Process for the production of thc

Abstract

The present invention provides a process for the production of THC comprising contacting a first non-halogenated non-polar solvent with a non-decarboxylated plant material; separating a first mixture comprising the non-halogenated non-polar solvent and THCA from the non-decarboxylated plant material; separating the first non-halogenated nonpolar solvent from the first mixture to yield an extract comprising THC and a first non-halogenated non-polar solvent content equal to or less than 5% w / w, as determined by GC-MS; mixing the THCA extract with a second non-halogenated non-polar solvent to yield a second mixture having a weight / volume ratio of THCA extract to the second non- halogenated non-polar solvent ranging from 1:0.15 to 1:0.5; maintaining the second mixture at an appropriate temperature and time to obtain THCA crystals; separating the THCA crystals from the second mixture; and decarboxylating the THCA crystals at a temperature ranging from 120°C to 160°C, during a time ranging from 30 to 110 minutes. The invention also relates to a THC having a purity of at least 95% w / w, containing 0.10% w / w CBC or less.

Description

[0001] Process for the production of THC

[0002] This application claims the benefit of European Patent Application EP24383421.5 filed on 20 December 2024.

[0003] Technical Field

[0004] The present invention belongs to the field of production of cannabinoid products from plant materials. In particular, the invention relates to a process for the production of THC from non-decarboxylated plant materials, and to a THC having a purity of at least 95% w / w and containing 0.10% w / w cannabichromene (CBC) or less, as determined by HPLC.

[0005] Background Art

[0006] The therapeutic use of tetrahydrocannabinol (THC) has gained significant importance in recent years for treating various health conditions, including chronic pain, nausea from chemotherapy, and muscle spasticity in multiple sclerosis. To effectively utilize THC, however, the active compound must be extracted and purified from the cannabis plant, which involves several complex steps. THC is primarily obtained from cannabis through a process called decarboxylation, which converts inactive cannabinoid acids into their active forms. Decarboxylation is crucial for maximizing the potency and effectiveness of THC, as well as other cannabinoids like cannabinol (CBN), cannabidiol (CBD) and cannabigerol (CBG).

[0007] When cannabis is freshly harvested, most cannabinoids are present in their acid form, meaning they contain a carboxyl group (-COOH) in their molecular structure. Decarboxylation is the process by which this carboxyl group is removed, activating compounds like tetrahydrocannabinolic acid (THCA) and converting it to THC. This conversion produces the active components of cannabis, which interact with the body’s endocannabinoid system to deliver therapeutic effects.

[0008] Decarboxylation can happen naturally over time as plant material is exposed to air or warmth; however, this process is slow. To expedite decarboxylation, heat is typically applied to the plant material. Decarboxylating plant material yields high quantities of neutral (non-acidic) cannabinoids, which are less polar and therefore easier to extract with non-polar solvents like hexane or CO2, commonly used in cannabinoid purification processes. However, direct decarboxylation of the plant material requires large furnaces, is energy-intensive, and demands a complex workflow. As a result, many opt to decarboxylate the extract after the initial extraction, which requires smaller furnaces and simplifies the process, however, purification of THC-containing extracts becomes difficult, which involves separating it from other compounds with very similar properties. After obtaining a decarboxylated THC-rich extract, as THC does not crystallize spontaneously, chromatography either solid-liquid or liquid-liquid is therefore required to purify the compound and achieve high purity levels.

[0009] Chromatography is an expensive technique due to the need for specialized equipment and significant amounts of solvents. Furthermore, chromatography equipment has serious limitations for the purification of products at industrial scale due to its maximum sample load capacity and low throughput. High-performance liquid chromatography (HPLC) methods are highly effective for precise analysis because they operate at small scales and under controlled conditions, enabling the separation of THC from cannabinoids like CBD. However, when the goal shifts from analytical purposes to production of THC, particularly industrial-scale production, a clear distinction must be made, as these contexts involve fundamentally different operational conditions and objectives.

[0010] Analytical chromatography operates at small scales, allowing precise control over variables and enabling the separation of the majority of compounds. However, scaling these methods for industrial production presents significant challenges. The load capacity of chromatographic systems is inherently limited, and increasing material throughput leads to overlapping compound peaks, reduced resolution, and poor separation efficiency. This makes the complete purification of THC via chromatographic techniques in an industrial setting infeasible. As a result, the final product in industrial contexts contains as minor components other cannabinoids, which is generally accepted to maintain economic and operational feasibility. While this compromise is practical, it is not the ideal scenario, as the presence of impurities may impact product quality. Thus, while analytical and production chromatography share principles, their goals and operational realities differ significantly, necessitating the use of alternative methods.

[0011] As mentioned above, obtaining high-purity THC through crystallization alone presents significant challenges because THC does not naturally form solid crystals, unlike some other cannabinoids like CBD or CBG. This lack of crystallization means THC remains in an oily, resinous form, which complicates separation and purification. Additionally, impurities and degradation byproducts, which may be present in trace amounts, are hard to remove without chromatography or other precise separation methods. As a result, crystallization lacks the selectivity and efficiency needed to achieve the high purity levels required for therapeutic-grade THC.

[0012] WO2016116628A1 discloses methods of purifying one or more cannabinoids from a plant material. The production of decarboxylated cannabinoids, such as CBG, involve decarboxylation of the plant material and subsequent crystallization. However, as mentioned above, crystallization of THC presents substantial challenges, and chromatographic techniques would be needed to obtain high purity THC and high purification yields.

[0013] Developing methods for obtaining high-purity THC without relying on chromatography is important for both economic and practical reasons. By finding alternative methods, the industry can streamline THC production, lower costs, and increase access to high-purity THC. Processes that enable the high-yield production of THC are currently a need for meeting increasing demand and improving the efficiency of THC-based product manufacturing. With efficient, high-yield extraction and purification methods, companies could meet market demands without dramatically increasing resource usage, which benefits both the industry and the environment. Eventually, patients would also benefit as the cost of a THC-based medicine would be much lower.

[0014] Summary of Invention

[0015] The inventors have developed a process for the production of high-purity THC from nondecarboxylated plant material which addresses the environmental and operational limitations inherent to state-of-the-art processes wherein decarboxylation is carried out over the plant material or on extracts derived from the plant, and which involve chromatographic techniques.

[0016] The inventors have surprisingly found a process which produces high-purity THC from non-decarboxylated plant material without compromising the yield of the overall process. To achieve this, the inventors have developed a process for the production of THC which involves extracting non-decarboxylated plant material, crystallizing THCA from an extract rich in this cannabinoid and then decarboxylating the crystalline THCA, in a controlled manner, until it is converted into THC, without the appearance of high percentages of degradation products. This process thus avoids the disadvantages associated with the direct decarboxylation of the plant material, such as the use of chromatography for the purification of THC, reducing waste and making the production process more cost- effective.

[0017] Advantageously, the process according to the invention allows to separate THC from other products which may influence its quality and potency. The separation of THC from other cannabinoids, especially CBC, using conventional chromatography techniques has not been achieved, since the load capacity of chromatographic systems is inherently limited, and increasing material throughput always leads to overlapping compound peaks, reduced resolution, and poor separation efficiency. THC and other cannabinoids such as CBC have very similar polarities and physical properties, causing them to exhibit close retention times during chromatographic separation. These compounds interact similarly with stationary phases, making it difficult to achieve full resolution, even with optimized elution conditions. As a result, co-elution persists, with non-negligible amounts of CBC remaining in THC fractions and vice versa. Although they may be separated for analytical purposes, when the separation is directed at obtaining pure THC, even extending chromatographic separation times to extreme lengths does not guarantee complete separation of THC and CBC due to their intrinsic chemical similarities, while excessively prolonged chromatographic runs introduce significant operational and environmental drawbacks. Additionally, longer separations consume more solvents, contributing to higher waste generation and environmental impact. As a result, THC industry opts for producing THC with small amounts of other cannabinoids, which is generally accepted to maintain economic and operational feasibility. However, as mentioned above, it reduces the potency and effects of THC. In contrast, the process according to the invention avoids the use of chromatographic techniques and operational limitations mentioned above and allows to obtain THC having a purity of at least 95% w / w and containing 0.10% w / w cannabichromene (CBC) or less, as determined by HPLC.

[0018] Accordingly, a first aspect of the invention relates to a process for the production of THC from non-decarboxylated plant material comprising: a) contacting a first non-halogenated non-polar solvent with a non-decarboxylated plant material; b) separating a first mixture comprising the first non-halogenated non-polar solvent and THCA from the non-decarboxylated plant material; c) separating the first non-halogenated non-polar solvent from the first mixture to yield an extract comprising THCA and a first non-halogenated non-polar solvent content equal to or less than 5% w / w, as determined by GC-MS; d) mixing the THCA extract with a second non-halogenated non-polar solvent to yield a second mixture having a weight / volume ratio of THCA extract to the second non- halogenated non-polar solvent ranging from 1 :0.15 to 1:0.5; e) maintaining the second mixture at an appropriate temperature and time to obtain THCA crystals; f) separating the THCA crystals from the second mixture; g) optionally, washing the THCA crystals with the same non-halogenated non-polar solvent of step d); and h) decarboxylating the THCA crystals at a temperature ranging from 120°C to 160°C, during a time ranging from 30 to 110 minutes, to yield THC. A second aspect of the invention relates to a THC having a purity of at least 95% w / w, containing 0.10% w / w CBC or less, as determined by HPLC.

[0019] Detailed description of the invention

[0020] All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a broader definition.

[0021] For the purposes of the invention, any ranges given include both the lower and the upper endpoints of the range. Ranges given, such as temperatures, quantities, times, sizes, and the like, should be considered approximate, unless specifically stated.

[0022] The term “THC” refers to tetrahydrocannabinol. The term “tetrahydrocannabinol” generally refers to multiple isomers, particularly the delta-9-THC isomer with chemical name (-)- trans-A9-tetrahydrocannabinol.

[0023] The term “THCA” refers to tetrahydrocannabinolic acid. The term “tetrahydrocannabinolic acid” generally refers to multiple isomers, particularly the delta-9-THCA isomer with chemical name (-)-trans-A9-tetrahydrocannabinolic acid.

[0024] The term “CBG” refers to cannabigerol. The term “cannabigerol” refers to 2-[(2E)-3,7- dimethylocta-2,6-dienyl]-5-pentyl-benzene-1,3-diol.

[0025] The term “CBGA” refers to cannabigerolic acid. The term “cannabigerolic acid” refers to 3- [(2E)-3,7-dimethylocta-2,6-dien-1-yl]-2,4-dihydroxy-6-pentylbenzoic acid.

[0026] The term “CBC” refers to cannabichromene or cannabichrome. The terms “cannabichromene” or “cannabichrome” refer to 2-methyl-2-(4-methylpent-3-enyl)-7- pentyl-5-chromenol.

[0027] The term “CBCA” refers to cannabichromenic acid. The term “cannabichromenic acid” refers 5-hydroxy-2-methyl-2-(4-methylpent-3-enyl)-7-pentylchromene-6-carboxylic acid.

[0028] The term “CBN” refers to cannabinol. The term “cannabinol” refers to 6,6,9-trimetil-3- pentil-benzo[c]chromen-1-ol. The term “CBNA” refers to cannabinolic acid. The term “cannabinolic acid” refers to 1- hydroxy-6,6,9-trimethyl-3-pentylbenzo[c]chromene-2-carboxylic acid.

[0029] The term “non-halogenated” refers to a compound which does not have a halogen (e.g., fluorine, chlorine, bromine, or iodine) attached to it.

[0030] The term “non-polar” refers to a compound which has zero dipole moment or lower than 1.3 Debye.

[0031] The term “extract” refers to mixture of substances obtained by a process comprising extraction of such substances from a plant or flower.

[0032] The term “weight / volume ratio” refers to the weight of a particular compound (in grams) divided by the volume of a second particular compound or total volume of a mixture (in millilitres). For instance, a weight / volume ratio of 1:0.35 between the THCA extract and the second non-halogenated non-polar solvent refers to 1 gram of THCA extract per 0.35 millilitres of the second non-halogenated non-polar solvent.

[0033] As used herein, "% by weight" or “% w / w” of a component refers to the amount of the single component relative to the total weight of the composition or, if specifically mentioned, of another component.

[0034] As mentioned above, the first aspect of the invention provides a process for the production of THC from non-decarboxylated plant material comprising: a) contacting a first non-halogenated non-polar solvent with a non-decarboxylated plant material; b) separating a first mixture comprising the first non-halogenated non-polar solvent and THCA from the non-decarboxylated plant material; c) separating the first non-halogenated non-polar solvent from the first mixture to yield an extract comprising THCA and a first non-halogenated non-polar solvent content equal to or less than 5% w / w, as determined by GC-MS; d) mixing the THCA extract with a second non-halogenated non-polar solvent to yield a second mixture having a weight / volume ratio of THCA extract to the second non- halogenated non-polar solvent ranging from 1 :0.15 to 1:0.5; e) maintaining the second mixture at an appropriate temperature and time to obtain THCA crystals; f) separating the THCA crystals from the second mixture; g) optionally, washing the THCA crystals with the same non-halogenated non-polar solvent of step d); and h) decarboxylating the THCA crystals at a temperature ranging from 120°C to 160°C, during a time ranging from 30 to 110 minutes, to yield THC.

[0035] This process avoids the need for direct decarboxylation of the plant material, eliminating the use of large furnaces and the significant energy expenditure they require.

[0036] Furthermore, it achieves THC with a purity of 95% w / w or higher by purifying and crystallizing THCA with high yield, without requiring chromatographic techniques, and minimizing degradation products and other impurities. This invention thereby reduces resource usage and offers practical, economic, and environmental benefits while delivering high-purity THC.

[0037] As demonstrated in the examples, the weight / volume ratio of the THCA extract to the second non-halogenated non-polar solvent is critical for achieving high crystallization yields. To this aim, it is also important separating the first non-halogenated non-polar solvent from the first mixture, resulting in an extract with a THCA content and a residual first non-halogenated non-polar solvent concentration of 5% w / w or less, and more advantageously 3% or less. Higher levels of this first non-halogenated non-polar solvent in the THCA extract have been shown to reduce crystallization yield.

[0038] In a particular embodiment, the first and second non-halogenated non-polar solvents have a zero dipole moment or lower than 1.3 Debye.

[0039] In a particular embodiment, the non-decarboxylated plant material has high content of THCA. The term “high content” when referred to THCA is intended to mean that the content of this cannabinoid in the non-decarboxylated plant material is higher than other cannabinoids. Therefore, in a particular embodiment, the non-decarboxylated plant material is a plant variety or mixture of plant varieties comprising a THCA content higher than other cannabinoids. In a particular embodiment, the plant material is cannabis. In a particular embodiment, the plant material is a cannabis variety. In a particular embodiment, the non-decarboxylated plant material is cannabis Moniek variety. In a particular embodiment, the non-decarboxylated plant material comprises flowers of cannabis plants, particularly female flowers of cannabis plants, and leaves. However, in a particular embodiment, crystallization of THCA extract is advantageously improved when the non-decarboxylated plant material consists essentially of female flowers of cannabis plants. That is to say that, in this latter embodiment, further plant material parts can be present, but only to the extent that these do not significantly affect the performance of crystallization compared to non-decarboxylated plant material consisting of female flowers of cannabis plants. In a particular embodiment, the weight / volume ratio of THCA extract to the second nonhalogenated non-polar solvent ranges from 1 :0.15 to 1 :0.35, preferably 1 :0.20 to 1 :0.35, more preferably 1 :0.25 to 1 :0:35. A weight ratio of the THCA crystals to the THCA extract of 1 :0.25 to 1 :0:35 has advantageously been shown to provide the best results in crystallization of THCA crystals from extracts of step e), particularly when the second nonhalogenated non-polar solvent is heptane or isooctane.

[0040] Contacting a first non-halogenated non-polar solvent with a non-decarboxylated plant material may be also expressed as incubating the non-decarboxylated plant material with the first non-halogenated non-polar solvent. In a particular embodiment, contacting a first non-halogenated non-polar solvent with a non-decarboxylated plant material is carried out for a time period of at least 5 minutes, at least 10 minutes, at least 15 minutes, for at least 30 minutes, for at least 45 minutes, for at least 1 hour, for at least 1.25 hours, for at least

[0041] 1 .5 hours, for at least 1 .75 hours, for at least 2 hours, for at least 2.25 hours, for at least

[0042] 2.5 hours, for at least 2.75 hours, for at least 3.0 hours, for at least 3.25 hours, for at least

[0043] 4.5 hours, for at least 4.75 hours, or for at least 5.0 hours. In a particular embodiment, contacting a first non-halogenated non-polar solvent with a non-decarboxylated plant material is carried out at a temperature of 0°C or higher, 4°C or higher, 8°C or higher, 12°C or higher, 16°C or higher, 20°C or higher or 24°C or higher. In a particular embodiment, contacting a first non-halogenated non-polar solvent with a non- decarboxylated plant material is carried out for a time period of at least 1 hour, and at a temperature of 16°C or higher.

[0044] In a particular embodiment, separating a first mixture comprising the non-halogenated non-polar solvent and THCA from the non-decarboxylated plant material comprises filtering to obtain the first mixture comprising the non-halogenated non-polar solvent and THCA, and the non-decarboxylated plant material.

[0045] In a particular embodiment, step a) and b) are repeated twice or more over the non- decarboxylated plant material, and the first mixtures obtained after each repetition of step b) are mixed together. In this embodiment, step c) is performed over the resulting combined first mixture. In another particular embodiment, step a) and b) are repeated twice or more over the non-decarboxylated plant material, and step c) is carried out over each of the first mixtures obtained after each repetition of step b).

[0046] In a particular embodiment, separating the first non-halogenated non-polar solvent from the first mixture to yield an extract comprising THCA and a first non-halogenated nonpolar solvent content equal to or less than 5% w / w, as determined by GC-MS (in an Agilent 7890B gas chromatograph equipped with a 7697A headspace autosampler and coupled to a 5977B mass spectrometer detector), may also be expressed as reducing the content of the first non-halogenated non-polar solvent in the first mixture to yield an extract comprising THCA and a first non-halogenated non-polar solvent content equal to or less than 5% w / w, as determined by GC-MS.

[0047] In a particular embodiment, mixing the THCA extract with a second non-halogenated nonpolar solvent of step d) comprises dissolving the THCA extract with the second non- halogenated non-polar solvent. In a particular embodiment, mixing the THCA extract with a second non-halogenated non-polar solvent of step d) comprises heating the THCA extract with the second non-halogenated non-polar solvent.

[0048] In a particular embodiment, the first and second non-halogenated non-polar solvent are heptane or isooctane.

[0049] In a particular embodiment, maintaining the second mixture at an appropriate temperature and time to obtain THCA crystals is carried out statically or under agitation.

[0050] In a particular embodiment, separating the THCA crystals from the second mixture comprises filtering the THCA crystals.

[0051] In a particular embodiment, step g) of the process comprises washing the THCA crystals with the same non-halogenated non-polar solvent of step d). In a particular embodiment, the temperature of the second non-halogenated non-polar solvent in step g) ranges from - 20°C to 15°C, from -20°C to 10°C, from -15°C to 15°C, from -10°C to 15°C, from -5°C to 15°C, from -5°C to 10°C, or from -5°C to 5°C.

[0052] In a particular embodiment, the first non-halogenated non-polar solvent is selected from the group consisting of pentane, hexane, petroleum ether, cyclohexane, heptane, benzene, toluene, isooctane, and diethyl ether.

[0053] In a particular embodiment, the first non-halogenated non-polar solvent is hexane.

[0054] In a particular embodiment, the second non-halogenated non-polar solvent is selected from the group consisting of pentane, petroleum ether, cyclohexane, heptane, benzene, toluene, isooctane, and diethyl ether.

[0055] In a particular embodiment, the second non-halogenated non-polar solvent is heptane or isooctane. The inventors have surprisingly found that if heptane or isooctane are used to yield a second mixture in step d) having a weight / volume ratio of THCA extract to the heptane or isooctane ranging from 1 :0.15 to 1 :0.5, the crystallization yield of THCA crystals in step e) is significantly increased. In current state of the art processes for the purification of cannabinolic acids, hexane is used for the crystallization. It would have been expected that, solvents such as heptane or isooctane, which have also a zero dipolar moment, would have rendered the same crystallization yield. However, heptane and isooctane unexpectedly provided higher crystallization yields than hexane when using the same crystallization conditions.

[0056] In a particular embodiment, the concentration of the first non-halogenated non-polar solvent in the THCA extract of step c) is equal to or less than 3% w / w, preferably equal to or less than 1 % w / w, as determined by GC-MS, more preferably equal to or less than 0.5% w / w, as determined by GC-MS. In a particular embodiment, the concentration of the first non-halogenated non-polar solvent in the THCA extract of step c) is equal to or less than 0.2% w / w, as determined by GC-MS. In a particular embodiment, the concentration of the first non-halogenated non-polar solvent in the THCA extract of step c) is equal to or less than 0.05% w / w, as determined by GC-MS.

[0057] In a particular embodiment, the appropriate temperature in step e) ranges is from -20°C to 30°C, from -15°C to 25°C, from -10°C to 25°C, from -5°C to 25°C, from 0°C to 25°C, from 5°C to 25°C, from 10°C to 25°C, or from 15°C to 25°C,. The inventors have found that the yield of the crystallization in step e) is the same in the range from -20°C to 30°C when the crystallization is carried out equal to or more than equal to or more than 8 hours. It is widely accepted that crystallization yield increases with lower temperature, however, the inventors advantageously found that in this particular case the crystallization can be carried out at room temperature (at about 15 to 25°C) without compromising the crystallization yield, which allows to reduce the overall energy requirements of the process. This is particularly important when THC is produced at large scale, since no cooling steps are necessary, and the energy expenditure is greatly diminished.

[0058] In a particular embodiment, the appropriate time in step e) is equal to or more than 8 hours, preferably equal to or more than 16 hours, more preferably equal to or more than 24 hours. Better crystallization yields were obtained when the second mixture was maintained a time equal to or more than 24 hours.

[0059] In a particular embodiment, the temperature in step h) ranges from 125°C to 160°C, from 125°C to 155°C, from 130°C to 155°C, from 130°C to 155°C, from 135°C to 155°C, or from 135°C to 150°C. In a particular embodiment, the temperature in step h) ranges from 130°C to 155°C. In a particular embodiment, decarboxylating the THCA crystals can also be expressed as heating the THCA crystals. In a particular embodiment, the time in step h) ranges from 45 to 100 minutes, from 40 to 90 minutes, from 45 to 90 minutes, from 50 to 90 minutes, from 55 to 90 minutes, from 60 to 90 minutes, from 65 to 90 minutes, from 70 to 90 minutes, from 50 to 85 minutes, from 50 to 80 minutes, from 50 to 75 minutes or from 50 to 70 minutes.

[0060] In a particular embodiment, the process is carried out without using chromatographic techniques for the purification of the THCA extract and the THC obtained. In other words, in a particular embodiment, the THCA extract, and the THC obtained are not purified through chromatographic techniques.

[0061] In a particular embodiment, separating the first non-halogenated non-polar solvent from the first mixture in step c) is carried out by evaporation or lyophilization, preferably evaporation. In a particular embodiment, evaporation comprises distillation.

[0062] In a particular embodiment, the process comprises contacting a first non-halogenated non-polar solvent with a cannabis variety. In a particular embodiment, the process comprises contacting a first non-halogenated non-polar solvent with a cannabis Moniek variety. In a particular embodiment, the process comprises contacting a first non- halogenated non-polar solvent with flowers of cannabis plants, particularly female flowers of cannabis plants. In a particular embodiment, the process comprises contacting a first non-halogenated non-polar solvent with a non-decarboxylated plant materials which consists of female flowers of cannabis plants.

[0063] The method according to the invention thus allows to obtain THC having a purity of 95% or greater, 96% or greater, 97% or greater, 98% or greater or 99% or greater as determined by the HPLC method as described in the examples.

[0064] In a particular embodiment, the process for the production of THC from nondecarboxylated plant material comprises: a) contacting a first non-halogenated non-polar solvent with a non-decarboxylated plant material; b) separating a first mixture comprising the first non-halogenated non-polar solvent and THCA from the non-decarboxylated plant material; c) separating the first non-halogenated non-polar solvent from the first mixture to yield an extract comprising THCA and a first non-halogenated non-polar solvent content equal to or less than 3% w / w, as determined by GC-MS; d) mixing the THCA extract with a second non-halogenated non-polar solvent to yield a second mixture having a weight / volume ratio of THCA extract to the second non- halogenated non-polar solvent ranging from 1 :0.15 to 1:0.5; e) maintaining the second mixture at an appropriate temperature and time to obtain THCA crystals; f) separating the THCA crystals from the second mixture; g) washing the THCA crystals with the same non-halogenated non-polar solvent of step d); and h) decarboxylating the THCA crystals at a temperature ranging from 135°C to 155°C, during a time ranging from 40 to 85 minutes, to yield THC.

[0065] In a particular embodiment, the process for the production of THC from nondecarboxylated plant material consists of: a) contacting a first non-halogenated non-polar solvent with a non-decarboxylated plant material; b) separating a first mixture comprising the first non-halogenated non-polar solvent and THCA from the non-decarboxylated plant material; c) separating the first non-halogenated non-polar solvent from the first mixture to yield an extract comprising THCA and a first non-halogenated non-polar solvent content equal to or less than 3% w / w, as determined by GC-MS; d) mixing the THCA extract with a second non-halogenated non-polar solvent to yield a second mixture having a weight / volume ratio of THCA extract to the second non- halogenated non-polar solvent ranging from 1 :0.15 to 1:0.5; e) maintaining the second mixture at an appropriate temperature and time to obtain THCA crystals; f) separating the THCA crystals from the second mixture; g) washing the THCA crystals with the same non-halogenated non-polar solvent of step d); and h) decarboxylating the THCA crystals at a temperature ranging from 120°C to 160°C, during a time ranging from 30 to 110 minutes, to yield THC.

[0066] In a particular embodiment, the process for the production of THC from non- decarboxylated plant material comprises: i) contacting a first non-halogenated non-polar solvent with a non-decarboxylated plant material; j) separating a first mixture comprising the first non-halogenated non-polar solvent and THCA from the non-decarboxylated plant material; k) separating the first non-halogenated non-polar solvent from the first mixture to yield an extract comprising THCA and a first non-halogenated non-polar solvent content equal to or less than 3% w / w, as determined by GC-MS; l) mixing the THCA extract with a second non-halogenated non-polar solvent to yield a second mixture having a weight / volume ratio of THCA extract to the second nonhalogenated non-polar solvent ranging from 1 :0.15 to 1:0.5; m) maintaining the second mixture at an appropriate temperature and time to obtain THCA crystals; n) separating the THCA crystals from the second mixture; o) washing the THCA crystals with the same non-halogenated non-polar solvent of step d); and p) decarboxylating the THCA crystals at a temperature ranging from 135°C to 155°C, during a time ranging from 40 to 85 minutes, to yield THC. wherein the first and second non-halogenated non-polar solvents have a zero dipole moment or lower than 1.3 Debye.

[0067] In a particular embodiment, the process for the production of THC from nondecarboxylated plant material consists of: i) contacting a first non-halogenated non-polar solvent with a non-decarboxylated plant material; j) separating a first mixture comprising the first non-halogenated non-polar solvent and THCA from the non-decarboxylated plant material; k) separating the first non-halogenated non-polar solvent from the first mixture to yield an extract comprising THCA and a first non-halogenated non-polar solvent content equal to or less than 3% w / w, as determined by GC-MS; l) mixing the THCA extract with a second non-halogenated non-polar solvent to yield a second mixture having a weight / volume ratio of THCA extract to the second non- halogenated non-polar solvent ranging from 1 :0.15 to 1:0.5; m) maintaining the second mixture at an appropriate temperature and time to obtain THCA crystals; n) separating the THCA crystals from the second mixture; o) washing the THCA crystals with the same non-halogenated non-polar solvent of step d); and p) decarboxylating the THCA crystals at a temperature ranging from 120°C to 160°C, during a time ranging from 30 to 110 minutes, to yield THC. wherein the first and second non-halogenated non-polar solvents have a zero dipole moment or lower than 1.3 Debye.

[0068] A second aspect of the invention provides a THC having a purity of at least 95% w / w, containing 0.20 w / w CBC or less, as determined by the HPLC using a Restek Raptor ARC18 (150x2.1 mm, 1.8pm particle size) column, and an isocratic method at a flow rate of 0.37 mL / min, the mobile phase was composed of 73% B (acetonitrile with 0.1% (v / v) formic acid) and 27% A (milli-Q water with 5 mM ammonium formate and 0.1% formic acid).

[0069] In a particular embodiment, the THC has a purity of at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, as determined by HPLC.

[0070] In a particular embodiment, the THC contains 0.10% w / w CBC or less, 0.08 w / w CBC or less, 0.05 w / w CBC or less, 0.03 w / w CBC or less, 0.01% w / w CBC or less, 0.008% w / w CBC or less, or 0.005% w / w CBC or less, as determined by HPLC.

[0071] In a particular embodiment, the THC contains 1.8% w / w THCA or less, 1.5% w / w THCA or less, 1.2% w / w THCA or less, 1.0% w / w THCA or less, 0.8% w / w THCA or less, 0.5% w / w THCA or less, 0.3% w / w THCA or less or 0.1% w / w THCA or less, as determined by the HPLC. In a particular embodiment, the THC is free from THCA.

[0072] In a particular embodiment, the THC contains 0.4 to 1% w / w CBN, 0.5 to 1% w / w CBN, 0.3 to 0.9% w / w CBN, 0.3 to 0.8% w / w CBN, 0.5 to 0.9% w / w CBN, or 0.5 to 0.8% w / w CBN, as determined by HPLC.

[0073] In a particular embodiment, the THC contains 0.04% w / w CBNA or less, 0.03% w / w CBNA or less, 0.02% w / w CBNA or less, 0.01% w / w CBNA or less, or 0.005% w / w CBNA or less, as determined by the HPLC. In a particular embodiment, the THC is free from CBNA.

[0074] In a particular embodiment, the THC contains 0.10% w / w CBC or less, 2% w / w THCA or less, 0.3 to 1% w / w CBN, and 0.05% w / w CBNA or less, as determined by HPLC.

[0075] In a particular embodiment, the THC is obtainable by the process as defined in first aspect of the invention. In a particular embodiment, the THC is obtainable by decarboxylating THCA crystals at a temperature ranging from 120°C to 160°C, during a time ranging from 30 to 110 minutes; preferably at a temperature ranging from 135°C to 155°C, during a time ranging from 40 to 85 minutes.

[0076] Maximizing decarboxylation of THCA is crucial for obtaining THC with adequate properties. Precise control over decarboxylation of THCA has been shown to be essential to ensure that THCA and CBNA levels are minimized, while maximizing THC content to obtain the desired effects and purity.

[0077] In a particular embodiment, the THCA crystals have a purity of at least 96 % w / w, preferably at least 97% w / w, more preferably at least 98% w / w, even more preferably at least 99% w / w, as determined by HPLC.

[0078] Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps.

[0079] Furthermore, the word “comprise” encompasses the case of “consisting of”. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular embodiments described herein.

[0080] Examples

[0081] Example 1. Process for the production of THC

[0082] Example 1.1:

[0083] 20.87 g of plant material of Cannabis sativa L. of Moniek variety, with high content in THCA, were extracted through three consecutive extractions of 20, 10, and 5 minutes each, using 150, 105, and 105 mL of hexane, respectively. After each extraction, the plant material was filtered, and the liquid mixtures recovered after filtration were mixed and the hexane was evaporated down to dryness (hexane content lower than 3% by GC-MS). About 5.5 g of THCA extract was obtained. The THCA was dissolved with 1.65 mL of heptane (weight volume ratio of THCA extract / heptane of 0.30) and left crystallizing for 24 hours at 25°C, in a sealed glass vial. The THCA crystals were filtered and rinsed 3 mL (solvent-to-crystal washing ratio is 0.55 mL / g approximately) of cold heptane (approx.

[0084] 5°C). Then, the THCA crystals were dried at room temperature (approx. 22°C) for one hour, obtaining 1.9 g of THCA with a purity greater than 95% w / w as determined by HPLC). 1.4 g of THC (98% w / w purity by HPLC) were obtained by decarboxylating the THCA crystals at a temperature of 146 °C for 46.16 minutes.

[0085] Example 1.2:

[0086] 22.5 g of plant material of Cannabis sativa L. of Moniek variety, with high content in THCA, were extracted through three consecutive extractions of 20, 10, and 5 minutes each, using 160, 110, and 110 mL of hexane, respectively. After each extraction, the plant material was filtered, and the liquid mixtures recovered after filtration were mixed and the hexane was evaporated down to dryness (hexane content lower than 3% by GC-MS). About 5.9 g of THCA extract was obtained. The THCA was dissolved with 0.9 mL of heptane (weight volume ratio of THCA extract / heptane of 1: 0.15) and left crystallizing for 24 hours at 25°C, in a sealed glass vial. The THCA crystals were filtered and rinsed 3.2 mL (solvent-to-crystal washing ratio is 0.55 mL / g approximately) of cold heptane (approx. 5°C). Then, the THCA crystals were dried at room temperature (approx. 22°C) for one hour, obtaining 1.1 g of THCA with a purity greater than 95% w / w as determined by HPLC. 0.96 g of THC (98% w / w purity by HPLC) were obtained by decarboxylating the THCA crystals at a temperature of 146 °C for 46.16 minutes.

[0087] Example 1.3:

[0088] 19.7 g of plant material of Cannabis sativa L. of Moniek variety, with high content in THCA, were extracted through three consecutive extractions of 20, 10, and 5 minutes each, using 140, 100, and 100 mL of hexane, respectively. After each extraction, the plant material was filtered, and the liquid mixtures recovered after filtration were mixed and the hexane was evaporated down to dryness (hexane content lower than 3% by GC-MS). About 5.18 g of THCA extract was obtained. The THCA was dissolved with 2.6 mL of heptane (weight volume ratio of THCA extract / heptane of 1 : 0.5) and left crystallizing for 72 hours at 25°C, in a sealed glass vial. The THCA crystals were filtered and rinsed 2.8 mL (solvent-to-crystal washing ratio is 0.55 mL / g approximately) of cold heptane (approx. 5°C). Then, the THCA crystals were dried at room temperature (approx. 22°C) for one hour, obtaining 1.3 g of THCA with a purity greater than 95% w / w as determined by HPLC. 1.1 g of THC (98% w / w purity by HPLC) were obtained by decarboxylating the THCA crystals at a temperature of 146 °C for 46.16 minutes.

[0089] Example 1.4:

[0090] 38 g of plant material of Cannabis sativa L. of Moniek variety, with high content in THCA, were extracted through three consecutive extractions of 20, 10, and 5 minutes each, using 265, 190, and 190 mL of hexane, respectively. After each extraction, the plant material was filtered, and the liquid mixtures recovered after filtration were mixed and the hexane was evaporated down to dryness (hexane content lower than 3% by GC-MS).

[0091] About 10 g of THCA extract was obtained. The THCA was dissolved with 2.5 mL of heptane (weight volume ratio of THCA extract / heptane of 1: 0.25) and left crystallizing for 24 hours at 25°C, in a sealed glass vial. The THCA crystals were filtered and rinsed with 5 mL (solvent-to-crystal washing ratio is 0.5 mL / g approximately) of cold heptane (approx. 5°C). Then, the THCA crystals were dried at room temperature (approx. 22°C) for one hour, obtaining 3 g of THCA with a purity greater than 95% w / w as determined by HPLC. 2.63 g of THC (98% w / w purity by HPLC) were obtained by decarboxylating the THCA crystals at a temperature of 141 °C for 84.9 minutes.

[0092] Example 1.5: 28 g of plant material of Cannabis sativa L. of Moniek variety, with high content in THCA, were extracted through three consecutive extractions of 20, 10, and 5 minutes each, using 200, 140, and 140 mL of hexane, respectively. After each extraction, the plant material was filtered, and the liquid mixtures recovered after filtration were mixed and the hexane was evaporated down to dryness (hexane content lower than 3% by GC-MS).

[0093] About 7.36 g of THCA extract was obtained. The THCA was dissolved with 1.8 mL of heptane (weight volume ratio of THCA extract / heptane of 1: 0.25) and left crystallizing for 24 hours at 25°C, in a sealed glass vial. The THCA crystals were filtered and rinsed with 4 mL (solvent-to-crystal washing ratio is 0.5 mL / g approximately) of cold heptane (approx. 5°C). Then, the THCA crystals were dried at room temperature (approx. 22°C) for one hour, obtaining 2.8 g of THCA with a greater than 95% w / w as determined by HPLC. 2.45 g of THC (98% w / w purity by HPLC) were obtained by decarboxylating the THCA crystals at a temperature of 141 °C for 84.9 minutes.

[0094] Comparative example 1.1

[0095] 38 g of plant material of Cannabis sativa L. of Moniek variety, with high content in THCA, were extracted through three consecutive extractions of 20, 10, and 5 minutes each, using 265, 190, and 190 mL of hexane, respectively. After each extraction, the plant material was filtered, and the liquid mixtures recovered after filtration were mixed and the hexane was evaporated down to dryness (hexane content lower than 3% by GC-MS).

[0096] About 10 g of THCA extract was obtained. The THCA was dissolved with 1 mL of heptane (weight volume ratio of THCA extract / heptane of 1: 0.1) and left crystallizing for 24 hours at 25°C, in a sealed glass vial. The THCA crystals were filtered and rinsed with 5 mL (solvent-to-crystal washing ratio is 0.5 mL / g approximately) of cold heptane (approx. 5°C). Then, the THCA crystals were dried at room temperature (approx. 22°C) for one hour, obtaining 1.5 g of THCA with a purity greater than 95% w / w as determined by HPLC. 1.31 g of THC (98% w / w purity by HPLC) were obtained by decarboxylating the THCA crystals at a temperature of 141 °C for 84.9 minutes.

[0097] Comparative example 1.2

[0098] 20.87 g of plant material of Cannabis sativa L. of Moniek variety, with high content in THCA, were extracted through three consecutive extractions of 20, 10, and 5 minutes each, using 150, 105, and 105 mL of hexane, respectively. After each extraction, the plant material was filtered, and the liquid mixtures recovered after filtration were mixed and the hexane was evaporated down to dryness (hexane content lower than 3% by GC-MS). About 5.5 g of THCA extract was obtained. The THCA was dissolved with 3.3 mL of hexane (weight volume ratio of THCA extract / hexane of 0.6) and left crystallizing for 24 hours at 25°C, in a sealed glass vial. The THCA crystals were filtered and rinsed 3 mL (solvent-to-crystal washing ratio is 0.55 mL / g approximately) of cold hexane (approx. 5°C). Then, the THCA crystals were dried at room temperature (approx. 22°C) for one hour, obtaining 1.05 g of THCA with a purity greater than 95% w / w as determined by HPLC. 0.77 g of THC (98% w / w purity by HPLC) were obtained by decarboxylating the THCA crystals at a temperature of 146 °C for 46.16 minutes.

[0099] High-performance liquid chromatography (HPLC) conditions

[0100] The HPLC conditions used in Examples 1, 2 and 3 for the quantification of THC, CBN, CBNA, THCA and CBC were the following: High performance liquid chromatography coupled to a diode array detector (HPLC-DAD) was employed to determine the weightbased purity of the sample. An Agilent 1260 Infinity series (Agilent Technologies, Inc, Santa Clara, USA) equipped with a G1329B autosampler and a G1316A DAD was utilized. For the chromatographic separation, a Restek Raptor ARC18 (150x2.1 mm, 1.8pm particle size, Restek Corporation, Bellefonte, Pennsylvania, USA) column was used. The separation of the compounds was carried out following an isocratic method at a flow rate of 0.37 mL / min. The mobile phase was composed of 73% B (acetonitrile with 0.1% (v / v) formic acid) and 27% A (milli-Q water with 5 mM ammonium formate and 0.1% formic acid) and the oven temperature was set at 35°C. The injected sample volume was 1 pL. Agilent LC OpenLAB software was employed for data treatment.

[0101] Reference solution consist of a solution of THC at 50 mg / L. System suitability test was established from six replicate injections of the reference solution. This reference solution was used to calculate the percentage of weight of THC in the substance to be examined. Additionally, a second reference solution containing multiple analytes (THC, THCA, CBN, CBNA and CBC) at 50 mg / L was analysed for the identification of potential degradation impurities in the substance to be examined. These results were expressed as percentage of area, also referred to as chromatographic purity.

[0102] For HPLC analysis, approximately 80 mg of the substance to be examined was dissolved in methanol and diluted to 25 mL with the same solvent, test solution (a). Subsequently, proper dilution of test solution (a) was performed to 25 mL with methanol, test solution (b), to reach a concentration of 50 mg / L of the main cannabinoid. Prior to HPLC-DAD analysis, test solution (b) was filtered through 0.22 pm syringe nylon filters.

[0103] Gas chromatography-mass spectrometry (GC-MS)

[0104] Quantification of residual solvents is based on procedure 2.4.24, Identification and Control of Residual Solvents, as outlined in the European Pharmacopoeia. While monograph 2.4.24 is a limit test, the procedure presented herein enables the precise quantification of residual solvents in samples using the standard addition method.

[0105] Sample Preparation: 0.1 g of the extract was weighed in a 20 mL crimp-sealable glass vial using a spatula. Then, 10 mL of dimethylformamide (DMF) was added using a doublemarked glass pipette, and the vial was immediately sealed. The sample was shaken until complete dissolution was achieved.

[0106] Standard Preparation: 0.25 g of ethanol was weighed in a 25 mL volumetric flask, which was then filled to the mark with DMSO. From this solution, five additional concentrations were prepared at 50, 100, 250, 500, and 750 ppm. These solutions were subsequently used to prepare the calibration curve via the standard addition method.

[0107] Calibration Curve: 200 pL of the dissolved sample, 4.8 mL of DMF, and 1 mL of each ethanol-in-DMSO standard solution were added to 10 mL crimp-sealable glass vials. Additionally, a blank solution was prepared with 5 mL of DMF and 1 mL of DMSO. The 0- point solution (i.e. , the sample without standard addition) was prepared by mixing 200 pL of the dissolved sample, 4.8 mL of DMF, and 1 mL of DMSO.

[0108] The analysis of the samples was performed on an Agilent 7890B gas chromatograph (Agilent Technologies, Inc., Santa Clara, USA) equipped with a 7697A headspace (HS) autosampler and coupled to a 5977B mass spectrometer detector. For chromatographic separation, an Agilent VF-624ms column (30 m x 0.32 mm I.D., 1.8 pm film thickness) was used. The sample was stabilized in the HS oven at 105°C for 45 minutes. After this period, the vial was pressurized with helium for 0.5 minutes at 10 psi, transferring the HS phase to the injection loop, which was maintained at a temperature of 105°C. The transfer line was set to 110°C and the injector port to 140°C. The oven temperature was programmed as follows: initial temperature 40°C hold for 5 min, increased at 10 °C / min to 150°C, holding for 5 min. Total analysis time was 21 min. Injection was performed in a 5 / 1 split mode, using helium as carrier gas at a flow rate of 1.2 mL / min. Ion source and quadrupole temperatures were maintained at 230 °C and 150 °C, respectively. The electron energy was fixed at 70 eV and data acquisition was set within a range from 40 to 60 m / z.

[0109] Example 2. THCA crystals decarboxylation

[0110] In these examples, 0.6 g of THCA with a purity greater than 99.9% by weight was weighed into a 12 mL glass vial and placed in an oven at a given temperature during different times, as shown in the table below. The % w / w of THCA, delta-9-THCA (9THC), cannabinol (CBN) and cannabinolic acid (CBNA) was determined by HPLC according to the method described above. The examples not according to the invention are referred to as Comparative examples (Comp. ex.).

[0111] Notwithstanding THC was yield in all cases, higher purity was obtained when THCA crystals were submitted to decarboxylation at temperatures equal to or greater than 140°C and time periods equal to or greater than 35 minutes.

[0112] Example 3. CBC content in THC

[0113] The purification efficiency and impurity profile of the process according to the invention was compared to conventional chromatographic techniques. To this aim, Example 8 of the document WO2019145552A1 was reproduced in different replicates but using a biphasic solvent system hexane:ethanol:water at proportions of 100:85:35 (Comparative examples

[0114] 3.1 to 3.7). The same quantity of the same starting non-decarboxylated plant material (also Cannabis Moniek variety) was used to prepare examples according to the process described in Example 1.1 of the present application (same ratios and treatment times, and equivalent amounts) but using different decarboxylation conditions, as indicated in the table below. The THC and CBC content of examples obtained according to Example 8 of WO2019145552A1 (Comp. ex. 3.1 to 3.7), and examples obtained according to Example

[0115] 1.1 of the present application (Ex. 3.1 to 3.7) are shown in the table below:

Claims

Claims1. A process for the production of THC from non-decarboxylated plant material comprising: a) contacting a first non-halogenated non-polar solvent with a non-decarboxylated plant material; b) separating a first mixture comprising the first non-halogenated non-polar solvent and THCA from the non-decarboxylated plant material; c) separating the first non-halogenated non-polar solvent from the first mixture to yield an extract comprising THCA and a first non-halogenated non-polar solvent content equal to or less than 5% w / w, as determined by GC-MS; d) mixing the THCA extract with a second non-halogenated non-polar solvent to yield a second mixture having a weight / volume ratio of THCA extract to the second non-halogenated non-polar solvent ranging from 1 :0.15 to 1 :0.5; e) maintaining the second mixture at an appropriate temperature and time to obtain THCA crystals; f) separating the THCA crystals from the second mixture; g) optionally, washing the THCA crystals with the same non-halogenated non-polar solvent of step d); and h) decarboxylating the THCA crystals at a temperature ranging from 120°C to 160°C, during a time ranging from 30 to 110 minutes, to yield THC. wherein the first and second non-halogenated non-polar solvents have a zero dipole moment or lower than 1.3 Debye.

2. The process according to claim 1, wherein the first non-halogenated non-polar solvent is selected from the group consisting of pentane, hexane, petroleum ether, cyclohexane, heptane, benzene, toluene, isooctane, and diethyl ether.

3. The process according to any of the claims 1-2, wherein the first non-halogenated nonpolar solvent is hexane.

4. The process according to any of the claims 1-3, wherein the second non-halogenated non-polar solvent is selected from the group consisting of pentane, petroleum ether, cyclohexane, heptane, benzene, toluene, isooctane, and diethyl ether.

5. The process according to claim 4, wherein the second non-halogenated non-polar solvent is heptane or isooctane.

6. The process according to any of the claims 1-5, wherein the concentration of the first non-halogenated non-polar solvent in the THCA extract of step c) is equal to or less than 3% w / w, preferably equal to or less than 1 % w / w, as determined by GC-MS.

7. The process according to any of the claims 1-6, wherein the appropriate time in step e) is equal to or more than 8 hours, preferably equal to or more than 16 hours, more preferably equal to or more than 24 hours.

8. The process according to any of the claims 1-7, wherein temperature in step h) ranges from 140°C to 150°C.

9. The process according to any of the claims 1-8, wherein the time in step h) ranges from 30 to 85 minutes.

10. The process according to any of the claims 1-9, wherein the appropriate temperature in step e) ranges from -20°C to 30°C, preferably from 15°C to 25°C.

11. The process according to any of the claims 1-10, wherein the weight / volume ratio of THCA extract to the second non-halogenated non-polar solvent ranges from 1 :0.20 to 1 :0.35, preferably from 1 :0.25 to 1 :0.35.

12. The process according to any of the claims 1-11 , wherein the process is carried out without using chromatographic techniques for the purification of the THCA extract and the THC obtained.

13. The process according to any of the claims 1-12, wherein separating the first mixture comprising the non-halogenated non-polar solvent and THCA from the nondecarboxylated plant material comprises filtering to obtain the first mixture comprising the non-halogenated non-polar solvent and THCA, and the non-decarboxylated plant material.

14. The process according to any of the claims 1-13, wherein separating the first non- halogenated non-polar solvent from the first mixture in step c) is carried out by evaporation or lyophilization.

15. The process according to any of the claims 1-14, wherein separating the THCA crystals from the second mixture comprises filtering the THCA crystals.

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