Cannabidiolic acid co-crystals

Abstract

The present invention relates generally to methods of characterizing cross-linking sites of a protein of interest. In particular, the present invention relates to using size exclusion chromatography, peptide mapping, and subunit analysis to identify and quantify cross-linking sites of a protein of interest, and to determine the contribution of cross-linking to the formation of high molecular weight species.

Description

[0001] Cross-references to related applications

[0002] This application claims priority and benefit to U.S. Provisional Patent Application No. 63 / 623,933, filed January 23, 2024, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0003] Cannabidiol (CBD) is one of the most abundant plant cannabinoids found in cannabis extracts and has potential medicinal uses. In the cannabis plant, CBD (… Figure 1A In the acidic form of cannabidiol (CBDA); Figure 1B The methods used to extract CBD from plants typically rely on heat to decarboxylate CBDA into CBD. However, because decarboxylation occurs under heat, light, or even over time, it is nearly impossible to extract pure CBDA that is not contaminated with CBD.

[0004] The lack of availability of CBDA has hindered the pharmacological exploration and development of its potential medicinal value. To date, limited studies on the potential pharmacological properties of CBDA have indicated that this cannabinoid itself possesses medicinal properties. For example, CBDA has shown medicinal activity through 5-HT... 1A The activation mechanism significantly inhibited nausea and vomiting in a rat model with greater potency than CBD (D. Bolognini et al., British Journal of Pharmacology, 2012; 168(6): 1456-1470). Studies have also shown that CBDA has potential anticancer benefits (S. Takeda, Journal of Natural Medicines, 2017; 71: 286-291). CBDA's ability to selectively inhibit COX-2 activity (S. Takeda, Drug Metab. Dispos., 2008; 36(9): 1917-1921) offers possibilities for exploring CBDA as an anti-inflammatory drug. Furthermore, like CBD, CBDA has the potential to treat depression through 5-HT... 1A The pathway shows promise. Due to CDBA's effect on 5-HT... 1A CBD's affinity for 5-HT 1ACBDA has 100 times the affinity for CBD, therefore it is likely to show greater efficacy than CBD in treating depression (D. Bolognini et al., British Journal of Pharmacology, 2012; 168(6): 1456-1470). For example, CBDA has shown to be more effective than CBD in treating epilepsy (WO2017025712).

[0005] Despite the significant potential of CBDA for pharmaceutical applications, the difficulties in extracting pure CBDA from cannabis plants, coupled with the chemical instability of CBDA, indicate that contamination with CBD is inevitable. Although CBDA can be synthesized, the inventors have found that the synthesized CBDA is not crystalline, and CBDA crystallization typically leads to CBDA degradation. Figure 2 Therefore, there is a need to develop new CBDA crystal forms that are stable against decarboxylation or degradation under typical storage conditions in order to fully explore the pharmaceutical potential of CBDA. Summary of the Invention

[0006] This invention provides cannabidiol cocrystals. The cannabidiol cocrystals can be used to prepare medicaments for treating diseases, conditions, and symptoms. In one exemplary embodiment, the composition comprises cannabidiol cocrystals. In one aspect, the cannabidiol cocrystals are selected from the group consisting of: cannabidiol L-phenylalanine cocrystals, cannabidiol vanillin cocrystals, cannabidiol betaine cocrystals, cannabidiol ethyl maltol cocrystals, cannabidiol L-proline cocrystals, and cannabidiol D-proline cocrystals. In another aspect, the cannabidiol cocrystals are selected from the group consisting of: 1:1 cannabidiol L-phenylalanine cocrystals, 1:1 cannabidiol vanillin cocrystals, 1:1 cannabidiol betaine cocrystals, 1:1 cannabidiol ethyl maltol cocrystals, 1:1 cannabidiol L-proline cocrystals, and 1:1 cannabidiol D-proline cocrystals.

[0007] In one aspect, the 1:1 cannabidiol-L-phenylalanine cocrystal is characterized by a powder X-ray diffraction pattern having at least three peaks selected from the following: 3.1, 6.4, 18.4, 19.8, and 23.7 °2θ ± 0.2 °2θ; or with Figure 3 A substantially similar powder X-ray diffraction pattern; or an infrared spectrum having at least three peaks selected from the following: 1606, 1409, 1296, 1240, and 1184 cm⁻¹. -1 ± 1 cm -1 ; or with Figure 7 They have essentially similar infrared spectra.

[0008] In one aspect, the 1:1 cannabidiol vanillin cocrystal is characterized by a powder X-ray diffraction pattern having at least three peaks selected from the following: 4.3, 7.5, 14.2, 19.4, 22.2 and 25.2 ± 0.2 °2θ; or with Figure 8 A substantially similar powder X-ray diffraction pattern; or an infrared spectrum having at least three peaks selected from the following: 1658, 1509, 1294, 1258, and 1151 cm⁻¹. -1 ± 1 cm -1 ; or with Figure 12 They have essentially similar infrared spectra.

[0009] In one aspect, the 1:1 cannabidiol betaine co-crystal is characterized by a powder X-ray diffraction pattern having at least three peaks selected from the following: 7.2, 11.0, 16.3, 18.4 and 23.6 ± 0.2 °2θ; or with Figure 13 A substantially similar powder X-ray diffraction pattern; or an infrared spectrum having at least three peaks selected from the following: 1723, 1589, 1371, 1261, and 887 cm⁻¹. -1 ± 1 cm -1 ; or with Figure 17 They have essentially similar infrared spectra.

[0010] In one aspect, the 1:1 cannabidiol ethyl maltol cocrystal is characterized by a powder X-ray diffraction pattern having at least three peaks selected from the group consisting of: 8.4, 16.0, 17.1, 18.0, and 19.7 ± 0.2 °2θ; or with Figure 18 A substantially similar powder X-ray diffraction pattern; or an infrared spectrum having at least three peaks selected from the following: 1526, 1410, 1376, 1260, and 1238 cm⁻¹. -1 ± 1 cm -1 ; or with Figure 22 They have essentially similar infrared spectra.

[0011] In one aspect, the 1:1 cannabidiol-L-proline cocrystal is characterized by a powder X-ray diffraction pattern having at least three peaks selected from the group consisting of: 7.4, 8.5, 15.2, 19.0, and 23.0 ± 0.2 °2θ; or with Figure 23 A substantially similar powder X-ray diffraction pattern; or an infrared spectrum having at least three peaks selected from the following: 1574, 1430, 1374, 1240, and 1172 cm⁻¹. -1 ± 1 cm -1 ; or with Figure 27 They have essentially similar infrared spectra.

[0012] In one aspect, the 1:1 cannabidiol D-proline cocrystal is characterized by a powder X-ray diffraction pattern having at least three peaks selected from the following: 4.8, 5.1, 9.1, 18.2, and 19.1 ± 0.2 °2θ; or with Figure 28 A substantially similar powder X-ray diffraction pattern; or an infrared spectrum having at least three peaks selected from the following: 1635, 1611, 1575, 1374, and 1244 cm⁻¹. -1 ± 1 cm -1 ; or with Figure 32 They have essentially similar infrared spectra.

[0013] In another exemplary embodiment, the composition comprises cannabidiol cocrystals and excipients. In one aspect, the cannabidiol cocrystals are selected from the group consisting of: L-phenylalanine cannabidiol cocrystals, vanillin cannabidiol cocrystals, betaine cannabidiol cocrystals, ethyl maltol cannabidiol cocrystals, L-proline cannabidiol cocrystals, and D-proline cannabidiol cocrystals. In another aspect, the cannabidiol cocrystals are selected from the group consisting of: 1:1 L-phenylalanine cannabidiol cocrystals, 1:1 vanillin cannabidiol cocrystals, 1:1 betaine cannabidiol cocrystals, ethyl maltol cannabidiol cocrystals, L-proline cannabidiol cocrystals, and D-proline cannabidiol cocrystals.

[0014] In another exemplary embodiment, the pharmaceutical composition comprises cannabidiol cocrystals and a pharmaceutically acceptable carrier. In one aspect, the cannabidiol cocrystals are selected from the group consisting of: cannabidiol L-phenylalanine cocrystals, cannabidiol vanillin cocrystals, cannabidiol betaine cocrystals, cannabidiol ethyl maltol cocrystals, cannabidiol L-proline cocrystals, and cannabidiol D-proline cocrystals. In another aspect, the cannabidiol cocrystals are selected from the group consisting of: 1:1 cannabidiol L-phenylalanine cocrystals, 1:1 cannabidiol vanillin cocrystals, 1:1 cannabidiol betaine cocrystals, 1:1 cannabidiol ethyl maltol cocrystals, 1:1 cannabidiol L-proline cocrystals, and 1:1 cannabidiol D-proline cocrystals.

[0015] In one aspect, the pharmaceutical composition comprises a therapeutically effective amount of cannabidiol cocrystal. In another aspect, the therapeutically effective amount of the cannabidiol cocrystal is about 0.01 mg / kg, about 0.02 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 50 mg / kg, about 200 mg / kg, about 500 mg / kg, about 50 mg, about 100 mg, about 250 mg, about 500 mg, about 750 mg, about 1,000 mg, about 1,500 mg, about 2,000 mg, about 50 mg to about 1,500 mg, about 100 mg to about 1,000 mg, or about 250 mg to about 750 mg. In another exemplary embodiment, a method of treating a patient's disease, condition, or symptom comprises administering to the patient a therapeutically effective amount of cannabidiol cocrystal or a pharmaceutical composition comprising a therapeutically effective amount of cannabidiol cocrystal and a pharmaceutically acceptable carrier. In one aspect, the cannabidiol cocrystal is selected from the group consisting of: L-phenylalanine cannabidiol cocrystal, vanillin cannabidiol cocrystal, betaine cannabidiol cocrystal, ethyl maltol cannabidiol cocrystal, L-proline cannabidiol cocrystal, and D-proline cannabidiol cocrystal. In another aspect, the cannabidiol cocrystal is selected from the group consisting of: 1:1 L-phenylalanine cannabidiol cocrystal, 1:1 vanillin cannabidiol cocrystal, 1:1 betaine cannabidiol cocrystal, ethyl maltol cannabidiol cocrystal, L-proline cannabidiol cocrystal, and D-proline cannabidiol cocrystal.

[0016] In one aspect, the patient is an animal. In another aspect, the patient is a human.

[0017] In one aspect, the therapeutically effective amount of the cannabidiol cocrystal is about 0.01 mg / kg, about 0.02 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 50 mg / kg, about 100 mg / kg, about 200 mg / kg, about 500 mg / kg, about 50 mg, about 100 mg, about 250 mg, about 500 mg, about 750 mg, about 1,000 mg, about 1,500 mg, about 2,000 mg, about 50 mg to about 1,500 mg, about 100 mg to about 1,000 mg, or about 250 mg to about 750 mg.

[0018] In one aspect, cannabidiol cocrystals are administered to the patient in the form of a solid, semi-solid, lyophilized powder, or liquid dosage form.

[0019] In another exemplary embodiment, a method for preparing a liquid pharmaceutical composition includes the step of dissolving cannabidiol cocrystals in a pharmaceutically acceptable solvent.

[0020] In one aspect, the cannabidiol cocrystal is selected from the group comprising: cannabidiol L-phenylalanine cocrystal, cannabidiol vanillin cocrystal, cannabidiol betaine cocrystal, cannabidiol ethyl maltol cocrystal, cannabidiol L-proline cocrystal, and cannabidiol D-proline cocrystal. In another aspect, the cannabidiol cocrystal is selected from the group comprising: 1:1 cannabidiol L-phenylalanine cocrystal, 1:1 cannabidiol vanillin cocrystal, 1:1 cannabidiol betaine cocrystal, 1:1 cannabidiol ethyl maltol cocrystal, 1:1 cannabidiol L-proline cocrystal, and 1:1 cannabidiol D-proline cocrystal. Attached Figure Description

[0021] Figure 1A The structure of cannabidiol was described.

[0022] Figure 1B The structure of cannabidiol acid was described.

[0023] Figure 2 X-ray powder diffraction (XRPD) patterns of synthetic cannabidiol were depicted.

[0024] Figure 3 XRPD patterns of a 1:1 cannabidiol-L-phenylalanine cocrystal according to an exemplary embodiment are depicted.

[0025] Figure 4Differential scanning calorimetry (DSC) traces of a 1:1 cannabidiol-L-phenylalanine cocrystal according to an exemplary embodiment are depicted.

[0026] Figure 5 Thermogravimetric analysis (TGA) traces of a 1:1 cannabidiol-L-phenylalanine cocrystal according to an exemplary embodiment are depicted.

[0027] Figure 6 A 1:1 cocrystal of cannabidiol and L-phenylalanine according to an exemplary embodiment is depicted. 1 H nuclear magnetic resonance (NMR) spectroscopy.

[0028] Figure 7 Infrared spectra of a 1:1 cannabidiol-L-phenylalanine cocrystal according to an exemplary embodiment were depicted.

[0029] Figure 8 XRPD patterns of a 1:1 cannabidiol vanillin cocrystal were depicted according to an exemplary embodiment.

[0030] Figure 9 DSC traces of a 1:1 cannabidiol vanillin cocrystal according to an exemplary embodiment are depicted.

[0031] Figure 10 TGA traces of a 1:1 cannabidiol vanillin cocrystal are depicted according to an exemplary embodiment.

[0032] Figure 11 A 1:1 cannabidiol vanillin cocrystal is depicted according to an exemplary embodiment. 1 H NMR spectrum.

[0033] Figure 12 The infrared spectrum of a 1:1 cannabidiol vanillin cocrystal according to an exemplary embodiment was depicted.

[0034] Figure 13 XRPD patterns of a 1:1 cannabidiol betaine cocrystal according to an exemplary embodiment are depicted.

[0035] Figure 14 DSC traces of a 1:1 cannabidiol betaine eutectic according to an exemplary embodiment are depicted.

[0036] Figure 15 TGA traces of a 1:1 cannabidiol betaine eutectic according to an exemplary embodiment are depicted.

[0037] Figure 16 A 1:1 cannabidiol-betaine eutectic is depicted according to an exemplary embodiment. 1 H NMR spectrum.

[0038] Figure 17 The infrared spectrum of a 1:1 cannabidiol betaine cocrystal according to an exemplary embodiment was depicted.

[0039] Figure 18 XRPD patterns of a 1:1 cannabidiol ethyl maltol cocrystal according to an exemplary embodiment are depicted.

[0040] Figure 19 DSC traces of a 1:1 cannabidiol ethyl maltol cocrystal according to an exemplary embodiment are depicted.

[0041] Figure 20 TGA traces of a 1:1 cannabidiol ethyl maltol cocrystal according to an exemplary embodiment are depicted.

[0042] Figure 21 A 1:1 cannabidiol ethyl maltol cocrystal is depicted according to an exemplary embodiment. 1 H NMR spectrum.

[0043] Figure 22 The infrared spectrum of a 1:1 cannabidiol ethyl maltol cocrystal according to an exemplary embodiment was depicted.

[0044] Figure 23 XRPD patterns of a 1:1 cannabidiol-L-proline cocrystal according to an exemplary embodiment are depicted.

[0045] Figure 24 DSC traces of a 1:1 cannabidiol-L-proline cocrystal according to an exemplary embodiment are depicted.

[0046] Figure 25 TGA traces of a 1:1 cannabidiol-L-proline cocrystal according to an exemplary embodiment are depicted.

[0047] Figure 26 A 1:1 cannabidiol-L-proline cocrystal is depicted according to an exemplary embodiment. 1 H NMR spectrum.

[0048] Figure 27 The infrared spectrum of a 1:1 cannabidiol L-proline cocrystal according to an exemplary embodiment was depicted.

[0049] Figure 28 XRPD patterns of a 1:1 cannabidiol D-proline cocrystal according to an exemplary embodiment are depicted.

[0050] Figure 29 DSC traces of a 1:1 cannabidiol D-proline cocrystal according to an exemplary embodiment are depicted.

[0051] Figure 30 TGA traces of a 1:1 cannabidiol D-proline cocrystal according to an exemplary embodiment are depicted.

[0052] Figure 31 A 1:1 cannabidiol D-proline cocrystal is depicted according to an exemplary embodiment. 1 H NMR spectrum.

[0053] Figure 32 The infrared spectrum of a 1:1 cannabidiol D-proline cocrystal according to an exemplary embodiment was depicted. Detailed Implementation

[0054] In recent years, scientific research on the potential medicinal value of plant cannabinoids (cannabidiol (CBD)) has advanced significantly. This has led to FDA approval for its use in treating rare forms of epilepsy and has resulted in a rapid expansion of the market for CBD-containing consumer products. While CBD is one of the most abundant plant cannabinoids found in cannabis extracts, it is typically present in the plant in an acidic form (cannabidiol acid (CBDA)). Methods for extracting CBD from plants generally rely on heat to decarboxylate the carboxylic acid form to CBD. More recently, methods using CO2 extraction have allowed for the retention of a certain percentage of CBDA. However, because decarboxylation occurs under heat, light, or even over time, it is nearly impossible to extract pure CBDA that is not contaminated with CBD.

[0055] The lack of availability of CBDA has hindered the pharmacological exploration and development of its potential medicinal value. To date, limited studies on the potential pharmacological properties of CBDA have indicated that this cannabinoid itself possesses medicinal properties. For example, CBDA has shown medicinal activity through 5-HT... 1A The activation mechanism of CBDA inhibited nausea and vomiting in a rat model with significantly greater potency than CBD (D. Bolognini et al., *British Journal of Pharmacology*, 2012; 168(6): 1456-1470). Studies have also shown that CBDA has potential anticancer benefits (S. Takeda, *Natural Medicine Journal*, 2017; 71: 286-291). CBDA's ability to selectively inhibit COX-2 activity (S. Takeda, *Drug Metabolism and Disposal*, 2008; 36(9): 1917-1921) offers possibilities for exploring CBDA as an anti-inflammatory drug. Furthermore, like CBD, CBDA has the potential to treat depression through 5-HT... 1A The pathway shows promise. Because CBDA has a positive effect on 5-HT... 1A CBD's affinity for 5-HT 1ACBDA has 100 times the affinity for CBD, therefore it is likely to show greater efficacy than CBD in treating depression (D. Bolognini et al., British Journal of Pharmacology, 2012; 168(6): 1456-1470). For example, CBDA has shown to be more effective than CBD in treating epilepsy (WO2017025712).

[0056] Despite the potential for significant pharmaceutical applications, the difficulties in extracting pure CBDA from cannabis plants, coupled with the chemical instability of CBDA, indicate that contamination with CBD is inevitable. Although CBDA can be synthesized, the inventors have found that the synthesized CBDA is not crystalline, and CBDA crystallization typically leads to its degradation. Figure 2 Therefore, there is a need to develop new CBDA crystal forms that are stable against decarboxylation or degradation under typical storage conditions in order to fully explore the pharmaceutical potential of CBDA.

[0057] The chemical composition and solid-state form (e.g., crystalline or amorphous) of an active pharmaceutical ingredient (API) are crucial to its pharmacological properties, such as bioavailability, and its development as a viable drug candidate. Each composition or crystal form may exhibit different solid-state (physical and chemical) properties. Differences in the physical properties exhibited by novel solid-state forms (e.g., polymorphs of APIs or cocrystals containing APIs, discussed below) can affect pharmaceutical and pharmacological properties such as storage, stability, compressibility, and density (important factors in formulation and product manufacturing) and / or solubility and dissolution rate (key factors in determining bioavailability). For example, the dissolution rate of the active ingredient in a patient's gastric juices may have therapeutic effects because it affects the rate at which an orally administered active ingredient can reach the patient's bloodstream.

[0058] The physical properties of an API can also significantly impact its ability to deliver a drug via the desired method. For example, in the case of drug administration via inhalation, physical properties associated with APIs in particulate form, such as morphology, density, surface energy, charge, hygroscopicity, stability, dispersibility, and / or agglomeration, may be relevant. The solid-state form of an API, as well as eutectic forms of APIs as described below, offer opportunities to address, engineer, and / or improve one or more of these properties, thereby improving delivery methods.

[0059] Where possible, obtaining the crystalline form of an API is particularly beneficial for drug development. This allows for better characterization of the chemical and physical properties of drug candidates and can reduce drug development time and costs. The crystalline form typically possesses better chemical and physical properties than the API in its amorphous state.

[0060] Desired properties of a particular API can be achieved by forming a cocrystal. An API cocrystal is a unique chemical composition of the API and the cocrystal forming agent, and typically exhibits unique crystallographic and spectroscopic properties when compared alone to a composition of the API and the cocrystal forming agent. The crystallographic and spectroscopic properties of the crystal form are typically measured using techniques such as X-ray powder diffraction (XRPD) and single-crystal X-ray crystallography. Cocrystals also often exhibit unique thermal behavior, which can be measured using techniques such as capillary melting point, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). Cocrystals may also have more favorable solid-state, physical, chemical, pharmaceutical, and / or pharmacological properties, and may be easier to handle than known forms or formulations of the API. For example, the solubility and / or dissolution properties of the cocrystal may differ from those of the API, and therefore may be more efficient in drug delivery. Cocrystal formation can also be used to avoid the formation of polymorphs of the drug. Therefore, novel pharmaceutical compositions comprising cocrystals of a given API may have different or superior properties compared to their existing pharmaceutical formulations.

[0061] Unlike salts, which have a neutral net charge but contain components with charge balance, cocrystals contain neutral species. Therefore, unlike salts, the stoichiometry of cocrystals cannot be determined based on charge balance. In fact, the stoichiometric ratio of the drug to the cocrystal forming agent in a cocrystal can be greater than or less than 1:1. The stoichiometric ratio of the API to the cocrystal forming agent is often a difficult-to-predict characteristic of cocrystals.

[0062] This invention discloses compositions comprising cannabidiol cocrystals, compositions comprising cannabidiol and one or more excipients, and, in particular, pharmaceutical compositions comprising cannabidiol cocrystals and pharmaceutically acceptable carriers. The invention also discloses methods for treating diseases, conditions, and symptoms with a therapeutically effective amount of cannabidiol cocrystals or pharmaceutical compositions comprising said cocrystals. The invention further provides the use of cannabidiol cocrystals in the preparation of medicaments for treating the diseases, conditions, and symptoms described herein.

[0063] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although similar or equivalent methods and materials may be used in practice or testing as described herein, specific methods and materials are described hereafter.

[0064] The term “a / an (a)” should be understood to mean “at least one / an”, and the terms “about” and “approximately” should be understood to allow for variations in the standard, as would be understood by one of ordinary skill in the art, and where the scope is provided, to include endpoints. As used herein, the terms “include,” “includes,” and “including” are intended to be non-limiting and are understood to mean “comprise,” “comprises,” and “comprising,” respectively.

[0065] In some exemplary embodiments, this disclosure provides a composition comprising cannabidiol cocrystal.

[0066] As used herein, the term "cocrystal" refers to a multicomponent crystal composed of two or more neutral molecules in a stoichiometric ratio, bonded together by non-covalent interactions (e.g., hydrogen bonds, van der Waals forces). In some exemplary embodiments, the components of the cocrystal may include an active pharmaceutical ingredient (API) and a cocrystal forming agent.

[0067] The terms "active pharmaceutical ingredient" or "API" refer to the bioactive component of a pharmaceutical product. An active pharmaceutical ingredient can refer to any substance or combination of substances used in a pharmaceutical product to provide pharmacological activity or otherwise have a direct effect on the diagnosis, cure, relief, treatment, or prevention of a disease, or on the restoration, correction, or alteration of physiological functions in animals. Non-limiting methods for preparing active pharmaceutical ingredients may include the use of fermentation processes, recombinant DNA, isolation and recovery from natural resources, chemical synthesis, or combinations thereof.

[0068] In some exemplary embodiments, the cannabidiol active pharmaceutical ingredient is formulated as a cannabidiol cocrystal. In some exemplary embodiments, the cannabidiol cocrystal may include, but is not limited to, cannabidiol L-phenylalanine cocrystal, cannabidiol vanillin cocrystal, cannabidiol betaine cocrystal, cannabidiol ethyl maltol cocrystal, cannabidiol L-proline cocrystal, and cannabidiol D-proline cocrystal. In some exemplary embodiments, the cannabidiol cocrystal may include, but is not limited to, 1:1 cannabidiol L-phenylalanine cocrystal, 1:1 cannabidiol vanillin cocrystal, 1:1 cannabidiol betaine cocrystal, 1:1 cannabidiol ethyl maltol cocrystal, 1:1 cannabidiol L-proline cocrystal, and 1:1 cannabidiol D-proline cocrystal. These cannabidiol cocrystals, their preparation, and their characterization are described in the examples and figures herein.

[0069] The term "cocrystallizer" refers to a cocrystallizing agent that interacts with an API (API) in a crystal lattice through non-covalent interactions. Cocrystallizers do not need to possess intrinsic activity, but they may have some activity. Some cocrystallizers may enhance the therapeutic effects of APIs. For pharmaceutical formulations, cocrystallizers can be pharmaceutically acceptable molecules that form cocrystallizations with APIs or their salts. Cocrystallizers can be non-ionized, such as benzoic acid, succinic acid, and caffeine; or they can be zwitterionic, such as L-lysine, L-arginine, or L-proline; or they can be salts, such as sodium benzoate or sodium succinate. Cocrystallizers can also include, but are not limited to, organic bases, organic salts, alcohols, aldehydes, amino acids, sugars, ionic inorganic substances, carboxylic acids, amines, flavoring agents, sweeteners, nutrients, aliphatic esters, aliphatic ketones, organic acids, aromatic esters, alkaloids, and aromatic ketones.

[0070] The properties of a component or its salt (such as an API or its salt) may be altered due to the formation of a eutectic. The eutectic may exhibit improved properties compared to the API itself or its salt form. These properties include, for example, melting point, solubility, dissolution, chemical stability, physical stability, and bioavailability.

[0071] In some exemplary embodiments, the cannabidiol cocrystal may be characterized by a powder X-ray diffraction pattern or infrared spectrum having certain peaks or signals, or a powder X-ray diffraction pattern or infrared spectrum substantially similar to those disclosed herein.

[0072] As used herein, the term "powder X-ray diffraction pattern" refers to the signal intensity of X-rays measured at various diffraction angles. For amorphous materials, an X-ray powder diffraction pattern may include one or more broad signals or peaks, while for crystalline materials, an X-ray powder diffraction pattern may include one or more sharp signals or peaks.

[0073] As used herein, the term “infrared spectrum” refers to the signal intensity of the measured infrared absorbance (or transmittance) relative to the frequency or wavelength of light.

[0074] As used herein, the terms “peak” or “signal” refer to the relative signal intensity within a given powder X-ray diffraction pattern or infrared spectrum.

[0075] As used herein, a powder X-ray diffraction pattern or infrared spectrum is “substantially similar to [a specific] pattern” when at least 90%, or at least 95%, at least 98%, or at least 99% of the signals in two powder X-ray diffraction patterns or two infrared spectra overlap. In determining “substantially similar,” those skilled in the art will understand that variations in intensity and / or signal location may exist in the powder X-ray diffraction pattern or infrared spectrum.

[0076] Therapeutic uses of cannabidiol cocrystals

[0077] Cannabidiol (CBD) can possess antiemetic, anticonvulsant, anti-inflammatory, antidepressant, and anticancer properties, and is known in the art to be used to treat various diseases, conditions, and symptoms. The CBD cocrystals of the present invention and pharmaceutical compositions containing CBD cocrystals can then also be used to treat such diseases, conditions, and symptoms.

[0078] Examples of such diseases, conditions, and symptoms include, but are not limited to, anxiety and stress, depression, schizophrenia, panic and anxiety, withdrawal symptoms from marijuana and tobacco addiction, the reward-promoting effect of morphine and cocaine, any type of autoimmune disease (type 1 diabetes and GVHD are specific and non-limiting examples), inflammation (Crohn's disease, colitis, pancreatitis, rheumatoid arthritis), infarct size reduction and increased blood flow during stroke, obesity, metabolic syndrome, diabetic retinopathy, nausea, myocardial, hepatic, and renal ischemia / reperfusion injury, neuronal damage (due to neurological diseases or injuries, Parkinson's disease, Huntington's disease, Alzheimer's disease), cerebral infarction, hepatic encephalopathy, pain, traumatic brain injury, cerebral ischemia, spinal cord injury, and memory rescuing. Effects, cancer and resistance to cancer chemotherapy, cancer cell migration (metastasis), angiogenesis, epilepsy and seizures, chronic inflammatory and neuropathic pain, airway obstruction, compulsive behaviors, and any combination thereof.

[0079] In another exemplary embodiment, the present invention discloses a method for treating such disease, condition, or symptom in a patient, the method comprising the steps of administering a therapeutically effective amount of cannabidiol cocrystal to the patient or administering a pharmaceutical composition comprising cannabidiol cocrystal to the patient.

[0080] As used herein, the term "patient" means any organism to which the pharmaceutical composition may be administered, for example, for experimental, diagnostic, preventative, cosmetic, and / or therapeutic purposes. Typical patients include animals (e.g., mammals such as mice, rats, rabbits; domestic animals such as dogs and cats; cattle, sheep, pigs, horses; non-human primates; and / or humans). In some embodiments, a patient has or is susceptible to one or more diseases, conditions, or symptoms. In some embodiments, a patient has been diagnosed with one or more diseases, conditions, or symptoms.

[0081] As used herein, the terms “treatment” or “treating” mean any treatment of a disease, symptom, or condition in a mammal, including prevention or resistance to the disease, symptom, or condition, even if clinical symptoms do not develop; suppression of the disease, symptom, or condition, i.e., preventing or inhibiting the development of clinical symptoms; and / or relief of the disease, symptom, or condition (including relief of discomfort associated with said symptom or condition), even if clinical symptoms subside. Those skilled in the art will understand that in human medicine, it is not always possible to distinguish between “prevention” and “suppression” because one or more eventual triggering events may be unknown, latent, or only identified long after one or more events have occurred. Therefore, as used herein, the term “prophylaxis” as an element of “treatment” is intended to encompass both “preventing” and “suppressing” a disease, symptom, or condition. The term “resistance” is intended to include “prophylaxis.”

[0082] As used herein, the term "administration" means administering a compound, composition, dosage form, etc., to a patient, subject, or system. Administration to a patient can be facilitated by any suitable route. For example, in some embodiments, administration may be via the bronchi, buccal, enterum, intradermal, intraarterial, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intracardiac, mucosal, nasal, oral, rectal, subcutaneous, sublingual, local, trachea, percutaneous, vaginal, and / or vitreous. In some embodiments, administration may involve intermittent dosing. In some embodiments, administration may involve continuous dosing for at least a selected time period.

[0083] Another aspect of the invention relates to the use of the cannabidiol cocrystal of the invention in the treatment of the diseases, conditions, and symptoms discussed above. Therefore, the invention further relates to the preparation of a medicament for treating such diseases, conditions, and symptoms.

[0084] Pharmaceutical compositions containing cannabidiol cocrystals

[0085] In another exemplary embodiment, the present invention discloses pharmaceutical compositions comprising cannabidiol cocrystals and a pharmaceutically acceptable carrier. As mentioned above, these pharmaceutical compositions can be used therapeutically to treat or prevent diseases such as those discussed above.

[0086] As used herein, the term "pharmaceutical composition" refers to an active pharmaceutical ingredient (API) formulated with one or more pharmaceutically acceptable carriers.

[0087] As used herein, the term "carrier" refers to an agent that can be added to a formulation to provide desired consistency, improve stability, and / or regulate osmotic pressure. Examples of common carriers include, but are not limited to, sugars, polyols, amino acids, surfactants, and / or polymers. The terms "carrier" and "excipient" have the same meaning and are used interchangeably.

[0088] As used herein, the term "therapeuticly effective dose" means, whether alone or in combination with one or more therapeutic agents, sufficient to partially or completely reduce the occurrence of one or more symptoms, features, and / or causes of a particular disease, condition, and / or symptom, or to partially or completely prevent the worsening of any of the foregoing conditions. Therapeuticly effective doses may be, for example, about 0.01 mg / kg, about 0.02 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 50 mg / kg, about 100 mg / kg, about 200 mg / kg, or about 500 mg / kg. Therapeutic effective doses may also be, for example, about 50 mg, about 100 mg, about 250 mg, about 500 mg, about 750 mg, about 1,000 mg, about 1,500 mg, about 2,000 mg, about 50 mg to about 1,500 mg, about 100 mg to about 1,000 mg, or about 250 mg to about 750 mg. The actual amount required to treat any particular disease, condition, or symptom in any particular patient may depend on a variety of factors, including, for example, the particular disease, condition, or symptom being treated; the disease state and its severity; the particular pharmaceutical composition used; the patient's age, weight, general health condition, sex, and diet; the mode of administration; the time of administration; the route of administration; and the excretion rate; the duration of treatment; any drugs used in combination with or in combination with the particular compound used; and other such factors well known in the medical field. These factors are discussed in Goodman and Gilman's "The Pharmacological Basis of Therapeutics", 10th edition, edited by A. Gilman, J. Hardman, and L. Limbird, McGraw-Hill Press, pp. 155-173, 2001, which is incorporated herein by reference.

[0089] The pharmaceutical compositions of the present invention can be in any pharmaceutical form containing cannabidiol cocrystals. In some exemplary embodiments, the pharmaceutical compositions can be formulated as solid, semi-solid, lyophilized powder, or liquid dosage forms. The pharmaceutical compositions can also be, for example, tablets, capsules, oral solutions, injectable compositions, topical compositions, inhalable compositions, or transdermal compositions. Liquid pharmaceutical compositions can be prepared using the cannabidiol cocrystals of the present invention and represent specific embodiments of the invention. For liquid pharmaceutical compositions, the cannabidiol cocrystals can be dissolved in a solvent (e.g., water) at the point of treatment and during treatment.

[0090] The term "dosage" refers to a physically discrete unit of one or more active pharmaceutical ingredients used to administer to a patient. Each dose contains a predetermined amount of one or more active pharmaceutical ingredients. The term "dosage form" refers to the physical form in which a drug is manufactured or administered.

[0091] Pharmaceutical compositions can also be formulated as chewable tablets, also known as gummy tablets. As is known in the art, chewable tablet formulations can be prepared from glycerin, gelatin, and water. Tablets typically also contain flavoring agents (such as fruit or candy flavors) and coloring agents to provide a pleasant taste and appearance to the formulation. Chewable tablets can also be made or molded into various shapes, such as, but not limited to, ovals, spheres, Platonic solids (e.g., tetrahedrons, cubes, octahedrons, etc.), rectangular prisms, cones, pyramids, cylinders, fruit slices, animals, cartoon characters, cars, etc. Exemplary chewable tablets of the present invention may contain desired amounts of eutectic, glycerin, gelatin, water, methylparaben, flavoring oil, and coloring agents.

[0092] Pharmaceutical compositions can also be formulated as sublingual or buccal preparations, tablet forms not typically used for oral administration. These small, hard, compressed tablets are designed to dissolve rapidly in the vascular mucosa of the oral cavity. Buccal tablets are placed in the buccal pouch (between the cheek and gum), and sublingual tablets are placed under the tongue. Because the buccal and sublingual regions are highly vascularized, the drug is rapidly absorbed into the bloodstream, resulting in a rapid onset of action. Drugs administered in this manner avoid first-pass metabolism because, unlike drugs adsorbed from the gastrointestinal tract (GI), the adsorbed drug bypasses the portal vein. Sublingual and buccal formulations can be prepared using pharmaceutically acceptable carriers and disintegrants known in the art, as well as flavoring agents and other additives, to improve palatability and enhance patient acceptance and compliance.

[0093] Inhalable compositions can be used to apply a pharmaceutical composition topically to the lungs or nasal cavity. Inhalable compositions may comprise dry powder inhaler formulations containing breathable particles of cannabidiol cocrystals that are inhaled by the treated patient. Commonly found in dry powder formulations are carrier particles to which the cocrystal particles can be attached. The carrier particles may contain any acceptable pharmacologically inert material or combination of materials. For example, the carrier particles may consist of one or more materials selected from: sugar alcohols; polyols such as sorbitol, mannitol, or xylitol; and crystalline sugars, including monosaccharides and disaccharides; inorganic salts such as sodium chloride and calcium carbonate; organic salts such as sodium lactate; and other organic compounds such as urea, polysaccharides such as cyclodextrin and dextrin. The carrier particles may be crystalline sugars, such as monosaccharides (e.g., glucose or arabinose) or disaccharides (e.g., maltose, sucrose, dextrose, or lactose). The cocrystals will be dispersed into the respiratory tract in a therapeutically effective amount.

[0094] The pharmaceutical composition may contain, for example, from about 0.1% to about 99.9% by weight of the cannabidiol cocrystal of the present invention, for example, from about 0.5% to about 99% by weight of the cannabidiol cocrystal of the present invention, and, for example, from 0.5% to 99.5% by weight of at least one suitable pharmaceutical excipient or solvent. In one embodiment, the composition may be from about 5% to about 75% by weight of the cannabidiol cocrystal of the present invention, wherein the remainder is at least one suitable excipient, solvent, or at least one other adjuvant, as discussed below.

[0095] Depending on the type of composition, the excipient or pharmaceutically acceptable carrier may be selected from any excipient or carrier known in the art, or a combination of said excipients or carriers. The selection of a pharmaceutically acceptable carrier depends on the form of the drug to be used and the desired method of administration. For the pharmaceutical compositions of the present invention, i.e., pharmaceutical compositions containing cannabidiol cocrystals, a carrier that maintains its crystal form should be selected. In other words, the carrier should not substantially alter the cannabidiol cocrystal. The carrier should also not be otherwise incompatible with the cannabidiol cocrystal used, such as due to any undesirable biological effects, or otherwise interacting harmfully with any other component of the pharmaceutical composition.

[0096] Pharmaceutical compositions can be prepared by methods known in the field of pharmaceutical formulations, for example, see Remington's Pharmaceutical Sciences, 18th edition (Mack Publishing Company, Easton, PA, 1990), which is incorporated herein by reference. In solid dosage forms, the cannabidiol cocrystals of the present invention can be mixed with at least one pharmaceutically acceptable excipient, such as sodium citrate or dicalcium phosphate, or (a) a filler or expander, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) a binder, such as cellulose derivatives, starch, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) a humectant, such as glycerin; or (d) a disintegrant. Examples of active ingredients include: (e) agar-agar, calcium carbonate, potato or cassava starch, alginate, croscarmellose sodium, complex silicates, and sodium carbonate; (f) solution retarder, such as paraffin; (g) absorption accelerator, such as quaternary ammonium compounds; (h) humectants, such as cetyl alcohol and glyceryl monostearate, magnesium stearate, etc.; (i) adsorbents, such as kaolin and bentonite; and (v) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

[0097] Pharmaceutically acceptable excipients known in the art can also be used in the compositions and pharmaceutical compositions of the present invention. These pharmaceutically acceptable excipients include, but are not limited to, preservatives, wetting agents, suspending agents, sweeteners, flavoring agents, fragrances, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, etc. If desired, the pharmaceutical composition may also contain trace amounts of excipients, such as wetting agents or emulsifiers, pH buffers, antioxidants, etc., such as citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.

[0098] The solid dosage forms described above can be prepared using coatings and shells known in the art (such as enteric coatings). These solid dosage forms may also contain a sedative and may have compositions that allow for the delayed release of one or more active compounds at a site in the intestine. Non-limiting examples of encapsulation compositions that can be used are polymeric substances and waxes. Where appropriate, the active compound may also be in a microencapsulated form together with one or more of the excipients mentioned above.

[0099] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar-agar and tragali gum, or mixtures thereof. The liquid dosage form may be aqueous and may contain pharmaceutically acceptable solvents and conventional liquid dosage form excipients known in the art, including but not limited to buffers, flavoring agents, sweeteners, preservatives, and stabilizers.

[0100] Compositions for rectal administration are, for example, suppositories, which can be prepared by mixing the cannabidiol cocrystal of the present invention with, for example, a suitable non-irritating excipient or carrier (such as cocoa butter, polyethylene glycol, or suppository wax, etc.), which may be solid at room temperature but liquid at body temperature, and thus melt and release the active component therein when placed in a suitable body cavity.

[0101] Compositions suitable for topical application include liquid or semi-liquid formulations such as liniments, lotions, gels, ointments, water-in-oil or oil-in-water emulsions (e.g., creams, ointments, pastes, or foams); or solutions or suspensions known in the art, such as drops. The compositions of the present invention may be intended for topical application, in which case the carrier may suitably comprise a solution, emulsion, ointment, or gel matrix. For example, the carrier or matrix may comprise one or more of the following: petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, diluents (e.g., water and alcohol), and emulsifiers and stabilizers. Thickeners may be present in the pharmaceutical composition for topical application. If intended for transdermal application, the composition may comprise a transdermal patch or an iontophoresis device. Topical formulations may contain compounds of the present invention at concentrations from about 0.1 w / v (weight / volume)% to about 10 w / v%.

[0102] In addition to the above-described topical application methods, various methods exist for the topical application of the active cannabidiol cocrystal of the present invention to the lungs. One such method may involve a dry powder inhaler formulation containing inhalable particles of the cannabidiol cocrystal of the present invention inhaled by the treated patient. Common for dry powder formulations are carrier particles to which the cannabidiol cocrystal particles can be attached. The carrier particles can be any acceptable pharmacologically inert material or combination of materials. For example, the carrier particles can consist of one or more materials selected from: sugar alcohols; polyols, such as sorbitol, mannitol, or xylitol; and crystalline sugars, including monosaccharides and disaccharides; inorganic salts, such as sodium chloride and calcium carbonate; organic salts, such as sodium lactate; and other organic compounds, such as urea; and polysaccharides, such as cyclodextrin and dextrin. The carrier particles can be crystalline sugars, such as monosaccharides (e.g., glucose or arabinose) or disaccharides (e.g., maltose, sucrose, dextrose, or lactose).

[0103] In addition to the aforementioned topical application methods, various methods exist for systemic administration of active cannabidiol cocrystals. One such method involves the inhalation of an aerosol suspension of inhalable particles containing the cannabidiol cocrystals of the present invention by the treated patient. The cannabidiol cocrystals are absorbed into the bloodstream through the lungs in a pharmaceutically effective amount. The inhalable particles can be liquid or solid, with a particle size small enough to pass through the mouth and throat upon inhalation.

[0104] Solid dosage forms are an embodiment of the pharmaceutical compositions of the present invention because the crystal form of the cannabidiol cocrystal can be maintained during preparation. Dosage forms for oral administration, including capsules, tablets, pills, powders, granules, and suspensions, can be used. Dosage forms for pulmonary administration, including metered-dose inhalers, dry powder inhalers, or aerosol formulations, can be used. In such solid dosage forms, the active compound can be mixed with at least one inert, pharmaceutically acceptable excipient (also referred to as a pharmaceutically acceptable carrier).

[0105] Cannabidiol cocrystals can also be used to formulate liquid or injectable pharmaceutical compositions. Application of cannabidiol cocrystals, either in pure form or in a suitable pharmaceutical composition, can be made by any recognized route of administration or by agents used for similar purposes. Thus, administration can be, for example, in solid, semi-solid, lyophilized powder, or liquid dosage forms (e.g., tablets, suppositories, pills, soft elastic capsules and hard gelatin capsules, powders, solutions, suspensions, or aerosols, e.g., in unit dosage forms suitable for easy administration of precise doses), orally, buccally, nasally, pulmonaryly, parenterally (intravenously, intramuscularly, or subcutaneously), topically, transdermally, intravaginally, intravesically, systemically, ocularly, or rectally. One route of administration can be oral administration using a convenient daily dosing regimen, which can be adjusted according to the severity of the condition to be treated.

[0106] In another exemplary embodiment, the present invention discloses a method for preparing a liquid pharmaceutical composition, the method comprising the step of dissolving cannabidiol cocrystals in a pharmaceutically acceptable solvent. As discussed above, the liquid pharmaceutical compositions of the present invention can be administered orally, parenterally (including by inhalation), and intravenously.

[0107] The invention will be more fully understood by referring to the following examples. However, the following examples should not be construed as limiting the scope of the invention.

[0108] Example

[0109] The cannabidiol cocrystal of the present invention was characterized using the following analytical methods:

[0110] X-ray powder diffraction characterization:X-ray powder diffraction patterns of the samples were acquired on a Bruker second-generation D2-Phaser diffractometer using CuKα radiation (30 V, 10 mA), an θ-2θ goniometer, a V4 receiving slit, a Ge monochromator, and a Lynxeye detector. The instrument was tested for performance using a certified corundum standard (NIST 1976). Data were collected at ambient temperature within an angular range of 2° to 35° 2θ (using a step size of 0.05° 2θ and a step length of 2.0 seconds) or within an angular range of 2° to 42° 2θ (using a step size of 0.025° 2θ and a step length of 5.0 seconds). Samples from ambient conditions were prepared as slabs using unground powder in an acceptance state. Approximately 20 mg of sample was gently packaged into sample holders, and all samples were analyzed using Diffrac Plus EVA v4.2.0.14.

[0111] Thermal analysis - Differential scanning calorimetry (DSC): DSC data were collected on a PerkinElmer Pyris 4000 DSC equipped with a 45-position sample holder. The instrument was validated using certified indium for energy and temperature calibration. Pre-determined sample volumes of 0.5–3.0 mg were placed in an aluminum dish with pinholes and heated from 30 °C to 350 °C at 20 °C / min. The sample was then purged with dry nitrogen at a rate of 60 ml / min. Instrument control, data acquisition, and analysis were performed using Pyris software v9.0.1.0203.

[0112] Thermogravimetric analysis (TGA): TGA data were collected on a PerkinElmer Pyris 1 TGA equipped with a 20-position autosampler. The instrument temperature was calibrated using certified weights and certified Alumel and Permalloy alloys. Pre-calculated sample volumes of 1–5 mg were loaded into pre-tapered, weighed aluminum crucibles and heated from ambient temperature to 400°C at 20°C / min. The samples were then purged with nitrogen at a rate of 20 ml / min. Instrument control, data acquisition, and analysis were performed using Pyris software v9.0.1.0203.

[0113] Solution proton NMR: Collection was performed using a JEOL EX 270 MHz spectrometer equipped with an autosampler. 1 ¹H-NMR spectroscopy. Samples were dissolved in a suitable deuterated solvent for analysis. Data were acquired using Delta NMR processing and control software version 4.3.

[0114] FT-IR: FT-IR spectra were obtained using a PerkinElmer Spectrum 2 spectrometer, with four scans and a 4cm depth. -1The resolution of the collection is 450 cm. -1 With 4000 cm -1 The FT-IR spectra were obtained between [a certain value]. A general-purpose ATR diamond attachment was used, and the data were analyzed using software version NIOS2 main branch 00.02.0064.

[0115] Gravitational vapor isotherm (GVS) analysis: Adsorption isotherms were obtained using a Hiden Isochema moisture adsorption analyzer (model IGASorp), controlled by IGASorp Systems Software V6.50.48. Samples were maintained at a constant temperature (25°C) via instrument control. Humidity was controlled by mixing dry and wet nitrogen streams at a total flow rate of 250 ml / min. The instrument was validated against relative humidity by measuring three calibrated Rotronic salt solutions (10%-50%-88%). Sample weight changes with humidity were monitored using a microbalance (accuracy + / - 0.005 mg). Defined amounts of sample were placed in a tare-weighed mesh stainless steel basket under ambient conditions. The sample was held at 50% RH for approximately 60 minutes, and then the initial desorption cycle was initiated. A complete experimental cycle typically consisted of three scans (desorption, adsorption, and desorption) performed at a constant temperature (25°C) and at 10% RH intervals within the 0-90% humidity range (60 minutes per humidity level). Perform data analysis in Microsoft Excel.

[0116] Example 1. 1:1 cannabidiol-L-phenylalanine cocrystal

[0117] 1.1 Preparation of 1:1 cannabidiol-L-phenylalanine cocrystal

[0118] A batch of 1:1 cannabidiol-L-phenylalanine cocrystals for characterization was prepared as follows: Cannabidiol acid (129 mg, 0.36 mmol) and L-phenylalanine (59 mg, 0.36 mmol) were milled together with nitromethane (1 drop) in a Retsch MM400 ball mill at 30 Hz for 3 × 10 min. The product was then dried under vacuum at 40 °C for 1 hour.

[0119] 1.2 XRPD characterization of 1:1 cannabidiol-L-phenylalanine cocrystal

[0120] Experimental XRPD diagram of 1:1 cannabinol-L-phenylalanine cocrystal is shown in... Figure 3 Table 1 lists the... Figure 2 The peak angles, °2θ ± 0.2 °2θ, and d-intervals identified in the experimental XRPD plots. A complete list of peaks or subsets thereof, and information obtained by comparing with... Figure 2 Basically, similar XRPD diagrams are likely sufficient to characterize the eutectic.

[0121] Table 1

[0122]

[0123] 1.3 TGA of 1:1 cannabidiol-L-phenylalanine cocrystal

[0124] Differential scanning calorimetry (DSC) traces ( Figure 4 The figure shows a single endothermic reaction, with a maximum peak temperature of 171.1 °C.

[0125] 1.4 TGA of 1:1 cannabidiol-L-phenylalanine cocrystal

[0126] Thermogravimetric analysis (TGA) traces ( Figure 5 The results showed no significant weight loss before 175°C. Within the temperature range of 175-210°C, approximately 9% weight loss was observed, which is expected to be due to decarboxylation of CBDA after the eutectic melts.

[0127] 1.5 1:1 cannabidiol-L-phenylalanine cocrystal 1 H NMR spectroscopy

[0128] Figure 6 The 1:1 cannabidiol-L-phenylalanine cocrystal shown in the image 1 The H NMR spectrum showed the following peaks: 1 HNMR (400MHz, MeOD) δ: 0.85-0.95 (3H), 1.28-1.39 (4H), 1.50-1.60 (2H), 1.64 (3H), 1.67 (3H), 1.70-1.78 (2H), 1.95-2.05 (1H), 2.15-2.25 (1H), 2.78-2.87 (2H), 2.95-3.10 (2H), 3.76-3.84 (1H), 3.92-4.04 (1H), 4.41-4.49 (2H), 5.20 (1H), 6.14 (1H) and 7.24-7.40 (5H). 1 The peak at 3.76–3.84 ppm in the 1H NMR spectrum corresponds to one proton of L-phenylalanine. A comparison of the integrals of this peak with the peak at 6.14 ppm (corresponding to one aromatic proton of cannabidiol) indicates that the API:cocrystal forming agent stoichiometry of the cocrystal is 1:1.

[0129] 1.6 Infrared spectrum of 1:1 cannabidiol-L-phenylalanine cocrystal

[0130] The experimental infrared spectrum of the 1:1 cannabidiol-L-phenylalanine cocrystal is shown in... Figure 7 In. Figure 6 The significant peaks identified in the experimental infrared spectra were 3374, 3085, 2923, 2857, 1622, 1606, 1576, 1498, 1466, 1441, 1409, 1370, 1337, 1296, 1263, 1240, 1200, 1184, 1163, 1112, 1076, 1041, 986, 963, 904, 859, 838, 814, 767, 747, 702, 674, 619, 598, 521, 485, and 457 cm⁻¹. -1 ± 1 cm -1 A complete list of peaks or a subset thereof, and by means of... Figure 7 Basically, similar infrared spectra are likely sufficient to characterize the cocrystal. For example, a 1:1 cannabidiol-L-phenylalanine cocrystal can be characterized by at least three peaks selected from the following: 1606, 1409, 1296, 1240, and 1184 cm⁻¹. -1 ± 1 cm -1 The peak at that location.

[0131] Example 2. 1:1 Cannabidiol-Vanillin Cocrystal

[0132] 2.1 Preparation of 1:1 cannabidiol-vanillin cocrystal

[0133] A batch of 1:1 cannabidiol-vanillin cocrystals for characterization was prepared as follows: Cannabidiol (137 mg, 0.38 mmol) and vanillin (56 mg, 0.37 mmol) were weighed into glass vials, and vanillin-saturated nitromethane (1 ml) was added. The resulting slurry was stirred at 5°C for 3 hours. The product was then filtered under vacuum and dried under vacuum at 30°C for 3 hours.

[0134] 2.2 XRPD characterization of 1:1 cannabidiol vanillin cocrystal

[0135] Experimental XRPD diagram of 1:1 cannabinol-vanillin cocrystal is shown in... Figure 8 Table 2 lists the... Figure 8 The peak angles, °2θ ± 0.2 °2θ, and d-intervals identified in the experimental XRPD plots. A complete list of peaks or subsets thereof, and information obtained by comparing with... Figure 8 Basically, similar XRPD diagrams are likely sufficient to characterize the eutectic.

[0136] Table 2

[0137]

[0138]

[0139] 2.3 DSC of 1:1 cannabidiol vanillin cocrystal

[0140] Differential scanning calorimetry (DSC) traces ( Figure 9 The figure shows a single endothermic reaction, with a maximum peak temperature of 59.2°C.

[0141] 2.4 TGA of 1:1 cannabidiol vanillin cocrystal

[0142] Thermogravimetric analysis (TGA) traces ( Figure 10 The results showed that there was no significant weight loss before 120°C.

[0143] 2.5 1:1 Cannabidiol-vanillin co-crystal 1 H NMR spectroscopy

[0144] Figure 11 The 1:1 cannabidiol vanillin cocrystal shown in the image 1 The H NMR spectrum showed the following peaks: 1 H NMR(400MHz, DMSO) δ: 0.80-0.89 (3H), 1.21-1.35 (4H), 1.40-1.52 (2H), 1.59 (3H), 1.60(3H), 1.62-1.71 (2H), 1.88-1.98 (1H), 2.04-2.17 (1H), 2.63-2.85 (2H), 2.95-3.10(1H), 3.84 (3H), 3.85-3.92 (1H), 4.36-4.47 (2H), 5.08 (1H), 6.15 (1H), 6.96 (1H), 7.35-7.45 (2H), 9.77 (1H) and 10.27 (1H). 1 The peak at 3.84 ppm in the 1H NMR spectrum corresponds to the three protons of the methoxy group of vanillin. A comparison of the integrals of this peak with the peak at 6.15 ppm (corresponding to one aromatic proton of cannabidiol) indicates that the API:cocrystal forming agent stoichiometry of the cocrystal is 1:1.

[0145] 2.6 Infrared spectrum of 1:1 cannabidiol vanillin cocrystal

[0146] Experimental infrared spectra of 1:1 cannabidiol vanillin cocrystals are shown in Figure 12 In. Figure 11The significant peaks identified in the experimental infrared spectrum were 3476, 3383, 2924, 2858, 1659, 1623, 1593, 1574, 1509, 1464, 1423, 1377, 1337, 1294, 1258, 1174, 1151, 1124, 1091, 1028, 997, 882, 857, 827, 770, 756, 731, 699, 655, 634, 622, 591, 533, and 479 cm⁻¹. -1 ± 1 cm -1 A complete list of peaks or a subset thereof, and by means of... Figure 12 Basically, similar infrared spectra are likely sufficient to characterize the cocrystal. For example, a 1:1 cannabidiol vanillin cocrystal can be characterized by at least three peaks selected from the following: 1658, 1509, 1294, 1258, and 1151 cm⁻¹. -1 ± 1 cm -1 The peak at that location.

[0147] Example 3. 1:1 cannabidiol-betaine cocrystal

[0148] 3.1 Preparation of 1:1 cannabidiol-betaine cocrystal

[0149] A batch of 1:1 cannabidiol-vanillin cocrystals for characterization was prepared as follows: cannabidiol acid (125 mg, 0.35 mmol) and betaine (59 mg, 0.36 mmol) were milled together with nitromethane (1 drop) in a Lecht MM400 ball mill at 30 Hz for 3 × 10 min. The product was then dried under vacuum at 40 °C for 1 h.

[0150] 3.2 XRPD characterization of 1:1 cannabidiol-betaine eutectic

[0151] Experimental XRPD diagram of 1:1 cannabinol-betaine cocrystal is shown in... Figure 13 Table 3 lists the... Figure 13 The peak angles, °2θ ± 0.2 °2θ, and d-intervals identified in the experimental XRPD plots. A complete list of peaks or subsets thereof, and information obtained by comparing with... Figure 13 Basically, similar XRPD diagrams are likely sufficient to characterize the eutectic.

[0152] Table 3

[0153]

[0154] 3.3 DSC of 1:1 cannabidiol-betaine eutectic

[0155] Differential scanning calorimetry (DSC) traces ( Figure 14The figure shows a single endothermic reaction, with a maximum peak temperature of 139.7°C.

[0156] 3.4 TGA of 1:1 cannabidiol-betaine cocrystal

[0157] Thermogravimetric analysis (TGA) traces ( Figure 15 The results showed no significant weight loss before 150°C. In the temperature range of 150-170°C, approximately 10% weight loss was observed, which is expected to be due to decarboxylation of CBDA after the eutectic melts.

[0158] 3.5 1:1 cannabidiol-betaine eutectic 1 H NMR spectroscopy

[0159] Figure 16 The 1:1 cannabidiol-betaine co-crystal shown in the image 1 The H NMR spectrum showed the following peaks: 1 H NMR(400MHz, DMSO) δ: 0.80-0.89 (3H), 1.21-1.35 (4H), 1.40-1.52 (2H), 1.59 (3H), 1.60(3H), 1.62-1.71 (2H), 1.88-1.98 (1H), 2.04-2.17 (1H), 2.63-2.85 (2H), 2.95-3.10(1H), 3.14 (9H), 3.66 (2H), 3.85-3.92 (1H), 4.36-4.47 (2H), 5.08 (1H) and 6.12 (1H). 1 The peak at 3.66 ppm in the 1H NMR spectrum corresponds to two protons of betaine. A comparison of the integrals of this peak with the peak at 6.12 ppm (corresponding to one aromatic proton of cannabidiol) indicates that the stoichiometry of API:cocrystal forming agent in the cocrystal is 1:1.

[0160] 3.6 Infrared spectrum of 1:1 cannabidiol-betaine eutectic

[0161] The experimental infrared spectrum of the 1:1 cannabidiol-betaine cocrystal is shown in... Figure 17 In. Figure 17 The significant peaks identified in the experimental infrared spectrum were 3067, 2960, 2390, 2855, 1723, 1627, 1589, 1474, 1456, 1437, 1371, 1325, 1261, 1210, 1185, 1147, 1106, 1037, 985, 927, 887, 833, 773, 723, 697, 634, 619, 605, 581, 534, and 477 cm⁻¹. -1± 1 cm -1 A complete list of peaks or a subset thereof, and by means of... Figure 17 Basically, similar infrared spectra are likely sufficient to characterize the cocrystal. For example, a 1:1 cannabidiol betaine cocrystal can be characterized by at least three peaks selected from the following: 1723, 1589, 1371, 1261, and 887 cm⁻¹. -1 ± 1 cm -1 The peak at that location.

[0162] Example 4: 1:1 cannabidiol ethyl maltol cocrystal

[0163] 4.1 Preparation of 1:1 cannabidiol ethyl maltol cocrystal

[0164] A batch of 1:1 cannabidiol-ethyl maltol cocrystals for characterization was prepared as follows: Cannabidiol (54 mg, 0.15 mmol) and ethyl maltol (18 mg, 0.13 mmol) were weighed into glass vials, and vanillin-saturated cyclohexane (1 ml) was added. The resulting slurry was placed in a shaker and aged for 48 hours (in an 8-hour cycle, from room temperature to 40°C; heated to 40°C for 4 hours, then cooled to room temperature for another 4 hours), followed by stirring at 5°C for 3 hours. The product was then filtered under vacuum and dried under vacuum at 30°C for 3 hours.

[0165] 4.2 XRPD characterization of 1:1 cannabidiol ethyl maltol cocrystal

[0166] Experimental XRPD diagram of 1:1 cannabinol ethyl maltol cocrystal is shown in... Figure 18 Table 4 lists the data in... Figure 18 The peak angles, °2θ ± 0.2 °2θ, and d-intervals identified in the experimental XRPD plots. A complete list of peaks or subsets thereof, and information obtained by comparing with... Figure 18 Basically, similar XRPD diagrams are likely sufficient to characterize the eutectic.

[0167] Table 4

[0168]

[0169] 4.3 DSC of 1:1 cannabidiol ethyl maltol cocrystal

[0170] Differential scanning calorimetry (DSC) traces ( Figure 19 The figure shows a single endothermic reaction, with a maximum peak temperature of 65.6°C.

[0171] 4.4 TGA of 1:1 cannabidiol ethyl maltol cocrystal

[0172] Thermogravimetric analysis (TGA) traces ( Figure 20 The results showed that there was no significant weight loss before 70°C.

[0173] 4.5 1:1 cannabidiol ethyl maltol cocrystal 1 H NMR spectroscopy

[0174] Figure 21 The 1:1 cannabidiol ethyl maltol cocrystal shown in the figure 1 The H NMR spectrum showed the following peaks: 1 HNMR (400MHz, MeOD) δ: 0.87-0.94 (3H), 1.21-1.27 (3H), 1.28-1.39 (4H), 1.50-1.60(2H), 1.64 (3H), 1.67 (3H), 1.70-1.78 (2H), 1.95-2.05 (1H), 2.15-2.25 (1H), 2.71-2.79 (2H), 2.79-2.89 (2H), 2.96-3.10 (1H), 3.92-4.04 (1H), 4.41-4.49 (2H), 5.20(1H), 6.14 (1H), 6.39 (1H) and 7.96 (1H). 1 The peak at 6.39 ppm in the 1H NMR spectrum corresponds to one proton of ethyl maltol. A comparison of the integrals of this peak with the peak at 6.14 ppm (corresponding to one aromatic proton of cannabidiol) indicates that the stoichiometry of API:cocrystal forming agent in the cocrystal is 1:1.

[0175] 4.6 Infrared spectrum of 1:1 cannabidiol ethyl maltol cocrystal

[0176] The experimental infrared spectrum of the 1:1 cannabidiol ethyl maltol cocrystal is shown in... Figure 22 In. Figure 22 The significant peaks identified in the experimental infrared spectra were 3379, 3068, 3030, 2955, 2923, 2856, 2832, 1621, 1586, 1526, 1469, 1456, 1435, 1376, 1336, 1260, 1238, 1197, 1166, 1109, 1088, 1068, 1040, 986, 937, 884, 867, 831, 779, 746, 700, 683, 619, 556, 525, 484, and 456 cm⁻¹. -1 ± 1 cm -1 A complete list of peaks or a subset thereof, and by means of... Figure 22Basically, similar infrared spectra are likely sufficient to characterize the cocrystal. For example, a 1:1 cannabidiol ethyl maltol cocrystal can be characterized by at least three peaks selected from the following: 1526, 1410, 1376, 1260, and 1238 cm⁻¹. -1 ± 1 cm -1 The peak at that location.

[0177] Example 5: 1:1 cannabidiol-L-proline cocrystal

[0178] 5.1 Preparation of 1:1 cannabidiol-L-proline cocrystal

[0179] A batch of 1:1 cannabidiol-L-proline cocrystals for characterization was prepared as follows: Cannabidiol acid (100 mg, 0.28 mmol) and L-proline (32 mg, 0.28 mmol) were weighed into glass vials, and nitromethane (1 ml) was added. The resulting slurry was placed in a shaker and aged for 48 hours (in an 8-hour cycle, from room temperature to 40°C; heated to 40°C for 4 hours, then cooled to room temperature for another 4 hours). The product was then filtered under vacuum and dried overnight under ambient conditions.

[0180] 5.2 XRPD characterization of 1:1 cannabidiol-L-proline cocrystal

[0181] Experimental XRPD diagram of 1:1 cannabinol-L-proline cocrystal is shown in... Figure 23 Table 5 lists the... Figure 23 The peak angles, °2θ ± 0.2 °2θ, and d-intervals identified in the experimental XRPD plots. A complete list of peaks or subsets thereof, and information obtained by comparing with... Figure 23 Basically, similar XRPD diagrams are likely sufficient to characterize the eutectic.

[0182] Table 6

[0183]

[0184] 5.3 DSC of 1:1 cannabidiol-L-proline cocrystal

[0185] Differential scanning calorimetry (DSC) traces ( Figure 24 The figure shows a single endothermic reaction, with a maximum peak temperature of 98.9°C.

[0186] 5.4 TGA of 1:1 cannabidiol-L-proline cocrystal

[0187] Thermogravimetric analysis (TGA) traces ( Figure 25The results showed no significant weight loss before 110°C. Within the temperature range of 110-170°C, approximately 10% weight loss was observed, which is expected to be due to decarboxylation of CBDA after the eutectic melts.

[0188] 5.5 1:1 cannabidiol-L-proline cocrystal 1 H NMR spectroscopy

[0189] Figure 26 The 1:1 cannabidiol-L-proline cocrystal shown in the image 1 The H NMR spectrum showed the following peaks: 1 H NMR (400MHz, MeOD) δ: 0.88-0.93 (3H), 1.28-1.38 (4H), 1.51-1.59 (2H), 1.64 (3H), 1.66(3H) 1.70-1.78 (2H), 1.94-2.04 (3H), 2.06-2.24 (2H), 2.25-2.36 (1H), 2.78-2.88(2H), 2.96-3.11 (1H), 3.18-3.28 (1H), 3.34-3.42 (1H), 3.95-4.03 (2H), 4.40-4.50(2H), 5.20 (1H) and 6.13 (1H). 1 The peak at 3.33–3.42 ppm in the 1H NMR spectrum corresponds to one proton of L-proline. A comparison of the integrals of this peak with the peak at 6.13 ppm (corresponding to one aromatic proton of cannabidiol) indicates that the API:cocrystal forming agent stoichiometry of the cocrystal is 1:1.

[0190] 5.6 Infrared spectrum of 1:1 cannabidiol-L-proline cocrystal

[0191] Experimental infrared spectra of 1:1 cannabidiol-L-proline cocrystals are shown in Figure 27 In. Figure 27 The significant peaks identified in the experimental infrared spectrum were 3384, 2955, 2926, 2859, 1614, 1574, 1430, 1374, 1338, 1262, 1240, 1194, 1172, 1108, 1092, 1036, 885, 846, 803, 778, 733, 673, 640, 618, 539, and 471 cm⁻¹. -1 ±1 cm -1 A complete list of peaks or a subset thereof, and by means of... Figure 27Basically, similar infrared spectra are likely sufficient to characterize the cocrystal. For example, a 1:1 cannabidiol-L-proline cocrystal can be characterized by at least three peaks selected from the following: 1574, 1430, 1374, 1240, and 1172 cm⁻¹. -1 ± 1 cm -1 The peak at that location.

[0192] Example 6: 1:1 cannabidiol D-proline cocrystal

[0193] 6.1 Preparation of 1:1 cannabidiol D-proline cocrystal

[0194] A batch of 1:1 cannabidiol-D-proline cocrystals for characterization was prepared as follows: Cannabidiol acid (56 mg, 0.16 mmol) and L-proline (18 mg, 0.16 mmol) were weighed into glass vials, and nitromethane (1 ml) was added. The resulting slurry was placed in a shaker and aged for 48 hours (in an 8-hour cycle, from room temperature to 40°C; heated to 40°C for 4 hours, then cooled to room temperature for another 4 hours). The product was then filtered under vacuum and dried overnight under ambient conditions.

[0195] 6.2 XRPD characterization of 1:1 cannabidiol D-proline cocrystal

[0196] Experimental XRPD diagram of 1:1 cannabinol D-proline cocrystal is shown in... Figure 28 Table 6 lists the... Figure 28 The peak angles, °2θ ± 0.2 °2θ, and d-intervals identified in the experimental XRPD plots. A complete list of peaks or subsets thereof, and information obtained by comparing with... Figure 28 Basically, similar XRPD diagrams are likely sufficient to characterize the eutectic.

[0197] Table 6

[0198]

[0199]

[0200] 6.3 DSC of 1:1 cannabidiol D-proline cocrystal

[0201] Differential scanning calorimetry (DSC) traces ( Figure 29 The figure shows a single endothermic reaction, with a maximum peak temperature of 114°C.

[0202] 6.4 TGA of 1:1 cannabidiol D-proline cocrystal

[0203] Thermogravimetric analysis (TGA) traces ( Figure 30The results showed no significant weight loss before 115°C. Within the temperature range of 115-170°C, approximately 10% weight loss was observed, which is expected to be due to decarboxylation of CBDA after the eutectic melts.

[0204] 6.5 1:1 cannabidiol D-proline cocrystal 1 H NMR spectroscopy

[0205] Figure 31 The 1:1 cannabidiol D-proline cocrystal shown in the image 1 The H NMR spectrum showed the following peaks: 1 H NMR(400MHz, MeOD) δ: 0.88-0.93 (3H), 1.28-1.38 (4H), 1.50-1.60 (2H), 1.64 (3H), 1.66(3H), 1.70-1.80 (2H), 1.94-2.04 (3H), 2.07-2.24 (2H), 2.25-2.36 (1H), 2.78-2.88(2H), 2.95-3.12 (1H), 3.18-3.28 (1H), 3.33-3.44 (1H), 3.94-4.03 (2H), 4.40-4.50(2H), 5.20 (1H) and 6.13 (1H). 1 The peak at 3.33–3.44 ppm in the 1H NMR spectrum corresponds to one proton of D-proline. A comparison of the integrals of this peak with the peak at 6.13 ppm (corresponding to one aromatic proton of cannabidiol) indicates that the API:cocrystal forming agent stoichiometry of the cocrystal is 1:1.

[0206] 6.6 Infrared spectrum of 1:1 cannabidiol D-proline cocrystal

[0207] Experimental infrared spectra of 1:1 cannabidiol D-proline cocrystals are shown in Figure 32 In. Figure 32 The significant peaks identified in the experimental infrared spectra were 3409, 3384, 3360, 2925, 2858, 1635, 1611, 1575, 1454, 1429, 1374, 1306, 1261, 1244, 1223, 1191, 1111, 1094, 1079, 1051, 1036, 1011, 994, 964, 929, 884, 873, 846, 819, 774, 731, 675, 646, 617, 589, 556, 538, 490, 466, and 452 cm⁻¹. -1 ± 1 cm -1 A complete list of peaks or a subset thereof, and by means of... Figure 32 Basically, similar infrared spectra are likely sufficient to characterize the cocrystal. For example, a 1:1 cannabidiol D-proline cocrystal can be characterized by at least three peaks selected from the following: 1635, 1611, 1575, 1374, and 1244 cm⁻¹. -1 ± 1 cm -1 The peak at that location.

[0208] Example 7: Solid-state stability study of cannabidiol cocrystal

[0209] The physical stability of the cannabidiol cocrystals was examined for signs of solid-form transformation, decomposition, or decarboxylation, and the results were compared with those of pure cannabidiol. To assess the storage potential of the cocrystals over a reasonable timeframe, standard accelerated storage conditions of 40°C and 75% relative humidity were selected. 50 mg of each of the following cocrystals—L-phenylalanine, vanillin, betaine, ethyl maltol, L-proline, and cannabidiol—were individually placed in sealed containers at 40°C and 75% relative humidity and monitored periodically over a 4-week period. The results of the study are shown in Table 7. All samples that did not decompose and remained solid were subsequently analyzed by XRPD to observe for any potential form changes. At the start of the study, all cocrystal samples were white solids, while pure cannabidiol was a grayish-white solid.

[0210] Table 7

[0211]

[0212] Within the first hour of the study, pure CBDA deliquesced and produced a liquid, which turned dark brown within another hour, indicating rapid decomposition under these storage conditions. The 1:1 cannabidiol ethyl maltol cocrystal and the 1:1 cannabidiol vanillin cocrystal also transformed into dark brown liquids within 2 and 3 weeks, respectively, indicating that while these cocrystals were more stable than pure cannabidiol under these storage conditions, they also began to decompose rapidly. After four weeks, XRPD analysis showed that the 1:1 cannabidiol L-proline cocrystal, while still possessing the same crystalline structure, had begun to change color, becoming a brownish-red solid. However, the 1:1 cannabidiol L-phenylalanine cocrystal and the 1:1 cannabidiol betaine cocrystal remained unchanged, still white solids, and XRPD analysis confirmed no solid-form transformation or dissociation occurred, indicating that these cocrystals were stable under these storage conditions. The results of this study indicate that, compared with pure CBDA, the 1:1 cannabidiol-L-phenylalanine cocrystal and the 1:1 cannabidiol-betaine cocrystal exhibit significantly superior storage properties and do not dissociate, decompose, or decarboxylate under accelerated conditions. The study also shows that, compared with other cocrystals of this invention, the 1:1 cannabidiol-L-phenylalanine cocrystal and the 1:1 cannabidiol-betaine cocrystal possess excellent storage properties.

Claims

1. A composition comprising: cannabidiol cocrystal.

2. The composition according to claim 1, wherein the cannabidiol cocrystal is selected from the group comprising: cannabidiol L-phenylalanine cocrystal, cannabidiol vanillin cocrystal, cannabidiol betaine cocrystal, cannabidiol ethyl maltol cocrystal, cannabidiol L-proline cocrystal, and cannabidiol D-proline cocrystal.

3. The composition according to claim 1, wherein the cannabidiol cocrystal is selected from the group comprising: 1:1 cannabidiol L-phenylalanine cocrystal, 1:1 cannabidiol vanillin cocrystal, 1:1 cannabidiol betaine cocrystal, 1:1 cannabidiol ethyl maltol cocrystal, 1:1 cannabidiol L-proline cocrystal and 1:1 cannabidiol D-proline cocrystal.

4. The composition according to claim 2, wherein the cannabidiol-L-phenylalanine cocrystal is characterized in that: Powder X-ray diffraction pattern having at least three peaks selected from the following: 3.1, 6.4, 18.4, 19.8, and 23.7 °2θ ± 0.2 °2θ; or A powder X-ray diffraction pattern that is substantially similar to Figure 3; or Infrared spectra with at least three peaks selected from the following: 1606, 1409, 1296, 1240, and 1184 cm⁻¹ -1 ± 1 cm -1 ;or The infrared spectrum is essentially similar to that in Figure 7.

5. The composition according to claim 2, wherein the cannabidiol vanillin cocrystal is characterized by: Powder X-ray diffraction patterns having at least three peaks selected from the following: 4.3, 7.5, 14.2, 19.4, 22.2, and 25.2 °2θ ± 0.2 °2θ; or A powder X-ray diffraction pattern that is substantially similar to Figure 8; or Infrared spectra with at least three peaks selected from the following: 1658, 1509, 1294, 1258, and 1151 cm⁻¹ -1 ± 1 cm -1 ;or The infrared spectrum is essentially similar to that in Figure 12.

6. The composition according to claim 2, wherein the cannabidiol-betaine eutectic is characterized in that: Powder X-ray diffraction pattern having at least three peaks selected from the following: 7.2, 11.0, 16.3, 18.4 and 23.6 °2θ ±0.2 °2θ; or A powder X-ray diffraction pattern that is substantially similar to Figure 13; or Infrared spectra with at least three peaks selected from the following: 1723, 1589, 1371, 1261, and 887 cm⁻¹. -1 ± 1 cm -1 ;or The infrared spectrum is essentially similar to that in Figure 17.

7. The composition according to claim 2, wherein the cannabidiol ethyl maltol cocrystal is characterized in that: Powder X-ray diffraction pattern having at least three peaks selected from the following: 8.4, 16.0, 17.1, 18.0 and 19.7 °2θ ±0.2 °2θ; or A powder X-ray diffraction pattern that is substantially similar to Figure 18; or Infrared spectra with at least three peaks selected from the following: 1526, 1410, 1376, 1260, and 1238 cm⁻¹ -1 ± 1 cm -1 ;or The infrared spectrum is basically similar to that in Figure 22.

8. The composition according to claim 2, wherein the cannabidiol-L-proline cocrystal is characterized in that: Powder X-ray diffraction pattern having at least three peaks selected from the following: 7.4, 8.5, 15.2, 19.0 and 23.0 °2θ ±0.2 °2θ; or A powder X-ray diffraction pattern that is substantially similar to Figure 23; or Infrared spectra with at least three peaks selected from the following: 1574, 1430, 1374, 1240, and 1172 cm⁻¹ -1 ± 1 cm -1 ;or The infrared spectrum is essentially similar to that in Figure 27.

9. The composition according to claim 2, wherein the cannabidiol D-proline cocrystal is characterized in that: Powder X-ray diffraction pattern having at least three peaks selected from the following: 4.8, 5.1, 9.1, 18.2, and 19.1 °2θ ±0.2 °2θ; or A powder X-ray diffraction pattern that is substantially similar to Figure 28; or Infrared spectra with at least three peaks selected from the following: 1635, 1611, 1575, 1374, and 1244 cm⁻¹ -1 ± 1 cm -1 ;or The infrared spectrum is essentially similar to that in Figure 32.

10. A composition comprising: cannabidiol cocrystal and excipient.

11. The composition according to claim 10, wherein the cannabidiol cocrystal is selected from the group comprising: cannabidiol L-phenylalanine cocrystal, cannabidiol vanillin cocrystal, cannabidiol betaine cocrystal, cannabidiol ethyl maltol cocrystal, cannabidiol L-proline cocrystal and cannabidiol D-proline cocrystal.

12. The composition according to claim 10, wherein the cannabidiol cocrystal is selected from the group comprising: 1:1 cannabidiol L-phenylalanine cocrystal, 1:1 cannabidiol vanillin cocrystal, 1:1 cannabidiol betaine cocrystal, 1:1 cannabidiol ethyl maltol cocrystal, 1:1 cannabidiol L-proline cocrystal and 1:1 cannabidiol D-proline cocrystal.

13. A pharmaceutical composition comprising: cannabidiol cocrystal and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to claim 13, wherein the cannabidiol cocrystal is selected from the group comprising: cannabidiol L-phenylalanine cocrystal, cannabidiol vanillin cocrystal, cannabidiol betaine cocrystal, cannabidiol ethyl maltol cocrystal, cannabidiol L-proline cocrystal and cannabidiol D-proline cocrystal.

15. The pharmaceutical composition according to claim 13, wherein the cannabidiol cocrystal is selected from the group comprising: 1:1 cannabidiol L-phenylalanine cocrystal, 1:1 cannabidiol vanillin cocrystal, 1:1 cannabidiol betaine cocrystal, 1:1 cannabidiol ethyl maltol cocrystal, 1:1 cannabidiol L-proline cocrystal and 1:1 cannabidiol D-proline cocrystal.

16. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition comprises a therapeutically effective amount of cannabidiol cocrystal.

17. The pharmaceutical composition of claim 16, wherein the therapeutically effective amount of the cannabidiol cocrystal is about 0.01 mg / kg, about 0.02 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 50 mg / kg, about 100 mg / kg, about 200 mg / kg, about 500 mg / kg, about 50 mg, about 100 mg, about 250 mg, about 500 mg, about 750 mg, about 1,000 mg, about 1,500 mg, about 2,000 mg, about 50 mg to about 1,500 mg, about 100 mg to about 1,000 mg, or about 250 mg to about 750 mg.

18. A method of treating a patient’s disease, condition, or symptom, the method comprising: administering to the patient a therapeutically effective amount of cannabidiol cocrystal or a pharmaceutical composition comprising a therapeutically effective amount of cannabidiol cocrystal and a pharmaceutically acceptable carrier.

19. The method of claim 18, wherein the cannabidiol cocrystal is selected from the group consisting of: cannabidiol L-phenylalanine cocrystal, cannabidiol vanillin cocrystal, cannabidiol betaine cocrystal, cannabidiol ethyl maltol cocrystal, cannabidiol L-proline cocrystal, and cannabidiol D-proline cocrystal.

20. The method of claim 18, wherein the cannabidiol cocrystal is selected from the group consisting of: 1:1 cannabidiol L-phenylalanine cocrystal, 1:1 cannabidiol vanillin cocrystal, 1:1 cannabidiol betaine cocrystal, 1:1 cannabidiol ethyl maltol cocrystal, 1:1 cannabidiol L-proline cocrystal and 1:1 cannabidiol D-proline cocrystal.

21. The method of claim 18, wherein the patient is an animal.

22. The method of claim 18, wherein the patient is a person.

23. The method of claim 18, wherein the therapeutically effective amount of the cannabidiol cocrystal is about 0.01 mg / kg, about 0.02 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 50 mg / kg, about 100 mg / kg, about 200 mg / kg, about 500 mg / kg, about 50 mg, about 100 mg, about 250 mg, about 500 mg, about 750 mg, about 1,000 mg, about 1,500 mg, about 2,000 mg, about 50 mg to about 1,500 mg, about 100 mg to about 1,000 mg, or about 250 mg to about 750 mg.

24. The method of claim 18, wherein the cannabidiol cocrystal is administered to the patient in the form of a solid, semi-solid, lyophilized powder, or liquid dosage form.

25. A method for preparing a liquid pharmaceutical composition, the method comprising the step of dissolving cannabidiol cocrystals in a pharmaceutically acceptable solvent.

26. The method of claim 25, wherein the cannabidiol cocrystal is selected from the group comprising: cannabidiol L-phenylalanine cocrystal, cannabidiol vanillin cocrystal, cannabidiol betaine cocrystal, cannabidiol ethyl maltol cocrystal, cannabidiol L-proline cocrystal, and cannabidiol D-proline cocrystal.

27. The method of claim 25, wherein the cannabidiol cocrystal is selected from the group comprising: 1:1 cannabidiol L-phenylalanine cocrystal, 1:1 cannabidiol vanillin cocrystal, 1:1 cannabidiol betaine cocrystal, 1:1 cannabidiol ethyl maltol cocrystal, 1:1 cannabidiol L-proline cocrystal and 1:1 cannabidiol D-proline cocrystal.

Images