Cannabidiol compositions having modified cannabinoid profiles

Abstract

This disclosure relates to the preparation of highly pure cannabidiol compounds by a novel synthetic route. The cannabidiol compounds can be prepared by the acid-catalyzed reaction of dihaloolivetol with menthadienol, followed by two crystallization steps. The highly pure cannabidiol compounds are produced in high yield, stereospecificity, or both, and exhibit very low levels of Δ-9-tetrahydrocannabinol during preparation and after storage. [Selected figure] Figure 11A

Description

[Technical field]

[0001] The subject matter described herein relates to the preparation of highly purified cannabidiol compounds by novel synthetic routes. The highly purified cannabidiol compounds are produced in high yield, stereospecificity, or both, and exhibit very low levels of Δ-9-tetrahydrocannabinol during preparation and after storage. [Background technology]

[0002] To date, over 100 phytocannabinoids have been isolated. See Pertwee, et al. “Hand book of Cannabis,” Oxford University Press, First Edition 2014, ISBN 978-0-19-966268-5. Phytocannabinoids are naturally derived cannabinoids that can be found in the cannabis plant. These compounds have been investigated, in part, based on their availability from natural sources. The term “cannabinoids” generally refers to chemicals isolated from C. sativa L. that exhibit a typical C21 terpenophilic skeleton, as well as their derivatives and transformation products.

[0003] In addition to the historical and anecdotal medicinal uses of cannabinoids, the FDA has approved cannabinoid-based products such as MARINOL, and many other regulatory agencies have approved SATIVEX. Many other cannabinoids are being investigated by the mainstream pharmaceutical industry for various indications. Examples of cannabinoids approved for either clinical use or in clinical trials include EPIDIOLEX (e.g., cannabidiol) for Dravet syndrome and Lennox-Gastaut syndrome, cannabidivarin for epilepsy, and tetrahydrocannabidivarin for diabetes.

[0004] Considerable research has been directed towards the preparation of cannabinoids via synthetic routes, thereby eliminating the need to obtain material through extraction of natural sources. However, in many cases, preparations containing cannabinoids also contain Δ-9-tetrahydrocannabinol. Δ-9-tetrahydrocannabinol is generally accepted to cause the "high" typically observed in recreational cannabis use and serves as the primary psychoactive component of marijuana. One of the main problems in the synthesis of cannabinoids has been the uncontrolled conversion of intermediate compounds to cyclized products such as Δ-9-tetrahydrocannabinol. The non-crystalline nature of cannabinoids further limits their availability purity. Thus, stocks of pure synthetic material are needed to investigate the pharmacological effects of cannabinoids and to facilitate precisely reproducible doses of the active ingredient used in their pharmacological properties.

[0005] The present disclosure relates to the preparation of cannabidiol compounds using novel synthetic routes that produce highly purified cannabidiol compounds in high yields, stereospecificity, or both, with very low levels of Δ-9-tetrahydrocannabinol during preparation and after storage. Summary of the Invention

[0006] In one aspect, the subject matter described herein is directed to a composition comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount less than 10 ppm.

[0007] Another embodiment of the subject matter described herein is a composition comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm upon storage for 2 years or less.

[0008] Another embodiment of the subject matter described herein is a composition comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol, wherein the ratio of cannabidiol to delta-9-tetrahydrocannabinol is less than 1:0.00001 as measured by HPLC.

[0009] Another aspect of the subject matter described herein is a formulation comprising cannabidiol and delta-9-tetrahydrocannabinol, and a pharma- ceutically acceptable excipient, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm.

[0010] Another aspect of the subject matter described herein is a method of preparing crystalline cannabidiol characterized as having an X-ray powder diffraction pattern substantially as shown in FIG. 11A, and less than 10 ppm delta-9-tetrahydrocannabinol, comprising crystallizing cannabidiol from isooctane.

[0011] Another aspect of the subject matter described herein is a method of preparing a cannabidiol composition, comprising: contacting a dihalo-olivetol with a menthadienol in the presence of a protic acid catalyst to prepare a dihalocannabidiol; contacting a dihalocannabidiol with a reducing agent to prepare a first cannabidiol composition; contacting a first cannabidiol composition with a first solvent; crystallizing a second cannabidiol composition from the first solvent; and recrystallizing the crystalline cannabidiol composition having less than 10 ppm delta-9-tetrahydrocannabinol from the second solvent.

[0012] Another aspect of the subject matter described herein is a method of recrystallizing cannabidiol from a mixture of cannabinoids to prepare a composition comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol, the method comprising: contacting said mixture of cannabinoids, e.g., cannabidiol and THC, with isooctane to form a solution; heating the solution to about 40° C.; Cooling the solution to about 32° C.; seeding the solution at about 32°C with (-)-cannabidiol to form a suspension; Warming the suspension to about 32° C. while stirring; Cooling the suspension to about -20°C; Separating solid material from the suspension; and washing the solid material with isooctane at about -20°C; and drying the solid material to obtain a crystalline composition comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol.

[0013] Another aspect of the subject matter described herein is a method of treating a disease in a subject, comprising: The method includes administering to the subject a composition comprising a therapeutic amount of cannabidiol and an amount of delta-9-tetrahydrocannabinol, the amount of delta-9-tetrahydrocannabinol being less than about 20 μg per day.

[0014] These and other aspects are described further herein. [Brief description of the drawings]

[0015] [Figure 1] Figure 1 shows the liquid chromatography mass spectrum of cannabidiol produced by protocol 1. The sample underwent recrystallization in n-heptane prior to analysis. [Diagram 2] Figure 1 shows the Fourier transform infrared spectrum of cannabidiol produced by protocol 1. The sample underwent recrystallization in n-heptane prior to analysis. [Diagram 3] Representative HPLC chromatograms of retention time marker samples are shown. [Figure 4]FIG. 2 shows a UPLC chromatogram of cannabidiol obtained by protocol 2. [Diagram 5] To demonstrate the method sensitivity, an overlay of HPLC chromatograms of diluent blank, cannabidiol, and cannabidiol spiked with 10 ppm D9-THC is shown. CBD spiked with 10 PPM THC is the top signal showing maximum intensity, samples not spiked with CBD provide moderate intensity, and the blank corresponds to the bottom row. [Figure 6A] FIG. 2 shows a chromatogram of cannabidiol sample 1 produced by protocol 3 and subjected to recrystallization in isooctane prior to HPLC experiments. The chromatogram is aligned against that of a 10 PPM THC working standard. [Figure 6B] FIG. 2 shows a chromatogram of cannabidiol sample 2 produced by Protocol 3 and subjected to recrystallization in isooctane prior to the HPLC experiment. The chromatogram is aligned against that of a 10 PPM THC working standard. [Figure 6C] 1 shows a close-up of the chromatogram of Sample 3, generated by Protocol 2. The chromatogram is aligned relative to that of a 10 PPM THC working standard. [Figure 6D] 1 shows a close-up of the chromatogram of Sample 4, generated by Protocol 1. The chromatogram is aligned relative to that of a 10 PPM THC working standard. [Figure 6E] 1 shows a close-up of the chromatogram of Sample 5, generated by Protocol 1. The chromatogram is aligned relative to that of a 10 PPM THC working standard. [Figure 6F] 1 shows a close-up of the chromatogram of Sample 6, generated by Protocol 1. The chromatogram is aligned relative to that of a 10 PPM THC working standard. [Figure 7A] 1 shows the 1-D proton NMR spectrum of cannabidiol. [Figure 7B] 2 shows the 2-D gCOSY NMR spectrum of cannabidiol. [Figure 7C] 2-D gHMBCad NMR spectrum of cannabidiol. [Figure 7D] 2-D gHSQCad NMR spectrum of cannabidiol. [Figure 7E] 2 shows the 2-D ROESYad NMR spectrum of cannabidiol. [Figure 7F] 1 shows chemical shift assignments for a cannabidiol sample. [Figure 8A] FIG. 1 shows a particle size distribution result analysis report for crude cannabidiol produced by Protocol 3 that was not subjected to recrystallization (Sample 7). [Figure 8B] FIG. 8B shows a particle size graph for the sample analyzed in FIG. 8A. [Figure 8C] FIG. 1 shows a particle size distribution result analysis report for crude cannabidiol produced by Protocol 3 that was not subjected to recrystallization (Sample 8). [Figure 8D] A particle size graph for the sample analyzed in FIG. 8C is shown. [Figure 8E] FIG. 1 shows a particle size distribution result analysis report for cannabidiol produced by Protocol 3 that underwent recrystallization in isooctane (Sample 1). [Figure 8F] A particle size graph for the sample analyzed in FIG. 8E is shown. [Figure 8G] FIG. 2 shows a particle size distribution results analysis report for cannabidiol produced by Protocol 3 that underwent recrystallization in isooctane (Sample 2). [Figure 8H] A particle size graph for the sample analyzed in FIG. 8G is shown. [Figure 8I] FIG. 1 shows a particle size distribution results analysis report for cannabidiol produced by Protocol 1 that underwent recrystallization in isooctane (Sample 9). [Figure 8J] A particle size graph for the sample analyzed in FIG. 8I is shown. [Figure 8K]Shown is a particle size distribution results analysis report for crude cannabidiol produced by protocol 3 that was not subjected to recrystallization (Sample 7). This is the second run of this sample, as shown in Figures 8A and 8B, showing the robustness of the method for measuring particle size. [Figure 8L] FIG. 8K shows a particle size graph for the sample analyzed. [Figure 8M] 1 shows the particle size distribution results analysis report for Sample 4 produced by Protocol 1, which did not undergo recrystallization. [Figure 8N] FIG. 8M shows a particle size graph for Sample 4 synthesized by Protocol 1, obtained under the conditions shown. [Figure 8O] 1 shows the particle size distribution results analysis report for Sample 5 produced by Protocol 1, which did not undergo recrystallization. [Figure 8P] FIG. 8O shows a particle size graph for Sample 5 synthesized by Protocol 1, obtained under the conditions shown. [Figure 8Q] 1 shows the particle size distribution results analysis report for Sample 6, which was produced by Protocol 1 and did not undergo recrystallization. [Figure 8R] FIG. 8Q shows a particle size graph for Sample 6 synthesized by Protocol 1, obtained under the conditions shown in FIG. [Figure 9A] 1 shows the particle size distribution results analysis report for Sample 10, synthesized by Protocol 1, which underwent recrystallization in isooctane. [Figure 9B] FIG. 9B shows a particle size graph for Sample 10 synthesized by Protocol 1, obtained under the conditions shown in FIG. 9A. [Figure 9C] 1 shows the particle size distribution results analysis report for Sample 4, synthesized by Protocol 1, which did not undergo recrystallization. [Figure 9D] FIG. 9C shows a particle size graph for Sample 4 synthesized by Protocol 1, obtained under the conditions shown in FIG. [Figure 9E] 1 shows the particle size distribution results analysis report for Sample 11, synthesized by Protocol 3, which underwent recrystallization in isooctane. [Figure 9F] FIG. 9E shows a particle size graph for Sample 11 synthesized by Protocol 3, obtained under the conditions shown in FIG. [Figure 9G] 1 shows the particle size distribution results analysis report for Sample 12, synthesized by Protocol 3, which underwent recrystallization in isooctane. [Figure 9H] FIG. 9G shows a particle size graph for Sample 12 synthesized by Protocol 3, obtained under the conditions shown in FIG. [Figure 9I] 1 shows the particle size distribution results analysis report for Sample 13, synthesized by Protocol 3, which underwent recrystallization in isooctane. [Figure 9J] FIG. 9I shows a particle size graph for sample 13 synthesized by protocol 3, obtained under the conditions shown in FIG. [Figure 9K] 1 shows the particle size distribution results analysis report for Sample 14, synthesized by Protocol 3, which underwent recrystallization in isooctane. [Figure 9L] FIG. 9K shows a particle size graph for Sample 14 synthesized by Protocol 14 obtained under the conditions shown in FIG. [Figure 9M] FIG. 13 shows the particle size distribution results analysis report for Sample 15, synthesized by Protocol 3, which underwent recrystallization in isooctane. [Figure 9N] FIG. 9M shows a particle size graph for Sample 15 synthesized by Protocol 3, obtained under the conditions shown. [Figure 9O] 13 shows additional particle size distribution results analysis reports for Sample 10, synthesized by Protocol 3, which underwent recrystallization in isooctane. [Figure 9P] FIG. 9O shows a particle size graph for sample 10 synthesized by protocol 3, obtained under the conditions shown. [Figure 10] Shown are microscopic images of various crude cannabidiol inputs recrystallized in isooctane. Images were taken with an optical Malvern G3 microscope operating at 2.5x objective magnification. [Figure 11A] FIG. 1 shows the X-ray pattern of cannabidiol (sample 9) produced by Protocol 1, which was subjected to recrystallization in isooctane. [Figure 11B] FIG. 1 shows an overlay of simulated (high intensity pattern) and experimentally derived (low intensity pattern) X-ray data for cannabidiol form A produced by Protocol 1 and subjected to recrystallization in isooctane. [Figure 12] 1 shows a differential scanning calorimetry thermogram of cannabidiol sample 2. This sample was produced by protocol 3 and underwent recrystallization in isooctane. [Figure 13A] 1 shows a TGA / SDTA analysis of cannabidiol. [Figure 13B] 1 shows a TGA-MS analysis of cannabidiol. [Figure 14] FIG. 2 shows chromatographs of a cannabidiol quinone standard (CBQ) and two cannabidiol samples, showing that the cannabidiol samples are essentially free of CBQ. [Figure 15A] FIG. 1 shows a UPLC chromatogram of an unstressed cannabidiol sample. [Figure 15B] FIG. 1 shows the PDA-UV spectrum of the main component (cannabidiol) of an unstressed cannabidiol sample. [Figure 16] 1 shows the X-ray powder diffraction pattern of sample 10 produced by Protocol 1 and subjected to recrystallization in isooctane. [Figure 17] FIG. 1 shows a DSC thermogram of cannabidiol from sample 4, produced by protocol 1. [Figure 18] FIG. 1 shows a DSC thermogram of sample 15 produced by Protocol 3 and subjected to recrystallization in isooctane. [Figure 19]FIG. 1 shows a DSC thermogram of sample 16 produced by Protocol 3 and subjected to recrystallization in isooctane. [Figure 20] FIG. 1 shows a differential scanning calorimetry thermogram of cannabidiol produced by Protocol 1. [Figure 21] 1 shows the X-ray pattern for sample 12, produced by protocol 3 and subjected to recrystallization in isooctane. [Figure 22] 1 shows the X-ray pattern for sample 17, produced by protocol 3 and subjected to recrystallization in isooctane. [Diagram 23] 1 shows the X-ray pattern for sample 18, produced by protocol 3 and subjected to recrystallization in isooctane. [Figure 24] 1 shows the X-ray pattern for sample 19, produced by protocol 3 and subjected to recrystallization in isooctane. [Figure 25A] FIG. 1 shows the impurity profile (UHPLC) of stressed CBD samples after exposure to acidic conditions for 6 hours. [Figure 25B] FIG. 1 shows the PDA-UV spectrum of the main compound (CBD) in the stressed sample after exposure to acidic conditions for 6 h. [Figure 26A] FIG. 1 shows the impurity profile (UHPLC) of stressed CBD samples after exposure to alkaline conditions for 6 hours. [Figure 26B] Figure 2 shows the PDA-UV spectrum of the main compound (CBD) of the stressed sample after exposure to alkaline conditions for 6 h. [Figure 26C] The absorption spectra of CBQ (peak 2-left) and CBD (peak 1-right) are shown. [Figure 27A] 1 shows the impurity profile for a CBD sample stressed under oxidizing conditions and heating to 80° C. for a period of 6 hours. [Figure 27B] FIG. 1 shows the PDA-UV spectrum of the main compound (CBD) of the stressed sample after exposure to oxidative conditions for 6 h. [Figure 28A]Figure 1 shows the impurity profile (UHPLC) of stressed CBD sample after 24 h irradiation. [Figure 28B] Figure 2 shows the PDA-UV spectrum of the main compound (CBD) in the stressed sample after 24 h of irradiation. [Figure 29A] FIG. 1 shows the impurity profile (UHPLC) of a stressed CBD sample after heating to 100° C. for 24 hours. [Figure 29B] Figure 2 shows the PDA-UV spectrum of the main compound (CBD) of the stressed sample after heating to 100°C for 24 hours. [Figure 30A] Figure 2 shows the impurity profile (UHPLC) of CBD samples stressed at 75% rh for 24 hours. [Figure 30B] Figure 2 shows the PDA-UV spectrum of the main compound (CBD) in the stressed sample after 24 h at 75% rh. [Diagram 31] 1 shows the solubility curves of crude CBD mother liquor and CBD in heptane. [Diagram 32] 13 shows images of crust formation after seed degradation during a temperature cycling study on the crystallization of crude CBD. [Diagram 33] Shown is a microscopic image (2.5x) of crude CBD after temperature cycling studies. [Diagram 34] 1 shows a typical operating line for the solubility and eventual crystallization of CBD in pure isooctane. [Diagram 35] Shown is CBD treated with activated carbon (left) and CBD not treated with activated carbon (right). [Diagram 36] 1 shows the impurity profile of the CBD reaction mixture before carbon treatment and before crystallization after carbon treatment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Disclosed herein is a novel synthetic route that produces highly purified cannabidiol compounds with high yield, stereospecificity, or both. The highly purified cannabidiol compounds exhibit very low levels of Δ-9-tetrahydrocannabinol during preparation and after storage. The synthetic route results in new compositions with previously unattainable levels of cannabidiol and Δ-9-tetrahydrocannabinol, and optionally other cannabinoids, and the compositions exhibit unexpected properties such as low levels of THC and long-term stability that maintains low levels of THC over extended periods of time. Long-term stability such that levels of Δ-9-tetrahydrocannabinol remain below 10 ppm is advantageous since levels of Δ-9-tetrahydrocannabinol are expected to increase over time. Any pharmaceutical preparations containing cannabidiol may have elevated levels of Δ-9-tetrahydrocannabinol, and the preparations may not be suitable for administration. In particular, such levels of Δ-9-tetrahydrocannabinol may limit the amount of cannabidiol that can be administered because Δ-9-tetrahydrocannabinol may accumulate in the body and reach undesirable levels, for example, greater than about 20 μg per day.

[0017] Many different routes to produce cannabinoids and related compounds have been reported. One route involves a variation of the Lewis acid catalyzed Friedel-Crafts alkylation of olivetol with menthadienol. For example, US 5,227,537 describes the reaction of equimolar amounts of olivetol and menthadienol in the presence of p-toluenesulfonic acid catalyst, which resulted in a 44% yield of cannabidiol after purification by column chromatography. US 7,674,922 describes a similar reaction using a Lewis acid catalyst instead of p-toluenesulfonic acid, which results in the formation of significant amounts of unwanted cannabidiol isomers along with cannabidiol. The reaction route described in the '922 patent resulted in a 47% yield of the desired cannabidiol, a 17.9% yield of cannabidiol, and 23% unreacted olivetol.

[0018] In addition, US 3,562,312 describes improved selectivity for the formation of cannabidiol by reacting 6-carbethoxyolivetol with a slight excess of menthadienol in methylene chloride in the presence of dimethylformamide, dineopentyl acetal as a catalyst. This route resulted in a 42% yield of cannabidiol-carboxylic acid ethyl ester after purification by chromatography.

[0019] Another route for the preparation of cannabidiol involves the use of carboxylic acid esters as protecting / directing groups on olivetol analogues. See, for example, Crombie, L. et al., in J. Chem. Research (S) 114, (M), pp 1301-1345 (1977). In the first step, alkyl resorcyl esters (e.g., 6-alkyl-2,4-dihydroxybenzoic acid esters) are condensed in high yields with unsaturated hydrocarbons, alcohols, ketones, or their derivatives, such as enol esters, enol ethers, and ketals, to give the corresponding 3-substituted 6-alkyl-2,4-dihydroxybenzoic acid esters. These preparation routes are referred to as acid-catalyzed terpenylation. In the second step, the intermediates bearing the ester functionality obtained in the first step are subjected to decarboxylative hydrolysis, which forms ester-free cannabinoids.

[0020] For example, improved selectivity has been achieved by protecting the 4-position of olivetol-related compounds with a carboxylic acid ester. The '922 patent describes the preparation of ethyl cannabidiol in 82% yield and 93.3% (AUC) purity. However, after NaOH hydrolysis, the route resulted in 57.5% yield and 99.8% purity (AUC). The '922 patent also describes the need to purify the formed cannabidiol, e.g., Δ-9-tetrahydrocannabinol, by esterification of the free hydroxyl, followed by purification of the cannabidiol ester, e.g., Δ-9-tetrahydrocannabinol ester. Purification was performed by crystallization, followed by hydrolysis of the ester to Δ-9-tetrahydrocannabinol. Such steps were required to achieve the purity required for pharmaceutical use.

[0021] The art presents difficulties in producing cannabidiol compounds in high yield, high stereospecificity, or both. Sources of these difficulties may include the non-crystalline nature of the material, which makes it difficult or impossible to separate and purify without chromatography. Also, the aromatic portion of the cannabidiol molecule is susceptible to oxidation. As such, the presence of oxidized cannabidiol products, including cannabidiol quinone derivatives (CBQs), requires additional investigation. Abnormal-cannabidiol (Ab-CBD), a positional isomer of cannabidiol, is another impurity commonly found in synthetic cannabidiol compositions.

[0022] The disclosed process offers many advantages over current methods for synthesizing pure cannabidiol compositions. As described in the art, Lewis acid catalyzed condensation of olivetol or olivetol esters with menthadienol to prepare cannabidiol or cannabidiolate esters results in low selectivity, low yields, and isomeric mixtures requiring laborious purification procedures. The disclosed process can achieve high yields, high purity, or both, without the need to use organoaluminum Lewis acid catalysts. The disclosed process can use a wide selection of catalysts, such as, for example, p-toluenesulfonic acid. Additionally, in the disclosed process, both the 4- and 6-positions of olivetol can be blocked with halogens selected from the group consisting of Br, F, I, and Cl. The positions can be blocked to control the conversion and prevent the formation of unwanted cannabidiol isomers. In addition, the process can be designed to form the corresponding halogen-substituted cannabidiol in high yield, high selectivity, or both, such as by using an excess of menthadienol equivalents relative to the halogen-substituted olivetol. Halogen-substituted cannabidiols also remain stable and cannot undergo uncontrolled conversion to one or more cyclization products. Halogen-substituted cannabidiols can also be readily converted to cannabidiol by contacting with a suitably selected reducing agent under mild conditions.

[0023] As mentioned above, the non-crystalline nature of cannabidiol limits its ability to undergo purification processes. It is generally accepted that the difficulty in crystallizing a substance is often related to the solubility of the material. The process of the present disclosure demonstrates that cannabidiol can be recrystallized in a suitable solvent under the conditions described herein with high yields and very low levels of Δ-9-tetrahydrocannabinol. These cannabidiol compositions are further shown to be relatively free of cannabidiol quinone and abnormal-cannabidiol impurities.

[0024] As described herein, recrystallization of the cannabidiol composition can purge THC to very low levels. When combined with the synthetic route disclosed herein, recrystallization has been shown to achieve concentrated cannabidiol compositions with as low as about 1.9 ppm THC and modified cannabidiol profiles. The data disclosed herein shows that the synthetic steps involved in the preparation of the cannabidiol composition provide desirably low levels of THC, which can be further reduced through the recrystallization process under the disclosed parameters. The synthetic method involves the use of specific reagents, solvents, and conditions, such as counterintuitively higher temperatures, that surprisingly achieve the desired cannabidiol composition without substantial conversion to the decomposition product THC. The composition also has high stability, as shown by the data disclosed herein.

[0025] The cannabidiol compositions disclosed herein further exhibit reduced levels of olivetol. Olivetol has been observed to be insufficiently purged during crystallization. Advantageously, the present method has been found to be capable of reducing the amount of olivetol impurity in crude cannabidiol with activated charcoal prior to crystallization. As such, the combined recrystallization and activated charcoal application in the methods disclosed herein provides cannabidiol compositions with both high yield and purity.

[0026] The subject matter disclosed herein will be described more fully hereafter. However, many modifications and other embodiments of the subject matter disclosed herein described will occur to those skilled in the art to which the subject matter disclosed herein pertains having the benefit of the teachings set forth in the preceding description. Therefore, it should be understood that the subject matter disclosed herein should not be limited to the specific embodiments disclosed, and modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein encompasses all alternatives, modifications, and equivalents. In the event that one or more of the incorporated documents, patents, and similar materials differ or conflict with this application, including but not limited to defined terms, term usage, described techniques, and the like, this application shall control. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0027] I. Definition As used herein, "stable" with respect to a solution or composition is intended to mean that CBD does not readily degrade into degradants beyond a maximum specified level under certain parameters. Advantageously, the compositions described herein maintain THC levels below about 10 ppm for extended periods of time.

[0028] As used herein, "CBD" refers to cannabidiol, including all stereoisomers. In certain embodiments, the cannabidiol is (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, also referred to herein as (-)-cannabidiol.

[0029] As used herein, "dibromo-CBD" refers to 3,5-dibromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol.

[0030] As used herein, "CBQ" refers to cannabidiol quinone derivatives.

[0031] As used herein, "Ab-CBD" refers to abnormal cannabidiol.

[0032] As used herein, "IPC" refers to in-process control.

[0033] As used herein, "API" refers to active pharmaceutical ingredient.

[0034] As used herein, "cCBD" refers to crude cannabidiol.

[0035] As used herein, "pCBD" refers to pure cannabidiol.

[0036] As used herein, "AAC" refers to accelerated aging conditions.

[0037] As used herein, "HT-PXRD" refers to high-throughput powder X-ray diffraction.

[0038] As used herein, "NMT" refers to "less than or equal to."

[0039] As used herein, "FIO" refers to "For Information Only."

[0040] A "patient" or "individual" or "subject" is a mammal. Mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the patient, individual, or subject is human.

[0041] As used herein, the term "therapeutic amount" refers to an amount of a therapeutic agent, compound, formulation, material, or composition described herein effective to achieve a particular biological result. Such result may include, but is not limited to, inhibition of disease as determined by any means suitable in the art.

[0042] As used herein, the term "pharmaceutical acceptable excipient" refers to an ingredient in a pharmaceutical formulation, other than the active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable excipients include, but are not limited to, buffers, carriers, stabilizers, or preservatives.

[0043] As used herein, "rh" refers to relative humidity.

[0044] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0045] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.

[0046] "Enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0047] Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule around its chiral center(s). The prefixes d and l, or (+) and (-), are used to indicate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. Compounds beginning with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, free of optical activity.

[0048] As used herein, "plant extract" refers to a composition prepared from a solvent extract from the whole Cannabis plant or parts thereof.

[0049] As used herein, "substantially free" refers to trace or trace levels of about 1% w / w or less. As used herein, "essentially free" refers to levels below trace amounts. In certain embodiments, essentially free refers to an amount that is not detectable by standard techniques.

[0050] Additional definitions are provided below.

[0051] II. Composition As used herein, 0.0001% of a composition is equal to 1 PPM, or 1 part per million, of that composition. For example, a 150 g sample of a composition comprising cannabidiol and 5 ppm delta-9-tetrahydrocannabinol contains 0.0005% or 0.00075 g delta-9-tetrahydrocannabinol. In certain embodiments, the compositions described herein can contain 99.9999% cannabidiol and 0.1 ppm THC or other components. In certain embodiments, the compositions described herein can contain 99.999% cannabidiol and 1.0 ppm THC or other components. In certain embodiments, the compositions described herein can contain 99.99% cannabidiol and 10 ppm THC or other components. The amount of the components described herein can be determined by any known method, for example, HPLC.

[0052] In embodiments, the subject matter described herein is directed to compositions comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount less than 10 ppm, hi embodiments, the delta-9-tetrahydrocannabinol is present in an amount less than 9 ppm, 8 ppm, 7 ppm, 6 ppm, 5 ppm, 4 ppm, 3 ppm, 2 ppm, or 1 ppm. In an embodiment, delta-9-tetrahydrocannabinol is present in an amount of from about 0.1 ppm to about 9 ppm, from about 0.1 ppm to about 8 ppm, from about 0.1 ppm to about 7 ppm, from about 0.1 ppm to about 6 ppm, from about 0.1 ppm to about 5 ppm, from about 0.1 ppm to about 4 ppm, from about 0.1 ppm to about 3 ppm, from about 0.1 ppm to about 2 ppm, from about 0.1 ppm to about 1 ppm, or from about 0.2 ppm to about 8 ppm, or from about 0.3 ppm to about 7 ppm, or from about 0.4 ppm to about 6 ppm, or from about 0.5 ppm to about 5 ppm, or from about 0.5 ppm to about 4 ppm, or from about 0.5 ppm to about 6 ppm, or from about 0.5 ppm to about 5 ppm. In embodiments, the subject matter described herein is directed to a composition comprising cannabidiol, delta-9-tetrahydrocannabinol, and CBQ, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 0.001% w / w.

[0053] In embodiments, the compositions exhibit enhanced stability. In certain embodiments, the compositions comprise cannabidiol and delta-9-tetrahydrocannabinol, and the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm when stored for 2 years or less, or when stored for 1 year or less, or when stored for 6 months or less. In certain embodiments, the compositions comprise cannabidiol and delta-9-tetrahydrocannabinol, and the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm when stored for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months, or at least 12 months. In certain embodiments, the compositions comprise cannabidiol and delta-9-tetrahydrocannabinol, and the delta-9-tetrahydrocannabinol is present in an amount of about 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, or 9 ppm when stored for at least 1 month. In certain embodiments, the composition comprises cannabidiol and delta-9-tetrahydrocannabinol, the delta-9-tetrahydrocannabinol being present in an amount of about 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, or 9 ppm upon storage for at least 2 months. In certain embodiments, the composition comprises cannabidiol and delta-9-tetrahydrocannabinol, the delta-9-tetrahydrocannabinol being present in an amount of about 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, or 9 ppm upon storage for at least 3 months. In certain embodiments, the composition comprises cannabidiol and delta-9-tetrahydrocannabinol, the delta-9-tetrahydrocannabinol being present in an amount of about 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, or 9 ppm upon storage for at least 4 months.In certain embodiments, the composition comprises cannabidiol and delta-9-tetrahydrocannabinol, the delta-9-tetrahydrocannabinol being present in an amount of about 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, or 9 ppm upon storage for at least 5 months. In certain embodiments, the composition comprises cannabidiol and delta-9-tetrahydrocannabinol, the delta-9-tetrahydrocannabinol being present in an amount of about 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, or 9 ppm upon storage for at least 6 months. In certain embodiments, the composition comprises cannabidiol and delta-9-tetrahydrocannabinol, the delta-9-tetrahydrocannabinol being present in an amount of about 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, or 9 ppm upon storage for at least 9 months. In certain embodiments, the composition comprises cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 1 ppm, 2 ppm, 3 ppm, 4 ppm, 5 ppm, 6 ppm, 7 ppm, 8 ppm, or 9 ppm upon storage for at least 12 months. In certain embodiments, the sample is stable after storage at room temperature and 60% relative humidity. In certain embodiments, the sample is stable after storage at room temperature and 60% relative humidity. In certain embodiments, the sample is stable after storage at 40° C. and 75% relative humidity. In certain embodiments, the sample is stable after storage under acidic, basic, oxidative, photolytic, and high stress conditions.In embodiments, after the storage periods referred to above, delta-9-tetrahydrocannabinol is present in an amount of from about 0.1 ppm to about 9 ppm, from about 0.1 ppm to about 8 ppm, from about 0.1 ppm to about 7 ppm, from about 0.1 ppm to about 6 ppm, from about 0.1 ppm to about 5 ppm, from about 0.1 ppm to about 4 ppm, from about 0.1 ppm to about 3 ppm, from about 0.1 ppm to about 2 ppm, from about 0.1 ppm to about 1 ppm, or from about 0.2 ppm to about 8 ppm, or from about 0.3 ppm to about 7 ppm, or from about 0.4 ppm to about 6 ppm, or from about 0.5 ppm to about 5 ppm, or from about 0.5 ppm to about 4 ppm, or from about 0.5 ppm to about 6 ppm, or from about 0.5 ppm to about 5 ppm.

[0054] In embodiments, the subject matter described herein is directed to compositions comprising cannabidiol, delta-9-tetrahydrocannabinol, and CBQ, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm and the CBQ is present in an amount of less than 10 ppm. In embodiments, the subject matter described herein is directed to compositions comprising cannabidiol, delta-9-tetrahydrocannabinol, and CBQ, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 0.001% w / w and the CBQ is present in an amount of less than 0.001% w / w. In embodiments, the subject matter described herein is directed to compositions comprising cannabidiol, delta-9-tetrahydrocannabinol, and CBQ, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 0.00001% w / w to about 0.001% w / w and the CBQ is present in an amount of about 0.00001% w / w to about 0.001% w / w. In certain embodiments, the subject matter described herein is directed to a composition comprising cannabidiol, delta-9-tetrahydrocannabinol, and CBQ, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 0.001% to about 5 PPM w / w, and the CBQ is present in an amount of about 0.001% to about 5 PPM w / w.

[0055] In an embodiment the composition comprises cannabidiol, delta-9-tetrahydrocannabinol and CBQ, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm and the CBQ is present in an amount of less than 10 ppm when stored for up to 2 years, or when stored for up to 1 year, or when stored for up to 6 months.

[0056] In an embodiment the composition comprises cannabidiol, delta-9-tetrahydrocannabinol and CBQ, and upon storage for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months or at least 12 months, the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm and the CBQ is present in an amount of less than 10 ppm.

[0057] In an embodiment the composition comprises cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol, and the ratio of cannabidiol to delta-9-tetrahydrocannabinol is less than 1:0.0001 as measured by HPLC.

[0058] In an embodiment the composition comprises cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol, where the ratio of cannabidiol to delta-9-tetrahydrocannabinol is less than 1:0.0001 as measured by HPLC, and less than 10 ppm CBQ, where the ratio of cannabidiol to CBQ is less than 1:0.0001 as measured by HPLC.

[0059] In an embodiment, the subject matter described herein is directed to a composition comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm, and wherein the cannabidiol is an amorphous solid or a crystalline material. In an embodiment, the subject matter described herein is directed to a composition comprising cannabidiol, delta-9-tetrahydrocannabinol, and CBQ, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm, and wherein the CBQ is present in an amount of less than 10 ppm, and wherein the cannabidiol is an amorphous solid or a crystalline material. In an embodiment, the cannabidiol is crystalline.

[0060] When the composition is crystalline, the cannabidiol may be crystalline polymorph form A. Crystalline polymorph form A has an X-ray powder diffraction pattern substantially as shown in Figure 11A. Crystalline polymorph form A has the following X-ray diffraction patterns: 5.07, 8.28, 9.30, 9.70, 10.20, 11.74, 12.49, 13.12, 13.80, 15.08, 15.35, 16.05, 16.57, 17.36, 17.93, 18.79, 18.96, 19.44, 19.79, 20.55, 20.82, 21.61, 22.11, 22.63, 23.02, 23.06, 24.04, 25.06, 26.08, 27.06, 28.08, 29.06, 30.04, 31.06, 32.08, 33.06, 34.04, 35.06, 36.08, 37.06, 38.08, 39.06, 40.06, 41.06, 42.06, 43.06, 44.06, 45.06, 46.06, 47.06, 48.06, 49.06, 50.06, 51.06, 52.06, 53.06, 54.06, 55.06, 56.06, 57.06, 58.06, 59.06, 60.06, 61.06, 62.06 Exhibiting a characteristic X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2θ ± 0.07 at 2.99, 23.68, 24.40, 25.28, 26.45, 26.76, 27.46, 27.70, 28.45, 29.06, 31.07, 32.60, 33.31, 34.03, 34.57, 35.31, 36.49, and 37.79.

[0061] When the composition is crystalline, the cannabidiol can be crystalline polymorphic form A. Crystalline polymorphic form A can be 5.07, 8.28, 9.30, 9.70, 10.20, 11.74, 12.49, 13.12, 13.80, 15.08, 15.35, 16.05, 16.57, 17.36, 17.93, 18.79, 18.96, 19.44, 19.79, 20.55, 20.82, 21.61, 22.11, 22.63, 22.70, 22.75, 22.76, 22.77, 22.78, 22.79 ... and at least one X-ray powder diffraction peak at degrees 2θ ±0.07 selected from the group consisting of 0.99, 23.68, 24.40, 25.28, 26.45, 26.76, 27.46, 27.70, 28.45, 29.06, 31.07, 32.60, 33.31, 34.03, 34.57, 35.31, 36.49, and 37.79.

[0062] When the composition is crystalline, the cannabidiol can be crystalline polymorphic form A. Crystalline polymorphic form A can be 5.07, 8.28, 9.30, 9.70, 10.20, 11.74, 12.49, 13.12, 13.80, 15.08, 15.35, 16.05, 16.57, 17.36, 17.93, 18.79, 18.96, 19.44, 19.79, 20.55, 20.82, 21.61, 22.11, 22.63, 22.70, 22.75, 22.76, 22.77, 22.78, 22.79 ... and at least two X-ray powder diffraction peaks at 2θ ± 0.07 degrees selected from the group consisting of 0.99, 23.68, 24.40, 25.28, 26.45, 26.76, 27.46, 27.70, 28.45, 29.06, 31.07, 32.60, 33.31, 34.03, 34.57, 35.31, 36.49, and 37.79.

[0063] When the composition is crystalline, the cannabidiol can be crystalline polymorphic form A. Polymorphic form A can be 5.07, 8.28, 9.30, 9.70, 10.20, 11.74, 12.49, 13.12, 13.80, 15.08, 15.35, 16.05, 16.57, 17.36, 17.93, 18.79, 18.96, 19.44, 19.79, 20.55, 20.82, 21.61, 22.11, 22.63, 22.9 9, 23.68, 24.40, 25.28, 26.45, 26.76, 27.46, 27.70, 28.45, 29.06, 31.07, 32.60, 33.31, 34.03, 34.57, 35.31, 36.49, and 37.79 inclusive.

[0064] When the composition is crystalline, the cannabidiol may be crystalline polymorphic Form A. Polymorphic Form A exhibits a characteristic X-ray powder diffraction pattern with peaks at 9.70, 11.74, 15.08, 17.36, and 18.79 2θ ± 0.07 degrees.

[0065] When the composition is crystalline, the cannabidiol may be crystalline polymorphic Form A. Polymorphic Form A exhibits a characteristic X-ray powder diffraction pattern with peaks at 9.70, 11.74, 12.49, 13.12, 13.80, 15.08, 17.36, 18.79, 20.55, and 22.11 2θ ±0.07 degrees.

[0066] When the composition is crystalline, the cannabidiol may be crystalline polymorph Form A, characterized by the differential scanning calorimetry thermogram shown in Figure 12. Crystalline polymorph Form A is characterized by a differential scanning calorimetry thermogram with an endotherm having an onset of about 67.72°C and a peak at about 68.12°C.

[0067] The compositions described herein are preferably free of cannabis plant extract materials. That is, while the compositions contain cannabinoids, the compositions preferably do not expressly contain the myriad of undesirable materials that can be contained in extracts from cannabis. Advantageously, cannabidiol is synthetically produced.

[0068] Other cannabinoids which may be present are cannabinol, cannabigerol, delta-8-tetrahydrocannabinol, cannabichromene, cannabicyclol, cannabidiarin, tetrahydrocannabivarin, cannabidivarin, cannabichromen-2-yl, cannabigerovarin, cannabiersoin, cannabiditran, 3,5-dibromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol ... -Bromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 4,6-dibromoolivetol, 4-bromo-5-pentylbenzene-1,3-diol, abnormal cannabidiol (ab-CBD), cannabidiol quinone derivatives (CBQ), 3,5-dibromo-5'-methyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1, 1'-biphenyl]-2,6-diol, 3,5-dibromo-4-ethyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 3-bromo-4-ethyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 4,6-dibromo-5-propylbenzene-1,3-diol, 4-bromo-5-propylbenzene-1, and 4-ethyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol.

[0069] Unexpectedly, the recrystallization described herein fully provides for the purging of extraordinary levels of THC from the composition. In certain embodiments, the amount of THC in the composition containing cannabidiol is reduced by at least 50% w / w, at least 60% w / w, at least 70% w / w, at least 80% w / w, at least 90% w / w, at least 91% w / w, at least 92% w / w, at least 93% w / w, at least 94% w / w, at least 95% w / w, at least 96% w / w, at least 97% w / w, at least 98% w / w, at least 99% w / w, up to about 99.999% w / w. Thus, the recrystallization method described herein can include reducing THC in the above amounts. In certain embodiments, the purged composition contains at least 99.99% cannabidiol and about 10 ppm THC, or about 9.9 ppm THC, or about 9.8 ppm THC, or about 9.7 ppm THC, or about 9.6 ppm THC, or about 9.5 ppm THC, or about 9.4 ppm THC, or about 9.3 ppm THC, or about 9.2 ppm THC, or about 9.1 ppm THC, or about 9.0 ppm THC, or about 8.9 ppm THC, or about 8.8 ppm THC, or about 8.7 ppm THC, or about 8.6 ppm THC, or about 8.5 ppm THC, or about 8.4 ppm THC, or about 8.3 ppm THC, or about 8.2 ppm THC, or is about 8.1 ppm THC, or about 8.0 ppm THC, or about 7.9 ppm THC, or about 7.8 ppm THC, or about 7.7 ppm THC, or about 7.6 ppm THC, or about 7.5 ppm THC, or about 7.4 ppm THC, or about 7.3 ppm THC, or about 7.2 ppm THC, or about 7.1 ppm THC, or about 7.0 ppm THC, or about 6.9 ppm THC, or about 6.8 ppm THC, or about 6.7 ppm THC, or about 6.6 ppm THC, or about 6.5 ppm THC, or about 6.4 ppm THC, or about 6.3 ppm THC, or about 6.2 ppm THC, or about 6.1 ppm THC, about 6.0 ppm THC, or about 5.9 ppm THC, or about 5.8 ppm THC, or about 5.7 ppm THC, or about 5.6 ppm THC, or about 5.5 ppm THC, or about 5.4 ppm THC, or about 5.3 ppm THC, or about 5.2 ppm THC, or about 5.1 ppm THC, or about 5.0 ppm or less THC, or about 4.9 ppm THC, or about 4.8 ppm THC, or about 4.7 ppm THC, or about 4.6 ppm THC, or about 4.5 ppm THC , about 4.4 ppm THC, or about 4.3 ppm THC, or about 4.2 ppm THC, or about 4.1 ppm THC, about 4.0 ppm or less THC, or about 3.9 ppm THC, or about 3.8 ppm THC, or about 3.7 ppm THC, or about 3.5 ppm THC, or about 3.4 ppm THC, or about 3.3 ppm THC, or about 3.2 ppm THC, about 3.1 ppm THC, or about 3.0 ppm or less THC, or about 2.9 ppm m THC, or about 2.8 ppm THC, or about 2.7 ppm THC, or about 2.6 ppm THC, or about 2.5 ppm THC, or about 2.4 ppm THC, or about 2.3 ppm THC, or about 2.2 ppm THC, or about 2.1 ppm THC, or about 2.0 ppm or less THC, or about 1.9 ppm THC, or about 1.8 ppm THC, or about 1.7 ppm THC, or about 1.6 ppm THC, or about 1.5 ppm THC, or about 1.4 ppm m THC, or about 1.3 ppm THC, or about 1.3 ppm THC, or about 1.2 ppm THC, or about 1.1 ppm THC, or about 1.0 ppm or less THC, or about 0.9 ppm THC, or about 0.8 ppm THC, or about 0.7 ppm THC, or about 0.6 ppm THC, or about 0.5 ppm THC, about 0.4 ppm THC, or about 0.3 ppm or less THC, or about 0.2 ppm THC, about 0.2 ppm or less THC.

[0070] In certain embodiments, the ratio of cannabidiol to THC is increased. In certain embodiments, the ratio of other cannabinoids present to THC is increased. The increase can be 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or more.

[0071] In embodiments, the compositions described herein comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol further comprise less than 0.15% w / w of 3,5-dibromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol and 3-bromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, and 0.5% w / w of 4-bromo-5-propylbenzene-1,3-diol and 4,6-di-bromoolivetol. In embodiments, the compositions described herein comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol further comprise 0.001 to 0.15% w / w of 3,5-dibromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol and 3-bromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, and 0.001 to 0.5% w / w of 4-bromo-5-propylbenzene-1,3-diol and 4,6-di-bromoolivetol. In embodiments, the compositions described herein comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol further comprise 0.0001 to 0.05% w / w of 3,5-dibromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol and 3-bromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, and 0.0001 to 0.05% w / w of 4-bromo-5-propylbenzene-1,3-diol and 4,6-di-bromoolivetol.In embodiments, the compositions described herein comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol further comprise 0.0001 to 0.01% w / w of 3,5-dibromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol and 3-bromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, and 0.0001 to 0.01% w / w of 4-bromo-5-propylbenzene-1,3-diol and 4,6-di-bromoolivetol. In certain embodiments, compositions comprising cannabidiol and less than 10 ppm THC are substantially free of halogenated intermediates, such as those listed above. In certain embodiments, compositions comprising cannabidiol and less than 10 ppm THC are essentially free of halogenated intermediates.

[0072] In certain embodiments, the compositions described herein may contain about 10% cannabidiol, up to 10 ppm THC, for example, 9 ppm, 8 ppm, 7 ppm, 6 ppm, 5 ppm, 4 ppm, 3 ppm, 2 ppm, 1 ppm or less, and an amount of additional ingredients, up to a total of 100%. In certain embodiments, the compositions described herein may contain about 20% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, up to a total of 100%. In certain embodiments, the compositions described herein may contain about 30% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, up to a total of 100%. In certain embodiments, the compositions described herein may contain about 40% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, up to a total of 100%. In certain embodiments, the compositions described herein may contain about 50% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, totaling up to 100%. In certain embodiments, the compositions described herein may contain about 60% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, totaling up to 100%. In certain embodiments, the compositions described herein may contain about 70% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, totaling up to 100%. In certain embodiments, the compositions described herein may contain about 80% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, totaling up to 100%. In certain embodiments, the compositions described herein may contain about 90% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, totaling up to 100%. In certain embodiments, the compositions described herein may contain about 91% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, totaling up to 100%. In certain embodiments, the compositions described herein may contain about 92% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, totaling up to 100%.In certain embodiments, the compositions described herein may contain about 93% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, totaling up to 100%. In certain embodiments, the compositions described herein may contain about 94% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, totaling up to 100%. In certain embodiments, the compositions described herein may contain about 96% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, totaling up to 100%. In certain embodiments, the compositions described herein may contain about 97% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, totaling up to 100%. In certain embodiments, the compositions described herein may contain about 98% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, totaling up to 100%. In certain embodiments, the compositions described herein may contain about 99% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, totaling up to 100%. In certain embodiments, the compositions described herein may contain about 99.9% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, totaling up to 100%. In certain embodiments, the compositions described herein may contain about 99.99% cannabidiol, up to 10 ppm THC, and an amount of additional ingredients, totaling up to 100%. In certain embodiments, the compositions described herein may contain 99.999% cannabidiol, and 1.0 ppm THC or other ingredients. In certain embodiments, the compositions described herein may contain 99.9999% cannabidiol, and 0.1 ppm THC or other ingredients.

[0073] In embodiments, the subject matter described herein is directed to a composition comprising cannabidiol, delta-9-tetrahydrocannabinol, and 4-monobromo-cannabidiol, where the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm and the 4-monobromo-cannabidiol is present in an amount of less than 400 ppm.In embodiments, the subject matter described herein is directed to a composition comprising cannabidiol, delta-9-tetrahydrocannabinol, and 4-monobromo-cannabidiol, where the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm and the 4-monobromo-cannabidiol is present in an amount of less than 300 ppm. In embodiments, the subject matter described herein is directed to compositions comprising cannabidiol, delta-9-tetrahydrocannabinol, and 4-monobromo-cannabidiol, where the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm and the 4-monobromo-cannabidiol is present in an amount of less than 200 ppm. In embodiments, the subject matter described herein is directed to compositions comprising cannabidiol, delta-9-tetrahydrocannabinol, and 4-monobromo-cannabidiol, where the delta-9-tetrahydrocannabinol is present in an amount of less than 0.001% w / w and the 4-monobromo-cannabidiol is present in an amount of less than 0.15% w / w. In embodiments, the subject matter described herein is directed to compositions comprising cannabidiol, delta-9-tetrahydrocannabinol, and 4-monobromo-cannabidiol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 0.001% w / w and the 4-monobromo-cannabidiol is present in an amount of less than 0.03% w / w. In certain embodiments, the subject matter described herein is directed to compositions comprising cannabidiol, delta-9-tetrahydrocannabinol, and 4-monobromo-cannabidiol, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 0.00001% w / w to about 0.001% w / w and the 4-monobromo-cannabidiol is present in an amount of about 0.00001% w / w to about 0.05% w / w.In certain embodiments, the subject matter described herein is directed to compositions comprising cannabidiol, delta-9-tetrahydrocannabinol, and 4-monobromo-cannabidiol, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 0.00001% to about 0.001% w / w and the 4-monobromo-cannabidiol is present in an amount of about 0.00001% to about 0.04% w / w. In certain embodiments, the subject matter described herein is directed to compositions comprising cannabidiol, delta-9-tetrahydrocannabinol, and 4-monobromo-cannabidiol, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 0.00001% to about 0.001% w / w and the 4-monobromo-cannabidiol is present in an amount of about 0.00001% to about 0.03% w / w. In certain embodiments, the subject matter described herein is directed to a composition comprising cannabidiol, delta-9-tetrahydrocannabinol, and 4-monobromo-cannabidiol, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 0.00001% to about 0.001% w / w and the 4-monobromo-cannabidiol is present in an amount of about 0.00001% to about 0.02% w / w. In certain embodiments, the subject matter described herein is directed to a composition comprising cannabidiol, delta-9-tetrahydrocannabinol, and 4-monobromo-cannabidiol, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 0.00001% to about 0.001% w / w and the 4-monobromo-cannabidiol is present in an amount of about 0.00001% to about 0.01% w / w. In certain embodiments, the subject matter described herein is directed to a composition comprising cannabidiol, delta-9-tetrahydrocannabinol, and 4-monobromo-cannabidiol, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 0.001% to about 5 PPM w / w, and the 4-monobromo-cannabidiol is present in an amount of about 0.001% to about 100 PPM w / w.In certain embodiments, the subject matter described herein is directed to a composition comprising cannabidiol, delta-9-tetrahydrocannabinol, and 4-monobromo-cannabidiol, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 0.001% to about 10 PPM w / w, and the 4-monobromo-cannabidiol is present in an amount of about 0.001% to about 100 PPM w / w.

[0074] In embodiments, the subject matter described herein is directed to a composition comprising cannabidiol, delta-9-tetrahydrocannabinol, and olivetol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm and the olivetol is present in an amount of less than 10 ppm. In embodiments, the subject matter described herein is directed to a composition comprising cannabidiol, delta-9-tetrahydrocannabinol, and olivetol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 0.001% w / w and the olivetol is present in an amount of less than 0.15% w / w. In embodiments, the subject matter described herein is directed to a composition comprising cannabidiol, delta-9-tetrahydrocannabinol, and olivetol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 0.001% w / w and the olivetol is present in an amount of less than 0.05% w / w. In certain embodiments, the subject matter described herein is directed to a composition comprising cannabidiol, delta-9-tetrahydrocannabinol, and olivetol, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 0.00001% to about 0.001% w / w, and the olivetol is present in an amount of about 0.00001% to about 0.05% w / w. In certain embodiments, the subject matter described herein is directed to a composition comprising cannabidiol, delta-9-tetrahydrocannabinol, and olivetol, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 0.001% to about 5 PPM w / w, and the olivetol is present in an amount of about 0.001% to about 300 PPM w / w.

[0075] In embodiments, the subject matter described herein is directed to compositions comprising cannabidiol, delta-9-tetrahydrocannabinol, and delta-8-tetrahydrocannabinol, where the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm and the delta-8-tetrahydrocannabinol is present in an amount of less than 10 ppm. In embodiments, the subject matter described herein is directed to compositions comprising cannabidiol, delta-9-tetrahydrocannabinol, and delta-8-tetrahydrocannabinol, where the delta-9-tetrahydrocannabinol is present in an amount of less than about 0.001% w / w and the delta-8-tetrahydrocannabinol is present in an amount of less than about 0.001% w / w. In certain embodiments, the subject matter described herein is directed to compositions comprising cannabidiol, delta-9-tetrahydrocannabinol, and delta-8-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 0.00001% to about 0.001% w / w and the delta-8-tetrahydrocannabinol is present in an amount of about 0.00001% to about 0.001% w / w. In certain embodiments, the subject matter described herein is directed to compositions comprising cannabidiol, delta-9-tetrahydrocannabinol, and delta-8-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 0.001% to about 5 PPM w / w and the delta-8-tetrahydrocannabinol is present in an amount of about 0.001% to about 5 PPM w / w. In certain embodiments, the subject matter described herein is directed to compositions comprising cannabidiol, delta-9-tetrahydrocannabinol, and delta-8-tetrahydrocannabinol, where the delta-9-tetrahydrocannabinol is present in an amount of about 0.001% to about 10 PPM w / w and the delta-8-tetrahydrocannabinol is present in an amount of about 0.001% to about 10 PPM w / w.

[0076] In embodiments, compositions described herein comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol further comprise less than 0.15% w / w 4-monobromo-cannabidiol, less than 0.15% w / w olivetol, and less than 0.10% w / w delta-8-tetrahydrocannabinol. In embodiments, compositions described herein comprising cannabidiol further comprise from about 0.001% w / w to about 10 PPM delta-9-tetrahydrocannabinol, from about 0.001% w / w to about 0.03% w / w olivetol, from about 0.001% w / w to about 10 PPM delta-8-tetrahydrocannabinol, and from about 0.001% w / w to about 0.02% w / w 4-monobromo-cannabidiol. In embodiments, the compositions described herein comprising cannabidiol further comprise from about 0.001% w / w to about 5 PPM delta-9-tetrahydrocannabinol, less than 0.03% w / w olivetol, less than 10 PPM delta-8-tetrahydrocannabinol, and less than 0.02% w / w 4-monobromo-cannabidiol.

[0077] In an embodiment, the crystalline polymorph form A has a particle size distribution. The particle size distribution D50 is also known as the median diameter or the mean value of the particle size distribution. It is the value of the particle diameter at 50% of the cumulative distribution. D10 is the diameter at which 10% of the mass of the sample is made up of particles with a diameter less than this value. D90 is the diameter at which 90% of the mass of the sample is made up of particles with a diameter less than this value.

[0078] In an embodiment, the crystalline polymorph form A has a d10 particle size in the range of about 1 μm to about 10 μm. In an embodiment, the crystalline polymorph form A has a d10 particle size in the range of about 8 μm to about 40 μm. In an embodiment, the crystalline polymorph form A has a d10 particle size in the range of about 15 μm to about 500 μm. In an embodiment, the crystalline polymorph form A has a d10 particle size in the range of about 1 μm to about 450 μm.

[0079] In embodiments, crystalline polymorph form A has a d50 particle size in the range of about 8 μm to about 40 μm. In embodiments, crystalline polymorph form A has a d50 particle size in the range of about 5 μm to about 600 μm, about 5 μm to about 100 μm, about 5 μm to about 75 μm, about 15 μm to about 50 μm, about 15 μm to about 30 μm, about 50 μm to about 600 μm, and about 2 μm to about 200 μm.

[0080] In embodiments, crystalline polymorph form A has a d90 particle size in the range of about 8 μm to about 500 μm. In embodiments, crystalline polymorph form A has a d90 particle size in the range of about 2 μm to about 400 μm, about 10 μm to about 350 μm, about 100 μm to about 200 μm, about 25 μm to about 150 μm, about 100 μm to about 150 μm, about 130 μm to about 180 μm, and about 100 μm to about 600 μm.

[0081] III. Preparations Pharmaceutical formulations of the therapeutic cannabidiol compositions (CBD) described herein can be prepared for various routes of administration. CBD with the desired purity is optionally mixed with one or more pharma- ceutically acceptable excipients (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.) in the form of a lyophilized formulation or aqueous solution for reconstitution.

[0082] CBD can be formulated according to standard pharmaceutical practice as a pharmaceutical composition. According to this aspect, a pharmaceutical composition is provided that includes CBD in association with one or more pharma- ceutically acceptable excipients. In an embodiment, the cannabidiol formulation includes cannabidiol and delta-9-tetrahydrocannabinol, and a pharma- ceutically acceptable excipient, and the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm.

[0083] A typical formulation is prepared by mixing CBD with an excipient such as a carrier and / or diluent. Suitable carriers, diluents, and other excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent, or other excipient used will depend on the means and purpose for which the CBD is being applied. Solvents are generally selected based on solvents recognized by those skilled in the art as safe (GRAS) for administration to mammals.

[0084] In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), and the like, and mixtures thereof. Acceptable diluents, carriers, excipients, and stabilizers are non-toxic to the recipient at the dosages and concentrations used, and include buffers such as phosphate, citric acid, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; serum albumin, gelatin, and the like. hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG).

[0085] The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, lubricants, processing aids, colorants, sweeteners, aromas, flavorings, and other known additives to provide an elegant presentation of the CBD or to aid in the manufacture of pharmaceutical products. The formulations may be prepared using conventional dissolution and mixing procedures.

[0086] Formulation may be carried out by mixing the compound at the desired purity at an appropriate pH at ambient temperature with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dosage and concentration used. The pH of the formulation will depend primarily on the particular application and the concentration of the compound, but may range from about 3 to about 8. Formulation in acetate buffer at pH 5 is a preferred embodiment.

[0087] CBD formulations can be sterile. In particular, formulations to be used for in vivo administration must be sterile. Such sterilization is readily accomplished by filtration through sterile filtration membranes.

[0088] CBD may typically be stored as a solid composition, a lyophilized formulation, or an aqueous solution.

[0089] Pharmaceutical compositions containing CBD can be formulated, dosed, and administered in a manner, i.e., amount, concentration, schedule, course, vehicle, and route of administration, consistent with good medical practice. Factors to be considered in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the dosing schedule, and other factors known to medical practitioners. The "therapeutic amount" of the compound to be administered is determined by such considerations and is the minimum amount necessary to prevent, ameliorate, or treat a coagulation factor-mediated disorder. Such an amount is preferably less than an amount that is toxic to the host or renders the host significantly more susceptible to bleeding.

[0090] CBD can be formulated into a pharmaceutical dosage form to provide an easily controllable dosage of the drug and allow patient compliance with the prescribed regimen. The pharmaceutical composition (or formulation) for application can be packaged in a variety of ways depending on the method used to administer the drug. Generally, the article for distribution includes a container having the pharmaceutical formulation placed therein in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. The container may also include a tamper-proof combination material to prevent inadvertent access to the package contents. Additionally, a label is affixed to the container that describes the contents of the container. The label may also include appropriate warnings.

[0091] The pharmaceutical composition may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as 1,3-butanediol. The sterile injectable preparation may also be prepared as a lyophilized powder. Acceptable vehicles and solvents that may be used are water, Ringer's solution, and physiological saline solution. In addition, sterile, fixed oils may be conventionally used as a solvent or suspending medium. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0092] The amount of CBD that can be combined with the carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. For example, a sustained release formulation intended for oral administration to humans may contain about 1-1000 mg of active material combined with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable dosages. For example, an aqueous solution intended for intravenous infusion may contain about 3-500 μg of active ingredient per milliliter of solution, such that infusion of a suitable volume can occur at a rate of about 30 mL / hour.

[0093] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0094] The formulations can be packaged in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water, immediately prior to use for injection. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, of an active ingredient, or an appropriate fraction thereof.

[0095] The subject matter thus further provides veterinary compositions comprising at least one active ingredient as defined above together with a veterinary carrier. The veterinary carrier may be a solid, liquid, or gaseous material that is useful for the purpose of administering the composition and is otherwise inert or acceptable in the veterinary field, and compatible with the active ingredient. These veterinary compositions may be administered parenterally or by any other desired route.

[0096] Formulations that include cannabidiol and THC, where THC is present at a level of less than about 10 ppm, can be administered such that the level of THC administered daily is less than 20 μg / day, but a therapeutically effective amount of cannabidiol is provided daily.In certain embodiments, a therapeutically effective amount of cannabidiol is provided daily, and the level of THC administered daily is 19 μg / day, 18 μg / day, 17 μg / day, 16 μg / day, 15 μg / day, 14 μg / day, 13 μg / day, 12 μg / day, 11 μg / day, 9 μg / day, 8 μg / day, 7 μg / day, 6 μg / day, 5 μg / day, 4 μg / day, 3 μg / day, 2 μg / day, or less than 1 μg / day, up to about 0.1 μg / day.

[0097] IV. Method Indications and methods of treatment It is contemplated that the cannabidiol composition (CBD) disclosed herein can be used to treat disease.Exemplary diseases include, but are not limited to, vomiting, pain, Huntington's disease, Tourette's syndrome, glaucoma, osteoporosis, schizophrenia, cancer, obesity, autoimmune disease, diabetic complications, infection with methicillin-resistant Staphylococcus aureus, nausea, depression, anxiety, hypoxic-ischemic injury, psychosis, and inflammatory disease.

[0098] Autoimmune diseases include, for example, acquired immune deficiency syndrome (AIDS), alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune lymphoproliferative syndrome (ALPS), autoimmune thrombocytopenic purpura (ATP), Behcet's disease, cardiomyopathy, celiac sprue-dermatitis herpetiformis, chronic fatigue immune deficiency syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy (CIPD), cicatricial pemphigoid, cold aggregation disease, CREST syndrome, Crohn's disease, Degos disease, juvenile dermatomyositis, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), and / or other autoimmune diseases. P), IgA nephropathy, insulin-dependent diabetes mellitus, juvenile chronic arthritis (Still's disease), juvenile rheumatoid arthritis, Meniere's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, Parkinson's disease, pernicious anemia, polyarteritis nodosa, polychondritis polyglandularis, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis ... These include arthritis, Raynaud's phenomenon, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma (also known as progressive systemic sclerosis (PSS) or systemic sclerosis (SS)), Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis / giant cell arteritis, ulcerative colitis, uveitis, vitiligo, and Wegener's granulomatosis.

[0099] Inflammatory disorder includes, for example, chronic and acute inflammatory disorder.Examples of inflammatory disorder include Alzheimer's disease, asthma, atopic allergy, allergy, atherosclerosis, bronchial asthma, eczema, glomerulonephritis, graft-versus-host disease, hemolytic anemia, osteoarthritis, inflammatory bowel disease, sepsis, stroke, tissue and organ transplantation, vasculitis, diabetic retinopathy and ventilator-induced lung injury.

[0100] Examples of cancer to be treated include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.More specific examples of such cancer include lung cancer, including squamous cell carcinoma (e.g. squamous cell carcinoma), small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric or stomach cancer, including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, anal cancer, penile cancer, and head and neck cancer.

[0101] CBD may be administered by any route appropriate to the condition being treated, including oral, intravenous, topical, as well as ocular (eye drops) and transdermal (skin patch) modes.

[0102] CBD can be used alone or in combination with other agents in therapy.For example, the cannabidiol composition can be co-administered with at least one additional therapeutic agent.Such combination therapy as described above includes combined administration (when two or more therapeutic agents are contained in the same or separate formulations) and separate administration, in which case the administration of the cannabidiol composition can be performed before, simultaneously with, and / or after the administration of the additional therapeutic agent and / or adjuvant.

[0103] How to Make Cannabidiol (CBD) Schemes 1-3 show exemplary methods for synthesizing pure cannabidiol compositions. [ka]

[0104] Referring to Scheme 1, a method for preparing 4,6-dibromoolivetol is provided. The method includes contacting olivetol with a brominating agent to form 4,6-dibromo-olivetol. [ka]

[0105] According to Scheme 2, the present disclosure relates to a process for the preparation of dibromo-CBD, the process can include contacting 4,6-dibromo-olivetol with menthadienol in the presence of a protic acid catalyst to form dibromo-CBD. [ka]

[0106] With reference to Scheme 3, the present disclosure further relates to the preparation of cannabidiol, the process can include dissolving dibromo-CBD in a solvent and treating it with a suitably selected reducing agent, such as sodium sulfite, in the presence of a base to form a first cannabidiol product.

[0107] The first cannabidiol product can then be dissolved in the first solvent to form a crystallized second cannabidiol product.

[0108] Crystallization / Recrystallization In another embodiment the disclosure relates to recrystallization of a second cannabidiol product, the process may include dissolving the second cannabidiol product in a second suitable solvent such as isooctane, heating the solution to about 40°C, cooling the solution to about 32°C, then seeding the solution with (-)-cannabidiol at about 32°C to prepare a suspension, the process further includes warming the suspension to about 32°C with stirring, cooling the suspension to -20°C, separating a solid material from the suspension, washing the solid material with isooctane at about -20°C, then drying the solid material to obtain a crystalline composition comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol.

[0109] The first cannabidiol composition can be crystallized in a suitable organic solvent, such as 2-butanone, ethyl acetate, 1-4-dioxane, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, dichloromethane, chloroform, n-heptane, toluene, isopropyl acetate, isooctane, n-decane, and anisole.

[0110] The second cannabidiol composition can be recrystallized in a suitable non-polar aprotic solvent, such as isooctane, chloroform, n-heptane, dichloromethane, diethyl ether, hexane, n-decane, and pentane.

[0111] In each crystallization process, seed crystals of the desired product can be used to induce crystallization.In a particular embodiment, in the preparation of CBD, the seed crystals are (-)-cannabidiol produced by Protocol 1 disclosed herein.In a particular embodiment, in the preparation of 4,6-dibromo-olivetol, the seed crystals are 4,6-dibromo-olivetol produced by Protocol 1 disclosed herein.

[0112] General Procedure In certain embodiments, olivetol can be substituted with Cl, I, or F in addition to Br to form dihaloolivetol. Each halogen can be selected from the group consisting of Br, F, I, and Cl, more specifically, Br, F, or Cl, or more specifically, Br or F, or even more specifically, Br.

[0113] In a particular embodiment, dihaloolivetol is contacted with menthadienol in the presence of a suitable protonic acid catalyst.Possible catalysts include p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, acetic acid, and sulfuric acid.The reaction can take place in a suitable solvent or mixture of solvents, such as methylene chloride, chloroform, 1,2-dichloroethane, cyclohexane, toluene, methylene bromide, bromoform, hexane, xylene, acetonitrile, tert-butyl methyl ether, or a combination thereof.The reaction can produce dihalocannabidiol.

[0114] The dihalocannabidiol can then be reduced to remove its halo substituents. The dihalocannabidiol can be reduced by contacting it with a suitably selected reducing agent, such as sodium sulfite, potassium sulfite, palladium on carbon in combination with hydrogen, in the presence of a suitably selected base, such as sodium hydroxide, triethylamine, sodium carbonate, tripotassium phosphate, and potassium tert-butoxide. The reduction reaction can take place in a suitably selected polar solvent or mixture of polar solvents, or a mixture of non-polar and polar solvents, such as methanol or a mixture of methanol and water, acetonitrile, ethanol, acetone, isopropanol, n-butanol, dichloromethane, tetrahydrofuran, tert-butyl methyl ether, or a mixture of an organic solvent and water. The polar solvent or mixture of polar solvents can also be selected from the group consisting of acetonitrile, methylene chloride, or a combination thereof.

[0115] The dihalo-cannabidiol may be contained in a non-aqueous solvent or mixture of solvents such as dichloromethane, toluene, tert-butylmethyl, and n-heptane. The non-aqueous solvent may also contain a desiccant. A desiccant may be added to remove adventitious moisture from the reaction mixture. The amount of desiccant in the dihalo compound solution may be up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30% (g desiccant / mL solvent). These values ​​may be used to define ranges such as about 1% to about 10%, or about 10% to about 20%.

[0116] The amount of desiccant can be about 5% to about 20% g / mL of anhydrous MgSO4 per mL of DCM. For example, if the reagents are anhydrous, e.g., MgSO4, dibromo-olivetol, pTSA, a smaller amount, e.g., 5% g / mL, can be used. If the reagents are monohydrates, e.g., dibromo-olivetol and pTSA monohydrate, a larger amount, e.g., 20% g / mL, can be used. In one embodiment, the amount can be about 14.5% g / mL. In some embodiments, if a compound, e.g., menthadienol, is present in excess, such as greater than about 3 eq, the amount of desiccant can be 0%.

[0117] The amount of desiccant per starting material can also be expressed as a molar ratio of desiccant to starting material. The amount can be about 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, or about 5:1. These values ​​can be used to define ranges, such as from about 1.5:1 to about 3.5:1.

[0118] The desiccant can be any agent or compound that does not interfere with the reaction and can remove moisture from the reaction mixture. The desiccant can be selected from the group consisting of anhydrous inorganic salts, molecular sieves, activated carbon, silica gel, or combinations thereof. In one embodiment, the desiccant is anhydrous magnesium sulfate.

[0119] The reaction between dihalo-olivetol and menthadienol was approximately 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3 for dihalo-olivetol. , 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, or 5.5 equivalents of menthadienol, or the relative amounts of menthadienol and dihaloolivetol. These values ​​can be used to define ranges such as about 0.5 to about 5 equivalents, or about 0.5 to about 3.5 equivalents, or about 1.1 to about 1.7 equivalents, etc.

[0120] Menthadienol can be added slowly to the dihaloolivetol or to a solution containing the dihaloolivetol. Menthadienol can be added to the dihaloolivetol compound or to a solution containing the dihaloolivetol over 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 16, 20, or about 24 hours. These values ​​can be used to define ranges such as about 2 to about 12 hours, or about 4 to about 8 hours. The compound can be added in increments or portions over a period of time. For example, the compound can be added over 7 hours as follows: t=0: 0.65 equivalents, t=1 hour: +0.65 equivalents, t=4 hours: +0.3 equivalents, and optionally t=7 hours: +0.1 equivalents.

[0121] After the addition of menthadienol, the reaction mixture can be stirred for an additional hour. The reaction mixture can be stirred for an additional 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 20, 24, 36, or 48 hours. These values ​​can be used to define ranges such as about 1 to about 3 hours, or about 6 to about 48 hours, or about 12 to about 24 hours, or about 14 to about 18 hours.

[0122] Those of skill in the art will recognize that the reaction or process step(s) described herein can proceed for a sufficient period of time until the reaction is complete, as determined by any method known to those of skill in the art, for example, chromatography (e.g., HPLC). In this context, a "completed reaction or process step" shall mean that the reaction mixture contains significantly reduced amounts of starting material(s) / reagent(s) / intermediate(s) and significantly reduced amounts of desired product(s) compared to the amounts of each present at the beginning of the reaction.

[0123] The amount of protonic acid catalyst, for example, p-toluenesulfonic acid, in the reaction between menthadienol and dihaloolivetol can be about 0.5 mol%, 1 mol%, 2 mol%, 3 mol%, 4 mol%, 5 mol%, 6 mol%, 7 mol%, 8 mol%, 9 mol%, 10 mol%, 20 mol%, 30 mol%, 40 mol%, 50 mol%, 60 mol%, 70 mol%, 80 mol%, 90 mol%, 100 mol%, or about 120 mol% relative to dihaloolivetol. These values ​​can be used to define ranges such as about 4 mol% to about 6 mol%, 20 mol% to about 80 mol%, or about 40 mol% to about 60 mol%, etc.

[0124] As used herein, the term "reducing agent" refers to an agent capable of adding one or more electrons to an atom, ion, or molecule. The reducing agent can be a sulfur-containing compound, or Pd / C in the presence of hydrogen. The sulfur-containing compound can be a sulfur-containing reducing agent capable of reducing a C-halogen bond to form a C-H bond.

[0125] Sulfur-containing compounds include, for example, hydrosulfide (H 2 S), sulfurous acid (H 2 SO 3 ), thiosulfite (H 2 SO 2 O 2 ), dithionite (H 2 S 2 O 4 ), disulfite (H 2 S 2 O 5 ), dithioic acid (H 2 S 2 O 2 ), trithionate (H 2 S 3 O 6 The sulfur-containing inorganic salt may be an alkali metal salt or an alkaline earth metal salt. For example, the salt may be Li + , Na + , K + , Rb + , Cs + , Fr + , B.E. 2+ , Mg 2+ , Ca 2+ , Sr 2+ , B.A. 2+ , or Ra 2+ In one embodiment, the salt may be a monovalent or divalent cation selected from Li + , Na + , K + , Mg 2+ , and Ca 2+ The compound may be selected from the group consisting of:

[0126] Sulfur-containing inorganic salts also include ammonium salts (NH 4 +) or a quaternary ammonium salt. For example, the sulfur-containing inorganic acid salt can be a tetra-alkylated ammonium salt, e.g., a quaternary ammonium salt substituted with four alkyl groups. The alkyl groups can be C 1 ~C 18 The tetraalkylated ammonium salt can be a tetramethylammonium salt, a tetraethylammonium salt, a tetrapropylammonium salt, a tetrabutylammonium salt, or a combination thereof.

[0127] Sulfur-containing inorganic acids or their salts also produce bisulfite ions (HSO 3 - ) and / or sulfite ions (SO 3 2- ) can dissociate into sulfurous acid (H 2 SO 3 ) is generally expressed as SO in water. 2 It exists as a solution (typically about 6%).

[0128] The molar ratio amount of base to dihalocannabidiol in the reduction reaction mixture can be about 0:1, 1:1, 1.5:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1 or more. These values ​​can define ranges such as from about 3.5:1 to about 4.5:1, or from about 4:1 to about 6:1.

[0129] The reduction reaction can be carried out at the reflux temperature, including elevated temperatures due to elevated pressure, of the solvent or solvent mixture for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 20, 24, 28, 30, 32, 36, or about 48 hours, or any time necessary to reach a desired endpoint (which can be determined, for example, by the percent conversion of the starting or intermediate materials).

[0130] In certain embodiments, contacting the dihalocannabidiol with a reducing agent to prepare a first cannabidiol composition further comprises contacting the first cannabidiol composition with activated carbon. In certain embodiments, the activated carbon is loose carbon (Norit CN, Cabot). In certain embodiments, the activated carbon is encapsulated carbon (R55SP or R53SP, Cuno). In certain embodiments, the carbon is preferably encapsulated carbon of type R55SP, manufactured by Cuno.

[0131] The reflux temperature can be 20°C, room temperature, 30°C, 40°C, 50°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 110°C, or about 120°C. These values ​​can be used to define ranges such as about 20°C to about 100°C, or about room temperature to about 50°C, or about 60°C to about 85°C, or about 72°C to about 76°C. In some embodiments, a subsequent distillation can be performed. The distillation can be performed at the same temperatures listed above, for example, 85°C.

[0132] The reflux pressure can be atmospheric pressure. In some embodiments, reflux can be performed at a pressure of about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, or about 4000 mbar. These values ​​can be used to define ranges such as about 900 to about 3000 mbar.

[0133] The compounds of the present disclosure can be prepared as individual enantiomers by enantiospecific synthesis or resolved from an enantiomer-enriched mixture. When the stereochemistry of the disclosed compounds is named or depicted, the named or depicted stereoisomer can be at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight, compared to all other stereoisomers. The percent pure by weight, compared to all other stereoisomers, is the ratio of the weight of one stereoisomer to the weight of the other stereoisomer. When a single enantiomer is named or depicted, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure by weight. The percent optical purity by weight is the ratio of the weight of an enantiomer to the weight of the enantiomer and its optical isomer.

[0134] The present disclosure can produce compounds of interest, such as cannabidiol, with high stereospecificity. The stereospecificity of the process of the present disclosure can be greater than about 60% ee, 75% ee, 80% ee, 85% ee, 90% ee, 95% ee, 97% ee, 98% ee, 99% ee. These values ​​can define ranges, such as about 90% ee and about 99% ee.

[0135] The present disclosure can produce a compound of interest, such as cannabidiol, in high yield. The yield of the process of the present disclosure can be greater than about 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. These values ​​can define ranges such as about 60% to about 85%, or about 90% to about 99%.

[0136] In certain embodiments, the coupling temperature is preferably −20° C. or higher.

[0137] In certain embodiments, it is preferred that the synthesis does not include a polymer filtration step.

[0138] In certain embodiments, the debromination solvent is preferably about 15 volumes or less of isopropanol:water (1:1). In certain embodiments, the debromination preferably occurs for about 36 hours or more.

[0139] In certain embodiments, after debromination, the mixture is preferably contacted with activated carbon.

[0140] In certain embodiments, the post-acid wash is preferably a buffer solution that is about pH 7.0, such as a phosphate buffer.

[0141] In certain embodiments, the post-base pH adjustment is preferably water with ascorbate.

[0142] In certain embodiments, it is preferred that the organic layer is dried by azeotropic distillation.

[0143] In certain embodiments, it is preferred that the coupling temperature is -20°C or higher, the synthesis does not include a polymer filtration step, the debromination solvent is about 15 volumes or less of isopropanol:water (1:1), the debromination occurs for about 36 hours or more, after debromination the mixture is contacted with activated carbon, the post acid wash is a buffer solution that is about pH 7.0 such as a phosphate buffer, the post base pH adjustment is water with ascorbate, and the organic layer is dried by azeotropic distillation.

[0144] The subject matter described herein is directed to the following embodiments.

[0145] 1. A composition comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount less than 10 ppm.

[0146] 2. The composition of embodiment 1, comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 8 ppm.

[0147] 3. The composition of embodiment 1, comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 6 ppm.

[0148] 4. The composition of embodiment 1, comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 4 ppm.

[0149] 5. The composition of embodiment 1, comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 3 ppm.

[0150] 6. The composition of embodiment 1, comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 2 ppm.

[0151] 7. The composition of embodiment 1, comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 0.1 ppm to 6 ppm.

[0152] 8. The composition of embodiment 1, comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 1 ppm to 5 ppm.

[0153] 9. The composition of any one of embodiments 1-8, wherein the cannabidiol is crystalline.

[0154] 10. The composition of any one of embodiments 1-9, wherein the cannabidiol is crystalline polymorphic form A.

[0155] 11. The composition of embodiment 10, wherein said crystalline polymorph Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 11A.

[0156] 12. The crystalline polymorphic form A is 5.07, 8.28, 9.30, 9.70, 10.20, 11.74, 12.49, 13.12, 13.80, 15.08, 15.35, 16.05, 16.57, 17.36, 17.93, 18.79, 18.96, 19.44, 19.79, 20.55, 20.82, 21.61, 22.11, 22.63, 22.99 11. The composition of embodiment 10, comprising at least one X-ray powder diffraction peak at degrees 2θ ± 0.07 selected from the group consisting of 23.68, 24.40, 25.28, 26.45, 26.76, 27.46, 27.70, 28.45, 29.06, 31.07, 32.60, 33.31, 34.03, 34.57, 35.31, 36.49, and 37.79.

[0157] 13. The crystalline polymorphic form A is 5.07, 8.28, 9.30, 9.70, 10.20, 11.74, 12.49, 13.12, 13.80, 15.08, 15.35, 16.05, 16.57, 17.36, 17.93, 18.79, 18.96, 19.44, 19.79, 20.55, 20.82, 21.61, 22.11, 22.63, 22.99 11. The composition of embodiment 10, comprising at least two X-ray powder diffraction peaks at degrees 2θ ± 0.07 selected from the group consisting of 23.68, 24.40, 25.28, 26.45, 26.76, 27.46, 27.70, 28.45, 29.06, 31.07, 32.60, 33.31, 34.03, 34.57, 35.31, 36.49, and 37.79.

[0158] 14. The crystalline polymorphic form A is 5.07, 8.28, 9.30, 9.70, 10.20, 11.74, 12.49, 13.12, 13.80, 15.08, 15.35, 16.05, 16.57, 17.36, 17.93, 18.79, 18.96, 19.44, 19.79, 20.55, 20.82, 21.61, 22.11, 22.63, 22.99 11. The composition of embodiment 10, comprising at least three X-ray powder diffraction peaks at degrees 2θ ± 0.07 selected from the group consisting of 23.68, 24.40, 25.28, 26.45, 26.76, 27.46, 27.70, 28.45, 29.06, 31.07, 32.60, 33.31, 34.03, 34.57, 35.31, 36.49, and 37.79.

[0159] 15. The composition of embodiment 10, wherein the crystalline polymorph Form A exhibits a characteristic X-ray powder diffraction pattern with peaks at 9.70, 11.74, 15.08, 17.36, and 18.79.44 2θ ± 0.07 degrees 2θ.

[0160] 16. The composition of embodiment 10, wherein the crystalline polymorph Form A exhibits a characteristic X-ray powder diffraction pattern with peaks at 9.70, 11.74, 12.49, 13.12, 13.80, 15.08, 17.36, 18.79, 20.55, and 22.11 2θ ± 0.07 degrees 2θ.

[0161] 17. The crystalline polymorphic form A is 5.07, 8.28, 9.30, 9.70, 10.20, 11.74, 12.49, 13.12, 13.80, 15.08, 15.35, 16.05, 16.57, 17.36, 17.93, 18.79, 18.96, 19.44, 19.79, 20.55, 20.82, 21.61, 22.11, 22.63, 22.9 11. The composition of embodiment 10, exhibiting a characteristic X-ray powder diffraction pattern having characteristic peaks expressed in degrees of 2θ ± 0.07 at: 9, 23.68, 24.40, 25.28, 26.45, 26.76, 27.46, 27.70, 28.45, 29.06, 31.07, 32.60, 33.31, 34.03, 34.57, 35.31, 36.49, and 37.79.

[0162] 18. The composition of embodiment 10, wherein said crystalline polymorphic Form A is characterized by the Differential Scanning Calorimetry thermogram shown in FIG.

[0163] 19. The composition of embodiment 10, wherein said crystalline polymorphic Form A is characterized by a differential scanning calorimetry thermogram with an endotherm having an onset of about 67.72°C and a peak at about 68.12°C.

[0164] 20. Cannabinol, cannabigerol, delta-8-tetrahydrocannabinol, cannabichromene, cannabicyclol, cannabidiarin, tetrahydrocannabivarin, cannabidivarin, cannabichromen-2-yl, cannabigerovarin, cannabiersoin, cannabiditran, 3,5-dibromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 3-bromo-5'-methyl-4-pentyl -2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 4,6-dibromoolivetol, 4-bromo-5-pentylbenzene-1,3-diol, abnormal cannabidiol (ab-CBD), cannabidiol quinone derivatives (CBQ), 3,5-dibromo-5'-methyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 3,5 -Dibromo-4-ethyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 3-bromo-4-ethyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 4,6-dibromo-5-propylbenzene-1,3-diol, 4-bromo-5-propylbenzene-1,3-diol, 4,6-dibromo-5-ethylbenzene- 20. The composition of any one of embodiments 1-19, further comprising at least one compound selected from the group consisting of 1,3-diol, 4-bromo-5-ethylbenzene-1,3-diol, 5'-methyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, and 4-ethyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol.

[0165] 21. The composition of any one of embodiments 1-20, wherein the composition does not comprise a plant extract material.

[0166] 22. A stable composition comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount less than 10 ppm upon storage for 2 years or less, for example at 25°C and 75% rh.

[0167] 23. The stable composition of embodiment 22, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm upon storage for 1 year or less.

[0168] 24. The stable composition of embodiment 22, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm upon storage for 6 months or less.

[0169] 25. The stable composition of embodiment 22, wherein the delta-9-tetrahydrocannabinol is present at about 0.1 ppm to about 9 ppm.

[0170] 26. The composition of any one of embodiments 22-25, wherein the cannabidiol is crystalline.

[0171] 27. A composition comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol, wherein the ratio of cannabidiol to delta-9-tetrahydrocannabinol is less than 1:0.0001 as measured by HPLC.

[0172] 28. The composition of embodiment 27, wherein the cannabidiol is crystalline.

[0173] 29. Cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount less than 10 ppm; and a pharma- ceutically acceptable excipient.

[0174] 30. The formulation of embodiment 29, wherein the formulation is in the form of a matrix.

[0175] 31. The formulation of embodiment 29, wherein the formulation is in the form of a liquid.

[0176] 32. The formulation of embodiment 31, wherein the liquid is vaporizable.

[0177] 33. The formulation of embodiment 29, wherein the formulation is in the form of granules.

[0178] 34. A method for preparing crystalline cannabidiol characterized by having an X-ray powder diffraction pattern substantially as shown in FIG. 11A, and less than 10 ppm delta-9-tetrahydrocannabinol, comprising crystallizing cannabidiol from isooctane.

[0179] 35. A method for preparing a cannabidiol composition comprising: contacting a dihalo-olivetol with a menthadienol in the presence of a protic acid catalyst to prepare a dihalocannabidiol; contacting a dihalocannabidiol with a reducing agent to prepare a first cannabidiol composition; contacting a first cannabidiol composition with a first solvent; crystallizing the second cannabidiol composition from the solvent; and recrystallizing the crystalline cannabidiol composition having less than 10 ppm delta-9-tetrahydrocannabinol from the second solvent.

[0180] 36. The method of embodiment 35, wherein the protic acid catalyst is selected from the group consisting of p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, acetic acid, and sulfuric acid.

[0181] 37. The method of embodiment 35 or 36, wherein the reducing agent is a sulfur-containing compound.

[0182] 38. The method of any one of embodiments 35-37, wherein the first solvent is selected from the group consisting of water, 2-butanone, ethyl acetate, 1,4-dioxane, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, dichloromethane, chloroform, n-heptane, toluene, isopropyl acetate, isooctane, n-decane, and anisole.

[0183] 39. The method of any one of embodiments 35-38, wherein the second solvent is selected from the group consisting of isooctane, chloroform, n-heptane, dichloromethane, diethyl ether, hexane, n-decane, and pentane.

[0184] 40. The method of any one of embodiments 35-39, wherein the dihalo-olivetol is contacted with the menthadienol in the presence of a protic acid catalyst at a temperature of about -33 °C to about -27 °C.

[0185] 41. The method of any one of embodiments 35-40, wherein the dihalo-olivetol is contacted with the menthadienol in the presence of a protic acid catalyst at a temperature of about -30°C.

[0186] 42. A method for recrystallizing cannabidiol from a mixture of cannabinoids to prepare a composition comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol, comprising: contacting the mixture of cannabinoids with isooctane to form a solution; heating the solution to about 40° C.; Cooling the solution to about 32° C.; seeding the solution at about 32°C with (-)-cannabidiol to form a suspension; Warming the suspension to about 32° C. while stirring; Cooling the suspension to −20° C.; Separating solid material from the suspension; and washing the solid material with isooctane at about -20°C; and drying the solid material to obtain a crystalline composition comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol.

[0187] 43. A method of treating a disease in a subject, comprising: A method comprising administering to the subject a composition comprising a therapeutic amount of cannabidiol and an amount of delta-9-tetrahydrocannabinol, wherein the amount of delta-9-tetrahydrocannabinol is less than about 20 μg per day.

[0188] 44. The method of embodiment 43, wherein the disease is selected from the group consisting of emesis, pain, inflammation, multiple sclerosis, Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease, epilepsy, glaucoma, osteoporosis, schizophrenia, cancer, and obesity.

[0189] 45. The composition of embodiment 10, wherein the crystalline polymorphic form A has at least one of: (a) a d10 particle size in the range of about 1 μm to about 10 μm; (b) a d50 particle size in the range of about 8 μm to about 40 μm; and (c) a d90 particle size in the range of about 8 μm to about 500 μm.

[0190] 46. ​​The composition of embodiment 10, wherein the crystalline polymorphic form A has a d50 particle size in the range of about 8 μm to about 40 μm.

[0191] 47. The composition of embodiment 10, wherein the crystalline polymorphic form A has a d90 particle size in the range of about 8 μm to about 500 μm.

[0192] 48. A composition comprising cannabidiol, a halogenated cannabidiol, and delta-9-tetrahydrocannabinol, wherein the cannabidiol is present in an amount of at least about 99.999% w / w of the composition, the delta-9-tetrahydrocannabinol is present in an amount less than 10 ppm, and the halogenated cannabidiol is present in an amount less than 10 ppm.

[0193] 49. The composition of embodiment 48, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 8 ppm.

[0194] 50. The composition of embodiment 48, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 6 ppm.

[0195] 51. The composition of embodiment 48, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 4 ppm.

[0196] 52. The composition of any one of embodiments 48-51, wherein the halogenated cannabidiol is a brominated cannabidiol.

[0197] 53. The composition of embodiment 52, wherein the brominated cannabidiol is 4-monobromo-CBD.

[0198] 54. The composition of embodiment 53, wherein the 4-monobromo-CBD is present in an amount of less than 5 ppm.

[0199] 55. The composition of embodiment 54, wherein the 4-monobromo-CBD is present in an amount from about 0.1 ppm to about 3 ppm.

[0200] 56. A concentrated composition comprising at least 99.999% cannabidiol and less than 10 ppm of total impurities, the impurities comprising halogenated cannabidiol.

[0201] 57. The composition of embodiment 56, wherein the impurities further comprise delta-9-tetrahydrocannabinol.

[0202] 58. The composition of embodiment 57, wherein the halogenated cannabidiol and the delta-9-tetrahydrocannabinol are present in a ratio of about 1:1 to about 5:1.

[0203] 59. A recrystallized composition comprising cannabidiol, a halogenated cannabidiol, and delta-9-tetrahydrocannabinol, wherein the cannabidiol is present in an amount of at least about 99.999% w / w of the composition, the delta-9-tetrahydrocannabinol is present in an amount less than 5 ppm, and the halogenated cannabidiol is present in an amount less than about 10 ppm, and the composition is solid.

[0204] 60. The recrystallized composition of embodiment 59, wherein the composition is recrystallized from isooctane.

[0205] 61. The recrystallized composition of embodiment 59 or 60, wherein the composition is a crystalline powder.

[0206] 62. A crystalline cannabidiol composition comprising cannabidiol and a halogenated cannabidiol, the composition being free of delta-9-tetrahydrocannabinol.

[0207] 63. The composition of any one of embodiments 48-59, wherein the composition does not contain a cannabinoid quinone.

[0208] 64. The composition of any one of embodiments 45-63, wherein said amount is present upon storage for 3 months or less.

[0209] 65. The composition of any one of embodiments 48-62, further comprising a pharma- ceutically acceptable excipient.

[0210] 66. A composition comprising at least 99.999% cannabidiol and less than 10 ppm total impurities, the impurities including halogenated cannabidiol; A suspension comprising: a solvent, the composition being insoluble or slightly insoluble in the solvent at or below 20°C.

[0211] 67. The suspension of embodiment 66, wherein the solvent is isooctane.

[0212] The disclosures of all cited references, including publications, patents, and patent applications, are expressly incorporated herein by reference in their entireties.

[0213] When an amount, concentration, or other value or parameter is given as either a range, a preferred range, or a list of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether the ranges are separately disclosed. When a range of numerical values ​​is recited herein, unless otherwise stated, the range is intended to include its endpoints, as well as all integers and fractions within the range. The scope of the present invention is not intended to be limited to the specific values ​​recited when defining the range.

[0214] The invention is further defined in the following examples. It should be understood that these examples, while indicating preferred embodiments of the invention, are given by way of illustration only. EXAMPLES

[0215] Unless otherwise stated, all reactions described herein were carried out under an argon or nitrogen atmosphere.

[0216] Example 1 - (Protocol 1) Preparation of cannabidiol, (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol Cannabidiol was prepared according to the present disclosure. [ka] [ka]

[0217] Olivetol (16.2 kg dry basis, 0.0897 kmol) was dissolved in dichloromethane (46 L / kg). The solution was cooled to -15°C and turned into a thin white suspension. Bromine (29.8 kg, 2.080 equivalents relative to olivetol) was then added at -15°C. The reaction mixture transformed into a red solution at the end of the addition and no gas evolution was observed. The mixture was dwelled for 5 minutes.

[0218] The process was monitored by IPC (in-process control).Once the solution was compliant (NMT 0.5%, 4-monobromolivetol), it was warmed to 0°C and then poured into a solution of dipotassium hydrogen phosphate (47.2 kg) and sodium sulfite (1.1 kg) in demineralized water (290.9 kg), while maintaining a quench temperature of 0-5°C.

[0219] The biphasic mixture was warmed to 25° C. and stirred for 30 minutes, after which the layers were allowed to settle. The top aqueous layer was discarded. The organic layer was concentrated to 97 L. Heptane was added (331.6 kg) and then distilled again at 50° C. under partial vacuum to 339 L.

[0220] The solution was cooled to 35° C., seeded with 4,6-dibromo-olivetol (23 g, 0.10 wt %) and allowed to dwell for 1 h. Finally, the reactor contents were cooled to −5° C. in 6 h±30 min to allow crystallization. The product was isolated, washed with cold (0° C.) heptane (33.2 kg) and dried at 40° C. under full vacuum. Yield: 23.9 kg (79% yield). Scheme 1 - Synthetic route for the preparation of 2-dibromo-CBD, (1'R,2'R)-3,5-dibromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol [ka]

[0221] A stock solution of dipotassium hydrogen phosphate (2.8 kg) in water (37.3 kg) was prepared. 4,6-dibromo-olivetol (31.9 kg, 0.0944 kmol), dichloromethane (283.6 kg, 6.7 vol), and menthadienol (9.3 kg, 0.65 equiv) were charged to a cryogenic reactor. The mixture was stirred to ensure dissolution, and then anhydrous magnesium sulfate (31.6 kg) was added. The suspension was cooled to -30°C, and then p-toluenesulfonic acid hydrate (8.8 kg) was added to induce the alkylation reaction. The mixture was allowed to dwell for 1 hour. Menthadienol was added in three portions (9.3 kg, 4.3 kg, and 1.4 kg, i.e., 0.65, 0.30, and 0.10 equiv) at least 2, 3, and 1 hour into the reaction, respectively.

[0222] Conversion was checked by IPC (NMT 0.5%, 4,6-dibromo-olivetol) and if not compliant the mixture was stirred further and the IPC was repeated. If the IPC was still not compliant, more menthadienol (1.4 kg, 0.10 equiv.) was added, stirred and the IPC was repeated.

[0223] The mixture was warmed to 0° C. and the suspended solids (Mg sulfate and p-toluenesulfonic acid) were filtered off. The cake was then washed with dichloromethane to recover the product.

[0224] The filtrate was quenched with demineralized water while maintaining the temperature below 20° C. The pH was adjusted to 6.5 with hydrogen phosphate stock solution. Once the temperature was adjusted to 25° C., the phases were allowed to settle and the aqueous layer was discarded.

[0225] The solution was concentrated under partial vacuum (700 mbar) to 64 L. Methanol (379 kg) was added to induce precipitation of the terpene polymer. Distillation was continued at a maximum of 30°C.

[0226] The resulting white slurry was cooled to -20°C. The polymer was then filtered and the filter was rinsed with methanol. The resulting (1'R,2'R)-3,5-dibromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol solution was obtained in 11% yield. Scheme 1-3-CBD, synthetic route for the preparation of (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol [ka]

[0227] In a glass-lined reactor, sodium sulfite (35.7 kg, 3.00 equiv.) and sodium ascorbate (1.6 kg, 0.083 equiv.) were dissolved in water. Dibromo-CBD solution (whole lot made from 31.9 kg of 4,6-dibromo-olivetol synthesized above) was added, followed by methanol when the solution was more than 11% concentrated. Finally, triethylamine (38.2 kg, 4.00 equiv.) was added as a base.

[0228] The mixture was heated to reflux and allowed to dwell for 24 hours. The conversion was then confirmed by IPC (residual monobromo-cannabidiol max 0.5%). Once the IPC was compliant, volatiles were removed by distillation until an internal temperature of 85°C was reached under ambient pressure. A dispersion of the product (as an oil) in water resulted. This was followed by the addition of demineralized water (127.6 kg) and n-heptane (319 kg).

[0229] The organic layer was extracted with water at pH 4.0 to remove residual trimethylamine, then it was re-extracted with water (159.5 kg) and potassium hydrogen phosphate at pH 6.7, and finally washed with water (159.5 kg).

[0230] The neutral organic layer was concentrated to 96 L and treated with charcoal (1.6 kg) slurried in n-heptane (32.7 kg) at 50° C. The charcoal was filtered off via abrasive filtration. Following this, the cake was washed with n-heptane (21.8 kg).

[0231] The solution was concentrated to 96 L and cooled to 20° C. (-)-Cannabidiol was then added as seeds. The suspension was cooled to -20° C. The product was isolated by centrifugation, washed with n-heptane and dried at 40° C. under full vacuum (dry IPC: n-heptane max. 3000 ppm). Yield: 75% (22.3 kg). Figures 1 and 2 show the liquid chromatography mass spectrum and Fourier transform infrared spectrum, respectively, of cannabidiol produced by protocol 1, which underwent recrystallization in n-heptane before analysis. Samples 4, 5, and 6 were produced according to protocol 1. Chromatograms for samples 4, 5, and 6 are provided in Figures 6D, 6E, and 6F.

[0232] Example 2 - (Protocol 2) Preparation of cannabidiol, (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol [ka]

[0233] Bromine (1.291 kg, 2.080 equiv. relative to olivetol) was added to a suspension of olivetol (0.7 kg, 3.88 mol) in dichloromethane (42 kg, 31.7 L) at -15°C. The reaction mixture was stirred for 5 min and then monitored by IPC to ensure complete conversion (NMT 0.5% 4-monobromoolivetol). An aqueous solution of dipotassium hydrogen phosphate (2.03 kg, 1.5 equiv.), sodium hydroxide (0.233 kg, 1.5 equiv.), and sodium sulfite (0.049 kg, 0.1 equiv.) was then added to the mixture at 20°C. The lower organic phase was separated at 27°C and dichloromethane was added at atmospheric pressure at approximately 6 mL / g. オリベトールThis was followed by the addition of n-heptane (14.35 kg). The solution was further concentrated at 50° C. (900-200 mbar) to azeotropically distill the remaining dichloromethane to a volume of approximately 20 mL / g. オリベトール The residual volume was allowed to reach 100%. The solution was seeded at 20-40°C, cooled to -5°C over a period of 6 hours, and stirred for at least 1 hour. The product was isolated by filtration, washed with cold n-heptane, and dried under vacuum at 40°C. Typical yield: 70-82% (22-23 g / L). Scheme 2 - Synthetic route for the preparation of 2-dibromo-CBD, (1'R,2'R)-3,5-dibromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol [ka]

[0234] 4,6-Dibromo-olivetol (100 g), menthadienol (29.3 g, 0.650 molar equivalents relative to 4,5-dibromo-olivetol), and magnesium sulfate (100 g, 2.81 molar equivalents) were suspended in dichloromethane (679 mL) in a cryogenic reactor. At -30°C, p-toluenesulfonic acid (28.1 g, 0.50 molar equivalents) was added to the solution. Additional amounts of menthadienol were added 1 h (0.650 molar equivalents 29.3 g) and 3 h (0.3 molar equivalents 13.5 g) after the reaction had started. Six hours after the reaction had started, the reaction was warmed to 0°C and quenched with water (800 mL). The layers were separated at 25°C. The organic phase was diluted with aqueous phosphate buffer (K 2 HPO 4 / KH 2 PO 4, pH 7). The organic phase was concentrated (25-40 °C, 700-1000 mbar) and methanol was added (solvent exchange). Residual dichloromethane was removed by distillation (<30 °C, 150 mbar). The mixture was cooled to -15 °C and the white precipitate was filtered off after 1 h. The filter cake was washed with methanol (-15 °C) and discarded. The resulting greenish / yellowish solution of dibromo-CBD in methanol was used directly in the next step. Yield in solution: about 95-99% (75 g / L). Scheme 3-2-CBD, synthetic route for the preparation of (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol [ka]

[0235] The dibromo-CBD solution in methanol obtained above was diluted with Na 2 SO 3 (112 g, 3.0 molar equivalents relative to 4,5-dibromo-olivetol) and an aqueous solution of Na ascorbate (5 g) were added at room temperature. Triethylamine (120 g, 4 molar equivalents) was added to the off-white suspension and the reaction was stirred at reflux for about 24 hours. The reaction solvent (methanol / trimethylamine / water) was partially distilled off at atmospheric pressure and n-heptane (1000 g) was added at 40°C. The suspension was acidified to pH 4.0 with concentrated HCl (18 g). After layer separation, the organic layer was washed with phosphate buffer (K 2 HPO 4 / KH 2 PO 4, pH 7) and sodium ascorbate, and finally with aqueous sodium ascorbate solution. The organic layer was concentrated, diluted again with n-heptane (684 g) and treated with activated charcoal at 27 °C for 1 h. The suspension was filtered at 27 °C and the charcoal was washed with n-heptane on the reactor. The solution was concentrated in vacuum (target assay: 25-30% of CBD in n-heptane) and the remaining organic layer was cooled to 20 °C, seeded with (-)-cannabidiol and stirred at 20 °C for 1 h. The suspension was cooled to 10 °C over 1 h and warmed again to 22 °C over 1 h. The suspension was stirred at 22 °C for 1 h and then further cooled to -20 °C within 6 h. After stirring at -20 °C for 1 h, the white suspension was filtered and the wet cake was washed with cold n-heptane on the reactor. The wet product was dried at 40 °C (<10 mbar) for 12-24 h. Typical yield: 75-86% (over two steps) (25 g / L). Sample 3 was produced by protocol 2. The chromatogram of this sample is provided in Figure 6C.

[0236] Example 3 - (Protocol 3) Preparation of cannabidiol, (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol [ka]

[0237] Bromine (1.291 kg, 2.080 equiv. relative to olivetol) was added to a suspension of olivetol (0.7 kg, 3.88 mol) in dichloromethane (42 kg, 31.7 L) at -15°C. The reaction mixture was stirred for 5 min and then monitored by IPC to ensure complete conversion (NMT 0.5% 4-monobromoolivetol). An aqueous solution of dipotassium hydrogen phosphate (2.03 kg, 1.5 equiv.), sodium hydroxide (0.233 kg, 1.5 equiv.), and sodium sulfite (0.049 kg, 0.1 equiv.) was added to the reaction mixture at 20°C. The lower organic phase was separated at 27°C and dichloromethane was added at atmospheric pressure at approximately 6 mL / g. オリベトールThis was followed by the addition of n-heptane (14.35 kg). The solution was further concentrated at 50° C. (900-200 mbar) to azeotropically distill the remaining dichloromethane, resulting in a volume of 20 mL / g. オリベトール A residual volume of 1000 mg / ml was reached. The solution was seeded at 20-40 °C, cooled to -5 °C over a period of 6 h, and stirred for 1 h. The product was isolated by filtration, washed with cold n-heptane, and dried in vacuum at 40 °C. Typical yield: 70-82% (22-23 g / L). Scheme 3 - Synthetic route for the preparation of 2-dibromo-CBD, (1'R,2'R)-3,5-dibromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol [ka]

[0238] 4,6-Dibromo-olivetol (50 g), menthadienol (0.65 equiv., 14.6 g), and magnesium sulfate (2.8 equiv., 50.0 g) were suspended in dichloromethane (5.5 mL / g, 275 mL) in a cryogenic reactor. At -20°C, p-toluenesulfonic acid (0.2 equiv., 5.7 g) was added. Additional amounts of menthadienol were added at 0.5 h (0.65 equiv., 14.6 g), 1 h (0.4 equiv., 7.9 g), and 2 h (0.1 equiv., 2.2 g) from the start of the reaction. Approximately 3 h after the start of the reaction, the reaction mixture was warmed to 0°C and quenched with water (5 mL / g, 250 mL). The layers were separated at 25°C. The organic phase was washed with an aqueous solution of dipotassium hydrogen phosphate (0.13 g / g, 6.5 g) and monopotassium hydrogen phosphate (0.065 g / g, 3.3 g) and water (5 mL / g, 250 mL). The organic phase solvent was exchanged into isopropanol (12 mL / g, 600 mL) under reduced pressure (0-50 °C, 100-1000 mbar). The resulting greenish / yellowish solution of dibromo-CBD in isopropanol was used directly in the next step. Estimated yield in solution: about 95-99%. Scheme 3-3-CBD, synthetic route for the preparation of (1'R,2'R)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol [ka]

[0239] The dibromo-CBD solution in isopropanol obtained in step 2 above was diluted with Na 2 SO 3 (3.0 equiv., 55.9 g / g) and an aqueous solution of Na ascorbate (0.05 g / g, 2.5 g). Triethylamine (4.0 equiv., 55.9 g) was added to the off-white suspension and the reaction was stirred at reflux for about 36 h. The reaction solvent (isopropanol / trimethylamine / water) was partially distilled off at atmospheric pressure and n-heptane (7 mL / g, 350 mL) was added at 40 °C. The suspension was acidified to pH 4.0 with concentrated HCl. After layer separation, the organic phase was washed with an aqueous solution of dipotassium hydrogen phosphate (0.13 g / g, 6.5 g) and monopotassium hydrogen phosphate (0.065 g / g, 3.3 g) and water (5 mL / g, 250 mL). After layer separation, the organic phase was washed with an aqueous solution of sodium ascorbate (0.05 g / g, 2.5 g) and water (5 mL / g, 250 mL). The organic layer was concentrated, diluted again with n-heptane (4 mL / g, 200 mL) and treated with activated charcoal at 27° C. The charcoal was washed on-board with n-heptane (3 mL / g, 150 mL). The solution was concentrated in vacuum and the remaining organic layer was cooled to 20° C., seeded with (−)-cannabidiol and stirred at 20° C. for 1 hour. The suspension was cooled to 10° C. over 1 hour and warmed again to 22° C. over 1 hour. The suspension was stirred at 22° C. for 1 hour and then further cooled to −20° C. over a period of 6 hours. After stirring at −20° C. for 1 hour, the white suspension was filtered and the wet cake was washed on-board with cold isooctane (1.5 mL / g, 75 mL). The wet product was dried at 40°C (<10 mbar) for 12-24 h. Typical yield: 65-75% (for two steps).

[0240] Example 4 - Recrystallization (-)-Cannabidiol (20 g) was dissolved in isooctane (80 mL) and heated to 40 °C. The solution was cooled to 32 °C, seeded with (-)-cannabidiol (0.20 g) and stirred at 32 °C for 1 h. The suspension was cooled to -20 °C over 3 h, the white suspension was filtered and the wet cake was washed with cold isooctane. The wet product was dried at 40 °C (<10 mbar) for 12-24 h. Typical yield: 90-96%. Table 1 shows the product characteristics of samples 1 and 2, produced by protocol 3 and subjected to recrystallization in isooctane. Chromatograms of these samples are shown in Figure 6A and Figure 6B. [Table 1]

[0241] Example 5: HPLC Method for Assay / Impurity Testing on Cannabidiol A method was developed for assay / impurity testing for cannabidiol. A Waters XBridge Shield RP18 3.5 μm, 3.0×150 mm column was used, operating at a column temperature of 35° C. and a UV wavelength of 225 nm. Mobile phase A was H 2 Mobile phase A was 0.05% (vol / vol) acetic acid / acetonitrile 95 / 5 (vol / vol) in 200 and mobile phase B was methanol. The sample diluent was 30 / 70 HO with a sample concentration of 0.3 mg / mL, a standard concentration of 0.3 mg / mL, and an injection size of 10 μL. 2 O / ACN (vol / vol). The mobile phase gradient followed is shown in Table 2. Figure 3 is a representative chromatogram of retention time marker samples obtained using this HPLC method. The UPLC chromatogram of cannabidiol isolated by protocol 2 is shown in Figure 4. [Table 2]

[0242] Example 6 - Ultra Performance Liquid Chromatography of Cannabidiol Ultra Performance Liquid Chromatography (UPLC) was used to check the purity of the cannabidiol product. An ACQUITY BEH C4 column, 150 mm length x 2.1 mm, was used. The column temperature was set at 30°C with a flow rate of 0.4 mL / min, a wavelength of 225 nm, and an injection volume of 4 μL. A linear gradient was programmed as shown in Table 3. [Table 3]

[0243] Example 7: Quantifying low levels of THC in cannabidiol An analytical method was developed using HPLC to measure low levels of delta-9-tetrahydrocannabinol in cannabidiol samples. A Waters XBridge C18 3.5 μm, 3.0x150mm column was used and operated at a temperature of 30°C, a UV wavelength of 225 nm, and an injection size of 20 μL. Mobile phase A was H 2 Mobile phase A was 0.02% (v / v) acetic acid in O, while mobile phase B was 0.02% (v / v) acetic acid in acetonitrile (ACN). The mobile phase gradient followed is shown in Table 4. [Table 4]

[0244] Preparation of THC stock solution Aliquots of 0.5 mL of D9-THC reference standard (Cerilliant, 1.0 mg / mL in MeOH) were diluted in sample diluent (70 / 30 acetonitrile / H 2 The standard stock solution was diluted with 0.001 mg / mL of D9-THC, vol / vol, into a 500 mL volumetric flask. The D9-THC concentration was 0.001 mg / mL in the standard stock solution, corresponding to 200 ppm of D9-THC relative to the CBD sample solution (nominal CBD concentration was 5.0 mg / mL).

[0245] Preparation of THC working standard solution An aliquot of 5 mL of the THC stock standard solution was diluted into a 100 mL volumetric flask using sample diluent. The D9-THC concentration was 0.00005 mg / mL in the working standard solution, corresponding to 10 ppm of D9-THC relative to the CBD sample solution.

[0246] Preparation of sample solutions Approximately 50 mg of cannabidiol sample was weighed into a 10 mL volumetric flask. The volumetric flask was diluted to volume using sample diluent and mixed well.

[0247] Sample set injection sequence A minimum of six working standards were injected prior to the sample set, and up to six injections of CBD samples were injected between the bracketed working standards.

[0248] calculation The amount of THC in each sample was calculated using the following formula:

number

[0249] Figure 5 shows an overlay of HPLC chromatograms of a diluent blank, a cannabidiol sample, and a cannabidiol sample spiked with 10 ppm D9-THC, demonstrating the method sensitivity. HPLC chromatograms of several samples and their THC determinations are shown in Figures 6A-6E. For reference, each chromatogram in Figures 6A-6F is shown relative to a 10 ppm THC working standard. For samples 1, 2, and 3, approximately 50.28 mg, 50.77 mg, and 55.60 mg of material were used. The results of these HPLC experiments are summarized in Table 5. [Table 5]

[0250] Samples were analyzed by the low HPLC THC method before and after recrystallization to determine the effect that recrystallization had on purging THC from the sample material. The results are summarized in Table 6. It can be seen that recrystallization provided an additional purging of about 90% of the THC. The level of THC in "pure" cannabidiol ranges from about 2-30 PPM. [Table 6]

[0251] In another series of experiments, cannabidiol samples were spiked with various amounts of THC. They were analyzed by HPLC prior to spiking. The spiked samples were then subjected to recrystallization and analyzed by HPLC to determine the amount of THC in the recrystallized cannabidiol product. The results of these studies are provided in Table 7. These spiking experiments showed greater than 95% THC purging. [Table 7]

[0252] Example 8: Characterization of cannabidiol by NMR spectroscopy For NMR spectroscopy experiments, cannabidiol produced by protocol 1 subjected to recrystallization in n-heptane was used (sample 16). Cannabidiol was dissolved in DMSO-d 6 The solution was delivered to a 5 mm NMR tube. 1-D proton spectra (Figure 7A), 2-D gCOSY (Figure 7B), gHMBCad (Figure 7C), gHSQCad (Figure 7D), and ROESYad (Figure 7E) spectra were acquired on an Agilent Inova-600 MHz spectrometer at 25 °C using standard VNMRJ pulse sequences. Proton chemical shifts were determined using the residual DMSO-d 6The signal was measured relative to the indirect dimension (2.50 ppm). Carbon chemical shifts were measured relative to the absolute chemical shift scale, referenced to TMS at 0 ppm and a Ξ value of 0.25145020. For the proton dimension, a spectral width of 6281 Hz was used, which was acquired at 16384 points for the 1-D spectra and 1875 points for the 2-D spectra. The pulse width was 7.25 μs. The 2D gCOSY spectra were acquired with 256 increments of 8 transients each. The gHSQC spectra were acquired with 96 increments of 16 transients each, and the gHMBC spectra were acquired with 200 increments of 16 transients each. The spectral width in the indirect dimension was 25633 Hz (160 ppm) for gHSQC and 34677 Hz (220 ppm) for gHMBC. All spectra were processed using MestreNova version 11.0.4-18998.

[0253] The proposed structure of the sample was confirmed by analysis of the 2-D gCOSY, ROESYad, gHSQC, and gHMBC spectra. The gHSQC spectrum was acquired with multiplicity editing, which provides some of the same information as the 1-D C13 DEPT spectrum, in that the methyl and methane groups appear as positive peaks and the methylene protons appear as negative peaks. The gHMBC spectrum provides the chemical shifts of all of the quaternary carbons that are 2-3 bonds away. The ROESY spectrum shows NOE correlations between protons that are close in space. NMR analysis yielded the chemical shift assignments shown in Figure 7F, confirming the proposed structure of the compound.

[0254] Example 9: Particle Size Distribution The particle size distribution of the cannabidiol samples was analyzed using a Mastersizer 2000. The method involved laser diffraction measuring the particle size distribution by volumetric standards. Approximately 1 g of each sample was weighed and transferred along the center of the sample tray. The sample feed gate was 6 mm to 8 mm. The instrument software parameters were set at 3 bar dispersion air pressure, 60% oscillatory feed rate, refractive index of 1.5295, absorptivity of 0.01, and a size range of 0.020 μm to 2000.000 μm. Figures 8A-8R show the result analysis report and respective particle size distribution graphs for each sample measured. A Malvern Pananalytical Morphologi G3 analyzer was used in another set of experiments to examine the sample volumetric size distribution. Result analysis reports for several samples are provided in Figures 9A-9P. These results are summarized in Table 8. Figure 10 shows the microscope images of various crude cannabidiol inputs that underwent recrystallization in isooctane. The images reveal a rod microstructure of the cannabidiol material. [Table 8]

[0255] Example 10: Stress stability test Cannabidiol samples obtained by protocol 1 were subjected to acidic, alkaline, and oxidative conditions to achieve at least 3% degradation or change in appearance. The effects of light, heat, and humidity on the stability of the drug substance were investigated. The assay and purity of the samples were analyzed by UPLC. The identity of unknown impurities was checked by LC-MS. The peak purity of cannabidiol after exposure to stress conditions was investigated by comparing the PDA-UV (photodiode array-ultraviolet) spectrum of cannabidiol with that of unstressed samples, as well as by LC-MS analysis of the cannabidiol peak. The assay of the unstressed samples in Figure 15A and Figure 15B was used as a reference to calculate the extent of degradation of CBD under representative stress conditions.

[0256] CBD Degradation = (1-[Assay of stressed sample] / [Assay of unstressed sample])*100%

[0257] A summary of the results from the stability stress testing can be seen in Table 9.

[0258] Acid stress In a 20 ml GC headspace vial, 150 mg of CBD was suspended in 8 mL of 0.1 M hydrochloric acid and heated to T=80° C. for 2, 4, and 6 h, respectively. Regardless of their reaction time, all samples resulted in a suspension of yellowish molten CBD in a clear, colorless aqueous solution. Figure 25A shows the impurity profile for a CBD sample stressed under acidic conditions for a period of 6 h and heated to 80° C. The PDA-UV spectrum is shown in Figure 26 and corresponds to the unstressed CBD sample (Figure 15B). In addition, LC-MS analysis of the CBD peak confirmed the peak purity, as no co-eluting compounds were detected.

[0259] Alkaline stress In a 20 ml GC headspace vial, 150 mg of CBD was suspended in 8 mL of 0.1 M sodium hydroxide and heated to T=80° C. for 2, 4, and 6 h, respectively. Regardless of their reaction time, all samples became suspensions of yellowish molten CBD in a purple aqueous solution. Figure 26A shows the impurity profile for the CBD sample stressed under basic conditions for a period of 6 h and heated to 80° C. Figure 26B shows the PDA-UV spectrum of the main component (CBD).

[0260] Oxidative stress In a 20 ml GC headspace vial, 150 mg of CBD was suspended in 8 mL of hydrogen peroxide (0.3% w / w) and heated to T=80° C. for 2, 4, and 6 h, respectively. Regardless of reaction time, each sample resulted in a suspension of yellowish molten CBD in a clear, colorless aqueous solution. Figure 27A shows the impurity profile for a CBD sample stressed under oxidizing conditions for a period of 6 h and heated to 80° C. Figure 27B shows the PDA-UV spectrum of the main compound (CBD) of the stressed sample after exposure to oxidizing conditions for 6 h. photolysis Approximately 150 mg of CBD was loaded into a Duran crystallizing dish and irradiated with an Atlas SUNTEST CPS+ light cabinet (UV300-400nm: 500W / m2, Lux400-800nm ​​55klux, 24h exposure = 1.320MLux hours) for a period of 24h. The light cabinet was thermostated at 24°C, so no dark control was necessary for the assessment of thermally induced degradation. After irradiation, the sample turned slightly yellow. Figures 28A and 28B show the corresponding impurity profile and PDA-UV spectrum after 24h exposure. The PDA spectrum corresponds to an unstressed CBD sample.

[0261] high temperature 150 mg of CBD was loaded into a 20 mL GC headspace vial and heated to 50, 60, 70, 80, 90, and 100° C. for 1 h. Another CBD sample (150 mg) was heated to 100° C. for 24 h. The two samples heated to 50° C. and 60° C. for 1 h became slightly yellow but did not change their physical state. The sample heated to 70° C. partially melted, but all samples heated to 80° C. or higher were completely melted and showed a yellow color. Figure 29A shows the impurity profile for the CBD sample heated to 100° C. for 24 h. Figure 29B shows the peak purity of the major component (CBD).

[0262] Humidity decomposition 150 mg of CBD was loaded into a Duran crystallizing dish and placed in a desiccator containing a dish filled with water. The desiccator was evacuated using a water jet pump and the conditions were maintained for 24 hours. Under humidity treatment, the CBD sample did not change its appearance after 24 hours at 75% rh. Figures 30A and 30B show the corresponding impurity profile and PDA-UV spectrum, respectively. [Table 9]

[0263] Under acidic conditions and simultaneous heating (80 °C) of the CBD sample, D9-THC was the main decomposition product. In addition, several isomers (m / z = 331) of hydration products of CBD and / or THC were observed. In general, only minor degradation of CBD (4%) was observed.

[0264] Under alkaline stress conditions, CBD showed a much more pronounced degradation (>38%), mainly resulting in the formation of several isomers of CBQ (=CBD quinone). In comparison with the spectrum of the unstressed CBD sample (Figure 15B), the first absorption maximum at 211.8 nm in Figure 26B is slightly hypsochromic shifted. The absorption maximum (202.0 nm) of the degradation product CBQ (peak 2 in Figure 26C) is blue-shifted in comparison with the CBD absorption maximum at 215.4 nm, so the hypsochromic shift of the CBD absorption maximum (211.8 nm) is probably the result of the CBQ peak tail overlapping with CBD between 9.40 and 10.00 min. Purity analysis of the CBD peak by LC-MS showed a product at m / z = 327 (besides m / z = 313), which corresponds to CBQ. However, this signal was also detected under non-alkaline (e.g., acidic) conditions and is attributed to the oxidation of CBD in the ionization chamber to form CBQ. CBD degradation proceeded further in the stock solution after assay and purity analysis, resulting in >80% degradation at the time of LC-MS analysis.

[0265] CBD oxidative stress conditions (H 2 O 2Exposure to 100 °C for 24 h resulted in slight decomposition of CBD (3%) forming hydroxy-CBD (CBD-OH), consistent with oxidative conditions induced by high temperature. For example, samples exposed to 100 °C for 24 h showed oxidized forms of CBD that could be assigned to hydroxy-CBD and hydroxy-CBQ (formally CBD+[O] and CBD+2[O], m / z=329 and m / z=345). No significant decomposition was observed at temperatures below 100 °C.

[0266] It is generally known that the impurities appearing at relative retention times of approximately 1.98, 2.00, and 2.03 were formed by dimerization of CBD at the head of the column during UPLC analysis. Without wishing to be bound by theory, H 2 O 2 As only very small amounts of CBD dimers were observed under stress conditions, the H 2 O 2 It is understood that the presence of quenches the formation of these isomeric CBD dimers.

[0267] Example 11: Cannabidiol stability study of CBD prepared via Protocol 1 Three different cannabidiol batches obtained by protocol 1 were packaged in two LD-polyethylene bags in HD-polyethylene drums and stored under four different storage conditions. The samples were checked against the specification limits shown in Table 10. The results of the stability experiments are summarized in Tables 11 to 22. [Table 10]

[0268] Appearance was stable within specifications over 12 months under all storage conditions, however, a slight color change from nearly white to slightly yellowish brown was observed after 9 months storage in all batches, regardless of storage conditions.

[0269] The UPLC assay was stable and within specification over the 12 month period for all batches and storage conditions. No trends were observed for batches stored at 5° C., 25° C., and 30° C. The batch stored at 40° C. showed a slight trend toward a decrease in the assay over the 6 month period tested.

[0270] UPLC purity was stable over 12 months when stored at 5° C. and 25° C. / 60% rh. No trends were observed.

[0271] UPLC purity was also stable and within specification over a period of 6 months when stored at elevated temperature, 30° C. / 75% rh.

[0272] At higher temperatures (40°C / 75%rh), all batches showed higher levels of Δ9-THC after 3 and 6 months. Also, the amounts of each unspecified impurity (after 3 months) and total impurities (after 6 months) were higher at 40°C / 75%rh. A decreasing trend in purity at 40°C / 75%rh was observed for all batches, mainly due to an increasing trend in the formation of Δ9-THC.

[0273] Moisture content was stable and within specification for all batches and storage conditions over a period of 6 months at 30°C / 75% or 40°C / 75%rh, and over 12 months when stored at 5°C or 25°C / 60%rh. [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22]

[0274] Example 12: Confirmation of cannabidiol crystal structure from cannabidiol recrystallized in isooctane from Protocol 1 High-resolution X-ray powder diffraction patterns were collected on a D8 Advance system equipped with a LynxEye solid-state detector. The radiation used to collect the data was CuKα1 (λ=1.54056A) monochromated by a germanium crystal. Patterns were collected without further processing in the range of 4-50°2θ, with steps of 0.016°2θ. All patterns were acquired at approximately 295K. Figure 11A shows the X-ray pattern of recrystallized CBD. Figure 11B shows an overlay of the simulated X-ray single crystal diffraction (top pattern) and the experimentally derived XRPD diffractogram (bottom pattern) of cannabidiol. Comparison of the simulated X-ray data with the experimentally derived diffractogram indicates that the cannabidiol batch is phase pure and composed only of form A. Cannabidiol is a phase-pure, crystalline form of P2 1 It crystallizes in space group 16. Figure 16, Figure 21, Figure 22, Figure 23, and Figure 24 show additional X-ray powder diffraction patterns of cannabidiol samples.

[0275] Example 13: Differential Scanning Calorimetry Experiments Sample 2, prepared by protocol 3 and subjected to recrystallization in isooctane, was used for the DSC experiments. Melting characteristics were obtained from DSC thermograms recorded on a heat flux DSC822e instrument (Mettler-Toledo GmbH, Switzerland). The DSC822e was calibrated for temperature and enthalpy with a small piece of indium (melting point at 156.6°C, ΔHf=28.45 Jg-1). The samples were sealed in standard 40 μl aluminium pans, pinhole shaped and heated in the DSC from 25°C to 300°C with a heating rate of 10°C min-1. Dry N 2 Gas, at a flow rate of 50 ml min-1, was used to purge the DSC instrument during measurements. Figure 12 shows the DSC thermogram of cannabidiol sample 2 produced by protocol 3 and subjected to recrystallization in isooctane. A single endothermic event is observed in Figure 12 at 68.12°C, corresponding to the melting of the API. Additional DSC thermograms are provided in Figures 17, 18, 19, and 20.

[0276] Example 14: Thermogravimetric mass spectrometry Mass loss due to solvent or water loss from the crystals was determined by TGA / SDTA. Monitoring the sample weight during heating in a TGA / SDTA851e instrument (Mettler-Toledo GmbH, Switzerland) generated weight vs. temperature curves. The TGA / SDTA851e was calibrated for temperature with indium and aluminum. Samples were weighed into 100 μl aluminum crucibles and sealed. A pinhole was created in the seal and the crucible was heated in the TGA from 25° C. to 300° C. at a heating rate of 10° C. min-1. Dry N 2Gas was used for purging. The evolved gases from the TGA samples were analyzed by a mass spectrometer Omnistar GSD 301 T2 (Pfeiffer Vacuum GmbH, Germany). The latter is a quadrupole mass spectrometer that resolves masses in the range of 0-200 amu. The TGA / SDTA and TGA-MS analyses of cannabidiol are shown in Figures 13A and 13B, respectively. No significant mass loss was observed prior to thermal decomposition. The SDTA signal showed an endothermic event at 62 °C, due to the melting of the API.

[0277] Example 15: Investigating other impurities The presence of other impurities in the CBD samples was further investigated. Figure 14 shows the chromatograms of a cannabidiol quinone standard (CBQ) for two cannabidiol samples prepared by protocol 3. It can be seen that the CBD samples are free of CBQ oxidation products.

[0278] Example 16: Solubility Experiments Quantitative thermodynamic solubility determinations were performed on crude cannabidiol obtained via Protocol 2 to aid in the selection of solvents for crystallization experiments. The results of the solubility determinations performed at ambient temperature are summarized in Table 23. The clear solutions obtained from each solubility determination experiment were evaporated and the resulting solids were analyzed by XRPD.

[0279] If the material precipitated as a solid, it was classified as Form A. However, in 11 experiments, the material obtained after evaporation was oil-like in appearance and could not be analyzed by XRPD. If no XRPD record was produced, the field was defined as "not applicable" (N / A). [Table 23]

[0280] Example 17: Crude CBG crystallization experiments Seeding was performed in the crystallization of CBD because supersaturated solutions often require very low temperatures or long times to induce self-nucleation. Various temperature cycles were investigated, typically proceeding within the 20-30°C range, with seeding also proceeding within that range (Protocols 1-3), followed by cooling to about -20°C. As shown in Protocol 4, Example 21, a temperature cycle was applied to the crystallization of the crude product by cooling from a seeding temperature of 26°C to 10°C, warming to 24°C, and finally cooling to the isolation temperature of -20°C. Without wishing to be bound by theory, it is believed that this temperature cycle helped to reduce crust formation, i.e., solids adhering to the walls of the crystal just above the liquid level, and there was evidence that this temperature cycle improved the purging of some impurities. CBD was finally cooled to a very low temperature of -20°C to maximize yield. As shown in Example 16, long chain hydrocarbons such as heptane, isooctane, and decane were found to have the lowest solubility of CBD, but even in these solvents, high losses of CBD could be achieved if the crystallization was not concentrated and cooled to low temperatures.

[0281] Seeding and isolation temperatures To determine the appropriate seeding temperature for CBD, a Crystal 16 apparatus was used to measure the solubility in crude CBD mother liquor, a mixture of heptane and process impurities, and pure heptane. Figure 31 shows the measured solubility data as a function of temperature. As shown, the crude CBD mother liquor has a significantly higher solubility than pure heptane, which may be due to impurities present in the mother liquor. The minimum volume for crystallization was determined by balancing the volumetric measurements of the process, the expected yield at a particular concentration, and the practicality of the seeding temperature. Crystallization at a volume of 3.5 L / kg was determined to be appropriate as this resulted in a CBD concentration of approximately 296 mg / ml, as shown by the operating line in Figure 31. At this concentration, the solubility temperature of CBD was 29-30 °C. Therefore, a seeding temperature of 26° C. was deemed suitable to provide a reasonable operating window in terms of temperature and crystallization volume parameters that would provide a supersaturated solution of CBD and ensure that CBD would crystallize when seeded (Protocol 4, Example 21).

[0282] To maximize yield, it has been found useful to cool the crystallization slurry to a very low temperature, about 20° C., as exemplified in Protocols 1-3 and Protocol 4 (Example 21). Replacing n-heptane with isooctane was briefly considered and studied, but the increase in yield was negligible when replacing n-heptane with isooctane in the crude crystallization, likely due to the presence of impurities in the crude mother liquor that strongly affect the solubility of CBD.

[0283] Temperature Cycling Temperature cycling during crystallization was used to reduce the observed crust formation that occurred above the liquid level of the crystallization slurry. A series of experiments were performed in which the crystallization volume was changed, either temperature cycling or straight ramp cooling was applied, and the seeding temperature was modified. The results are summarized in Table 24. As shown, the seeding temperature appeared to have a significant effect on the amount of crust formed. Figure 32 shows a photograph of the crust formed after seeding for each of the experiments. To reduce the relative supersaturation, the seeding temperature could be increased so that the seeding point was closer to the solubility curve.

[0284] In addition, as shown in Table 24, temperature cycling appeared to significantly improve the purging of an unknown impurity with an RRT of 1.98 (Example 21). An RRT of 1.98 was observed in the crude CBD. Analysis of the impurity by mass indicated that it could be a CBD analogue combined with two menthadienol molecules. This impurity purged at 86-88% when temperature cycling was applied to the crystallization versus 77-79% when no temperature cycling was applied. As such, temperature cycling was deemed advantageous to reduce this impurity to a level that comfortably met the unknown impurity specification (NMT 0.10%).

[0285] Temperature cycling also affected the particle size and settling rate of the slurry. Without wishing to be bound by theory, it is known that temperature cycling increases the particle size distribution due to dissolution of smaller particles when reheating the slurry. An increase in particle size was also observed in these experiments when temperature cycling was applied (Figure 33), and this also appeared to affect the settling rate as larger particles settled much faster based on visual observation. [Table 24]

[0286] Example 18: Recrystallization Experiments Recrystallization experiments were performed to screen for potential CBD polymorphs and to evaluate the ability of recrystallized CBD to flush out impurities. The following recrystallization methods were performed: - evaporative crystallization from a solvent mixture, -Anti-solvent crystallization, - cooling crystallization, -Single solvent dropwise grinding, - Crystallization by collision cooling, - Vapor diffusion crystallization in solution, and -Crystallization by liquid diffusion. In each method, the starting material consisted of crystallized CBD form A.

[0287] Evaporative crystallization from solvent mixtures Without wishing to be bound by theory, the general principle behind evaporative crystallization using solvent anti-solvent mixtures is that the solvent evaporates, first precipitating the API to some extent, and then this material acts as a seed when the anti-solvent evaporates. The first evaporation step is slow, followed by a faster final evaporation phase. The solvent mixtures and their respective vapor pressures are presented in Table 25 along with XRPD analysis of the solids. All crystalline samples were Form A both before and after the solids were exposed to the accelerated aging conditions. An oil-like material was obtained from the acetonitrile / water solvent mixture that could not be analyzed by XRPD, and therefore this sample was not exposed to the accelerated aging conditions. [Table 25] Results of evaporative crystallization experiments from solvent mixtures. Cannabidiol was dissolved in a mixture of solvent and anti-solvent (50 / 50, vol / vol). The solvent was allowed to evaporate slowly, after which the anti-solvent evaporated more rapidly. The resulting solids were analyzed by XRPD before and after 2 days of exposure to 40°C / 75% RH (AAC). Experiments that resulted in oily materials were analyzed by XRPD and therefore not exposed to AAC (defined as not applicable).

[0288] Antisolvent crystallization For the anti-solvent crystallization experiments, a clear solution of approximately 60 mg / mL CBD was prepared. Briefly, 1 volume of cannabidiol solution was added to 4 volumes of anti-solvent. If solids precipitated, they were collected by centrifugation. Solids were analyzed by XRPD after drying under ambient conditions and after drying under deep vacuum. The mother liquor was evaporated to complete dryness and the remaining solid was also analyzed. All solids were analyzed by XRPD before and after exposure to accelerated aging conditions (40°C / 75% RH) for 2 days. The results of the XRPD analysis of the precipitated solids are outlined in Table 26. The XRPD results of the evaporation of the mother liquor are presented in Table 27.

[0289] A solid precipitated immediately from the combination of methanol with water. To facilitate precipitation, samples were placed at 5° C. for 24 hours. Under these conditions, the sample from dichloromethane with 2,2,4-trimethylpentane showed precipitation. XRPD analysis showed Form A. Evaporation of all other samples resulted in either Form A or an oil-like material that could not be analyzed by XRPD. If no XRPD record was produced, the field is defined as "not applicable" (N / A). [Table 26] [Table 27]

[0290] Cooling crystallization Cooling crystallization was performed by preparing a clear solution of CBD at a maximum concentration of approximately 60 mg / mL. The solution was slowly cooled to 0° C. and held at this temperature for 48 hours. The precipitated solids were collected, dried under ambient conditions, and analyzed by XRPD. If no solids precipitated, the mother liquor was slowly evaporated and the remaining solids were analyzed by XRPD. All solids were exposed to accelerated aging conditions for 48 hours and analyzed again by XRPD. The results are presented in Table 28. Cannabidiol precipitated upon cooling from pentane and heptane. XRPD analysis revealed that these solids were identical to the starting material Form A. Precipitation of the mother liquor resulted in either crystalline or oil-like samples with Form A. Exposure to accelerated aging conditions had no effect on crystallinity and none of the oil crystallized. If no XRPD records were generated, the field is defined as "not applicable" (N / A). [Table 28]

[0291] Collision cooling crystallization As a variation of the cooling crystallization experiment described above, several impingement cooling crystallizations were performed. To adjust the solubility of cannabidiol, impingement cooling experiments were performed in solvent mixtures. A clear solution of 50 mg / mL cannabidiol was prepared in the solvent mixture and rapidly cooled in an ice bath. The vials were then placed at -20°C for 48 hours. The precipitated solids and mother liquor were treated as described above for the regular cooling crystallization experiments. The results are shown in Table 29. Only heptane / pentane cooling resulted in precipitation of solids. The solids appeared in the same polymorphic form as the starting material Form A. Evaporation of the other mother liquors also resulted in Form A or an oil-like material. Exposure to accelerated aging conditions (40°C / 75% RH) for 2 days had no effect on the physical appearance of the samples. If no XRPD records were produced, the field is defined as "not applicable" (N / A) in Table 29. [Table 29]

[0292] Crystallization by single-solvent drop grinding For the milling experiments, 40 mg of cannabidiol was placed in a stainless steel container with 10 μL of solvent and two steel beads. The vial was shaken at 30 Hz for 1 hour, after which the solid was collected for XRPD analysis. The results of these experiments are summarized in Table 30. All of the samples were classified as Form A based on HT-XRPD analysis. Exposure to accelerated aging conditions for 2 days did not result in any physical changes. [Table 30]

[0293] Vapor diffusion crystallization in solution Clear solutions of cannabidiol (approximately 100 mg / mL) were prepared in the solvents shown in Table 31. The open vial was placed in a larger container with anti-solvent and the vapor was allowed to diffuse into the cannabidiol solution for two weeks. However, the effect of the anti-solvent was too low to induce any precipitation of cannabidiol, so it was decided to evaporate the mother liquor and analyze the remaining solid. The results are presented in Table 31. A crystalline solid was only seen after evaporation of the toluene / 2,2,4-trimethylpentane solution. XRPD analysis of this solid confirmed that it was Form A. All other samples yielded an oily material. Exposure to accelerated aging conditions had no effect on the physical appearance of the samples. [Table 31]

[0294] Liquid diffusion crystallization The results of the diffusion experiments are given in Table 32. A solution of approximately 75 mg / mL cannabidiol was prepared and a layer of anti-solvent was carefully added to the vial. These experiments were performed with water as the anti-solvent due to the larger difference in density between the solvent and anti-solvent. With the exception of the experiments from 1,4-dioxane, diethylene glycol, DMSO, and diethanolamine, the results resulted in crystalline precipitation. XRPD analysis of these solids showed Form A. Exposure of the solids to accelerated aging conditions for 2 days had no effect on the solid morphology. [Table 32]

[0295] Example 19: Recrystallization of pure cannabidiol in isooctane Isooctane was selected as the final crystallization solvent due to its low solubility and similar properties to heptane, i.e., low viscosity and boiling point compared to other higher hydrocarbons (Table 33). The crystallization in isooctane was designed by mapping the solubility curve, as shown in Figure 34. Based on the desire to maximize solubility and yield, an isooctane volume of 4.0 L / kg was selected as the appropriate crystallization concentration. Prior to crystallization, it was desired to completely dissolve the CBD in isooctane and filter the process stream. This dissolution and filtration was performed by charging 3.5 L / kg of isooctane (CBD concentration of 286 mg / ml), heating to 40°C, and filtering the process stream to ensure that the filtered stream did not fall below 38°C, where crystallization could occur. Based on the solubility curve in Figure 34, the appropriate temperature to ensure seeding of the crystallization was 32°C before cooling to -20°C for isolation. The isolation temperature of -20°C was selected to maximize the yield of CBD from the final crystallization. [Table 33]

[0296] Example 20: Stability study of CBD prepared via protocol 3 Cannabidiol prepared via Protocol 3 underwent a stability study. One batch each of cannabidiol (crude), cannabidiol API (pure), and cannabidiol (twice recrystallized) were packaged in bulk containers of double low density polyethylene (LDPE) bags in high density polyethylene amber bottles. The stability of the material was then evaluated at several different storage conditions (5°C, 25°C / 60% RH, and 40°C / 75% RH). For 3 months of stability, the acceptance criteria were met at the 25°C / 60% RH and 40°C / 75% RH conditions. For 5 months of stability, only the 40°C / 75% RH condition was tested. All acceptance criteria were met. The cannabidiol was evaluated against the specifications in Table 34. The results for each of the three samples are provided in Tables 35-40. [Table 34] [Table 35] [Table 36] [Table 37] [Table 38] [Table 39] [Table 40]

[0297] As shown by the stability data above, the visual analysis, HPLC assay analysis, and impurity results were all within specifications. In addition, no growth of Δ9-THC was observed at ppm levels. Furthermore, based on previous stability studies, water content was not considered a stability-indicating test since CBD is not hygroscopic. Thus, water content was not consistently tested throughout the stability program.

[0298] Example 21: Protocol 4 Bromine (102.4 kg, 1.07 molar equivalents) was added to a suspension of olivetol (55 kg, basis) in dichloromethane (3366 kg) at -15°C and the reaction mixture was stirred. Reaction completion was confirmed by HPLC (IPC). The reaction was quenched by transferring to an aqueous (947 L) solution of potassium phosphate dibasic (79.8 kg), sodium hydroxide (61.1 kg), and sodium sulfite (3.85 kg). The solution was warmed and the organic phase was separated. Dichloromethane was partially distilled off at atmospheric pressure. n-heptane (1650 L) was added and the solution was further concentrated under reduced pressure to remove residual dichloromethane. The intermediate was crystallized by addition of water (110 L) and cooling. The solid was filtered, washed with n-heptane, and dried to give 4,6-dibromo-olivetol.

[0299] 4,6-Dibromo-olivetol (500 g, basis), menthadienol (146 g, 0.65 molar equivalents), and magnesium sulfate (499 g, 2.8 molar equivalents) were suspended in dichloromethane (2.5 L) and cooled to -25°C. p-Toluenesulfonic acid catalyst (56 g, 0.2 molar equivalents) was added to initiate the reaction. Additional portions of menthadienol were added 0.5 h (146 g, 0.65 molar equivalents) and 1.0 h (90 g, 0.40 molar equivalents) after the start of the reaction. Reaction completion was confirmed by HPLC (IPC). After complete reactant conversion, the reaction was warmed and quenched with water (4 L). The layers were separated. The organic phase was washed with pH 7 aqueous phosphate buffer (2.5 L). The organic phase solvent was switched to isopropanol under reduced pressure (solvent exchange) while maintaining a constant volume. The dibromo-CBD solution in isopropanol was combined with an aqueous (3.5 L) solution of sodium sulfite (559 g, 3.0 molar equivalents) and sodium L-ascorbate (25 g). Triethylamine (599 g, 4.0 molar equivalents) was added and the reaction was stirred at reflux (approximately 80 °C) for approximately 36 hours (30-42 hours). Reaction completion was confirmed by HPLC (IPC). The reaction solvent (isopropanol / trimethylamine / water) was partially distilled off at atmospheric pressure to 8.0 volumes and n-heptane (3 L) was added. The suspension was acidified to pH 4.0 with concentrated HCl. After layer separation, the organic layer was washed with pH 7 ascorbic acid / sodium phosphate buffer (2.5 L) and aqueous sodium ascorbate solution (2.5 L). The organic layer was concentrated by distillation (vacuum) and treated with activated charcoal. The solution was concentrated to 3.5 volumes by distillation (vacuum). The organic solution was cooled to 26° C., seeded with cannabidiol (5.0 g) and stirred at 26° C. for 1 hour. The suspension was cooled to 10° C. and warmed again to 24° C. The suspension was stirred at 24° C. for 1 hour and then further cooled to −20° C. over 3 hours. The white suspension was filtered and the wet cake was washed with cold isooctane (1.5 L). The wet product was dried to obtain crude cannabidiol.

[0300] Cannabidiol (100 g) was dissolved in isooctane (400 mL) and heated to 40° C. The solution was cooled to 32° C., seeded with cannabidiol (1 g) and stirred at 32° C. for 1 h. The suspension was cooled to −20° C. over 3 h, the white suspension was filtered and the wet cake was washed with cold isooctane (400 mL). The wet product was dried at 40° C. (<10 mbar) until drying was complete to obtain cannabidiol API.

[0301] Confirmatory batches for three representative lots of starting material prepared by Protocol 4 are provided in Tables 41 and 42. Analysis of potential impurities is provided in Table 43. [Table 41] [Table 42] [Table 43]

[0302] Example 22: Protocol 5 Cannabidiol obtained via protocol 2 underwent a rework procedure. Briefly, cannabidiol (100 kg) was dissolved in isopropanol (298.7 kg) and combined with an aqueous (4.0 L) solution of Na ascorbate (5.0 kg) at room temperature (15-60 °C). Triethylamine (64.4 kg) was added and the reaction was stirred at reflux (79-81 °C) for approximately 1 h. The reaction solvent (isopropanol / triethylamine / water) was partially distilled off at atmospheric pressure up to 5 volumes and n-heptane (342 kg) was added (25-40 °C). The suspension was acidified to pH 4.0 with concentrated HCl. After layer separation, the organic layer was washed with ascorbic acid / sodium phosphate buffer (pH 7) and finally with an aqueous (4.0 L) sodium ascorbate (5.0 kg) solution. The organic layer was diluted with n-heptane (136.8 kg) and passed through a polished filter. The solution was concentrated to 4 volumes by distillation (200 mbar vacuum). The organic solution was cooled to approximately 30°C, seeded with CBD and stirred at the seeding temperature for 1 h. The suspension was cooled to -10°C over 3 h. After stirring at -10°C for 1 h, the white suspension was filtered and the wet cake was washed with cold isooctane on the reactor. The wet product was (optionally) dried at 40°C (<10 mbar) for 12-24 h.

[0303] CBD (wet or dry) from the previous step was dissolved in isooctane (259.1 kg) and heated to 40 °C. The solution was cooled to 32 °C, seeded with CBD (1.0 kg) and stirred at 32 °C for 1 h. The suspension was cooled to -10 °C over 3 h, the white suspension was filtered and the wet cake was washed with cold isooctane. The wet product was dried at 40 °C (<10 mbar) for 12-24 h.

[0304] Example 23: Stability study of CBD prepared via protocol 5 Four different batches of CBD prepared by Protocol 5 were packaged in double low density polyethylene (LDPE) bags in high density polyethylene amber bottles. The stability of the material was then evaluated at different storage conditions (5°C, 25°C / 60% RH and 40°C / 75% RH). The specifications at which the samples were evaluated are provided in Table 44. The results for each of the four samples are provided in Tables 45-48. [Table 44] [Table 45] [Table 46] [Table 47] [Table 48] [Table 49]

[0305] The appearance analysis, HPLC assay, and impurity results were within specifications, as shown by the data in Tables 45-48. The water content was also within specifications.

[0306] Example 24: Carbon Treatment Experiments Carbon treatment was utilized to (i) improve the color of the CBD product and (ii) remove olivetol, an impurity that poorly purges during crystallization, prior to crystallization of the crude CBD. Figure 35 shows the improvement in color of the crude CBD product after treatment with carbon. This color was found to persist in the final crystallization of pure CBD. Figure 36 shows the impurity profile before and after carbon treatment by HPLC. The impurity profile shows the reduction of olivetol. It was concluded that activated carbon is a strong adsorbent of olivetol and is an effective means of reducing the presence of this impurity from the process.

[0307] In the CBD synthesis, various activated carbon types were tested. In some experiments, loose carbon (Norit® CN, Cabot) was placed in the reactor and stirred with the CBD solution in heptane in the reactor and filtered before crystallization. In other preparations of CBD, carbon treatments with encapsulated carbons were tried and developed. In these experiments, Cuno encapsulated carbon of type R55SP was used. Treatment with this carbon type was found to be very effective. Another Cuno carbon type, R53SP, was tested but did not prove to be as effective as R55SP. Without wishing to be bound by theory, it is generally understood that different carbon types can adsorb impurities with different efficiencies. Table 49 summarizes the carbon types that were tried in the CBD process. [Table 50]

[0308] Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for.

[0309] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the subject matter described herein, and the present disclosure is in no way limited to only the methods and materials described.

[0310] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter belongs and are consistent with Singleton et al. (1994) Dictionary of Microbiology and Molecular Biology, 2nd Ed., J. Wiley & Sons, New York, NY, and Janeway, C., Travers, P., Walport, M., Shlomchik (2001) Immunobiology, 5th Ed., Garland Publishing, New York.

[0311] Throughout this specification and the claims, the words "comprise", "comprises" and "comprising" are used in their non-exclusive sense, unless the context otherwise requires. It is understood that the embodiments described herein include embodiments that "consist of" and / or "consist essentially of".

[0312] As used herein, the term "about" when referring to a value is meant to encompass variations from a particular amount, in some embodiments, ±50%, in some embodiments, ±20%, in some embodiments, ±10%, in some embodiments, ±5%, in some embodiments, ±1%, in some embodiments, ±0.5%, and in some embodiments, ±0.1%, as such variations are appropriate for practicing the disclosed methods or using the disclosed compositions.

[0313] When a range of values ​​is provided, unless the context clearly dictates otherwise, each intervening value between the upper and lower limits of that range, and at any other stated or intervening value within that stated range, is included to the tenth of the unit of the lower limit. The upper and lower limits of these smaller ranges that may be independently included in smaller ranges are also included, subject to any specifically excluded limits in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included.

[0314] Many modifications and other embodiments of what is described herein will come to mind to one skilled in the art to which the subject matter pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. It is to be understood, therefore, that the subject matter is not to be limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. [Item 1] A composition comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm. [Item 2] The composition of item 1, comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 8 ppm. [Item 3] The composition of item 1, comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 6 ppm. [Item 4] The composition of item 1, comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 4 ppm. [Item 5] The composition of item 1, comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 3 ppm. [Item 6] The composition of item 1, comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 2 ppm. [Item 7] The composition of item 1, comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 0.1 ppm to 6 ppm. [Item 8] The composition of item 1, comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of about 1 ppm to 5 ppm. [Item 9] The composition of item 1, wherein the cannabidiol is crystalline. [Item 10] The composition of item 1, wherein the cannabidiol is crystalline polymorphic form A. [Item 11] The composition of item 10, wherein the crystalline polymorphic form A has an X-ray powder diffraction pattern substantially as shown in FIG. 11A. [Item 12] The crystalline polymorphic form A is 5.07, 8.28, 9.30, 9.70, 10.20, 11.74, 12.49, 13.12, 13.80, 15.08, 15.35, 16.05, 16.57, 17.36, 17.93, 18.79, 18.96, 19.44, 19.79, 20.55, 20.82, 21.61, 22.11, 22.63, 22.99, 2 Item 11. The composition according to item 10, comprising at least one X-ray powder diffraction peak at 2θ ± 0.07 degrees selected from the group consisting of 3.68, 24.40, 25.28, 26.45, 26.76, 27.46, 27.70, 28.45, 29.06, 31.07, 32.60, 33.31, 34.03, 34.57, 35.31, 36.49, and 37.79. [Item 13] The crystalline polymorphic form A is 5.07, 8.28, 9.30, 9.70, 10.20, 11.74, 12.49, 13.12, 13.80, 15.08, 15.35, 16.05, 16.57, 17.36, 17.93, 18.79, 18.96, 19.44, 19.79, 20.55, 20.82, 21.61, 22.11, 22.63, 22.99, 2 Item 11. The composition according to item 10, comprising at least two X-ray powder diffraction peaks at 2θ ± 0.07 degrees selected from the group consisting of 3.68, 24.40, 25.28, 26.45, 26.76, 27.46, 27.70, 28.45, 29.06, 31.07, 32.60, 33.31, 34.03, 34.57, 35.31, 36.49, and 37.79. [Item 14] The crystalline polymorphic form A is 5.07, 8.28, 9.30, 9.70, 10.20, 11.74, 12.49, 13.12, 13.80, 15.08, 15.35, 16.05, 16.57, 17.36, 17.93, 18.79, 18.96, 19.44, 19.79, 20.55, 20.82, 21.61, 22.11, 22.63, 22.99, 2 Item 11. The composition according to item 10, comprising at least three X-ray powder diffraction peaks at 2θ ± 0.07 degrees selected from the group consisting of 3.68, 24.40, 25.28, 26.45, 26.76, 27.46, 27.70, 28.45, 29.06, 31.07, 32.60, 33.31, 34.03, 34.57, 35.31, 36.49, and 37.79. [Item 15] The composition of item 10, wherein the crystalline polymorphic Form A exhibits a characteristic X-ray powder diffraction pattern with peaks at 9.70, 11.74, 15.08, 17.36, and 18.79 2θ ± 0.07 degrees. [Item 16] The composition of item 10, wherein the crystalline polymorph Form A exhibits a characteristic X-ray powder diffraction pattern with peaks at 9.70, 11.74, 12.49, 13.12, 13.80, 15.08, 17.36, 18.79, 20.55, and 22.11 2θ ± 0.07 degrees. [Item 17] The crystalline polymorphic form A is 5.07, 8.28, 9.30, 9.70, 10.20, 11.74, 12.49, 13.12, 13.80, 15.08, 15.35, 16.05, 16.57, 17.36, 17.93, 18.79, 18.96, 19.44, 19.79, 20.55, 20.82, 21.61, 22.11, 22.63, 22.99 11. The composition of claim 10, exhibiting a characteristic X-ray powder diffraction pattern having peaks at 2θ±0.07 degrees at 2θ of 23.68, 24.40, 25.28, 26.45, 26.76, 27.46, 27.70, 28.45, 29.06, 31.07, 32.60, 33.31, 34.03, 34.57, 35.31, 36.49, and 37.79. [Item 18] The composition of item 10, wherein the crystalline polymorphic form A is characterized by the differential scanning calorimetry thermogram shown in Figure 12. [Item 19] The composition of item 10, wherein the crystalline polymorphic form A is characterized by a differential scanning calorimetry thermogram with an endotherm having an onset of about 67.72°C and a peak at about 68.12°C. [Item 20] Cannabinol, cannabigerol, delta-8-tetrahydrocannabinol, cannabichromene, cannabicyclol, cannabijalin, tetrahydrocannabivarin, cannabidivarin, cannabichromen-2-yl, cannabigerovarin, cannabielsoin, cannabicitran, 3,5-dibromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 3-bromo-5'-methyl-4-pentyl -2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 4,6-dibromoolivetol, 4-bromo-5-pentylbenzene-1,3-diol, abnormal cannabidiol (ab-CBD), cannabidiol quinone derivatives (CBQ), 3,5-dibromo-5'-methyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 3,5-dibromo-4-ethyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 3-bromo-4-ethyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 4,6-dibromo-5-propylbenzene-1,3-diol, 4-bromo-5-propylbenzene-1,3-diol, 4,6-dibromo-5-ethyl Item 1. The composition according to item 1, further comprising at least one compound selected from the group consisting of 5-ethyl-2-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 5'-methyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, and 4-ethyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol. [Item 21] The composition according to item 1, which does not contain a plant extract material. [Item 22] A stable composition comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm when stored for 2 years or less. [Item 23] The stable composition of item 22, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm upon storage for one year or less. [Item 24] The stable composition of item 22, wherein the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm when stored for 6 months or less. [Item 25] The stable composition according to Item 22, wherein the delta-9-tetrahydrocannabinol is present at about 0.1 ppm to about 9 ppm. [Item 26] The composition of item 22, wherein the cannabidiol is crystalline. [Item 27] ​​A composition comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol, wherein the ratio of cannabidiol to delta-9-tetrahydrocannabinol is less than 1:0.0001 as measured by UPLC. [Item 28] The composition described in Item 27, wherein the cannabidiol is crystalline. [Item 29] Cannabidiol, delta-9-tetrahydrocannabinol, said delta-9-tetrahydrocannabinol being present in an amount less than 10 ppm; and a pharma- ceutically acceptable excipient. [Item 30] The formulation according to Item 29, wherein the formulation is in the form of a matrix. [Item 31] The formulation according to Item 29, wherein the formulation is in a liquid form. [Item 32] The formulation described in Item 31, wherein the liquid is vaporizable. [Item 33] The formulation according to Item 29, wherein the formulation is in the form of granules. [Item 34] A method for preparing crystalline cannabidiol characterized by having an X-ray powder diffraction pattern substantially as shown in FIG. 11A, and less than 10 ppm delta-9-tetrahydrocannabinol, comprising crystallizing cannabidiol from isooctane. [Item 35] A method for preparing a cannabidiol composition, comprising: contacting a dihalo-olivetol with a menthadienol in the presence of a protic acid catalyst to prepare a dihalocannabidiol; contacting the dihalocannabidiol with a reducing agent to prepare a first cannabidiol composition; contacting the first cannabidiol composition with a first solvent; Crystallizing the second cannabidiol composition from the solvent; and recrystallizing the crystalline cannabidiol composition having less than 10 ppm delta-9-tetrahydrocannabinol from the second solvent. [Item 36] The method according to Item 35, wherein the protonic acid catalyst is selected from the group consisting of p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, acetic acid, and sulfuric acid. [Item 37] The method according to Item 35, wherein the reducing agent is a sulfur-containing compound. [Item 38] The method according to Item 35, wherein the first solvent is selected from the group consisting of 2-butanone, ethyl acetate, 1,4-dioxane, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, dichloromethane, chloroform, n-heptane, toluene, isopropyl acetate, isooctane, n-decane, and anisole. [Item 39] The method according to item 35, wherein the second solvent is selected from the group consisting of isooctane, chloroform, n-heptane, dichloromethane, diethyl ether, hexane, n-decane, and pentane. [Item 40] The method according to Item 35, wherein the dihaloolivetol is contacted with the menthadienol in the presence of a protic acid catalyst at a temperature of about -33°C to about -27°C. [Item 41] The method according to item 35, wherein the dihaloolivetol is contacted with the menthadienol in the presence of a protic acid catalyst at a temperature of about -30°C. [Item 42] A method for preparing a composition comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol by recrystallizing cannabidiol from a mixture of cannabinoids, comprising: contacting said mixture of cannabinoids with isooctane to form a solution; heating the solution to about 40° C.; cooling the solution to about 32°C; seeding said solution at about 32°C with (-)-cannabidiol to form a suspension; Warming the suspension to about 32° C. while stirring; cooling the suspension to −20° C.; separating solid material from the suspension; and washing the solid material with isooctane at about -20°C; and drying the solid material to obtain a crystalline composition comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol. [Item 43] A method for treating a disease in a subject, comprising: The method comprises administering to the subject a composition comprising a therapeutic amount of cannabidiol and an amount of delta-9-tetrahydrocannabinol, wherein the amount of delta-9-tetrahydrocannabinol is less than about 20 μg per day. [Item 44] The method according to Item 43, wherein the disease is selected from the group consisting of vomiting, pain, inflammation, multiple sclerosis, Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease, epilepsy, glaucoma, osteoporosis, schizophrenia, cancer, and obesity. [Item 45] The composition of item 10, wherein the crystalline polymorphic form A has at least one of: (a) a d10 particle size in the range of about 1 μm to about 10 μm; (b) a d50 particle size in the range of about 8 μm to about 40 μm; and (c) a d90 particle size in the range of about 8 μm to about 500 μm. [Item 46] The composition of item 10, wherein the crystalline polymorphic form A has a d50 particle size in the range of about 8 μm to about 40 μm. [Item 47] The composition of item 10, wherein the crystalline polymorphic form A has a d90 particle size in the range of about 8 μm to about 500 μm. [Item 48] A composition comprising cannabidiol, a halogenated cannabidiol, and delta-9-tetrahydrocannabinol, wherein the cannabidiol is present in an amount of at least about 99.999% weight / weight of the composition, the delta-9-tetrahydrocannabinol is present in an amount less than 10 ppm, and the halogenated cannabidiol is present in an amount less than 10 ppm. [Item 49] The composition of item 48, wherein the halogenated cannabidiol is a brominated cannabidiol. [Item 50] The composition described in Item 49, wherein the brominated cannabidiol is 4-monobromo-CBD. [Item 51] The composition described in Item 50, wherein the 4-monobromo-CBD is present in an amount of less than 5 ppm. [Item 52] A concentrated composition comprising at least 99.999% cannabidiol and less than 10 ppm of total impurities, wherein the impurities include halogenated cannabidiol. [Item 53] A recrystallized composition comprising cannabidiol, a halogenated cannabidiol, and delta-9-tetrahydrocannabinol, wherein the cannabidiol is present in an amount of at least about 99.999% weight / weight of the composition, the delta-9-tetrahydrocannabinol is present in an amount of less than 5 ppm, and the halogenated cannabidiol is present in an amount of less than about 10 ppm, and the composition is solid. [Item 54] A crystalline cannabidiol composition comprising cannabidiol and a halogenated cannabidiol, wherein the composition does not contain delta-9-tetrahydrocannabinol. [Item 55] A composition comprising at least 99.999% cannabidiol and less than 10 ppm total impurities, the impurities including halogenated cannabidiol; a solvent, wherein the composition is insoluble or slightly insoluble in the solvent at or below 20°C.

Claims

1. 1. A recrystallized composition comprising cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount less than 10 ppm.

2. cannabidiol and delta-9-tetrahydrocannabinol, wherein (a) the delta-9-tetrahydrocannabinol is present in an amount less than 8 ppm, or (b) the delta-9-tetrahydrocannabinol is present in an amount less than 6 ppm; or (c) the delta-9-tetrahydrocannabinol is present in an amount less than 4 ppm; or (d) the delta-9-tetrahydrocannabinol is present in an amount less than 3 ppm; or (e) the delta-9-tetrahydrocannabinol is present in an amount less than 2 ppm; or (f) the delta-9-tetrahydrocannabinol is present in an amount of 0.1 ppm to 6 ppm; or (g) the composition of claim 1, wherein the delta-9-tetrahydrocannabinol is present in an amount from 1 ppm to 5 ppm.

3. 2. The composition of claim 1, wherein the cannabidiol is crystalline polymorphic form A.

4. The crystalline polymorphic form A is (i) exhibits a characteristic X-ray powder diffraction pattern having peaks at 9.70, 11.74, 15.08, 17.36, and 18.79 2θ ± 0.07 degrees; or (ii) the composition of claim 3, exhibiting a characteristic X-ray powder diffraction pattern having peaks at 9.70, 11.74, 12.49, 13.12, 13.80, 15.08, 17.36, 18.79, 20.55, and 22.11 2θ ± 0.07 degrees.

5. 4. The composition of claim 3, wherein the crystalline polymorph Form A is characterized by a differential scanning calorimetry thermogram with an endotherm having an onset of 67.72°C and a peak at 68.12°C.

6. cannabinol, cannabigerol, delta-8-tetrahydrocannabinol, cannabichromene, cannabicyclol, cannabijalin, tetrahydrocannabivarin, cannabidivarin, cannabichromen-2-yl, cannabigerovarin, cannabielsoin, cannabicitran, 3,5-dibromo-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 3-bromo-5'-methyl-4-pentyl -2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 4,6-dibromoolivetol, 4-bromo-5-pentylbenzene-1,3-diol, abnormal cannabidiol (ab-CBD), cannabidiol quinone derivative (CBQ), 3,5-dibromo-5'-methyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 3 , 5-dibromo-4-ethyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 3-bromo-4-ethyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, 4,6-dibromo-5-propylbenzene-1,3-diol, 4-bromo-5-propylbenzene-1,3-diol, 4,6-dibromo-5-ethyl 2. The composition of claim 1, further comprising at least one compound selected from the group consisting of benzene-1,3-diol, 4-bromo-5-ethylbenzene-1,3-diol, 5'-methyl-2'-(prop-1-en-2-yl)-4-propyl-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol, and 4-ethyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol.

7. 10. The composition of claim 1 which is free of plant extract materials.

8. A stable composition comprising recrystallized cannabidiol and delta-9-tetrahydrocannabinol, wherein the delta-9-tetrahydrocannabinol is present in an amount less than 10 ppm upon storage for 2 years or less.

9. (i) the delta-9-tetrahydrocannabinol is present in an amount less than 10 ppm upon storage for one year or less; or (ii) the delta-9-tetrahydrocannabinol is present in an amount of less than 10 ppm upon storage for six months or less; or (iii) the delta-9-tetrahydrocannabinol is present at 0.1 ppm to 9 ppm.

10. 1. A recrystallized composition comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol, wherein the ratio of cannabidiol to delta-9-tetrahydrocannabinol is less than 1:0.0001 as measured by UPLC.

11. Cannabidiol and Delta-9-tetrahydrocannabinol, said delta-9-tetrahydrocannabinol being present in an amount less than 10 ppm. A recrystallized composition comprising: and a pharma- ceutically acceptable excipient.

12. The formulation of claim 11, wherein the formulation is in the form of a matrix, liquid, or granule.

13. 11. A method for preparing crystalline cannabidiol characterized as having an X-ray powder diffraction pattern substantially as shown in FIG. 11A and less than 10 ppm delta-9-tetrahydrocannabinol comprising crystallizing cannabidiol from isooctane.

14. 1. A method for preparing a cannabidiol composition comprising: contacting a dihalo-olivetol with a menthadienol in the presence of a protic acid catalyst to prepare a dihalocannabidiol; contacting the dihalocannabidiol with a reducing agent to prepare a first cannabidiol composition; contacting the first cannabidiol composition with a first solvent; Crystallizing the second cannabidiol composition from the solvent; and recrystallizing the crystalline cannabidiol composition having less than 10 ppm delta-9-tetrahydrocannabinol from the second solvent.

15. 1. A method for recrystallizing cannabidiol from a mixture of cannabinoids to prepare a composition comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol, comprising: contacting said mixture of cannabinoids with isooctane to form a solution; Heating the solution to 40° C.; Cooling the solution to 32°C; seeding said solution at 32°C with (−)-cannabidiol to form a suspension; Warming the suspension to 32° C. while stirring; cooling the suspension to −20° C.; separating solid material from the suspension; and washing the solid material with isooctane at −20° C.; drying the solid material to obtain a crystalline composition comprising cannabidiol and less than 10 ppm delta-9-tetrahydrocannabinol.

16. A medicament for treating a disease in a subject, comprising:

11. A medicament comprising a compound according to claim 1, 8 or 10, wherein said treatment comprises administering therapeutic amounts of cannabidiol and delta-9-tetrahydrocannabinol of less than 20 μg per day.

17. 4. The composition of claim 3, wherein the crystalline polymorph Form A has at least one of: (a) a d10 particle size in the range of 1 μm to 10 μm; (b) a d50 particle size in the range of 8 μm to 40 μm; and (c) a d90 particle size in the range of 8 μm to 500 μm.

18. A composition comprising at least 99.999% cannabidiol and less than 10 ppm total impurities, said impurities comprising halogenated cannabidiol; a solvent, wherein the composition is insoluble or slightly insoluble in the solvent at or below 20°C.

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