in the art from the figures, descriptions and claims included herein. Moreover, while specific advantages have been enumerated above, various embodiments may include all, some or none of the enumerated advantages.

In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the figures and by study of the following detailed descriptions.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 is a block diagram representing a process for the preparation of an aqueous cannabinoid composition, according to some embodiments.

Figure 2 is a HPLC chromatogram resulting from the elution of the formulation of the present invention. DETAILED DESCRIPTION

[0056] In the following description, various aspects of the disclosure will be described. For the purpose of explanation, specific configurations and details are set forth in order to provide a thorough understanding of the different aspects of the disclosure. However, it will also be apparent to one skilled in the art that the disclosure may be practiced without specific details being presented herein. Furthermore, well- known features may be omitted or simplified in order not to obscure the disclosure.

[0057] Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0058] according to some embodiments, there is provided a process for the preparation of an aqueous cannabinoid composition, the process comprising:

(b) optionally removing the non-aqueous solvent to provide a dry extract;

[0059] Reference is now made to Figure 1, which is a block diagrams representing the process of the present invention, according to some embodiments.

[0060] According to some embodiments, the process of the present invention includes a preliminary step of grinding raw cannabis plant material. According to some embodiments, this step is optional and performed before the extraction steps, which follow the grinding. For example, the cannabis material may be purchased and provided to the following extraction steps (e.g., to step 1010) as ground material or as cannabis material which is processed otherwise.

[0061] Thus, according to some embodiments, the present process comprises step 1000 of grinding raw cannabis plant material.

[0062] According to some embodiments, the process further comprises the step of contacting cannabis plant material with a non-aqueous solvent, to provide a non- aqueous extract comprising at least one cannabinoid acid and insoluble plant material.

[0063] According to some embodiments, the process further comprises step 1010 of contacting cannabis plant material with a non-aqueous solvent.

[0064] According to some embodiments, the contact of the cannabis plant material with the non-aqueous solvent results in a non-aqueous extract. According to some embodiments, the contact of the cannabis plant material with the non-aqueous solvent results in a non-aqueous composition. According to some embodiments, the non- aqueous extract is a non-aqueous composition. According to some embodiments, the non-aqueous extract is a liquid composition. According to some embodiments, the non- aqueous extract is a liquid solution, suspension or emulsion. Each possibility represents a separate embodiment of the present invention. According to some embodiments, the non-aqueous extract is a liquid solution.

[0065] According to some embodiments, the non-aqueous extract comprises at least 80% non-aqueous solvent w/w. According to some embodiments, the non-aqueous extract comprises at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85% or at least 90% non-aqueous solvent w/w. Each possibility represents a separate embodiment of the present invention. According to some embodiments, the non-aqueous extract comprises at least 80% non-aqueous solvent v/v. According to some embodiments, the non-aqueous extract comprises at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85% or at least 90% non-aqueous solvent v/v w. Each possibility represents a separate embodiment of the present invention. Embodiments relating to the non-aqueous solvent are detailed below.

[0066] According to some embodiments, the non-aqueous extract comprises at least one cannabinoid acid. According to some embodiments, the at least one cannabinoid acid is extracted from the cannabis plant material. According to some embodiments, the at least one cannabinoid acid is present in the cannabis plant material prior to conducting the present process. According to some embodiments, the at least one cannabinoid acid is tetrahydrocannabinolic acid. According to some embodiments, the non-aqueous extract comprises at least 5% cannabinoid acid(s) w/w. According to some embodiments, the non-aqueous extract comprises at least 1%, at least 2%, at least 3%, at least 4%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9% or at least 10%, cannabinoid acid(s) w/w. According to some embodiments, the non- aqueous extract comprises at least 5% cannabinoid acid(s) v/v. According to some embodiments, the non-aqueous extract comprises at least 1%, at least 2%, at least 3%, at least 4%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9% or at least 10%, cannabinoid acid(s) v/v. Each possibility represents a separate embodiment of the present invention.

[0067] It is to be understood that the unit w/w% refers to weight percent or fraction. For example, 5% cannabinoid acid(s) w/w refers to a composition, which comprises 5 grams of cannabinoid acid(s) per 100 grams of the composition (i.e. the composition includes 95 grams of other components). It is also to be understood that the unit v/v% refers to volume percent or fraction. For example, 5% cannabinoid acid(s) v/v refers to a 100 milliliter composition, which comprises 5 milliliter of cannabinoid acid(s) (e.g. the cannabinoid acid(s) is diluted with sufficient solvent).

[0068] It is to be understood that the phrase "insoluble plant material", which is mentioned with respect to some of the products of step 1010, refers to any plant material originated in the cannabis plant, which is insoluble in the non-aqueous solvent used in this step, according to some embodiments.

[0069] Thus, according to some embodiments, the process comprises step 1010 of contacting cannabis plant material with a non-aqueous solvent, to provide a non- aqueous extract comprising at least one cannabinoid acid and insoluble plant material. According to some embodiments, the contacting cannabis plant material of step 1010 is the ground cannabis plant material produced in step 1010.

[0070] The term "extract" is a substance made by extracting a part of a raw material, typically a plant material. The extracting is often performed by using a solvent such as an aqueous solvent, an organic solvent or other liquids (e.g., liquid or supercritical CO₂, which is neither aqueous not organic) and combinations of such liquids. The term extract, as used herein, includes both the extracted material within the solvent phase (e.g., a solution, emulsion or suspension) or as a dried material after removing the solvent phase. When referring to such concentrated extracts, which were removed from their solvent(s), the extracts are occasionally referred herein as a "dry extract" or "dried extract", terms which are interchangeable herein.

[0071] As used herein, the term "solvent extraction" refers to the process of separating components of a mixture by using a solvent which possesses greater solubilizing ability for one component, and may therefore separate said one component from at least a second component which is less miscible than said one component with said solvent. It is to be understood that "component" may refer to more than one compound, according to some embodiments.

[0072] The term "solvent," as used herein, refers to a substance that dissolves a species of interest, like cannabinoids, cannabinoid acids and the like, resulting in a liquid phase, which includes the solvent and the species of interest. The liquid phase may be a solution, according to some embodiments, but it is not limited to a solution and may also be an emulsion or suspension. A solvent is a liquid in the conditions, in which it is being used as a solvent (e.g., during dissolution or extraction), but it is not necessarily a liquid at standard conditions for temperature and pressure (e.g. STP). For example, supercritical - or liquid carbon dioxide is a conventional solvent, although carbon dioxide is a gas at room temperature and 1 atmosphere, and sulfolane is also a conventional solvent, although it has melting point of 27.5°C. Thus, the term solvent as used in this specification all dissolving agents which are capable of being used for the indicated purposes. The term "solvent" includes co-solvents as well as single component solvents.

[0073] According to some embodiments, the non-aqueous solvent of step 1010 is a non-toxic solvent. According to some embodiments, the non-aqueous solvent of step (a) is a non-toxic solvent.

[0074] Specifically, the product of the present process is to be used for inhalation by a human subject, according to some embodiments, and it is thus preferable than the solvent is non-toxic to ensure that residues thereof in the resulting composition will not harm the health of the subject. According to some embodiments, the non-aqueous solvent of step 1010 is not methanol. According to some embodiments, the non-aqueous solvent of step 1010 is devoid of methanol. [0075] According to some embodiments, the non-aqueous solvent of step 1010 is a single species solvent. According to some embodiments, the non-aqueous solvent of step 1010 comprises a mixture of solvents.

[0076] According to some embodiments, the non-aqueous solvent is an organic solvent.

[0077] As used herein the term "organic solvent" refers to an organic molecule capable of at least partially dissolving another substance (i.e., the solute). Organic solvents may be liquids at room temperature, according to some embodiments. In some embodiments, the organic solvent may be formed by the combination of two or more organic solvents.

[0078] According to some embodiments, the organic solvent is an alcohol, an ether, an ester, an amide, an aldehyde, a sulfoxide, a sulfone, an aromatic hydrocarbon, a halogenated aromatic cycle, an alkane, a haloalkane, a ketone, a nitrile, and combinations thereof.

[0079] According to some embodiments, the organic solvent is selected from the group consisting of: ethanol, n-propanol, isopropanol, 1 -butanol, 2-butanol, sec- butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, neopentanol, 3 -methyl- 1- butanol, 2-methyl- 1 -butanol, 3-methyl-2 -butanol, 2-methyl-2-butanol, ethylene glycol, ethylene glycol monomethyl ether, diethyl ether, methyl ethyl ether, ethyl propyl ether, methyl propyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, dihydrofuran, furan, pyran, dihydropyran, tetrahydropyran, acetone, ethyl methyl ketone, diethyl ketone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, dimethyl formamide, dimethyl acetamide, acetamide, N-methylpyrrolidone, acetonitrile, propionitrile, methyl acetate, ethyl acetate, propyl acetate, acetaldehyde, methyl formate, ethyl formate, ethyl propionate, methyl propionate, chloroform, dichloromethane, tetrachloroethylene, chlorobenzene, toluene, benzene, xylene, hexane, hexanes, petroleum ether, pentane, pentanes, heptane, octane, heptanes, octanes, nonanes, decanes, cyclopentane, cyclohexane, cycloheptane and combinations thereof. Each possibility represents a separate embodiment of the present invention. According to some embodiments, the organic solvent is selected from the group consisting of: ethanol, n-propanol, isopropanol, 1- butanol, 2-butanol, sec -butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, neopentanol, 3 -methyl- 1 -butanol, 2-methyl- 1 -butanol, 3-methyl-2-butanol, 2-methyl- 2-butanol, ethylene glycol, ethylene glycol monomethyl ether, diethyl ether, methyl ethyl ether, ethyl propyl ether, methyl propyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, dihydrofuran, furan, pyran, dihydropyran, tetrahydropyran, acetone, ethyl methyl ketone, diethyl ketone, tetrachloroethylene, dimethyl sulfoxide, dimethyl sulfone, sulfolane, dimethyl formamide, dimethyl acetamide, acetamide, N- methylpyrrolidone, acetonitrile, propionitrile, methyl acetate, ethyl acetate, propyl acetate, acetaldehyde, methyl formate, ethyl formate, ethyl propionate, methyl propionate, chloroform, dichloromethane, chlorobenzene, toluene, benzene, xylene and combinations thereof. Each possibility represents a separate embodiment of the present invention.

[0080] According to some embodiments, the organic solvent comprises an alcohol selected from the group consisting of: ethanol, n-propanol, isopropanol, 1 -butanol, 2- butanol, sec -butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, neopentanol, 3- methyl-1 -butanol, 2-methyl- 1 -butanol, 3-methyl-2-butanol, 2-methyl-2-butanol, ethylene glycol, ethylene glycol monomethyl ether and a combination thereof.

[0081] According to some embodiments, the organic solvent comprises an ether selected from the group consisting of: diethyl ether, methyl ethyl ether, ethyl propyl ether, methyl propyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, dihydrofuran, furan, pyran, dihydropyran, tetrahydropyran and a combination thereof.

[0082] According to some embodiments, the organic solvent comprises a ketone selected from the group consisting of: acetone, ethyl methyl ketone, diethyl ketone and a combination thereof.

[0083] According to some embodiments, the organic solvent comprises a sulfoxide or a sulfone selected from the group consisting of: dimethyl sulfoxide, dimethyl sulfone, sulfolane and a combination thereof.

[0084] According to some embodiments, the organic solvent comprises an amide selected from the group consisting of: dimethyl formamide, dimethyl acetamide, acetamide, N-methylpyrrolidone and a combination thereof.

[0085] According to some embodiments, the organic solvent comprises a nitrile selected from the group consisting of: acetonitrile, propionitrile and a combination thereof. [0086] According to some embodiments, the organic solvent comprises an ester or al aldehyde selected from the group consisting of: methyl acetate, ethyl acetate, propyl acetate, acetaldehyde, methyl formate, ethyl formate, ethyl propionate, methyl propionate and a combination thereof.

[0087] According to some embodiments, the organic solvent comprises a haloalkane selected from the group consisting of: chloroform, dichloromethane and a combination thereof. It is to be understood that the term "haloalkane", as used herein, refers to either mono-halogenated or poly-halogenated species.

[0088] According to some embodiments, the organic solvent comprises an aromatic hydrocarbon or a halogenated aromatic cycle, selected from the group consisting of: chlorobenzene, toluene, benzene, xylene and a combination thereof.

[0089] According to some embodiments, the organic solvent comprises an alkane selected from the group consisting of: hexane, hexanes, petroleum ether, pentane, pentanes, heptane, octane, heptanes, octanes, nonanes, decanes, cyclopentane, cyclohexane, cycloheptane and a combination thereof.

[0090] According to some embodiments, the organic solvent is a polar organic solvent.

[0091] The term "polar solvent" as used herein means a solvent that tends to interact with other compounds or itself through acid-base interactions, hydrogen bonding, dipole- dipole interactions, or by dipole-induced dipole interactions.

[0092] According to some embodiments, the polar organic solvent is selected from the group consisting of: ethanol, n-propanol, isopropanol, 1 -butanol, 2-butanol, sec- butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, neopentanol, 3 -methyl- 1- butanol, 2-methyl- 1 -butanol, 3-methyl-2 -butanol, 2-methyl-2-butanol, ethylene glycol, ethylene glycol monomethyl ether, diethyl ether, methyl ethyl ether, ethyl propyl ether, methyl propyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, dihydrofuran, furan, pyran, dihydropyran, tetrahydropyran, acetone, ethyl methyl ketone, diethyl ketone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, dimethyl formamide, dimethyl acetamide, acetamide, N-methylpyrrolidone, acetonitrile, propionitrile, methyl acetate, ethyl acetate, propyl acetate, acetaldehyde, methyl formate, ethyl formate, ethyl propionate, methyl propionate, chloroform, dichloromethane, tetrachloroethylene and combinations thereof. Each possibility represents a separate embodiment of the present invention. According to some embodiments, the polar organic solvent is an alcohol, an ether, an ester, an amide, an aldehyde, a sulfoxide, a sulfone, a ketone, a nitrile, and combinations thereof. Optional alcohols, ethers, esters, amides, aldehydes, sulfoxides, sulfones, ketones and nitriles are specified above.

[0093] According to some embodiments, the organic solvent is a non-polar organic solvent.

[0094] The term "non-polar solvent" as used herein means a solvent that is not a polar solvent. Non-polar solvents interact with other compounds or themselves predominantly through dispersion forces. Non-polar solvents interact with polar solvents mainly through dipole-induced dipole interactions or through dispersion forces.

[0095] Non-polar organic solvents suitable for use in the invention may be selected from acyclic or cyclic, saturated or unsaturated aliphatic hydrocarbons and aromatic hydrocarbons, each of which is optionally substituted by one or more halogens, and combinations thereof. In particular embodiments, the non-polar organic solvent is selected from C5-C10 alkanes, C5-C10 cycloalkanes, C6-C14 aromatic hydrocarbons and combinations thereof. According to some embodiments, the C5-C10 alkane is selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclohexane, and isomers and mixtures thereof. According to some embodiments, the non-polar organic solvent is selected from the group consisting of: chlorobenzene, toluene, benzene, xylene, hexane, hexanes, petroleum ether, pentane, pentanes, heptane, octane, heptanes, octanes, nonanes, decanes, cyclopentane, cyclohexane, cycloheptane and combinations thereof. Each possibility represents a separate embodiment of the present invention.

[0096] According to some embodiments, the non-aqueous solvent is a non-organic solvent.

[0097] According to some embodiments, the non-aqueous solvent is selected from the group consisting of liquid CO₂, supercritical CO₂ and a perfuoroalkane. According to some embodiments, the non-aqueous solvent is selected from the group consisting of liquid CO₂ and supercritical CO₂.

[0098] According to some embodiments, the organic solvent is selected from the group consisting of: ethanol, n-propanol, isopropanol, 1 -butanol, 2-butanol, sec- butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, neopentanol, 3 -methyl- 1- butanol, 2-methyl- 1 -butanol, 3-methyl-2 -butanol, 2-methyl-2-butanol, ethylene glycol, ethylene glycol monomethyl ether, diethyl ether, methyl ethyl ether, ethyl propyl ether, methyl propyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, dihydrofuran, furan, pyran, dihydropyran, tetrahydropyran, acetone, ethyl methyl ketone, diethyl ketone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, dimethyl formamide, dimethyl acetamide, acetamide, N-methylpyrrolidone, acetonitrile, propionitrile, methyl acetate, ethyl acetate, propyl acetate, acetaldehyde, methyl formate, ethyl formate, ethyl propionate, methyl propionate, chloroform, dichloromethane, tetrachloroethylene, chlorobenzene, toluene, benzene, xylene, hexane, hexanes, petroleum ether, pentane, pentanes, heptane, octane, heptanes, octanes, nonanes, decanes, cyclopentane, cyclohexane, cycloheptane, liquid CO₂, supercritical CO₂ and a perfuoroalkane and combinations thereof. Each possibility represents a separate embodiment of the present invention. According to some embodiments, the organic solvent is selected from the group consisting of: ethanol, n-propanol, isopropanol, 1 -butanol, 2-butanol, sec -butanol, t- butanol, 1-pentanol, 2-pentanol, 3-pentanol, neopentanol, 3 -methyl- 1 -butanol, 2- methyl-1 -butanol, 3-methyl-2-butanol, 2-methyl-2-butanol, ethylene glycol, ethylene glycol monomethyl ether, diethyl ether, methyl ethyl ether, ethyl propyl ether, methyl propyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, dihydrofuran, furan, pyran, dihydropyran, tetrahydropyran, acetone, ethyl methyl ketone, diethyl ketone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, dimethyl formamide, dimethyl acetamide, acetamide, N-methylpyrrolidone, acetonitrile, propionitrile, methyl acetate, ethyl acetate, propyl acetate, acetaldehyde, methyl formate, ethyl formate, ethyl propionate, methyl propionate, chloroform, dichloromethane, tetrachloroethylene, chlorobenzene, toluene, benzene, xylene, liquid CO₂, supercritical CO₂ and a perfuoroalkane and combinations thereof. Each possibility represents a separate embodiment of the present invention.

[0099] Thus, according to some embodiments, the non-aqueous solvent of step (a) is selected from the group consisting of supercritical CO₂, liquid CO₂, an alcohol, an ester, a ketone, an ether, an alkane, a haloalkane and combinations thereof. According to some embodiments, the non-aqueous solvent of step 1010 is selected from the group consisting of supercritical CO₂, liquid CO₂, an alcohol, an ester, a ketone, an ether, an alkane, a haloalkane and combinations thereof. According to some embodiments, the non-aqueous solvent is selected from the group consisting of supercritical CO₂, liquid CO₂, ethanol, n-propanol isopropanol, ethyl acetate, acetone, diethyl ether, tetrahydrofuran, methyl tert-butyl ether, pentane, hexane, heptane, dichloromethane, chloroform and combinations thereof.

[00100] According to some embodiments, the non-aqueous solvent is selected from the group consisting of ethanol, acetone, hexane and combinations thereof. According to some embodiments, the non-aqueous solvent is ethanol. According to some embodiments, the non-aqueous solvent is hexane. According to some embodiments, the non-aqueous solvent is acetone.

[00101] According to some embodiments, the term "cannabis plant" refers to a plant of cannabis genus. According to some embodiments, the plant material is selected from Cannabis Indica, Cannabis Sativa and cannabis species engineered to have high THC/THCA content. According to some embodiments, the cannabis species is a THCA enriched cannabis species.

[00102]

[00103] According to some embodiments, the cannabis plant material of step 1000 is a THCA-enriched cannabis species. According to some embodiments, the cannabis plant material of step 1010 is a THCA-enriched cannabis species.

[00104] According to some embodiments, the cannabis plant material of step 1000 comprises tetrahydrocannabinolic acid (THCA). According to some embodiments, the cannabis plant material of step 1010 comprises tetrahydrocannabinolic acid (THCA).

[00105] According to some embodiments, the non-aqueous extract produced in step 1010 comprises at least one cannabinoid acid.

[00106] The term "cannabinoid", as used herein, includes all major and minor cannnabinoids found in natural cannabis and hemp material that can be isolated from a natural source or reproduced by synthetic means. This includes delta-9- Tetrahydrocannabinol (THC), delta-9-Tetrahydrocannabinolic acid (THCA), delta-8- Tetrahydrocannabinol, Cannabidiol (CBD), Cannabidiolic acid (CBDA), Cannabinol (CBN), Cannabinolic acid (CBNA), tetrahydrocannabinovarin (THCV), cannabidivarin (CBDV), cannabigerol (CBG), cannabigerolic acid (CBGA) and cannabichromene (CBC). The term "cannabinoid" also includes basic salts of the acid mentioned above, for example, THCA-sodium salt and THCA-potassium salt.

[00107] The term "tetrahydrocannabinolic acid" and "THAC acid" are interchangeable and refer to common derivatives of THC, which are substituted in position 2 of the aromatic ring by a carboxylic acid. THC has two dominant isomers, Δ⁹-THC and Δ⁸-THC. Accordingly, THC A has corresponding Δ⁹ and Δ⁸ isomers. The chemical structures of the parent tetrahydrocannabinols (Δ⁹-THC and Δ⁸-THC) and tetrahydrocannabinolic acids (Δ⁹-THCA and Δ⁸-THCA) are presented below:

It is to be understood that although the natural THC isomers include an n-C₅H₁₁ chain in position 3, derivatives of THC may include other substituents. Therefore, the term tetrahydrocannabinolic acid includes corresponding structures, in which position 3 is substituted by a group, which is either an n-C₅H₁₁ or a different chemical group. [00108] The term "tetrahydrocannabinolic acid" should be interpreted broadly referring to all possible stereoconfigurations and salts of the relevant formula. Specifically, the natural THC includes two vicinal asymmetric positions, position 6a and position 10a, as shown above. The two vicinal asymmetric positions exist in trans relative configuration, and both are designated R absolute configuration. Thus, the (6aR,10aR) absolute configuration is the preferred configuration for tetrahydrocannabinolic acids of the current invention, however, said tetrahydrocannabinolic acids are not limited to this configuration According to some embodiments, positions 6a and 10a of the THCA acid are in trans relative configuration. According to some embodiments, position 6a has R absolute configuration. According to some embodiments, position 10a has R absolute configuration. According to some embodiments, the THCA acid has the (6aR,10aR) absolute configuration.

[00109] According to some embodiments, the at least one cannabinoid acid comprises tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) or a combination thereof.

[00110] According to some embodiments, the at least one cannabinoid acid comprises THCA.

[00111] As used herein, the term “contacting” means exposing to, combining and/or bringing together.

[00112] According to some embodiments, the contacting cannabis plant material with a non-aqueous solvent is performed for a period of time of at least 5 minutes. According to some embodiments, the contacting cannabis plant material with a non- aqueous solvent is performed for a period of time of at least 15 minutes. According to some embodiments, the contacting cannabis plant material with a non-aqueous solvent is performed for a period of time of at least 60 minutes. According to some embodiments, the contacting cannabis plant material with a non-aqueous solvent is performed for a period of time of at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, at least 2 hours, at least 3 hours, at least 4 hours, at least 6 hours, least 12 hours or at least 24 hours. Each possibility represents a separate embodiment of the present invention.

[00113] According to some embodiments, the weight ratio between the cannabis plant material and the non-aqueous solvent in step 1010 is in the range of 1:1 to 1:100. According to some embodiments, the weight ratio between the cannabis plant material and the non-aqueous solvent in step 1010 is in the range of 1:1.5 to 1:90. According to some embodiments, the weight ratio between the cannabis plant material and the non- aqueous solvent in step 1010 is in the range of 1:2 to 1:80. According to some embodiments, the weight ratio between the cannabis plant material and the non-aqueous solvent in step 1010 is in the range of 1:3 to 1:70. According to some embodiments, the weight ratio between the cannabis plant material and the non-aqueous solvent in step 1010 is in the range of 1:4 to 1:60. According to some embodiments, the weight ratio between the cannabis plant material and the non-aqueous solvent in step 1010 is in the range of 1:5 to 1:50. According to some embodiments, the weight ratio between the cannabis plant material and the non-aqueous solvent in step 1010 is in the range of 1:8 to 1:40. According to some embodiments, the weight ratio between the cannabis plant material and the non-aqueous solvent in step 1010 is in the range of 1:10 to 1:35. According to some embodiments, the weight ratio between the cannabis plant material and the non-aqueous solvent in step 1010 is in the range of 1:15 to 1:25.

[00114] According to some embodiments, step 1010 further comprises mixing the cannabis plant material in the non-aqueous solvent. According to some embodiments, the contacting includes mixing. According to some embodiments, the mixing entails stirring. According to some embodiments, the stirring includes mechanical or magnetic stirring. According to some embodiments, the mixing entails shaking the plant material in the non-aqueous solvent. According to some embodiments, the mixing includes performing sonication of the plant material in the non-aqueous solvent. According to some embodiments, step 1010 is devoid of performing sonication.

[00115] It is to be understood that mixing the cannabis plant material in the non- aqueous solvent may include a combination of stirring, shaking and/or sonicating, and the like.

[00116] According to some embodiments, the contacting of the cannabis plant material with the non-aqueous solvent in step 1010 entails macerating the cannabis plant material in the non-aqueous solvent.

[00117] According to some embodiments, the contacting of the cannabis plant material with the non-aqueous solvent in step 1010 entails soaking the cannabis plant material in the non-aqueous solvent. [00118] It is to be understood that the soaking of step 1010 may include any of the embodiments specified with respect to mixing and/or contacting herein, according to some embodiments. For example, each of the embodiments relating to contacting time and mixing procedures (e.g., stirring, shaking etc.) may also relate to the soaking stage, according to some embodiments.

[00119] Also, as known in the art, in order to achieve exhaustive extraction, sometimes repeated extractions are performed. According to some embodiments, the process comprises repeating step 1010 at least twice or three times. Each possibility represents a separate embodiment of the present invention.

[00120] According to some embodiments, the present process further comprises step 1020 of isolating the non-aqueous extract from the insoluble plant material.

[00121] According to some embodiments, the present process further comprises step 1030 of contacting the insoluble plant material with a second portion of a non-aqueous solvent, to provide an additional non-aqueous extract comprising at least one cannabinoid acid and insoluble plant material.

[00122] According to some embodiments, when steps 1020 and 1030 are performed, the additional non-aqueous extract(s) may be isolated from insoluble plant material and combined with the non-aqueous extract produced in step 1010 or with the isolated non- aqueous extract produced in step 1020.

[00123] It is to be understood that steps 1020 and 1030 may be repeated a number of times, it order to exhaustively extract the plant material, according to some embodiments. It is also to be understood that the optional extraction of step 1030 can be defined by any of the embodiments elaborated above with respect to the extraction of step 1010, according to some embodiments. Sometimes it may be preferable to perform non-identical extractions in steps 1010 and 1030. For example, according to some embodiments, step 1010 may include contacting the cannabis plant material with a first non-aqueous solvent, and step 1030 may include contacting the insoluble cannabis plant material with a second non-aqueous solvent, wherein the first and second solvents are different. According to some embodiments, each of the non-aqueous solvents may be as elaborated above with respect to the non-aqueous solvents of step 1010. [00124] It is to be understood that steps 1020 and 1030 are optional, as shown in Figure 1 (via dashed arrows) and may improve the total cannabinoid acid yield. These steps may be repeated once or more, e.g., until further extractions do not produce further cannabinoid material, according to some embodiments. Thereafter, the extract of any of steps 1010, 1020 and/or 1030 can be taken for the next step of the process.

[00125] Also, it is to be understood that performing step 1020 may be beneficial for the rest of the present process, as residual insoluble plant material may interfere with further processing of the obtained extract, according to some embodiments.

[00126] According to some embodiments, isolating the non-aqueous liquid extract from the insoluble plant material in step 1020 is performed by filtration, centrifugation or both. According to some embodiments, isolating the non-aqueous extract from the insoluble plant material in step 1020 is performed by filtration. According to some embodiments, isolating the non-aqueous extract from the insoluble plant material in step 1020 is performed by centrifugation. According to some embodiments, isolating the non-aqueous extract from the insoluble plant material in step 1020 is performed by filtration and centrifugation. According to some embodiments, isolating the non- aqueous extract from the insoluble plant material in step 1020 comprises filtration of non-aqueous extract from the insoluble plant material and then centrifugation of the non-aqueous liquid extract, to remove insoluble plant remains.

[00127] According to some embodiments, the filtration of step 1020 is performed using a mesh filter. According to some embodiments, the centrifugation of step 1020 is performed using a centrifuge at a spin rate in the range of 1,000 to 10,000 RPM. According to some embodiments, the rate is about 5,000 RPM. According to some embodiments, the centrifugation is performed for 2 to 30 minutes. According to some embodiments, the centrifugation is performed for about 5 minutes.

[00128] The term "filtration" refers to the act of removing solid particles greater than a predetermined size from a feed comprising a mixture of solid particles and liquid. It will be appreciated that the extract may contain solid particles smaller than the predetermined particle size.

[00129] The term “centrifugation” refers to a mechanical process which involves the use of the centrifugal force to separate particles from a solution according to their size, shape, density, medium viscosity and rotor speed. The denser components of the mixture migrate away from the axis of the centrifuge, while the less dense components of the mixture migrate towards the axis. According to some embodiments, used herein, centrifugation and derived forms include any type of centrifugation, in particular using centrifuges suited for industrial scale of operation, e.g., disk stack centrifuges, decanter centrifuges, solid bowl centrifuges etc.

[00130] It is to be understood that step 1010 and optional steps 1000, 1020 and 1030 are referred in the summary and claims of the present disclosure as step (a).

[00131] A process for the successful preparation of an aqueous solution comprising at least one cannabinoid acid salt, wherein the aqueous solution has a pH of at least 8.5, is disclosed in PCT/IL2021/050311. The process of PCT/IL2021/050311 does not include step (a). Specifically, the process of PCT/IL2021/050311 does not include any of steps 1010 and optional steps 1020 and 1030. However, despite being successful in achieving the desired composition, the process of PCT/IL2021/050311 is sometimes cumbersome, as the direct contact of the cannabis plant material with basic aqueous compositions tends to result in soaking the water into the plant material, to form a swollen material, which is difficult to process and extract. The addition of present step (a) results in a non-aqueous extract, which comprises cannabinoid acid(s), and is easier to manipulate. The non-aqueous solvent may thereafter be removed from the non- aqueous extract, to commence the process in a easier fashion and improved yield, according to some embodiments.

[00132] According to some embodiments, the process of the present invention further comprises step (b) of optionally removing the non-aqueous solvent to provide a dry extract. According to some embodiments, the process further comprises step 1040 of removing the non-aqueous solvent.

[00133] According to some embodiments, the removal of the non-aqueous solvent in step 1040 result in a dry extract. According to some embodiments, the dry extract of step 1040 comprises the at least one cannabinoid acid.

[00134] As defined above, the terms “dry extract” and "dried extract" are interchangeable and refer to a dried material after removing the solvent phase. It is to be understood that the solvent is not required to be completely removed in order for the extract to be considered dry or dried. At least some, or preferably most of the solvent is to be removed. More preferably the solvent is to be substantially removed, according to some embodiments.

[00135] It is to be understood that, according to some embodiments, step 1040 is optional and is following step 1010 or following optional step 1020 or 1030 (after combining the non-aqueous liquid phases). The liquid non-aqueous liquid phases of steps 1010, 1020 and 1030 include the non-aqueous solvent(s), according to some embodiments. The non-aqueous solvent is not required in the final cannabinoid composition produced by the present process, and its removal may be carried out optionally in step 1040 or later after the aqueous extraction (i.e. after step (c), step 1080).

[00136] According to some embodiments, the process comprises step 1040 of removing the non-aqueous solvent of step 1010. According to some embodiments, the process comprises step 1040 of removing the non-aqueous solvent of step 1020. According to some embodiments, the process comprises step 1040 of removing the non- aqueous solvent of step 1030.

[00137] As described herein, the dry extract produced in step 1040 comprises cannabinoid acid(s), which are thermally sensitive compounds. Specifically, cannabinoid acids, such as THCA, are prone to decarboxylation, which result in water insoluble cannabinoids (e.g., THC), according to some embodiments. The present process aims to maximize the water-soluble cannabinoid acids (which are later converted into their salt form, c.f., step (c) step 1080), and therefore, minimizing the decarboxylation is desired. Typically, THCA undergoes rapid decarboxylation at around 120°C. Therefore, the present process, including in step 1040, preferably avoids heating any of the intermediate or final compositions comprising cannabinoid acids to temperatures in the range.

[00138] According to some embodiments, the process is devoid of heating above 120°C. According to some embodiments, the process is devoid of heating above 100°C.

According to some embodiments, the process is devoid of heating above 80°C.

According to some embodiments, the process is devoid of heating above 60°C.

According to some embodiments, the process is devoid of heating above 50°C.

According to some embodiments, the process is devoid of heating. According to some embodiments, the process is devoid of heating any of the extracts above 120°C. According to some embodiments, the process is devoid of heating any of the extracts above 100°C. According to some embodiments, the process is devoid of heating any of the extracts above 80°C. According to some embodiments, the process is devoid of heating any of the extracts above 60°C. According to some embodiments, the process is devoid of heating any of the extracts above 50°C. According to some embodiments, the process is devoid of heating any of the extracts.

[00139] According to some embodiments, removing the non-aqueous solvent in step 1040 is performed by evaporating the non-aqueous solvent at ambient temperature, boiling the non-aqueous solvent at ambient temperature, boiling or evaporating the non- aqueous solvent at elevated temperature, freeze-drying the non-aqueous solvent, performing rotary evaporation, applying of high vacuum or by a combination thereof. Each possibility represents a separate embodiment of the invention.

[00140] According to some embodiments, removing the non-aqueous solvent in step 1040 is performed by evaporating the non-aqueous solvent at ambient temperature. According to some embodiments, removing the non-aqueous solvent in step 1040 is performed by performing rotary evaporation. According to some embodiments, removing the non-aqueous solvent in step 1040 is performed by applying of high vacuum.

[00141] Specifically, many organic solvents are conventionally evaporated using rotary evaporation, which applies reduced pressure to the composition, optionally with heating to promote the evaporation.

[00142] Also, it is to be understood that when the non-aqueous solvent is liquid or supercritical CO₂, it may be easily removed without any vacuum or heating as CO₂ is a gas at room temperature.

[00143] According to some embodiments, removing the non-aqueous solvent in step 1040 is performed by boiling the non-aqueous solvent at ambient temperature.

[00144] According to some embodiments, removing the non-aqueous solvent in step 1040 is performed by boiling or evaporating the non-aqueous solvent at elevated temperature.

[00145] According to some embodiments, removing the non-aqueous solvent in step 1040 is performed by freeze-drying the non-aqueous solvent. [00146] Freeze drying is a technology, wherein high vacuum is applied to a composition, which has been frozen, such that the solvent is a solid.

[00147] According to some embodiments, step 1040 comprises removing at least 50% of the non-aqueous solvent. According to some embodiments, step 1040 comprises removing at least 50% of the non-aqueous solvent. According to some embodiments, step 1040 comprises removing at least 60% of the non-aqueous solvent. According to some embodiments, step 1040 comprises removing at least 70% of the non-aqueous solvent. According to some embodiments, step 1040 comprises removing at least 80% of the non-aqueous solvent. According to some embodiments, step 1040 comprises removing at least 90% of the non-aqueous solvent. According to some embodiments, step 1040 comprises removing at least 95% of the non-aqueous solvent. According to some embodiments, step 1040 comprises removing at least 98% of the non-aqueous solvent. According to some embodiments, step 1040 comprises removing at least 99% of the non-aqueous solvent.

[00148] According to some embodiments, step 1040 comprises substantially removing of the non-aqueous solvent. According to some embodiments, the dried extract of step 1040 is substantially devoid of the non-aqueous solvent. According to some embodiments, the dried extract of step 1040 is substantially devoid of any organic solvent. According to some embodiments, the dried extract of step 1040 is substantially devoid of any toxic organic solvent. According to some embodiments, the dried extract of step 1040 is substantially devoid of any toxic solvent.

[00149] Specifically, as mentioned above, the optional step 1040 provides an opportunity to remove the non-aqueous solvent, which was introduced in the earlier step(s). Since cannabinoid compositions are typically designed to be administered to human subjects (e.g., via inhalation), and since some of the non-aqueous solvents are toxic upon such administration, it is preferable to substantially remove the non-aqueous solvent, according to some embodiments.

[00150] As used herein, “substantially devoid” means that a preparation, formulation or composition according to the invention that generally contains less than 5%, less than 3%, less than 1% or less than 0.5% of the stated substance. Each possibility represents a separate embodiment of the invention. The % fractions are typically determined in the w/w% scale. Thus, a composition, which weighs 100 grams, out of which less than 5, 3, 1 or 0.5 grams are of a toxic solvent(s), is considered to be substantially devoid of toxic solvent(s).

[00151] According to some embodiments, the dry extract of step 1040 comprises no more than 20% organic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 15% organic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 10% organic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 5% organic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 4% organic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 2% organic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 1% organic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 0.5% organic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 0.2% organic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no detectable amounts of organic solvents.

[00152] According to some embodiments, the dry extract of step 1040 comprises no more than 20% toxic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 15% toxic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 10% toxic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 5% toxic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 4% toxic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 2% toxic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 1% toxic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 0.5% toxic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 0.2% toxic solvents w/w. According to some embodiments, the dry extract of step 1040 comprises no detectable amounts of toxic solvents.

[00153] According to some embodiments, the dry extract of step 1040 comprises no more than 20% of the non-aqueous solvent(s) w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 15% of the non-aqueous solvent(s) w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 10% of the non-aqueous solvent(s) w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 5% of the non-aqueous solvent(s) w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 4% of the non-aqueous solvent(s) w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 2% of the non-aqueous solvent(s) w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 1% of the non-aqueous solvent(s) w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 0.5% of the non-aqueous solvent(s) w/w. According to some embodiments, the dry extract of step 1040 comprises no more than 0.2% of the non-aqueous solvent(s) w/w. According to some embodiments, the dry extract of step 1040 comprises no detectable amounts of the non-aqueous solvent(s).

[00154] According to some embodiments, the process further comprises step 1050, following step 1040 of measuring the amount of solvent(s) in the dried extract. According to some embodiments, the measured solvent(s) is the non-aqueous solvent(s). According to some embodiments, the measured solvent(s) is any organic solvent(s). According to some embodiments, the measured solvent(s) is any toxic organic solvent(s). According to some embodiments, the measured solvent(s) include specific toxic organic solvent(s). According to some embodiments, the measured solvent(s) is any toxic solvent(s). According to some embodiments, the measured solvent(s) include specific toxic solvent(s).

[00155] According to some embodiments, the process further comprises step 1060 of determining if the measured amount of the solvent(s) is over a predetermined threshold and repeating step 1040 if the amount is over the predetermined threshold. According to some embodiments, if the amount is not over the predetermined threshold the process proceeds to step 1070 or 1080.

[00156] According to some embodiments, the predetermined threshold is 20%, 15%, 10%, 5%, 3%, 1%, 0.5% or 0.1%. Each possibility represents a separate embodiment of the invention.

[00157] According to some embodiments, the process further comprises step 1070 of measuring the amount of the at least one cannabinoid acid in the extract. According to some embodiments, the process further comprises step 1070 of measuring the amount of the at least one cannabinoid acid in the extract formed in the preceding step. According to some embodiments, step 1070 of comprises measuring the amount of the at least one cannabinoid acid in the dried extract of any of steps 1040, 1050 and 1060 or in the liquid non-aqueous extract of any of steps 1010, 1020, 1030. According to some embodiments, step 1070 of comprises measuring the amount of the at least one cannabinoid acid in the dried extract step 1040. According to some embodiments, step 1070 of comprises measuring the amount of the at least one cannabinoid acid in the dried extract step 1050. According to some embodiments, step 1070 of comprises measuring the amount of the at least one cannabinoid acid in the dried extract step 1060. According to some embodiments, step 1070 of comprises measuring the amount of the at least one cannabinoid acid in the non-aqueous extract of step 1010. According to some embodiments, step 1070 of comprises measuring the amount of the at least one cannabinoid acid in the non-aqueous extract of step 1020. According to some embodiments, step 1070 of comprises measuring the amount of the at least one cannabinoid acid in the non-aqueous extract of step 1030.

[00158] As detailed below, the step following step 1070 is step 1080, in which the cannabinoid acid(s) is dissolved with a basic aqueous solution, which results in a basic cannabinoid acid salt solution, according to some embodiments. It is preferable that the composition produced in step 1080 is standard and includes relatively high cannabinoid acid salt concentration, according to some embodiments. For this sake, according to some embodiments, the amount of cannabinoid acid prior to step 1080 may be measured, so that appropriate amount of aqueous base can be added in step 1080. According to some embodiments, the measurement in optional step 1070 allows to determine and control the amount of aqueous base can be added in step 1080.

[00159] According to some embodiments, the measurement of the amount of at least one cannabinoid acid in the extract in step 1070 is selected from the group consisting of: gas chromatography (GC), high pressure liquid chromatography (HPLC) or both. For example, measurement of the amount of at least one cannabinoid acid in the extract in step 1070 may be achieve by comparing with a known amount of an analytical standard in GC and/or HPLC, as known in the art, according to some embodiments. [00160] It is to be understood that optional steps 1040, 1050, 1060 and 1070 are referred in the summary and claims of the present disclosure as step (b).

[00161] According to some embodiments, the process of the present invention further comprises step (c) of contacting the extract of step (a) or (b) with an appropriate amount of an aqueous base wherein the amount is appropriate for forming an aqueous cannabinoid solution comprising the at least one cannabinoid acid in a deprotonated form at a concentration in the range of 1% to 15% w/w.

[00162] According to some embodiments, the process of the present invention further comprises step 1080 of contacting the extract with an aqueous base. According to some embodiments, the process of the present invention further comprises step 1080 of contacting the extract with an appropriate amount of an aqueous base.

[00163] It is to be understood that the extract contacted with the aqueous base in step 1080 may be any one of the dried extracts of steps 1040, 1050, 1060 and 1070 or in the liquid non-aqueous extract of any of steps 1010, 1020, 1030 and 1070 based on which optional steps are carried out.

[00164] According to some embodiments, the amount of aqueous base contacted with the extract in step 1080 is sufficient for forming an aqueous cannabinoid solution comprising the at least one cannabinoid acid in a deprotonated form at a predetermined concentration.

[00165] It can be appreciated by the skilled in the are that cannabinoid acids, as other organic acids are somewhat acidic, and thus may undergo deprotonation of the carboxylic hydrogen at moderate - to high pH values. Such deprotonation may result in a that cannabinoid acid mono-basic salt via a single deprotonation. Furthermore, several cannabinoid acids, such as THCA, are phenol derivative, i.e., they include a slightly acidic hydroxyl bonded to the aromatic ring (e.g., position 1 of THCA). Such slight acidity is facilitated through resonative electronic-withdrawing effects from the carbonyl at position 2 and inductive electronic-withdrawing effects from the oxygen at position 5 (see above, in the definition of tetrahydrocannabinolic acid). Without wishing to be bound by any theory of mechanism of action, at higher pH values the aromatic hydroxyl of the cannabinoid acid(s) (e.g., THCA) is protonated to form dibasic cannabinoid acid salt(s), which are water soluble and stable in such aqueous conditions. [00166] Therefore, according to some embodiments, the sufficient or appropriate amount of aqueous base in step 1080 may be calculated or appreciated otherwise. According to some embodiments, the sufficient or appropriate amount of aqueous base in step 1080 may be calculated based on any one or more variables selected from the group consisting of: the amount of cannabinoid acid(s) in the extract, the concentration of the aqueous base, the pH of the aqueous base, the volume of the aqueous base, and the like.

[00167] According to some embodiments, the amount of aqueous base contacted with the extract in step 1080 is appropriate for forming an aqueous cannabinoid solution comprising the at least one cannabinoid acid in a deprotonated form at a predetermined concentration, wherein the predetermined concentration is at least 1% w/w. According to some embodiments, the predetermined concentration is at least 2% w/w. According to some embodiments, the predetermined concentration is at least 3% w/w. According to some embodiments, the predetermined concentration is at least 4% w/w. According to some embodiments, the predetermined concentration is at least 5% w/w. According to some embodiments, the predetermined concentration is at least 6% w/w. According to some embodiments, the predetermined concentration is at least 7% w/w. According to some embodiments, the predetermined concentration is at least 8% w/w. According to some embodiments, the predetermined concentration is at least 9% w/w. According to some embodiments, the predetermined concentration is at least 10% w/w. According to some embodiments, the predetermined concentration is at least 1% v/v. According to some embodiments, the predetermined concentration is at least 2% v/v. According to some embodiments, the predetermined concentration is at least 3% v/v. According to some embodiments, the predetermined concentration is at least 4% v/v. According to some embodiments, the predetermined concentration is at least 5% v/v. According to some embodiments, the predetermined concentration is at least 6% v/v. According to some embodiments, the predetermined concentration is at least 7% v/v. According to some embodiments, the predetermined concentration is at least 8% v/v. According to some embodiments, the predetermined concentration is at least 9% v/v. According to some embodiments, the predetermined concentration is at least 10% v/v.

[00168] According to some embodiments, the predetermined concentration is in the range of 1% to 20% w/w. According to some embodiments, the predetermined concentration is in the range of 1% to 20% w/w. According to some embodiments, the predetermined concentration is in the range of 1% to 15% w/w. According to some embodiments, the predetermined concentration is in the range of 1% to 10% w/w. According to some embodiments, the predetermined concentration is in the range of 2% to 10% w/w. According to some embodiments, the predetermined concentration is in the range of 3% to 10% w/w. According to some embodiments, the predetermined concentration is in the range of 4% to 10% w/w. According to some embodiments, the predetermined concentration is in the range of 5% to 10% w/w. According to some embodiments, the predetermined concentration is in the range of 3% to 8% w/w. According to some embodiments, the predetermined concentration is in the range of 1% to 20% v/v. According to some embodiments, the predetermined concentration is in the range of 1% to 20% v/v. According to some embodiments, the predetermined concentration is in the range of 1% to 15% v/v. According to some embodiments, the predetermined concentration is in the range of 1% to 10% v/v. According to some embodiments, the predetermined concentration is in the range of 2% to 10% v/v. According to some embodiments, the predetermined concentration is in the range of 3% to 10% v/v. According to some embodiments, the predetermined concentration is in the range of 4% to 10% v/v. According to some embodiments, the predetermined concentration is in the range of 5% to 10% v/v. According to some embodiments, the predetermined concentration is in the range of 3% to 8% v/v.

[00169] According to some embodiments, the appropriate amount of an aqueous base is determined based on the measured amount of the at least one cannabinoid acid, as measure in step 1070. According to some embodiments, the appropriate amount of an aqueous base is determined based on: the measured amount of the at least one cannabinoid acid, as measure in step 1070, the pH of the aqueous base, the base concentration in the aqueous base, or based on any combination thereof.

[00170] Specifically, basic aqueous salt solutions of cannabinoid acids may be produced in pure scientific research, for the subsequent isolation and chemical/physical characterization of the cannabinoid acids and salts. In such cases, the amount of water and bases are not being controlled, and are used in excess in order to extract the entire compounds of scientific interest. The present process, however, is directed to the production of aqueous cannabinoid compositions, which are for administration to users, and therefore, are required to have standard cannabinoid concentrations, which are relatively high, according to some embodiments. Thus, the present process recites contacting the extract with an appropriate amount of an aqueous base, which will result in acceptable product, which has a concentration suitable of administration, e.g., via inhalation, according to some embodiments.

[00171] According to some embodiments, the aqueous cannabinoid solution formed in step 1080 comprises the at least one cannabinoid acid in a deprotonated form at a predetermined concentration. The predetermined concentration is as described herein above.

[00172] According to some embodiments, the contacting of the extract with the aqueous base in step 1080 is performed for a period of time of at least 5 minutes. According to some embodiments, the contacting of the extract with the aqueous base in step 1080 is performed for a period of time of at least 15 minutes. According to some embodiments, the contacting of the extract with the aqueous base in step 1080 is performed for a period of time of at least 60 minutes. According to some embodiments, the contacting of the extract with the aqueous base in step 1080 is performed for a period of time of at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, at least 2 hours, at least 3 hours, at least 4 hours, at least 6 hours, least 12 hours or at least 24 hours. Each possibility represents a separate embodiment of the present invention.

[00173] According to some embodiments, step 1080 further comprises mixing the cannabinoid acids in the aqueous base solution. According to some embodiments, the contacting includes mixing. According to some embodiments, the mixing entails stirring. According to some embodiments, the stirring includes mechanical or magnetic stirring. According to some embodiments, the mixing entails shaking the extract in the aqueous base solution. According to some embodiments, the mixing includes performing sonication of the extract in the aqueous base. According to some embodiments, step 1080 is devoid of performing sonication.

[00174] As detailed herein, the extract contacted with the aqueous base in step 1080 may be any one of the dried extracts of steps 1040, 1050, 1060 and 1070 or in the liquid non-aqueous extracts of any of steps 1010, 1020, 1030 and 1070, according to some embodiments. The nature of the contacting is somewhat different in the case of dried extracts and in the case of liquid non-aqueous extract. Specifically, as can be appreciated by the skilled in the art, upon contacting a dried extract with the aqueous base, any compound, which is soluble in the basic aqueous solution (e.g., cannabinoid acids, such as THCA) will eventually dissolve therein, while any insoluble compound solution (e.g., neutral cannabinoids, such as THC), will remain as undissolved material out of the solution, which will constitute the main phase. However, upon contacting a non-aqueous extract, which is composed mainly of a non-aqueous solvent, a phase separation may result, according to some embodiments. Specifically, it is known that many solvents (e.g., alkanes, ethers, haloalkanle, aromatics) are water insoluble, and upon their contacting with water phase separation is witnessed. This phenomenon is often employed in liquid-liquid extractions. Liquid-liquid extraction (LLE), also known as solvent extraction and partitioning, is a method to separate compounds or metal complexes, based on their relative solubilities in two different immiscible liquids, usually water and an organic solvent. Thus, in embodiments referring to processes which are devoid of step 1040, a liquid-liquid extraction may be done between the non- aqueous phase and the basic aqueous, according to some embodiments. In such cases, the liquid-liquid extraction may also be referred as acid-base extraction, where the organic acids (e.g., the cannabinoid acid, such as THCA basic salt) will reside in the basic aqueous phase, and the other organic material (e.g., neutral cannabinoids, such as THC) will reside in the non-aqueous phase. Small scale equipment for LLEs (e.g., separatory funnel) as well as large scale equipment are known in the art.

[00175] The term “contacting” with respect to the operation of step 1080 is as defined with respect to step 1010.

[00176] According to some embodiments, the contacting of the extract the aqueous base is performed for a period of time of at least 5 minutes. According to some embodiments, the contacting of the extract the aqueous base is performed for a period of time of at least 15 minutes. According to some embodiments, the contacting of the extract the aqueous base is performed for a period of time of at least 60 minutes. According to some embodiments, the contacting of the extract the aqueous base is performed for a period of time of at least at least 5 minutes, at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 90 minutes, at least 2 hours, at least 3 hours, at least 4 hours, at least 6 hours, least 12 hours or at least 24 hours. Each possibility represents a separate embodiment of the present invention. [00177] According to some embodiments, step 1080 further comprises mixing the extract in the aqueous base. According to some embodiments, the contacting includes mixing. According to some embodiments, the mixing entails stirring. According to some embodiments, the stirring includes mechanical or magnetic stirring. According to some embodiments, the mixing entails shaking the extract with the aqueous base. According to some embodiments, the mixing includes performing sonication. According to some embodiments, step 1010 is devoid of performing sonication.

[00178] It is to be understood that mixing the extract and the cannabinoid acid thereof in the aqueous base solution may include a combination of stirring, shaking and/or sonicating, and the like.

[00179] According to some embodiments, the contacting of the extract with the aqueous base solution in step 1080 entails macerating the dry extract in the aqueous base solution.

[00180] According to some embodiments, the contacting of the dry extract with the aqueous base solution in step 1080 entails soaking the dry extract in the aqueous base solution.

[00181] It is to be understood that the soaking of step 1080 may include any of the embodiments specified with respect to mixing and/or contacting herein, according to some embodiments. For example, each of the embodiments relating to contacting time and mixing procedures (e.g., stirring, shaking etc.) may also relate to the soaking stage, according to some embodiments.

[00182] Also, as known in the art, in order to achieve exhaustive dissolution and acid-base reaction, sometimes repeated dissolutions are performed. According to some embodiments, the process comprises repeating step 1080 at least twice or three times. Each possibility represents a separate embodiment of the present invention.

[00183] According to some embodiments, step 1080 is the final step of the present process and produces the product aqueous cannabinoid composition. Therefore, some embodiment relating to the cannabinoid solution produced in step 1080 (step (c)) may similarly be applicable for the aqueous cannabinoid composition produced by the present process. According to some embodiments, the process further comprises step 1090 of collecting the aqueous cannabinoid composition. According to some embodiments, the process further comprises step 1090 of collecting the aqueous cannabinoid composition formed in step 1080.

[00184] According to some embodiments, the aqueous cannabinoid solution of step 1080 comprises the at least one cannabinoid acid in a deprotonated form at a concentration in the range of 4% to 6% w/w. According to some embodiments, the aqueous cannabinoid solution of step 1080 comprises the at least one cannabinoid acid in a deprotonated form at a concentration in the range of 1% to 10% w/w. According to some embodiments, the aqueous cannabinoid solution of step 1080 comprises the at least one cannabinoid acid in a deprotonated form at a concentration in the range of 2.5% to 10% w/w. According to some embodiments, the aqueous cannabinoid solution of step 1080 comprises the at least one cannabinoid acid in a deprotonated form at a concentration in the range of 3% to 7% w/w.

[00185] According to some embodiments, the aqueous base of step 1080 comprises water and a basic compound. According to some embodiments, the aqueous base of step 1080 consists of water and a basic compound.

[00186] According to some embodiments, the aqueous base of 1080 comprises a metal hydroxide, a metal carbonate or a combination thereof. Each possibility represents a separate embodiment of the present invention. According to some embodiments, the aqueous base of 1080 comprises a metal hydroxide. According to some embodiments, the basic compound is a metal hydroxide.

[00187] According to some embodiments, the aqueous base of step 1080 comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate or a combination thereof. Each possibility represents a separate embodiment of the present invention.

[00188] According to some embodiments, the aqueous base of step 1080 is selected from the group consisting of: sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide and any combination thereof. According to some embodiments, the aqueous base of step 1080 is selected from the group consisting of: sodium hydroxide, potassium hydroxide and any combination thereof.

[00189] According to some embodiments, the aqueous base comprises a hydroxide anion at a concentration in the range of 0.01M to 0.5M. According to some embodiments, the aqueous base comprises a hydroxide anion at a concentration in the range of 0.01M to 0.5M, 0.03M to 0.4M, 0.04M to 0.3M, 0.05M to 0.2M or 0.075M to 0.15M. Each possibility represents a separate embodiment of the present invention.

[00190] According to some embodiments, the aqueous base has a pH in the range of 12 to 13.5. According to some embodiments, the aqueous base has a pH in the range of 11 to 13.5, 11.5 to 13.5, 11.5 to 13, 12 to 13.5, 12.5 to 13.5, 11 or about 13. Each possibility represents a separate embodiment of the present invention.

[00191] According to some embodiments, the aqueous cannabinoid composition produced in step 1080 has a pH in the range of 9.5 to 11.5. According to some embodiments, the aqueous cannabinoid composition produced in step 1080 has a pH in the range of 10 to 11.5. According to some embodiments, the aqueous cannabinoid composition produced in step 1080 has a pH in the range of 10.5 to 11.5. According to some embodiments, the aqueous cannabinoid composition produced in step 1080 has a pH of about 11.

[00192] Specifically, it was found that the cannabinoid acid are both water-soluble stable in their salt form at pH values of around 11.

[00193] As detailed herein, step 1080 include contacting the extract with an appropriate amount of an aqueous base, according to some embodiments, wherein the amount of aqueous base contacted with the extract in step 1080 is appropriate for forming an aqueous cannabinoid solution comprising the at least one cannabinoid acid in a deprotonated form at a predetermined concentration. As further detailed herein, the optional measurement of the amount of cannabinoid acid(s) in step 1070 may serve as an indication to the appropriate amount of an aqueous base to be added in step 1080, according to some embodiments. Alternatively or in addition, measurements may be performed during the addition of the aqueous base in step 1080, in order to determine when enough aqueous base has been added, according to some embodiments. It is to be understood that such measurements may be done on the composition as a whole or on aliquot(s).

[00194] According to some embodiments, step 1080 comprises: adding the aqueous base to the extract gradually, while measuring the amount of at least one of: the at least one cannabinoid acid and the deprotonated cannabinoid acid, and ceasing the addition of aqueous base based on the measured amount.

[00195] According to some embodiments, ceasing the addition of aqueous base based on the measured amount entails ceasing the addition of aqueous base, upon the measured concentration of the at least one cannabinoid acid is below a predetermined threshold. According to some embodiments, the predetermined threshold of measured cannabinoid acid concentration, below which the addition of aqueous base is ceased, is 2%, 1.5%, 1%, 0.5%, 0.25% or 0.1% w/w compared to the total weight of the aqueous cannabinoid solution. Each possibility represents a separate embodiment of the present invention. According to some embodiments, the predetermined threshold of measured cannabinoid acid concentration, below which the addition of aqueous base is ceased, is 15%, 10%, 7.5%, 5%, 2.5% or 1% w/w compared to the weight of the cannabinoid acid as measured in step 1070. Each possibility represents a separate embodiment of the present invention.

[00196] According to some embodiments, ceasing the addition of aqueous base based on the measured amount entails ceasing the addition of aqueous base, upon the measured concentration of the deprotonated cannabinoid acid is over a predetermined threshold. According to some embodiments, the predetermined threshold of measured deprotonated cannabinoid acid concentration, above which the addition of aqueous base is ceased, is 3%, 4%, 4.5%, 5%, 5.5% or 6% w/w compared to the total weight of the aqueous cannabinoid solution. Each possibility represents a separate embodiment of the present invention.

[00197] According to some embodiments, step 1080 comprises: adding the aqueous base to the extract gradually, while measuring the amount of both the at least one cannabinoid acid and the deprotonated cannabinoid acid, and ceasing the addition of aqueous base based on both measured amounts. [00198] According to some embodiments, wherein step 1080 comprises: adding the aqueous base to the extract gradually, while measuring the amount of at least one of cannabinoid acid, and ceasing the addition of aqueous base, upon the measured amount of deprotonated cannabinoid acid being equal or lower than a predetermined value.

[00199] According to some embodiments, wherein step 1080 comprises: adding the aqueous base to the extract gradually, while measuring the amount of at least one of deprotonated cannabinoid acid, and ceasing the addition of aqueous base, upon the measured amount of deprotonated cannabinoid acid being equal or higher than a predetermined value, which indicates that the concentration of the deprotonated cannabinoid acid in the aqueous cannabinoid solution is in the range of 1% to 15% w/w.

[00200] According to some embodiments, the measurement of the protonated or deprotonated cannabinoid acid in step 1080 is carried out using gas chromatography (GC), high pressure liquid chromatography (HPLC) or both. For example, measurement of the amount of the protonated or deprotonated cannabinoid acid may be achieve by comparing with a known amount of an analytical standard in GC and/or HPLC, as known in the art, according to some embodiments.

[00201] It is to be understood that optional step 1080 is referred in the summary and claims of the present disclosure as step (c).

[00202] According to some embodiments, the process further comprises step 1100 of measuring the amount of the deprotonated at least one cannabinoid acid in the aqueous cannabinoid solution of step 1080, after completing the addition of the aqueous base. According to some embodiments, as shown in subsequent step 1110, if the amount of the deprotonated at least one cannabinoid acid is below a predetermined threshold, the process further comprises additional steps 1120, 1130 and 1140. According to some embodiments, if the amount of the deprotonated at least one cannabinoid acid is above a predetermined threshold, the process proceeds to one of steps 1150, 1160, 1170 or finalized at step 1090. According to some embodiments, the predetermined threshold is 1% w/w, based on the total weight of the aqueous cannabinoid solution. According to some embodiments, the predetermined threshold is 1% w/w, based on the total weight of the aqueous cannabinoid solution. According to some embodiments, the predetermined threshold is 2% w/w, based on the total weight of the aqueous cannabinoid solution. According to some embodiments, the predetermined threshold is 3% w/w, based on the total weight of the aqueous cannabinoid solution. According to some embodiments, the predetermined threshold is 4% w/w, based on the total weight of the aqueous cannabinoid solution. According to some embodiments, the predetermined threshold is 5% w/w, based on the total weight of the aqueous cannabinoid solution. According to some embodiments, the predetermined threshold is 6% w/w, based on the total weight of the aqueous cannabinoid solution.

[00203] As detailed herein, measurement of deprotonated cannabinoid acid below a predetermined threshold in step 1110 indicated insufficient production of product, according to some embodiments. In this case, according to some embodiments, improved yield may be achieved via an additional acid-base sequence of steps, in which an acid is added to the basic aqueous composition (step 1120) to form protonated cannabinoid acid precipitate; the precipitate is separated from the aqueous phase (step 1030) and re-dissolved in an aqueous base (1040).

[00204] According to some embodiments, if the amount of the deprotonated at least one cannabinoid acid is below a predetermined threshold the process further comprises step 1120 adding an acid to the composition produced in step 1080.

[00205] According to some embodiments, the acid is a mineral acid. According to some embodiments, the acid is an aqueous acid. According to some embodiments, the acid is selected from the group consisting of: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and a combination thereof.

[00206] According to some embodiments, step 1120 comprises adding an acid to the composition produced in 1080 to a pH in the range of 1-5. According to some embodiments, the addition is to a pH in the range of 2-5, 3-5 or 3.5 to 4.5. Each possibility represents a separate embodiment of the present invention.

[00207] According to some embodiments, step 1120 comprises adding an acid to the composition produced in 1080 thereby precipitating the at least one cannabinoid acid or salt thereof. According to some embodiments, step 1120 comprises adding an acid to the composition produced in 1080 thereby precipitating the at least one cannabinoid acid or salt thereof and forming an acidic aqueous solution. [00208] According to some embodiments, the process further comprises step 1130 of separating the precipitate of step 1120 from the acidic aqueous solution. According to some embodiments, the separation of step 1130 comprises filtering the precipitated cannabinoid acid from the acidic aqueous solution. According to some embodiments, the separation of step 1130 further comprises washing the precipitate from residual acidic aqueous solution with water. According to some embodiments, step 1130 comprises repeating said washing two or three times. Each possibility represents a separate embodiment of the present invention.

[00209] According to some embodiments, the process further comprises step 1140 of dissolving the precipitated cannabinoid acid of step 1130 in a second aqueous base. According to some embodiments, the process further comprises step 1140 of dissolving the precipitated cannabinoid acid of step 1130 in a second aqueous base, thereby forming a purified aqueous cannabinoid solution comprising the at least one cannabinoid acid in a deprotonated form. According to some embodiments, the process further comprises step 1140 of dissolving the precipitated cannabinoid acid of step 1130 in a second aqueous base, thereby forming a purified aqueous cannabinoid solution comprising the at least one cannabinoid acid in a deprotonated form at a concentration in the range of 1% to 15% w/w.

[00210] According to some embodiments, the aqueous cannabinoid solution of step 1140 comprises the at least one cannabinoid acid in a deprotonated form at a concentration in the range of 4% to 6% w/w. According to some embodiments, the aqueous cannabinoid solution of step 1140 comprises the at least one cannabinoid acid in a deprotonated form at a concentration in the range of 1% to 10% w/w. According to some embodiments, the aqueous cannabinoid solution of step 1140 comprises the at least one cannabinoid acid in a deprotonated form at a concentration in the range of 2.5% to 10% w/w. According to some embodiments, the aqueous cannabinoid solution of step 1140 comprises the at least one cannabinoid acid in a deprotonated form at a concentration in the range of 3% to 7% w/w.

[00211] According to some embodiments, the process of the present invention further comprises step 1150 of adding concentrated base to the aqueous cannabinoid solution of step 1080 or step 1140. According to some embodiments, the process of the present invention further comprises step 1150 of adding concentrated base to the aqueous cannabinoid solution of step 1080. According to some embodiments, the process of the present invention further comprises step 1150 of adding concentrated base to the aqueous cannabinoid solution of step 1140.

[00212] According to some embodiments, the addition of the concentrated base to the aqueous cannabinoid solution in step 1150 is made so the resulting pH of the aqueous cannabinoid solution adjusted to be in the range of 10 to 11.5. According to some embodiments, the addition of the concentrated base to the aqueous cannabinoid solution is made so the resulting pH of the aqueous cannabinoid solution adjusted to be in the range of 10 to 11.5, 9.5 to 11.5 or 10.5 to 11.5. Each possibility represents a separate embodiment of the present invention.

[00213] According to some embodiments, the concentrated base in step 1150 is a concentrated aqueous base solution or a neat base. According to some embodiments, the concentrated base in step 1150 is neat NaOH.

[00214] According to some embodiments, the process further comprises optional step 1160 of isolating the aqueous cannabinoid solution formed in step 1080 from residual insoluble plant material. According to some embodiments, the process further comprises optional step 1160 of isolating the aqueous cannabinoid solution formed in any one of steps 1080, 1140 or 1150 from residual insoluble plant material.

[00215] According to some embodiments, isolating the aqueous cannabinoid solution from the insoluble plant material in step 1160 is performed by filtration, centrifugation or both. According to some embodiments, isolating the aqueous cannabinoid solution from the insoluble plant material in step 1160 is performed by filtration. According to some embodiments, isolating the aqueous cannabinoid solution from the insoluble plant material in step 1160 is performed by centrifugation. According to some embodiments, isolating the aqueous cannabinoid solution from the insoluble plant material in step 1160 is performed by filtration and centrifugation. According to some embodiments, isolating the aqueous cannabinoid solution from the insoluble plant material in step 1160 comprises filtration of the aqueous cannabinoid solution from the insoluble plant material and then centrifugation of the aqueous cannabinoid solution, to remove insoluble plant remains.

[00216] According to some embodiments, the filtration of step 1160 is performed using a mesh filter. According to some embodiments, the centrifugation of step 1160 is performed using a centrifuge at a spin rate in the range of 1,000 to 10,000 RPM. According to some embodiments, the rate is about 5,000 RPM. According to some embodiments, the centrifugation is performed for 2 to 30 minutes. According to some embodiments, the centrifugation is performed for about 5 minutes.

[00217] According to some embodiments, the process further comprises optional step 1170 of removing residual organic solvents from the aqueous cannabinoid solution.

[00218] The term “residual” as used herein refers to the portion of organic solvent remaining behind in a composition after removal of a majority of the organic solvent by physical separation, such as filtration, and/or low temperature flash evaporation.

[00219] In Figure 1 optional steps are presented inside dashed rectangular blocks. Optional steps may be performed as part of the process of the present invention, according to some embodiments, and they are also designated in the Figure as “OPT.”, standing for "optional". If an optional step is not performed, the process may proceed to the next step, according to some embodiments. Rhombus-shaped block are designating decisions, where upon, e.g., a measured result, the process proceed in a certain fashion. Arrows are generally full line, shown the direction of process progress.

[00220] Optional step 1020 has one arrow pointed to step 1030 and another arrow pointed to step 1040. Each of the routes, individually, or can complete that present process, as both are optional, according to some embodiments. Also, both step 1030 and 1040 can be performed, according to some embodiments, e.g. in the route: (previous step)

(next step); or in the route: (previous

p (next step). Also, as both step 1030 and 1040 are optional, step 1020, if performed, may proceed directly to step 1080.

[00221] Optional step 1040 has one arrow pointed to step 1050 and another arrow pointed to step 1070. Each of the routes, individually, or can complete that present process, as both are optional, according to some embodiments. Also, both step 1050 and 1070 can be performed, according to some embodiments, e.g. in the route: (previous step) (next

step). Also, as both step 1050 and 1070 are optional, step 1040, if performed, may proceed directly to step 1080.

[00222] Similarly, step 1080 may either proceed directly to final step 1090, without further steps or indirectly via any one or more of steps 1100, 1110, 1120, 1130, 1140, 1150, 1160 and/or 1170. The following are optional, non-limiting routes according to some embodiments:

[00233] According to some embodiments, there is provided an aqueous cannabinoid composition prepared by a process as disclosed herein.

[00234] According to some embodiments, the aqueous cannabinoid composition formed by the process of the present invention is substantially devoid of organic solvents. According to some embodiments, the aqueous cannabinoid composition is substantially devoid of any toxic organic solvent. According to some embodiments, the dried extract of step 1040 is substantially devoid of any toxic solvent.

[00235] According to some embodiments, the aqueous cannabinoid composition comprises no more than 2% organic solvents w/w. According to some embodiments, the aqueous cannabinoid composition comprises no more than 1% organic solvents w/w. According to some embodiments, the aqueous cannabinoid composition comprises no more than 0.5% organic solvents w/w. According to some embodiments, the aqueous cannabinoid composition comprises no more than 0.2% organic solvents w/w. According to some embodiments, the aqueous cannabinoid composition comprises no more than 0.1% organic solvents w/w. According to some embodiments, the aqueous cannabinoid composition comprises no detectable amounts of organic solvents. According to some embodiments, the aqueous cannabinoid composition comprises no more than 1% hexane w/w. According to some embodiments, the aqueous cannabinoid composition comprises no more than 0.1% hexane w/w.

[00236] According to some embodiments, the aqueous cannabinoid composition comprises at least 90% w/w water.

[00237] According to some embodiments, the aqueous cannabinoid composition is for use in the administration of the cannabinoid via inhalation.

[00238] According to some embodiments, there is provided a cannabinoid composition, the composition comprises an aqueous solution comprising at least one cannabinoid compound, wherein the aqueous solution has a pH of at least 8.5, wherein the aqueous solution is prepared by the process of the present invention. According to some embodiments, the cannabinoid compound is a deprotonated cannabinoid acid.

[00239] According to some embodiments, the cannabinoid composition is suitable for use in the administration of a cannabinoid via inhalation

[00240] According to some embodiments, the aqueous solution has a pH of at least 8.5, at least 9 at least 9.5 at least 10 at least 10.5, or at least 11. Each possibility represents a separate embodiment of the present invention.

[00241] The term "solution" as used herein broadly refers to a combination, mixture and/or admixture of ingredients having at least one liquid component. Thus, the term "aqueous solution" refers to any solution, in which at least one of its liquid components is water, wherein at least 50% of its weight is water. Aqueous solutions typically include water in greater quantity or volume than a solute. Typical additional solvents include alcohols, aldehydes, ketones, sulfoxides, sulfones, nitriles and/or any other suitable solubilizing molecule or carrier compound. Preferably, "solution" refers broadly to a mixture of miscible substances, where one substance dissolves in a second substance. More preferably, in a solution the essential components are homogeneously mixed and that the components are subdivided to such an extent that there is no appearance of light scattering visible to the naked eye when a one-inch diameter bottle of the mixture is viewed in sunlight. [00242] According to some embodiments, the composition is provided in a kit, wherein the kit comprises the cannabinoid composition of the present invention and further comprises instructions for use via inhalation.

[00243] According to some embodiments, the cannabinoid composition is consisting of the aqueous solution.

[00244] As used herein the terms "formulation" and "compositions" generally refer to any mixture, solution, suspension or the like that contains an active ingredient, such as cannabinoid, and, optionally, a carrier. The carrier may be any carrier acceptable for smoking, that is compatible for delivery with the active agent.

[00245] According to some embodiments, the concentration of the at least one cannabinoid compound in the aqueous solution is in the range of 0.1% to 10% w/w. According to some embodiments, the concentration of the at least one cannabinoid compound in the aqueous solution is in the range of 0.5% to 10% w/w. According to some embodiments, the concentration of the at least one cannabinoid compound in the aqueous solution is in the range of 1% to 10% w/w. According to some embodiments, the concentration of the at least one cannabinoid compound in the aqueous solution is in the range of 2% to 10% w/w. According to some embodiments, the concentration of the at least one cannabinoid compound in the aqueous solution is in the range of 4% to 6% w/w.

[00246] As used herein, the term "about" refers to a range of values ± 20%, or ± 10% of a specified value. For example, the phrase "the percentage is about 5% w/w " includes ± 20% of 5, or from 4% to 6%, or from 4.5% to 5.5%.

[00247] According to some embodiments, the at least one cannabinoid is the sole active ingredient in the cannabinoid composition. According to some embodiments, the composition comprises cannabinoid(s) as the only active ingredient.

[00248] According to some embodiments, the cannabinoid composition further comprises at least one carrier acceptable for inhalation. According to some embodiments, the carrier is stable under basic pH conditions. According to some embodiments, the carrier is water soluble under basic pH conditions. According to some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, which is acceptable for inhalation. According to some embodiments, the pharmaceutically acceptable carrier is stable under basic pH conditions. According to some embodiments, the pharmaceutically acceptable carrier is water soluble under basic pH conditions.

[00249] According to some embodiments, the cannabinoid composition further comprises at least one stabilizer. According to some embodiments, the stabilizer is stable under basic pH conditions. According to some embodiments, the stabilizer is water soluble under basic pH conditions.

[00250] According to some embodiments, the cannabinoid composition further comprises at least one additive selected from the group consisting of a propellant, an anti-coughing agent and a flavorant. According to some embodiments, the cannabinoid composition further comprises at least one additive selected from the group consisting of, an anti-coughing agent and a flavorant. According to some embodiments, the cannabinoid composition further comprises at least one anti-coughing agent. According to some embodiments, the cannabinoid composition further comprises at least one flavorant.

[00251] Thus, according to some embodiments, the process further comprises adding to the formed solution a carrier, stabilizer, propellant, an anti-coughing agent, flavorant or a combination thereof (not numbered in Figure 1). Each possibility represents a separate embodiment of the present invention. According to some embodiments, the additive is approved for use in inhaling solutions. According to some embodiments, the additive is stable at basic aqueous conditions. According to some embodiments, the additive is soluble at basic aqueous conditions.

EXAMPLES

[00252] Example 1: Preparation of formulation for inhalation (ethanol extraction)

[00253] The formulation for inhalation analyzed in the experiments below included a stable aqueous composition of tetrahydrocannabinolic acid (THCA) adjusted to pH ~ 9.5. The stable aqueous composition was prepared by grinding a 1.8 gr sample of THCA-enriched cannabis species and placing the ground plant material in a glass vessel. About 0.1 liters of ethanol was added to the glass vessel and the mixture was stirred/left over night. All the material was then transferred from the glass vessel to a stainless-steel mesh and the plant material was macerated by application of physical pressure. The liquid contents were then centrifuged and a clear ethanol solution was separated from the solids and collected. The solution was visibly clear. The solution was heated gently to evaporate ethanol until it was concentrated to about 10 ml. The formed solution was measured by HPLC to contain about 37.87 mg/ml THCA.

[00254] An aliquot of 2.64 ml of the above ethanolic solution was placed in a glass vial and dried under air-flow. One milliliter (1 ml) of a 0.1M aqueous NaOH solution was added to the dried extract and agitated using a vortex. The mixture was centrifuged to remove sediments. The pH of the clear liquid mixture was about 9.5 and the THCA concentration was measured by HPLC to be 66 mg/ml (6.6%).

[00255] The formulation was aerosolized from an electronic vaporizer designed by Omega Life Science for aerosolization of aqueous compositions. The aerosol was collected and its pH was measured to be substantially neutral, indicating that the THCA underwent decarboxylation to form the pH neutral compound THC in the aerosol

[00256] Example 2: Preparation of formulation for inhalation (acetone extraction)

[00257] Another formulation for inhalation includes a stable aqueous composition of tetrahydrocannabinolic acid (THCA) adjusted to pH ~ 9.5. The stable aqueous composition is prepared by grinding a 1.8 gr sample of THCA-enriched cannabis species and placing the ground plant material in a glass vessel. About 0.1 liters of acetone are added to the glass vessel and the mixture is stirred/left over night. All the material is then transferred from the glass vessel to a stainless-steel mesh and the plant material was macerated by application of physical pressure. The liquid contents are then centrifuged and a clear acetone solution is separated from the solids and collected. The solution was visibly clear. The solution is heated gently to evaporate acetone until it is concentrated to about 10 ml. The formed solution is measured by HPLC to contain about 30-40 mg/ml THCA.

[00258] An aliquot of 2.64 ml of the above acetone solution is placed in a glass vial and dried under air-flow. One milliliter (1 ml) of a 0.1M aqueous NaOH solution is added to the dried extract and agitated using a vortex. The mixture is centrifuged to remove sediments. The pH of the clear liquid mixture is about 9.5 and the THCA concentration is measured by HPLC to be about 50-70 mg/ml (5-7 %). [00259] Example 3: Preparation of formulation for inhalation (acetonitrile extraction)

[00260] Another formulation for inhalation includes a stable aqueous composition of tetrahydrocannabinolic acid (THCA) adjusted to pH ~ 9.5. The stable aqueous composition is prepared by grinding a 1.8 gr sample of THCA-enriched cannabis species and placing the ground plant material in a glass vessel. About 0.1 liters of acetonitrile are added to the glass vessel and the mixture is stirred/left over night. All the material is then transferred from the glass vessel to a stainless-steel mesh and the plant material was macerated by application of physical pressure. The liquid contents are then centrifuged and a clear acetonitrile solution is separated from the solids and collected. The solution was visibly clear. The solution is heated gently to evaporate acetonitrile until it is concentrated to about 10 ml. The formed solution is measured by HPLC to contain about 30-40 mg/ml THCA.

[00261] An aliquot of 2.64 ml of the above acetonitrile solution is placed in a glass vial and dried under air-flow. One milliliter (1 ml) of a 0.1M aqueous NaOH solution is added to the dried extract and agitated using a vortex. The mixture is centrifuged to remove sediments. The pH of the clear liquid mixture is about 9.5 and the THCA concentration is measured by HPLC to be about 50-70 mg/ml (5-7 %).

Example 4: Analysis of the formulation for inhalation

The exemplary formulation was checked for the relative amounts of the cannabinoids THC and THCA in a Dionex ultimate 3000 HPLC system with the mobile phase being 90% acetonitrile/ 10% water/0.1% formic acid and the stationary phase being reverse phase C18 column. The column oven temperature was set to 35°C and the flow was set to 1 ml/min. The UV detection was at 220nm. The elution time were compared with elution times of THC and THCA as known in the literature.

Figure 2 is showing the chromatogram resulting from the elution of the formulation of Example 1, without further processing, with the mobile phase being 90% acetonitrile/ 10% water/0.1% formic acid. This chromatogram shows a large peak at retention time of about 5.9 minutes, which is comparable with the value of a THCA sample, and a small peak at about 3.8 minutes, which is comparable with the value of a THC sample. Therefore, it is concluded that the formulation of the current invention comprises mainly THCA, which in basic conditions appears as a basic salt.

Example 5: Mass Distribution on Impactor parts:

Particle size distribution testing was conducted using cascade impactor validated method with the basic aqueous composition of tetrahydrocannabinolic acid of Example 1. The limits for the median diameter range from 0.36 to 11.72 micron. The results are presented in Figure 3 and relate to the formulation of example 1 aerosolized with an electronic vaporizer mentioned in Example 1.

Relative mass of the aerosolized solution was measured against its particle size, which was measured between 0.46 micrometers and over 11.72 micrometers.

Figure 3 is a chart representing Mass Distribution on Impactor parts in an aerosol depicting the relative mass of the aerosol in each particle diameter size group, where the particle diameter groups are: below 0.36 micron, 0.36 to 0.54 microns; 0.54 to 0.83 microns; 0.83 to 1.36 microns; 1.36 to 2.3 microns; 2.3 to 3.99 microns; 3.99 to 6.4 microns; 6.4 to 11.72 microns; and over 11.72 microns.

As can be seen in Figure 3, the majority of aerosol mass was provided in droplets having diameters below 0.36 micron.

Finally, Figure 4 is a chart representing cumulative Mass Distribution of the aerosol in the experiment. It depicts the cumulative mass fraction vs. the droplet size in micrometers. The 50% mark in the cumulative percentage axis represents the estimated value of particle size, above which the droplets are responsible to half to mass and below which the droplets are responsible to the other half. The MMAD was measured to be 0.043 micron and the GSD 4.80 micron.

[00262] Although the invention is described in conjunction with specific embodiments thereof, it is evident that numerous alternatives, modifications and variations that are apparent to those skilled in the art may exist. It is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth herein. Other embodiments may be practiced, and an embodiment may be carried out in various ways. Accordingly, the invention embraces all such alternatives, modifications and variations that fall within the scope of the appended claims.

Claims

1. A process for the preparation of an aqueous cannabinoid composition, the process comprising:

(b) optionally removing the non-aqueous solvent to provide a dry extract;

2. The process according to claim 1, wherein the non-aqueous solvent of step (a) is a non-toxic solvent.

3. The process according to claim 1, wherein the non-aqueous solvent of step (a) is selected from the group consisting of supercritical CO₂, liquid CO₂, an alcohol, an ester, a ketone, an ether, an alkane, a haloalkane and combinations thereof.

4. The process according to claim 3, wherein the non-aqueous solvent is selected from the group consisting of supercritical CO₂, liquid CO₂, ethanol, n- propanol isopropanol, ethyl acetate, acetone, diethyl ether, tetrahydrofuran, methyl tert-butyl ether, pentane, hexane, heptane, dichloromethane, chloroform and combinations thereof.

5. The process according to claim 4, wherein the non-aqueous solvent is selected from the group consisting of ethanol, acetone, hexane and combinations thereof.

6. The process according to any one of claims 1 to 5, wherein the aqueous base of step (c) comprises a metal hydroxide, a metal carbonate or a combination thereof.

7. The process according to any one of claims 1 to 5, wherein the aqueous base of step (c) comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate or a combination thereof.

8. The process according to any one of claims 1 to 6, wherein the aqueous base comprises a hydroxide anion at a concentration in the range of 0.01M to 0.5M.

9. The process according to any one of claims 1 to 8, wherein the aqueous base has a pH in the range of 12 to 13.5.

10. The process according to any one of claims 1 to 9, wherein the aqueous cannabinoid solution of step (c) comprises the at least one cannabinoid acid in a deprotonated form at a concentration in the range of 4% to 6% w/w.

11. The process according to any one of claims 1 to 10, wherein the aqueous cannabinoid composition has a pH in the range of 9.5 to 11.5.

12. The process according to any one of claims 1 to 10, wherein step (c) further comprises adding concentrated base to the aqueous cannabinoid solution thereby adjusting the pH of the aqueous cannabinoid solution to be in the range of 10 to 11.5.

13. The process according to any one of claims 1 to 12, wherein the aqueous cannabinoid composition is substantially devoid of organic solvents.

14. The process according to any one of claims 1 to 13, comprising step (b) of removing the non-aqueous solvent to provide a dry extract.

15. The process according to claim 14, wherein removing the non-aqueous solvent to provide a dry extract is performed by evaporating the non-aqueous solvent at ambient temperature, boiling the non-aqueous solvent at ambient temperature, boiling or evaporating the non-aqueous solvent at elevated temperature, freeze-drying the non-aqueous solvent, performing rotary evaporation, applying of high vacuum or by a combination thereof.

16. The process according to any one of claims 14 to 15, wherein the dry extract comprises no more than 1% organic solvents w/w.

17. The process according to any one of claims 1 to 16, wherein step (c) further comprises removing residual organic solvents from the aqueous cannabinoid solution.

18. The process according to any one of claims 1 to 17, wherein step (c) further comprises isolating the aqueous cannabinoid solution from residual insoluble plant material.

19. The process according to claim 18, wherein isolating the aqueous cannabinoid solution from residual insoluble plant material is performed by filtration, centrifugation or both.

20. The process according to any one of claims 14 to 16, wherein step (b) further comprises measuring the amount of the at least one cannabinoid acid in the dry extract, wherein step (c) further comprises determining the appropriate amount of an aqueous base based on the measured amount of the at least one cannabinoid acid.

21. The process according to any one of claims 1 to 20, wherein step (c) comprises: adding the aqueous base to the extract of step (a) or (b) gradually, while measuring the amount of at least one of: the at least one cannabinoid acid and the deprotonated cannabinoid acid, and ceasing the addition of aqueous base based on the measured amount.

22. The process according to claim 21, wherein step (c) comprises: adding the aqueous base to the extract of step (a) or (b) gradually, while measuring the amount of at least one of deprotonated cannabinoid acid, and ceasing the addition of aqueous base, upon the measured amount of deprotonated cannabinoid acid being equal or higher than a predetermined value, which indicates that the concentration of the deprotonated cannabinoid acid in the aqueous cannabinoid solution is in the range of 1% to 15% w/w.

23. The process according to claim 21, wherein step (c) comprises: adding the aqueous base to the extract of step (a) or (b) gradually, while measuring the amount of at least one of cannabinoid acid, and ceasing the addition of aqueous base, upon the measured amount of deprotonated cannabinoid acid being equal or lower than a predetermined value.

24. The process according to any one of claims 1 to 23, wherein step (a) further comprises isolating the non-aqueous extract from the insoluble plant material.

25. The process according to claim 24, wherein isolating the non-aqueous extract from the insoluble plant material is performed by filtration, centrifugation or both.

26. The process according to any one of claims 1 to 25, wherein step (a) comprises grinding raw cannabis plant material and contacting the ground cannabis plant material with a non-aqueous solvent, to provide a non-aqueous extract comprising at least one cannabinoid acid and insoluble plant material.

27. The process according to any one of claims 1 to 26, wherein the contacting of the cannabis plant material with the non-aqueous solvent in step (a) entails soaking the cannabis plant material in the non-aqueous solvent of at least 15 minutes.

28. The process according to claim 27, wherein the soaking is performed for of at least 60 minutes.

29. The process according to any one of claims 1 to 28, wherein the process further comprises the steps of:

(d) adding an acid to the composition produced in step (c) to a pH in the range of 1-5, thereby precipitating the at least one cannabinoid acid or salt thereof and forming an acidic aqueous solution;

(e) separating the precipitated at least one cannabinoid acid or salt thereof from the acidic aqueous solution; and

(f) dissolving the precipitated at least one cannabinoid acid or salt thereof in a second aqueous base, thereby forming a purified aqueous cannabinoid solution comprising the at least one cannabinoid acid in a deprotonated form at a concentration in the range of 1% to 15% w/w.

30. The process according to claim 29, wherein the acid of step (d) is a mineral acid.

31. The process according to any one of claims 29 to 30, wherein the pH of the acidic aqueous solution of step (d) is in the range of 3.5 to 4.5.

32. The process according to any one of claims 29 to 31, wherein the second aqueous base of step (f) comprises a hydroxide anion at a concentration in the range of 0. 01M to 0.5M.

33. The process according to any one of claims 1 to 32, wherein the cannabis plant material comprises a THCA-enriched cannabis species.

34. The process according to any one of claims 1 to 33, wherein the at least one cannabinoid acid comprises tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) or a combination thereof.

35. The process according to claim 34, wherein the at least one cannabinoid acid comprises THCA.

36. An aqueous cannabinoid composition prepared by a process according to any one of claims 1 to 35.

37. The aqueous cannabinoid composition according to claim 36, comprising at least 90% w/w water.

38. The aqueous cannabinoid composition according to any one of claims 1 to 37, which is for use in the administration of the cannabinoid via inhalation.