Novel cocrystals of methylxanthines, their polymorphs and methods thereof

Abstract

The present invention relates to co-crystals of methylxanthines with stilbenoids as co-formers, their polymorphic forms, and methods for their preparation. De-bittering of methylxanthines is carried out by co-crystallization using stilbenoids as co-formers. The present invention further relates to the preparation of polymorphic forms of de-bittering co-crystals and their use in dietary supplements and pharmaceutical compositions.

Description

[Technical Field]

[0001] The present invention relates to co-crystals of methylxanthines with stilbenoids as co-formers, their polymorphic forms, and methods for their preparation. De-bittering of methylxanthines is carried out by co-crystallization using stilbenoids as co-formers. The present invention further relates to the preparation of polymorphic forms of de-bittering co-crystals and their use in dietary supplements and pharmaceutical compositions. [Background technology]

[0002] Caffeine, theacrine, theobromine, methylliberine, theophylline, and methylxanthines, such as paraxanthine, are purine alkaloids that are said to have similar neuroenergetic effects. They have been identified in the seeds and leaves of various Coffea species. Initially, caffeine accumulates in the young leaves of the coffee plant, but it is gradually replaced by theacrine, theobromine, and methylliberine in the mature leaves.

[0003] Pterostilbene, chemically known as trans-3,5-dimethoxy-4'-hydroxystilbene, is a naturally occurring stilbene found naturally in the bark of many trees and various berries, including grapes, as well as in plants commonly used in traditional folk medicine. It is structurally related to resveratrol. It has been characterized as a dietary supplement with potential antioxidant, anticancer, anti-inflammatory, proapoptotic, antineoplastic, and cytoprotective properties, and has been reported to reduce plasma glucose levels and lower the LDL / HDL cholesterol ratio. Upon administration, pterostilbene has been reported to exert its antioxidant activity by scavenging reactive oxygen species (ROS), thereby preventing oxidative stress and ROS-induced cellular damage.

[0004] The use of pterostilbene to ameliorate oxidative stress and improve working memory and compositions containing pterostilbene are described in US2009 / 0069444. Due to the perceived health benefits of pterostilbene, consumption of foods containing this compound, such as berries and grapes, has increased.

[0005] WO2011097372A3 discloses cocrystals of pterostilbene, including pterostilbene:caffeine cocrystal, pterostilbene:carbamazepine cocrystal, pterostilbene:glutaric acid cocrystal, and pterostilbene:piperazine cocrystal.

[0006] US9468645B2 discloses a stable aqueous composition of at least one biologically active form of a purine alkaloid compound structurally related to caffeine for oral administration, the composition comprising: a) 1,3,7,9-tetramethyluric acid (theacrine), (O(2),2-methoxy-1,9-dimethyl-7H-purine-6,8-dione (liberine), and (O(2),1,7,9-trimethyluric acid (methylliberine), collectively referred to as theacrine species, in which the basic uric acid structure is partially or fully methylated at positions 2, 3, or 4; and b) at least one aqueous buffer solution having a pH range of about 1.5 to 9.0.

[0007] EP3068240A1 discloses a dietary supplement comprising theacrine and optionally other active ingredients that modulate the effect of theacrine.

[0008] US20210100266 discloses an energy supplement composition containing caffeine and methylliberin.

[0009] Methylxanthines are known to have very good health benefits, but their use is limited by their bitter taste, and therefore it is necessary to mask the bitter taste or to improve the palatability of these dietary supplements by debittering them.Unacceptable palatability is a major problem in the development of dietary supplement formulations, because it often hinders patient adherence.Therefore, masking the bitter taste of methylxanthines is a major goal in the development of dietary supplement formulations and is widely recognized as a key aspect in modern drug development.

[0010] Co-crystallization of two or more pure nutraceutical compounds by crystal engineering to create new functional materials with improved taste and bioavailability is of great commercial interest to both the pharmaceutical and food industries. Thus, there remains a need in the art to provide compositions containing methylxanthines that have good taste, are not bitter, and have improved bioavailability. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] US2009 / 0069444 [Patent Document 2] WO2011097372A3 [Patent Document 3] US9468645B2 [Patent Document 4] EP3068240A1 [Patent Document 5] US20210100266 Summary of the Invention [Problem to be solved by the invention]

[0012] It is therefore an object of the present invention to provide co-crystals of methylxanthines with stilbenoids that have a pleasant taste and are not bitter.

[0013] Another object of the present invention is to provide co-crystals of methylxanthines using stilbenoids, more specifically pterostilbene and resveratrol, as crystal formers to mask the taste of methylxanthines.

[0014] It is a further object of the present invention to provide a method for the preparation of co-crystals of methylxanthines using stilbenoids, more specifically pterostilbene and resveratrol, as crystal formers, and compositions containing same.

[0015] It is a further object of the present invention to provide a process for the preparation of polymorphic forms of co-crystals of methylxanthines with pterostilbene and resveratrol. [Means for solving the problem]

[0016] In accordance with the above objectives, the present invention provides co-crystals of methylxanthines with stilbenoids as co-formers, and polymorphic forms thereof, which co-crystals exhibit a pleasant taste and lack the bitter taste of methylxanthines.

[0017] The methylxanthine is selected from theacrine, theobromine, methylliberine, caffeine, paraxanthine and theophylline.

[0018] The stilbenoids are selected from hydroxy derivatives of styrene, preferably pterostilbene and resveratrol.

[0019] In a preferred embodiment, the present invention provides (a) Theacrine: Pterostilbene (b) Theobromine: Pterostilbene (c) Methylliberine: Pterostilbene (d) Paraxanthine: Pterostilbene (e) Caffeine: Pterostilbene and (f) Theophylline: Resveratrol The present invention provides a debittering cocrystal of a methylxanthine with a stilbenoid, which comprises:

[0020] In another embodiment, the methylxanthine and coformer present in the co-crystal are in a molar ratio of 1:4 to 4:1, preferably 1:1.

[0021] In yet another aspect, the present invention provides novel co-crystals of theacrine and pterostilbene, having co-crystalline polymorphic forms Form 1, Form II, Form III, Form IV, and Form V, and methods for their preparation.

[0022] Therefore, the present invention provides approximately 12.78 (100%), 14.18 (90.2%), 14.69 (17.9%), 15.55 (19.0%), 17.45 (11.8%), 19.04 (9.1%), 22.28 (12.0%), 23.46 (14.4%), 27.90 (5.0%), 28.80 (5.6%), 29.50 (7.3%), 31.50 (7.6%), 33.04 (10.1%), 38.90 (14.2%), 41.02 (6.1%), 41.93 (4.7%), 53.16 (4.5%), 72.73 (8.4%) ±0.2°. Crystalline theacrine:pterostilbene co-crystalline polymorph Form I is provided, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at 2θ.

[0023] According to another aspect, the present invention provides a method for the treatment of rhodopsin-related ... 2. The present invention provides crystalline theacrine:pterostilbene cocrystal polymorph Form II, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at 9.12 (2.7%), 29.87 (3.6%), 31.76 (5.8%), 32.10 (6.2%), 33.33 (6.1%), 35.73 (1%), 37.02 (1.5%), 39.20 (9.0%), 40.66 (1.0%), 45.00 (1.4%), 46.38 (1.8%), 47.41 (1.2%), 48.05 (1.7%), 54.61 (2.8%), 55.46 (2.4%), and 72.69 (2.5%) ±0.2° 2θ.

[0024] In another aspect, the present invention provides a method for producing a hologram of about 12.90 (64.2%), 14.32 (100%), 15.64 (13.3%), 17.45 (8.2%), 19.17 (6.6%), 21.69 (10.5%), 22.38 (7.9%), 23.58 (10.0%), 25.07 (7.0%), 26.19 (6.1%), 26.98 (9.6%), 28.86 (1.9%), 29.59 (2.8%), 31.58 (2.7%), 33.12 (3.7%), 38.98 (7%), 41.10 (1.4%), 43.62 (1.1%), 47.80 (1.0%), and 72.70 (2.7%) ±0.2°. Provided is crystalline theacrine:pterostilbene co-crystalline polymorph Form III, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at 2θ.

[0025] In yet another embodiment, the present invention provides a method for the production of a medicament containing ... 47.30 (1.1%), 47.95 (1.9%), 49.04 (1.0%), 53.36 (1.5%), 72.68 (3.3%), and 88.31 (1.0%).

[0026] In another aspect, the present invention provides crystalline theacrine:pterostilbene cocrystal polymorph Form V, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at about 12.83 (17.0%), 14.33 (100%), 15.72 (18.8%), 19.15 (3.5%), 20.06 (3.5%), 22.10 (8.8%), 23.55 (6.5%), 27.17 (5.8%), 31.73 (4.8%), 33.71 (2.0%), 37.88 (1.4%), 39.19 (6.2%), 41.07 (1.4%), 41.54 (2.2%), 43.86 (1.0%) ± 0.2 degrees 2θ.

[0027] In yet another embodiment, the present invention provides a method for the production of 11.75 (30.21%), 13.38 (63.19%), 15.37 (7.89%), 17.31 (10.2%), 19.35 (95.4%), 23.46 (44.3%), 26.98 (100%), 29.35 (14.1%), 31.65 (6.5%), 34.30 (2%), 40.25 (10.2%), 42.25 (10.2%), 46.25 (10.2%), 48.25 (10.2%), 49.35 (14.1%), 51.25 (10.2%), 52.25 (10.2%), 53.25 (10.2%), 54.25 (10.2%), 55.25 (10.2%), 56.25 (10.2%), 57.25 (10.2%), 58.25 (10.2%), 59.25 (10.2%), 60.25 (6.2%), 61.25 (6.2%), 62.25 (6.2%), 63.25 (6.2%), 64.25 (6.2%), 65.25 (6.2%), 66.25 (6.2%), 67.25 (6.2%), 68.25 (6.2%), 69.25 (6.2%), 70.25 (7.2%), 71.25 (7.2%), 72.25 (7.2%), 73.25 (7.2%), 74.25 (7.2%), 75.25 ( 0.2° 2θ,35.93(6.2%), 39.15(5.4%), 40.67(3.6%), 42.08(3.2%), 44.61(2.9%), 48.89(2.4%), 50.06(2.9%), 52.53(2.4%), 55.83(2.2%), 72.73(6.96%), 88.42(2.4%)±0.2° 2θ.

[0028] In yet another aspect, the present invention provides methylliberin and pterostilbene co-crystalline polymorphic forms Form 1, Form II, Form III, and Form IV, and methods for their preparation.

[0029] In another embodiment, the present invention provides a method for producing a medicament containing a compound having a methyl group ... Provided is a crystalline methylliberine:pterostilbene co-crystal polymorph Form I, characterized by an X-ray powder diffraction pattern with one or more peaks at 2θ.

[0030] In another embodiment, the present invention provides a method for the production of 12.43 (68.3%), 13.49 (100%), 15.65 (11.9%), 16.60 (11%), 18.12 (4.6%), 20.13 (15.3%), 21.30 (7.2%), 22.16 (6.2%), 23.34 (1.5%), 24.08 (4.4%), 25.69 ( 17.62 (1.7%), 26.91 (16.8%), 27.31 (22.4%), 29.91 (1.3%), 30.82 (1.2%), 31.29 (1.6%), 34.51 (1.3%), 36.24 (1.4%), 37.94 (3.7%), 42.82 (1.0%), 44.67 (1.1%), 72.70 (2.5%) ± 0.2° 2θ.

[0031] In one aspect, the present invention provides crystalline methylliberine:pterostilbene cocrystal polymorph Form III, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at about 13.20 (100%), 15.35 (16.1%), 16.50 (11.8%), 17.90 (3.2%), 19.88 (13.3%), 20.83 (3.9%), 22.06 (5.0%), 23.05 (1.3%), 23.88 (4.1%), 25.60 (14.9%), 36.03 (1.1%), 42.05 (1.2%), and 72.67 (7.7%) ± 0.2 degrees 2θ.

[0032] In another embodiment, the present invention provides a method for producing a medicament containing ... 2. The present invention provides crystalline methylliberine:pterostilbene cocrystal polymorph Form IV, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at 0.24 (10.5%), 25.84 (100%), 27.48 (81.2%), 33.31 (2.7%), 34.78 (5.1%), 35.01 (4.9%), 36.44 (3.5%), 38.10 (8.2%), 40.78 (1.5%), 43.12 (4.9%), 46.52 (2.7%), 47.75 (1.7%), 49.85 (1.4%) ±0.2° 2θ.

[0033] In yet another aspect, the present invention provides novel polymorphic forms of caffeine and pterostilbene cocrystal Form 1, Form II, Form III, and Form IV, and methods for their preparation.

[0034] Thus, the present invention provides approximately 11.90 (28.6%), 15.03 (100%), 16.81 (51.2%), 19.06 (53.5%), 21.65 (44.4%), 25.81 (94.2%), 26.35 (91.04%), 28.16 (10.4%), 29.54 (6.7%), 31.32 (4.8%), 32.52 (10.3%), 35.74 (3.6%), 36.99 (3.8%), 39.36 (3.7%), 40.93 (7.3%), 43.66 (5.7%), 45.45 (3.6%), 49.83 (2.1%), 72.74 (8.5%) and 88.35 (3.3%) ±0.2°. Provided is crystalline caffeine:pterostilbene co-crystalline polymorph Form I, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at 2θ.

[0035] In another aspect, the present invention provides crystalline caffeine:pterostilbene cocrystal polymorph Form II, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at about 12.83 (2.19%), 17.04 (5.43%), 19.41 (5.24%), 22.25 (6.28%), 26.31 (100%), 28.67 (3.8%), 30.04 (1.6%), 32.96 (2.3%), 41.34 (1.1%), and 53.94 (1.7%) ± 0.2 degrees 2θ.

[0036] In another aspect, the present invention provides crystalline caffeine:pterostilbene cocrystal polymorph Form III, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at about 10.53 (18.3%), 12.18 (4.9%), 14.01 (23.04%), 15.56 (25.3%), 17.22 (21.0%), 19.35 (16.7%), 22.13 (13.7%), 24.02 (4.3%), 26.51 (100%), 28.57 (20.4%), 30.22 (4.0%), 31.82 (4.1%), 36.23 (1.1%), 43.3 (1.8%), 46.52 (1.1%), 53.52 (1.1%), and 72.72 (2.2%) ± 0.2 degrees 2θ.

[0037] In another embodiment, the present invention provides a method for producing a medicament containing a compound having a medicament containing ... , 26.7 (94.8%), 28.51 (17.7%), 30.00 (13.0%), 32.48 (10.0%), 36.36 (10.3%), 38.15 (12.0%), 40.00 (8.1%), 41.28 (10.4%), 43.26 (7.5%), 46.34 (14.8%), 50.19 (8.5%), 53.95 (9.2%), 56.00 (5.7%) ± 0.2° 2θ.

[0038] In yet another aspect, the present invention provides novel co-crystals of paraxanthine with pterostilbene and methods for their preparation.

[0039] Accordingly, the present invention provides a crystalline paraxanthine:pterostilbene cocrystal characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at about 11.31 (12.8%), 15.88 (71.8%), 19.86 (18.7%), 21.28 (26.0%), 22.52 (33.6%), 24.9 (83.2%), 26.96 (100%), 29.00 (12.3%), 29.21 (19.3%), 30.41 (14.3%), 32.45 (9.9%), 38.8 (6.5%), 40.68 (5.2%), 44.84 (4.9%), 50.55 (3.6%), 55.48 (4.4%) ±0.2 degrees 2θ.

[0040] In yet another aspect, the present invention provides novel theophylline:resveratrol co-crystals and methods for their preparation.

[0041] Therefore, approximately: 10.30 (9.4%), 12.40 (30.7%), 13.81 (100%), 15.21 (9.4%), 16.27 (14.1%), 17.21 (4.5%), 19.22 (21.1%), 20.76 (13.0%), 22.30 (8.4%), 23.52 (8.4%), 24.84 (47.9%), 25.36 (33.6%), 26.64 (7.4%) , 28.26 (8.6%), 30.68 (8.9%), 32.88 (3.3%), 34.96 (1.1%), 36.46 (1.5%), 37.61 (1.1%), 38.45 (2.0%), 39.84 (1.4%), 42.16 (2.3%), 45.91 (1.3%), 52.26 (1.3%), 72.73 (4.1%), and 88.35 (1.2%) ± 0.2° 2θ.

[0042] In one aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (a) dissolving the coformer in a solvent at 35-55°C to obtain a clear solution, followed by adding a methylxanthine; (b) stirring the mixture at a temperature of 40-60°C to obtain a clear solution; (c) gradually cooling the solution to room temperature and maintaining said temperature for a period of 10 to 20 hours to allow co-crystallization; and (d) allowing the co-crystals thus formed to separate by settling, followed by filtration, washing and drying. and (c) providing a method for preparing said debittered co-crystals of methylxanthines and their polymorphic forms, comprising:

[0043] The solvent for the process is selected from water, C1-C5 alcohols, lower organic acids such as formic acid, acetic acid, propanoic acid, butyric acid, ethers, esters, ketones, alone or in mixtures thereof.

[0044] In an alternative embodiment, a method for preparing debittered co-crystals comprises mechanically grinding a mixture of methylxanthines and stilbenoids in a molar ratio of 1:4 to 4:1, preferably 1:1, to obtain the desired co-crystals.

[0045] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (a) dissolving the coformer in a solvent at 35-55°C to obtain a clear solution, followed by adding a methylxanthine; (b) stirring the mixture at a temperature of 40-60°C to obtain a clear solution; (c) gradually cooling the solution to room temperature and maintaining said temperature for a period of 10 to 20 hours to allow co-crystallization; and (d) allowing the co-crystals thus formed to separate by settling, followed by filtration, washing and drying. The present invention provides a method for masking the bitter taste of methylxanthines, comprising:

[0046] In yet another embodiment, a method for masking the bitterness of a methylxanthine selected from theacrine, theobromine, methylliberine, caffeine, paraxanthine, or theophylline comprises mechanically grinding a mixture of the methylxanthine and pterostilbene or resveratrol in a molar ratio of 1:4 to 4:1, preferably 1:1, to obtain the desired debittered co-crystal.

[0047] In one embodiment, the mechanical milling is carried out in the presence or absence of a solvent. In yet another embodiment, the coformer slurrying is carried out in an alcoholic solvent or a mixture of an alcoholic solvent and water, or in an organic acid.

[0048] In yet another aspect, the present invention provides a dietary supplement / pharmaceutical composition comprising co-crystals of theacrine, theobromine, methylliberine, caffeine, paraxanthine and theophylline and polymorphic forms thereof in association with one or more suitable carriers, wherein the co-former selected from pterostilbene or resveratrol masks the bitter taste of the methylxanthines by blocking the sensory receptors responsible for taste. [Brief explanation of the drawings]

[0049] [Figure 1A] FIG. 1 shows dissolution data for different theacrine-pterostilbene cocrystal systems plotted according to a zero-order equation. [Figure 1B] FIG. 1 shows dissolution data for different theacrine-pterostilbene cocrystal systems plotted according to a linear equation. [Figure 1C] FIG. 1 shows dissolution data for different theacrine-pterostilbene cocrystal systems plotted according to the Higuchi square root equation. [Figure 2A] FIG. 1 shows dissolution data of different methylliberin-pterostilbene cocrystal systems plotted according to a zero-order equation. [Figure 2B] FIG. 1 shows dissolution data of different methylliberin-pterostilbene cocrystal systems plotted according to a linear equation. [Figure 2C] FIG. 1 shows dissolution data of different methylliberin-pterostilbene cocrystal systems plotted according to the Higuchi square root equation. [Figure 3A] FIG. 1 shows dissolution data for different caffeine-pterostilbene cocrystal systems plotted according to a zero-order equation. [Figure 3B] FIG. 1 shows dissolution data for different caffeine-pterostilbene cocrystal systems plotted according to a linear equation. [Figure 3C] FIG. 1 shows dissolution data for different caffeine-pterostilbene cocrystal systems plotted according to the Higuchi square root equation. [Figure 4A]FIG. 1 shows dissolution data for different theophylline-resveratrol cocrystal systems plotted according to a zero-order equation. [Figure 4B] FIG. 1 shows dissolution data for different theophylline-resveratrol cocrystal systems plotted according to a linear equation. [Figure 4C] FIG. 1 shows dissolution data for different theophylline-resveratrol cocrystal systems plotted according to the Higuchi square root equation. [Figure 5] FIG. 1 shows dissolution data for the theobromine-pterostilbene cocrystal system plotted according to a zero-order equation. [Figure 6] FIG. 1 shows the % availability of the active ingredient as a function of time for various co-crystal systems. DETAILED DESCRIPTION OF THE INVENTION

[0050] The foregoing descriptions of specific embodiments of the present invention have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teachings.

[0051] Pterostilbene, resveratrol, theacrine, theobromine, methylliberine, paraxanthine, caffeine and theophylline used in the present invention are commercially available synthetic compounds.

[0052] The terms coformer, cocrystal, nutraceutical, and pharmaceutical as used in this application have the same meaning as used in the scientific literature.

[0053] Taste evaluation is an increasingly important aspect of the development of any oral dosage form. Bitter taste is the most problematic due to its intuitive association with toxicity. There are various taste-masking techniques that can be used to inhibit bitter taste, such as polymer coating, co-crystal formation or complexation with cyclodextrins, etc.

[0054] The present inventors have surprisingly found that when methylxanthines, such as theacrine, theobromine, methylliberine, caffeine and paraxanthine, are prepared as co-crystals with pterostilbene, or when theophylline is prepared as a co-crystal with resveratrol, the bitter taste of theacrine, theobromine, methylliberine, paraxanthine, caffeine and theophylline is completely reduced or eliminated.

[0055] In certain embodiments, the present invention relates to co-crystals of methylxanthines with stilbenoids as co-formers, which co-crystals exhibit a pleasant taste and lack the bitter taste of the methylxanthines.

[0056] The methylxanthine is selected from theacrine, theobromine, methylliberine, paraxanthine, caffeine, and theophylline.

[0057] In certain embodiments, the present invention relates to co-crystals derived from methylxanthines selected from theacrine, theobromine, methylliberine, paraxanthine, caffeine, and theophylline, alone or in mixtures thereof, with a co-former selected from stilbenoids, and polymorphs thereof, which co-crystals exhibit a pleasant taste and lack the bitter taste of the methylxanthines.

[0058] The stilbenoids are selected from hydroxy derivatives of styrene, preferably pterostilbene and resveratrol.

[0059] In one embodiment, the present invention provides: (a) Theacrine: Pterostilbene (b) Theobromine: Pterostilbene (c) Methylliberine: Pterostilbene (d) Paraxanthine: Pterostilbene (e) caffeine: pterostilbene, and (f) Theophylline: Resveratrol and polymorphic forms thereof, which exhibit a pleasant taste and lack the bitter taste of methylxanthines.

[0060] The methylxanthine and coformer present in the co-crystal are in a molar ratio of 1:4 to 4:1, especially a 1:1 ratio.

[0061] In one embodiment, the co-crystal of theacrine:pterostilbene (1:1) is 1 Characterized by HNMR (400 MHz, dmso-d6): δ 3.19 (3H, s), 3.39 (3H, s), 3.52 (3H, s), 3.63 (3H, s), 3.76 (6H, s), 6.36 (1H, s), 6.70 (2H, s), 6.76 (2H, d, J = 8.4Hz), 6.93 (1H, d, J = 16.4Hz), 7.15 (1H, d, J = 16.4Hz), 7.41 (2H, d, J = 8.4Hz), 9.59 (1H, s).

[0062] In another embodiment, the co-crystal of theobromine:pterostilbene (1:1) is 1 Characterized by HNMR (400 MHz, dmso-d6): δ 3.33 (3H, s), 3.76 (6H, s), 3.84 (3H, s), 6.36 (1H, t, J = 2.4Hz), 6.71 (2H, t, J = 2.4Hz), 6.77 (2H, d, J = 8.8Hz), 6.94 (1H, d, J = 16.4Hz), 7.15 (1H, d, J = 16.4Hz), 7.41 (2H, d, J = 8.8Hz), 7.97 (1H, s), 9.60 (1H, s), 11.12 (1H, s).

[0063] The cocrystal of methylliberine:pterostilbene (1:1) 1Characterized by HNMR (400 MHz, dmso-d6): δ 3.21 (3H, s), 3.31 (3H, s), 3.40 (3H, s), 3.76 (6H, s), 4.01 (3H, s), 6.36 (1H, t, J = 2 Hz), 6.71 (2H, d, J = 1.6 Hz), 6.76 (2H, d, J = 8.8 Hz), 6.93 (1H, d, J = 16.8 Hz), 7.15 (1H, d, J = 16.8 Hz), 7.41 (2H, d, J = 8.8 Hz), 9.59 (1H, s).

[0064] The caffeine:pterostilbene (1:1) cocrystal is 1 Characterized by HNMR (400 MHz, DMSO-d): δ 3.20 (3H, s), 3.40 (3H, s), 3.76 (6H, s), 3.86 (3H, s), 6.36 (1H, t, J = 2.0 Hz), 6.71 (2H, d, J = 2.0 Hz), 6.76 (2H, d, J = 8.8 Hz), 6.93 (1H, d, J = 16.4 Hz), 7.15 (1H, d, J = 16.4 Hz), 7.41 (2H, d, J = 8.4 Hz), 7.99 (1H, s), 9.59 (1H, s).

[0065] The paraxanthine:pterostilbene (1:1) cocrystal is 1 Characterized by HNMR (400 MHz, DMSO-d6): δ 3.17 (3H, s), 3.76 (6H, s), 3.85 (3H, s), 6.36 (1H, s), 6.71 (2H, s), 6.76 (2H, d, J = 8.4 Hz), 6.94 (1H, d, J = 16.8 Hz), 7.15 (1H, d, J = 16.4 Hz), 7.41 (2H, d, J = 8.0 Hz), 7.92 (1H, s), 9.59 (1H, s), 11.84 (1H, s).

[0066] Theophylline:resveratrol (1:1) cocrystal is 1 Characterized by HNMR (400 MHz, dmso-d): δ 3.24 (3H, s), 3.44 (3H, s), 6.12 (1H, t, J = 2 Hz), 6.39 (2H, d, J = 2 Hz), 6.75 (2H, d, J = 8.4 Hz), 6.81 (1H, d, J = 16.4 Hz), 6.92 (1H, d, J = 16.4 Hz), 7.38 (2H, d, J = 8.4 Hz), 8.04 (1H, s), 9.21 (2H, s), 9.54 (1H, s), 13.57 (1H, s).

[0067] Accordingly, the present invention provides a method for debittering methylxanthines, comprising co-crystallization of methylxanthines with either pterostilbene or resveratrol in a 1:4 to 4:1 ratio, preferably a 1:1 ratio.

[0068] The co-crystallization method can be carried out using either or both a solvent.

[0069] In one aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (a) dissolving the coformer in a solvent at 35-55°C to obtain a clear solution, followed by adding a methylxanthine; (b) stirring the mixture at a temperature of 40-60°C to obtain a clear solution; (c) gradually cooling the solution to room temperature and maintaining said temperature for a period of 10 to 20 hours to allow co-crystallization; and (d) allowing the co-crystals thus formed to separate by settling, followed by filtration, washing and drying. The present invention provides a method for the preparation of co-crystals of methylxanthines and their polymorphs with a coformer, comprising:

[0070] The solvent for the process is selected from water, C1-C5 alcohols, lower organic acids such as formic acid, acetic acid, propanoic acid, butyric acid, ethers, esters, ketones, alone or in mixtures thereof.

[0071] In an alternative embodiment, the method for preparing debittered methylxanthines comprises mechanically grinding a mixture of methylxanthines and stilbenoids in a molar ratio of 1:4 to 4:1, preferably a 1:1 ratio.

[0072] In another embodiment, the present invention provides (a) dissolving a methylxanthine selected from theacrine, theobromine, methylliberine, caffeine, paraxanthine or theophylline in a suitable solvent or mixture of solvents, followed by addition of a coformer selected from pterostilbene or resveratrol in a molar ratio of 1:4 to 4:1, preferably 1:1; (b) allowing the mixture to stir until a clear solution is obtained; (c) allowing the solution of step (a) to stand to separate the co-crystals thus formed, followed by filtration, washing and drying to obtain the desired co-crystals. The present invention provides a method for masking the bitter taste of methylxanthines, comprising:

[0073] In yet another embodiment, a method for masking the bitter taste of a methylxanthine selected from theacrine, theobromine, methylliberine, caffeine, paraxanthine, or theophylline comprises mechanically grinding a mixture of the methylxanthine and pterostilbene or resveratrol in a molar ratio of 1:4 to 4:1, preferably a 1:1 ratio, to obtain the desired co-crystal.

[0074] Thus, in one embodiment, the present invention relates to a method for masking the bitter taste of teacrine by forming a co-crystal with pterostilbene as a coformer, which involves dissolving theacrine with pterostilbene in a molar ratio of 1:4 to 4:1, preferably 1:1, in a suitable solvent. In an alternative embodiment, the present invention discloses a method for masking the bitter taste of teacrine by forming a co-crystal with pterostilbene as a coformer, which comprises mechanically grinding theacrine and pterostilbene in a molar ratio of 1:4 to 4:1, preferably 1:1.

[0075] In another embodiment, the present invention discloses a method for masking the bitter taste of theobromine by forming a co-crystal with pterostilbene as a coformer, which involves dissolving theobromine with pterostilbene in a molar ratio of 1:4 to 4:1, preferably 1:1, in a suitable solvent. In an alternative embodiment, the present invention relates to a method for masking the bitter taste of theobromine by forming a co-crystal with pterostilbene as a coformer, which comprises the step of mechanically grinding theobromine and pterostilbene in a molar ratio of 1:4 to 4:1, preferably 1:1.

[0076] In yet another embodiment, the present invention discloses a method for masking the bitter taste of methylliberine by forming a co-crystal with pterostilbene as a coformer, which involves dissolving methylliberine together with pterostilbene in a molar ratio of 1:4 to 4:1, preferably 1:1, in a suitable solvent. In an alternative embodiment, the present invention discloses a method for masking the bitter taste of methylliberine by forming a co-crystal with pterostilbene as a coformer, which comprises mechanically grinding methylliberine and pterostilbene in a molar ratio of 1:4 to 4:1, preferably 1:1.

[0077] In yet another embodiment, the present invention relates to a method for masking the bitter taste of caffeine by the formation of a novel polymorph of a co-crystal with pterostilbene as a coformer, which involves dissolving caffeine with pterostilbene in a molar ratio of 1:4 to 4:1, preferably 1: 1, in a suitable solvent. In an alternative embodiment, the present invention provides a method for masking the bitter taste of caffeine by the formation of a co-crystal with pterostilbene as a coformer, which comprises the step of mechanically grinding caffeine and pterostilbene in a molar ratio of 1:4 to 4:1, preferably a 1:1 ratio.

[0078] In a further embodiment, the present invention relates to a method for masking the bitter taste of paraxanthine by forming a co-crystal with pterostilbene as a coformer, which involves dissolving paraxanthine together with pterostilbene in a molar ratio of 1:4 to 4:1, preferably 1:1, in a suitable solvent. In an alternative embodiment, the present invention discloses a method for masking the bitter taste of paraxanthine by forming a co-crystal with pterostilbene as a coformer, which comprises mechanically grinding paraxanthine and pterostilbene in a molar ratio of 1:4 to 4:1, preferably 1:1.

[0079] In yet another embodiment, the present invention relates to a method for masking the bitter taste of theophylline by forming a co-crystal with resveratrol as a coformer, which involves dissolving theophylline with resveratrol in a molar ratio of 1:4 to 4:1, preferably 1:1, in a suitable solvent. In an alternative embodiment, the present invention discloses a method for masking the bitter taste of theophylline by forming a co-crystal with resveratrol as a coformer, which comprises mechanically grinding theophylline with resveratrol in a molar ratio of 1:4 to 4:1, preferably 1:1.

[0080] The solvent for the process is selected from C1-C5 alcohols; water; acids, such as formic acid, acetic acid, propanoic acid, butyric acid; ethers, esters, ketones, etc., alone or in mixtures thereof.

[0081] In a further embodiment, the mechanical grinding is carried out in the presence or absence of a solvent, which, when used, is selected from C1-C5 alcohols, water, acids such as formic acid, acetic acid, propanoic acid, butyric acid, ethers, esters, ketones, etc., alone or in mixtures thereof.

[0082] In yet another embodiment, the theacrine, theobromine, methylliberine, paraxanthine, caffeine, theophylline, pterostilbene, and resveratrol used in the present invention are chemically synthesized compounds.

[0083] In yet another embodiment, the present invention provides a novel co-crystal of theacrine with pterostilbene.

[0084] In another embodiment, the present invention provides a method for the preparation of co-crystals of theacrine with pterostilbene in a 1:1 ratio and its various polymorphic forms.

[0085] In additional embodiments, the present invention provides theacrine and pterostilbene co-crystalline polymorphs Form I; Form II; Form III and Forms IV, V and methods for their preparation.

[0086] Therefore, the present invention provides approximately 12.78 (100%), 14.18 (90.2%), 14.69 (17.9%), 15.55 (19.0%), 17.45 (11.8%), 19.04 (9.1%), 22.28 (12.0%), 23.46 (14.4%), 27.90 (5.0%), 28.80 (5.6%), 29.50 (7.3%), 31.50 (7.6%), 33.04 (10.1%), 38.90 (14.2%), 41.02 (6.1%), 41.93 (4.7%), 53.16 (4.5%), 72.73 (8.4%) ±0.2°. Crystalline theacrine:pterostilbene co-crystalline polymorph Form I is provided, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at 2θ.

[0087] In another embodiment, the present invention provides a method for the treatment of a cancer of the genus A. In another embodiment, the present invention provides a method for the treatment of a cancer of the genus A. In another embodiment, the present invention provides a method for the treatment of a cancer of the genus A. Disclosed is crystalline theacrine:pterostilbene cocrystal polymorph Form II, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at 29.12 (2.7%), 29.87 (3.6%), 31.76 (5.8%), 32.10 (6.2%), 33.33 (6.1%), 35.73 (1%), 37.02 (1.5%), 39.20 (9.0%), 40.66 (1.0%), 45.00 (1.4%), 46.38 (1.8%), 47.41 (1.2%), 48.05 (1.7%), 54.61 (2.8%), 55.46 (2.4%), and 72.69 (2.5%) ± 0.2 degrees 2θ.

[0088] In yet another embodiment, the present invention provides a method for producing a gyroscopically accurate ... The present invention relates to crystalline theacrine:pterostilbene co-crystalline polymorph Form III, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at 2θ.

[0089] According to another embodiment, the present invention provides a method for producing a medicament for the treatment of pulmonary arterial ulcers, comprising administering to a patient a medicament for the treatment of ulcers, the method ... 47.30 (1.1%), 47.95 (1.9%), 49.04 (1.0%), 53.36 (1.5%), 72.68 (3.3%), and 88.31 (1.0%).

[0090] In another embodiment, the invention relates to crystalline theacrine:pterostilbene cocrystal polymorph Form V, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at about 12.83 (17.0%), 14.33 (100%), 15.72 (18.8%), 19.15 (3.5%), 20.06 (3.5%), 22.10 (8.8%), 23.55 (6.5%), 27.17 (5.8%), 31.73 (4.8%), 33.71 (2.0%), 37.88 (1.4%), 39.19 (6.2%), 41.07 (1.4%), 41.54 (2.2%), 43.86 (1.0%) ± 0.2 degrees 2θ.

[0091] In another embodiment, the present invention provides a composition comprising a medicament for the treatment of a patient with ... 19%), 35.93 (6.2%), 39.15 (5.4%), 40.67 (3.61%), 42.08 (3.2%), 44.61 (2.87%), 48.89 (2.4%), 50.06 (2.9%), 52.53 (2.36%), 55.83 (2.22%), 72.73 (6.96%), 88.42 (2.35%) ± 0.2° 2θ.

[0092] In a further embodiment, the present invention provides novel cocrystals of methylliberine with pterostilbene. Thus, in a further embodiment, the present invention provides methylliberine and pterostilbene cocrystal polymorphs Form 1, Form II, Form III, and Form IV, and methods for their preparation.

[0093] According to another aspect, the present invention provides a method for producing a gyroscopically accurate ... Provided is a crystalline methylliberin:pterostilbene co-crystal polymorph Form I, characterized by an X-ray powder diffraction pattern having one or more peaks at 2θ.

[0094] In another embodiment, the present invention provides a method for producing a medicament containing ... (17%), 26.91 (16.8%), 27.31 (22.4%), 29.91 (1.3%), 30.82 (1.2%), 31.29 (1.6%), 34.51 (1.3%), 36.24 (1.4%), 37.94 (3.7%), 42.82 (1.0%), 44.67 (1.1%), 72.70 (2.5%) ± 0.2° 2θ.

[0095] In another embodiment, the present invention discloses crystalline methylliberine:pterostilbene cocrystal polymorph Form III, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at about 13.20 (100%), 15.35 (16.1%), 16.50 (11.8%), 17.90 (3.2%), 19.88 (13.3%), 20.83 (3.9%), 22.06 (5.0%), 23.05 (1.3%), 23.88 (4.1%), 25.60 (14.9%), 36.03 (1.1%), 42.05 (1.2%), and 72.67 (7.7%) ± 0.2 degrees 2θ.

[0096] In another embodiment, the present invention provides a method for the production of a medicament containing ... Disclosed is crystalline methylliberine:pterostilbene cocrystal polymorph Form IV, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at 4.24 (10.5%), 25.84 (100%), 27.48 (81.2%), 33.31 (2.7%), 34.78 (5.1%), 35.01 (4.9%), 36.44 (3.5%), 38.10 (8.2%), 40.78 (1.5%), 43.12 (4.9%), 46.52 (2.7%), 47.75 (1.7%), 49.85 (1.4%) ± 0.2 degrees 2θ.

[0097] In additional embodiments, the present invention discloses novel polymorphic forms of caffeine and pterostilbene cocrystal Form 1, Form II, Form III, and Form IV, and methods for their preparation.

[0098] The polymorphic forms of the methylxanthine co-crystals of the present invention are functionally similar to the co-crystals and mask the bitter taste of the methylxanthines.

[0099] Thus, the present invention provides approximately 11.90 (28.6%), 15.03 (100%), 16.81 (51.2%), 19.06 (53.5%), 21.65 (44.4%), 25.81 (94.2%), 26.35 (91.04%), 28.16 (10.4%), 29.54 (6.7%), 31.32 (4.8%), 32.52 (10.3%), 35.74 (3.6%), 36.99 (3.8%), 39.36 (3.7%), 40.93 (7.3%), 43.66 (5.7%), 45.45 (3.6%), 49.83 (2.1%), 72.74 (8.5%) and 88.35 (3.3%) ±0.2°. The present invention relates to crystalline caffeine:pterostilbene co-crystalline polymorph Form I, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at 2θ.

[0100] In another embodiment, the present invention discloses crystalline caffeine:pterostilbene cocrystal polymorph Form II, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at about 12.83 (2.19%), 17.04 (5.43%), 19.41 (5.24%), 22.25 (6.28%), 26.31 (100%), 28.67 (3.8%), 30.04 (1.6%), 32.96 (2.3%), 41.34 (1.1%), and 53.94 (1.7%) ± 0.2 degrees 2θ.

[0101] In another embodiment, the present invention provides a method for producing a medicament containing a compound having a molecular weight of about 10.53 (18.3%), 12.18 (4.9%), 14.01 (23.04%), 15.56 (25.3%), 17.22 (21.0%), 19.35 (16.7%), 22.13 (13.7%), 24.02 (4.3%), 26.51 (100%), 28.57 (20.4%), 30.22 (4.0%), 31.82 (4.1%), 36.23 (1.1%), 43.3 (1.8%), 46.52 (1.1%), 53.52 (1.1%), and 72.72 (2.2%) ±0.2°. Disclosed is crystalline caffeine:pterostilbene co-crystalline polymorph Form III, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at 2θ.

[0102] According to another aspect, the present invention provides a method for treating pulmonary embolism comprising administering to a subject a pulmonary embolism of approximately 10.49 (100%), 12.24 (18.5%), 13.92 (35.3%), 14.18 (53.8%), 15.49 (41.5%), 15.60 (63.8%), 17.08 (36.3%), 19.3 (24.9%), 19.5 (60.2%), 22.13 (35.6%), 23.77 (12.7%), 26.06 (79.5%). , 26.7 (94.8%), 28.51 (17.7%), 30.00 (13.0%), 32.48 (10.0%), 36.36 (10.3%), 38.15 (12.0%), 40.00 (8.1%), 41.28 (10.4%), 43.26 (7.5%), 46.34 (14.8%), 50.19 (8.5%), 53.95 (9.2%), 56.00 (5.7%) ± 0.2° 2θ.

[0103] In another embodiment, the present invention discloses a novel co-crystal of paraxanthine with pterostilbene.

[0104] Thus, a co-crystal of paraxanthine with pterostilbene in a 1:1 ratio is characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at about 11.31 (12.8%), 15.88 (71.8%), 19.86 (18.7%), 21.28 (26.0%), 22.52 (33.6%), 24.9 (83.2%), 26.96 (100%), 29.00 (12.3%), 29.21 (19.3%), 30.41 (14.3%), 32.45 (9.9%), 38.8 (6.5%), 40.68 (5.2%), 44.84 (4.9%), 50.55 (3.6%), 55.48 (4.4%) ± 0.2° 2θ.

[0105] In another embodiment, the present invention discloses a novel co-crystal of theophylline with resveratrol. Thus, the co-crystal of theophylline with resveratrol in a 1:1 ratio has the following values: approximately 10.30 (9.4%), 12.40 (30.7%), 13.81 (100%), 15.21 (9.4%), 16.27 (14.1%), 17.21 (4.5%), 19.22 (21.1%), 20.76 (13.0%), 22.30 (8.4%), 23.52 (8.4%), 24.84 (47.9%), 25.3 The compound is characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at ±0.2° 2θ: 6 (33.6%), 26.64 (7.4%), 28.26 (8.6%), 30.68 (8.9%), 32.88 (3.3%), 34.96 (1.1%), 36.46 (1.5%), 37.61 (1.1%), 38.45 (2.0%), 39.84 (1.4%), 42.16 (2.3%), 45.91 (1.3%), 52.26 (1.3%), 72.73 (4.1%), and 88.35 (1.2%).

[0106] These polymorphic forms are reliably characterized by peak positions in the X-ray diffractogram, which produces a fingerprint of the crystalline form and can distinguish it from all other crystalline and amorphous forms of theacrine, methylliberine, theobromine, caffeine, or paraxanthine with pterostilbene. Measurements of 2θ values ​​are accurate to within ±0.2 degrees. All powder diffraction patterns were measured on a PANalytical X'Pert3 X-ray powder diffractometer using a copper Kα radiation source.

[0107] In one embodiment, the present invention discloses a composition comprising an effective amount of a co-crystal of a methylxanthine selected from theacrine, theobromine, methylliberine, caffeine, paraxanthine, and theophylline with a co-former selected from a stilbenoid, or a polymorph thereof, and one or more excipients.

[0108] The excipients are selected from one or more of binders, fillers, lubricants, emulsifiers, suspending agents, sweeteners, preservatives, buffers, wetting agents, disintegrants, diluents, flavors, colorants, suitable polymeric foaming agents, additives, and mixtures thereof.

[0109] The additive is selected from the group consisting of microcrystalline cellulose, lactose, sucrose, fructose, glucose, dextrose, dibasic calcium phosphate, calcium sulfate, cellulose, methylcellulose, cellulose derivatives, kaolin, mannitol, lactitol, maltitol, xylitol, sorbitol, sugar alcohols, dry starch, dextrin, maltodextrin, polysaccharides, and mixtures thereof.

[0110] In yet another embodiment, the present invention relates to a dietary supplement or pharmaceutical dosage form comprising a co-crystal of a methylxanthine selected from theacrine, theobromine, methylliberine, caffeine, paraxanthine, and theophylline with a coformer selected from a stilbenoid, or a polymorph thereof.

[0111] In another embodiment, the present invention relates to a pharmaceutical composition for dermatological use comprising an effective amount of a co-crystal of a methylxanthine selected from theacrine, theobromine, methylliberine, caffeine, paraxanthine and theophylline with a coformer selected from a stilbenoid, or a polymorph thereof, and one or more excipients.

[0112] A dietary supplement or pharmaceutical dosage, wherein the dosage form is an oral dosage form selected from the group consisting of tablets, capsules, powders, suspensions, and lozenges.

[0113] The coformers selected from pterostilbene or resveratrol used in the present invention mask the bitter taste of methylxanthines by blocking the sensory receptors involved in taste.

[0114] Taste is the sensory perception when a dietary supplement or medicine is placed in the oral cavity. Preference testing provides information on whether a subject likes or dislikes a product. Taste evaluation trials are designed by using statistical tools to minimize or reduce bias in responses within and between human volunteers. For sensory analysis, one of the important parts is testing the taste buds of healthy volunteers.

[0115] Smell, taste and texture are the three main components that affect the palatability of a product. Palatability refers to the spontaneous acceptance and consumption of a pharmaceutical composition, which can be measured by acceptance, palatability and consumption tests; if the test subjects have a spontaneous acceptance rate of 90% or more, the product is considered to be palatable.

[0116] Therefore, roundtable evaluations were performed on a set of eight panelists every other day for six days. Prior to the test, panelists were asked to consume water and unsalted crackers to cleanse the palate.

[0117] On day 1, theacrine and an equal concentration (amount) of theacrine:pterostilbene cocrystal were ingested by all panelists for sensory analysis.

[0118] On the second day, theobromine and an equal concentration (amount) of theobromine:pterostilbene cocrystal were ingested by all panelists for sensory analysis.

[0119] On the third day, methylliberine and an equal concentration (amount) of methylliberine:pterostilbene cocrystal were ingested by all panelists for sensory analysis.

[0120] On the fourth day, caffeine and an equal concentration (amount) of caffeine:pterostilbene cocrystal were ingested by all panelists for sensory analysis.

[0121] On the fifth day, paraxanthine and an equal concentration (amount) of paraxanthine:pterostilbene cocrystal were ingested by all panelists for sensory analysis.

[0122] On day 6, theophylline and an equal concentration (amount) of theophylline:resveratrol cocrystals were ingested by all panelists for sensory analysis.

[0123] Results were recorded by individual panelists for each form, indicating their preference (like) and dislike (dislike) for consumption. Sensory testing results showed a clear preference for the cocrystals of the present invention over pure theacrine, theobromine, methylliberine, caffeine, paraxanthine, and theophylline by all eight panelists, since the bitter taste of theacrine, theobromine, methylliberine, caffeine, paraxanthine, and theophylline is completely masked in the cocrystal form. The results are provided in Table 1 below.

[0124] As is evident from the table below, a clear preference was shown by the panelists for the co-crystallized methylxanthine compounds over the pure methylxanthines, which conclusively indicates that pterostilbene and resveratrol de-bitter the methylxanthines by masking their bitter taste.

[0125] In further embodiments, the cocrystal compositions of the present invention produce various health benefits based on dosage form, such as improved memory, attention, focus, relaxation, and increased energy and stamina.

[0126] Additionally, the crystal formers, namely pterostilbene and resveratrol, are safe and tested dietary supplements and synergistically improved the dietary supplement effects of theacrine, theobromine, methylliberine, caffeine, paraxanthine, and theophylline.

[0127] In one embodiment, dissolution studies of methylxanthine cocrystals with the coformers pterostilbene and resveratrol were evaluated. In all cases, the dissolution rate was observed not to follow zero-order kinetics, meaning that the dissolution rate was independent of the amount of available active ingredient. The cocrystals have lower solubility, slower release rates, and are therefore more bioavailable than their pure forms (Figures 1 to 6).

[0128] experiment: The following examples, including preferred embodiments, serve to illustrate the practice of this invention, it being understood that the matters set forth are by way of example and for purposes of exemplary discussion of preferred embodiments of the invention.

[0129] General method for the synthesis of cocrystals: In a general synthetic method for preparing the novel cocrystals, the coformer (pterostilbene or resveratrol) is added to a suitable solvent and dissolved at 45-50°C to obtain a clear solution, followed by the addition of methylxanthines (theacrine, theobromine, methylliberine, paraxanthine, caffeine, and theophylline). Stirring is continued at 45-50°C for 30 minutes to obtain a clear solution. The reaction mass is gradually cooled to room temperature and maintained at the same temperature for 12-18 hours to crystallize the corresponding cocrystals. Suitable solvents that can be used for the synthesis of the cocrystals are selected from the group consisting of C1-5 alcohols, water, formic acid, acetic acid, propanoic acid, butyric acid; ethers, esters, ketones, etc., alone or in mixtures thereof. The following additional techniques can also be used to prepare the methylxanthine cocrystals of the present invention: neat grinding, solvent drop grinding, reaction crystallization, antisolvent addition, cooling crystallization, and slow solvent evaporation. [Example]

[0130] Example 1: Preparation of theacrine:pterostilbene (1:1) cocrystal (Form I) To a stirred solution of theacrine (5.0 g, 22.3 mmol) in a mixture of water (20 mL) and methanol (30 mL) at 65-70°C, pterostilbene (5.72 g, 22.3 mmol) was added, and the mixture was stirred until a clear solution was obtained. It was allowed to stand at room temperature for 24 hours, during which time crystals separated. It was filtered, washed with a water:methanol mixture (3 mL, 1:1.5), and dried under vacuum in an oven at 40-45°C. Yield: 9.82 g, mp: 143-145°C. 1 HNMR (400 MHz, dmso-d6): δ 3.19 (3H, s), 3.39 (3H, s), 3.52 (3H, s), 3.63 (3H, s), 3.76 (6H, s), 6.36 (1H, s), 6.70 (2H, s), 6.76 (2H, d, J = 8.4Hz), 6.93 (1H, d, J = 16.4Hz), 7.15 (1H, d, J = 16.4Hz), 7.41 (2H, d, J = 8.4Hz), 9.59 (1H, s).PXRD: 12.78 (100%), 14.18 (90.2%), 14.69 (17.9%), 15.55 (19.0%), 17.45 (11.8%), 19.04 (9.1%), 22.28 (12.0%), 23.46 (14.4%), 27.90 (5.0%), 28.80 (5.6%), 29.50 (7.3%), 31.50 (7.6%), 33.04 (10.1%), 38.90 (14.2%), 41.02 (6.1%), 41.93 (4.7%), 53.16 (4.5%), 72.73 (8.4%) ± 0.2° 2θ. DSC: A sharp endotherm was observed at 146.22 °C.

[0131] Example 2: Preparation of theobromine:pterostilbene (1:1) cocrystal Theobromine and pterostilbene (1:1) were placed in a mortar and acetic acid was added. The resulting mixture was ground with a pestle for 1 hour. It was then dried in an oven at 40-45°C under vacuum. 1HNMR (400 MHz, dmso-d6): δ 3.33 (3H, s), 3.76 (6H, s), 3.84 (3H, s), 6.36 (1H, t, J = 2.4Hz), 6.71 (2H, t, J = 2.4Hz), 6.77 (2H, d, J = PXRD: 11.75 (30.20%), 13.38 (63.10%), 15.37 (7.80%), 17.31 (10.10%), 19.35 (95.40%), 23.46 (44.30%), 26.98 (100%), 29.35 (14.10%), 31.65 (6.40%), 34.30 (2.10%), 35.93 (6.20%), 39.15 (5.40%), 40.67 (3.60%), 42.08 (3.20%), 44.61 (2.80%), 48.89 (2.40%), 50.06 (2.90%), 52.53 (2.3%), 55.83 (2.2%), 72.73 (6.90%), 88.42 (2.30%) ± 0.2° 2θ. DSC: A sharp endotherm was observed at 93°C.

[0132] Example 3: Preparation of methylliberine:pterostilbene (1:1) cocrystal (form I) To a stirred solution of methylliberin (5.80 g, 25.9 mmol) in a mixture of water (10 mL) and methanol (30 mL) at 65-70°C, pterostilbene (6.63 g, 25.9 mmol) was added, and the mixture was stirred at the same temperature until a clear solution was obtained. It was then allowed to come to room temperature and stand at room temperature for 24 hours, during which time crystals separated. The crystals thus formed were filtered, washed with a water:methanol mixture (3 mL, 1:3), and dried in an oven at 40-45°C under vacuum. Yield: 11.8 g, mp: 130-132°C. 1HNMR (400 MHz, dmso-d6): δ 3.21 (3H, s), 3.31 (3H, s), 3.40 (3H, s), 3.76 (6H, s), 4.01 (3H, s), 6.36 (1H, t, J = 2 Hz), 6.71 (2H, d, J = 1.6 Hz), 6.76 (2H, d, J = 8.8 Hz), 6.93 (1H, d, J = 16.8 Hz), 7.15 (1H, d, J = 16.8 Hz), 7.41 (2H, d, J = 8.8 Hz), 9.59 (1H, s).PXRD: 12.25 (87.7%), 13.33 (100%), 15.52 (24.8%), 16.44 (6.6%), 17.98 (6.0%), 19.99 (16.5%), 21.12 (8.6%), 21.99 (5.2%), 23.93 (4.5%), 25.44 (6.6%), 27.05 (11.1%), 28.76 (3.9%), 34.75 (3.8%), 37.81 (5.8%), 40.49 (3.0%), 42.78 (4.9%), 44.64 (3.9%), 72.73 (5.8%) ± 0.2° DSC: A sharp endotherm was observed at 132.54°C.

[0133] Example 4: Preparation of theophylline:resveratrol (1:1) co-crystals To a stirred solution of theophylline (0.5 g, 2.8 mmol) in a mixture of water (2 mL) and methanol (2 mL) at 80-83°C, resveratrol (0.63 g, 2.8 mmol) was added, and the mixture was stirred at the same temperature until clear. The clear solution was allowed to stand at room temperature for 24 hours, during which time crystals separated. They were filtered, washed with a water:ethanol mixture (3 mL, 1:3), and dried under vacuum in an oven at 40-45°C. Yield: 0.79 g, mp: 201-216°C. 1HNMR (400 MHz, dmso-d6): δ 3.24 (3H, s), 3.44 (3H, s), 6.12 (1H, t, J = 2 Hz), 6.39 (2H, d, J = 2 Hz), 6.75 (2H, d, J = 8.4 Hz), 6.81 (1H, d, J = 16.4 Hz), 6.92 (1H, d, J = 16.4 Hz), 7.38 (2H, d, J = 8.4 Hz), 8.04 (1H, s) 9.21 (2H, s), 9.54 (1H, s), 13.57 (1H, s).PXRD: 10.30 (9.4%), 12.40 (30.7%), 13.81 (100%), 15.21 (9.4%), 16.27 (14.1%), 17.21 (4.5%), 19.22 (21.1%), 20.76 (13.0%), 22.30 (8.4%), 23.52 (8.4%), 24.84 (47.9%), 25.36 (33.6%), 26.64 (7.4%) , 28.26 (8.6%), 30.68 (8.9%), 32.88 (3.3%), 34.96 (1.1%), 36.46 (1.5%), 37.61 (1.1%), 38.45 (2.0%), 39.84 (1.4%), 42.16 (2.3%), 45.91 (1.3%), 52.26 (1.3%), 72.73 (4.1%), and 88.35 (1.2%) ± 0.2° 2θ. A sharp endotherm was observed at 201.95 °C.

[0134] Example 5: Preparation of caffeine:pterostilbene (1:1) cocrystal (Form I) To a stirred solution of caffeine (5.0 g, 25.7 mmol) in a mixture of water (10 mL) and methanol (30 mL) at 65-70°C, pterostilbene (6.6 g, 25.7 mmol) was added and the mixture was stirred until a clear solution was obtained. It was allowed to stand at room temperature for 15 hours, during which time crystals separated. It was filtered, washed with a water:methanol mixture (3 mL, 1:1.5), and dried under vacuum in an oven at 40-45°C. Yield: 10.8 g, mp: 116-120°C. 1HNMR (400 MHz, DMSO-d6): δ 3.20 (3H, s), 3.40 (3H, s), 3.76 (6H, s), 3.86 (3H, s), 6.36 (1H, t, J = 2.0 Hz), 6.71 (2H, d, J = 2.0 Hz), 6.76 (2H, d, J = 8.8 Hz), 6.93 (1H, d, J = 16.4 Hz), 7.15 (1H, d, J = 16.4 Hz), 7.41 (2H, d, J = 8.4 Hz), 7.99 (1H, s), 9.59 (1H, s).PXRD: 11.90 (28.6%), 15.03 (100%), 16.81 (51.2%), 19.06 (53.5%), 21.65 (44.4%), 25.81 (94.2%), 26.35 (91.04%), 28.16 (10.4%), 29.54 (6.7%), 31.32 (4.8%), 32.52 (10.3%), 35.74 (3.6%), 36.99 (3.8%), 39.36 (3.7%), 40.93 (7.3%), 43.66 (5.7%), 45.45 (3.6%), 49.83 (2.1%), 72.74 (8.5%) and 88.35 (3.3%) ±0.2° 2θ, DSC: A sharp endotherm was observed at 117.30°C.

[0135] Example 6: Preparation of paraxanthine:pterostilbene (1:1) cocrystal Paraxanthine (70 mg, 0.388 mmol) and pterostilbene (0.099 g, 0.388 mmol) were placed in a mortar and acetic acid was added. The resulting mixture was ground with a pestle for 1 hour. It was then dried in an oven at 40-45°C under vacuum. Yield (0.120 g), mp: 193.4-207.8°C. 1HNMR (400 MHz, dmso-d6):δ 3.17 (3H, s), 3.76 (6H, s), 3.85 (3H, s), 6.36 (1H, s), 6.71 (2H, s), 6.76 (2H, d, J = 8.4 Hz), 6.94 (1H, PXRD: 11.31 (12.8%), 15.88 (71.8%), 19.86 (18.7%), 21.28 (26.0%), 22.52 (33.6%), 24.9 (83.2%), 26.96 (100%), 29.00 (12.3%), 29.21 (19.3%), 30.41 (14.3%), 32.45 (9.9%), 38.8 (6.5%), 40.68 (5.2%), 44.84 (4.9%), 50.55 (3.6%), 55.48 (4.4%) ± 0.2° 2θ. DSC: A sharp endotherm was observed at 204.17 °C.

[0136] polymorph Example 7: Preparation of theacrine and pterostilbene cocrystal: polymorphic form-II To a stirred solution of theacrine (2.0 g, 8.9 mmol) in a mixture of water (3 mL) and ethanol (10 mL) at 65-70°C, pterostilbene (2.29 g, 8.9 mmol) was added and the mixture was stirred until a clear solution was obtained. It was allowed to stand at room temperature for 24 hours, during which time crystals separated. They were filtered, washed with a water:ethanol mixture (3 mL, 1:3), and dried in an oven at 40-45°C under vacuum. Yield: 3.5 g, mp: 144-146°C. PXRD: 10.98 (4.8%), 13.06 (33.6%), 14.45 (65.5%), 15.09 (38.6%), 15.85 (32.3%), 17.71 (6.6%), 19.18 (13.9%), 20.21 (28.7%), 21.44 (6.8%), 22.58 (11.1%), 23.73 (9.5%), 26.40 (59.7%), 27.21 (100%), 28.29 (10.1%), 29.12 (2.6%), 29.87 (3.6%) %), 31.76(5.8%), 32.10(6.3%), 33.33(6.1%), 35.73(1%), 37.02(1.5%), 39.20(9.0%), 40.66(1.0%), 42.21(0.9%), 45.00(1.4%), 46.38(1.8%), 47.41(1.3%), 48.05(1.8%), 53.41(2.8%), 54.61(2.5%), 55.46(0.6%) and 72.69(2.5%) ±0.2° 2θ.

[0137] Example 8: Preparation of theacrine and pterostilbene cocrystal: polymorphic form-III To a stirred solution of theacrine (2.0 g, 8.9 mmol) in a mixture of water (4 mL) and acetone (4 mL) at 65-70°C, pterostilbene (2.29 g, 8.9 mmol) was added, and the mixture was stirred until a clear solution was obtained. It was allowed to stand at room temperature for 24 hours, during which time crystals separated. They were filtered, washed with a water:acetone mixture (3 mL, 1:1), and dried in an oven at 40-45°C under vacuum. Yield: 3.52 g, mp: 143-145°C. PXRD: 12.90 (64.3%), 14.32 (100%), 15.64 (13.3%), 17.45 (8.3%), 19.17 (6.7%), 21.69 (10.5%), 22.38 (7.9%), 23.58 (10.0%), 25.07 (7.1%), 26.19 (6.1%), 26.98 (9.6%), 27.93 (0.8%), 28.86 (1.9%), 29.59 (2.8%), 31.58 (2.7%), 33.12 (3.7%), 38.98 (7%), 41.10 (1.4%), 43.62 (1.1%), 47.80 (1.0%), and 72.70 (2.7%) ±0.2° 2θ.

[0138] Example 9: Preparation of theacrine and pterostilbene cocrystal: polymorphic form-IV. To a stirred solution of theacrine (2.0 g, 8.9 mol) in a mixture of water (2 mL) and isopropanol (5 mL) at 65-70°C, pterostilbene (2.29 g, 8.9 mmol) was added and the mixture was stirred until a clear solution was obtained. It was allowed to stand at room temperature for 24 hours, during which time crystals separated. It was filtered, washed with a water:isopropanol mixture (3 mL, 1:2.5), and dried in an oven at 40-45°C under vacuum. Yield: 4.05 g; mp: 143-145°C. PXRD: 12.98 (100%), 14.38 (97.8%), 15.72 (18.6%), 17.66 (14.9%), 19.38 (10.3%), 21.72 (7.5%), 22.47 (9.1%), 23.69 (12.8%), 25.14 (8.1%), 26.16 (11.6%), 27.00 (17.2%), 28.03 (2.5%), 29.69 (4.4%), 30.83 (1.1%), 31.66 ( 4.3%), 33.25(7.2%), 36.88(1.1%), 39.12(11.6%), 41.21(2.1%), 43.62(1.3%), 44.06(1.7%), 44.83(1.3%), 45.99(1.0%), 47.30(1.2%), 47.95(1.9%), 49.04(1.0%), 53.36(1.6%), 72.68(3.4%) and 88.31(1.0%) ±0.2° 2θ.

[0139] Example 10: Preparation of theacrine and pterostilbene cocrystal: polymorphic form-V. To a stirred solution of theacrine (2.0 g, 8.9 mol) in formic acid (3 mL) at 65-70°C, pterostilbene (2.29 g, 8.9 mol) was added, and the mixture was stirred until a clear solution was obtained. It was allowed to stand at room temperature for 24 hours, during which time crystals separated. They were filtered, washed with water, and dried in an oven at 40-45°C under vacuum. Yield: 2.8 g; mp: 143-146°C. PXRD: 12.83(17.1%), 14.33(100%), 15.72(18.8%), 19.15(3.6%), 20.06(3.5%), 22.10(8.8%), 23.55(6.5%), 27.17(5 .9%), 31.73(4.9%), 33.71(2.0%), 37.88(1.4%), 39.19(6.2%), 41.07(1.4%), 41.54(2.2%), 43.86(1.1%)±0.2° 2θ.

[0140] Example 11: Preparation of methylliberin and pterostilbene cocrystal: polymorphic form-II. To a stirred solution of methylliberin (2.0 g, 8.9 mmol) in a mixture of water (3 mL) and ethanol (10 mL) at 65-70°C, pterostilbene (2.29 g, 8.9 mmol) was added and the mixture was stirred until a clear solution was obtained. It was allowed to stand at room temperature for 24 hours, during which time crystals separated. They were filtered, washed with a water:methanol mixture (3 mL, 1:3), and dried in an oven at 40-45°C under vacuum. Yield: 3.37 g; mp: 129-132°C. PXRD: 12.43 (68.3%), 13.49 (100%), 15.65 (11.9%), 16.60 (11%), 18.12 (4.6%), 20.13 (15.4%), 21.30 (7.2%), 22.16 (6.3%), 23.34 (1.6%), 24.08 (4.4%), 25.69 (17.1%), 2 6.91(16.9%), 27.31(22.4%), 29.91(1.4%), 30.82(1.3%), 31.29(1.6%), 34.51(1 .3%), 36.24(1.4%), 37.94(3.7%), 42.82(1.0%), 44.67(1.1%), 72.70(2.5%)±0.2° 2θ.

[0141] Example 12: Preparation of methylliberin and pterostilbene (1:1) cocrystal: polymorphic form-III. To a stirred solution of methylliberin (2.0 g, 8.9 mmol) in a mixture of water (4 mL) and acetone (4 mL) at 65-70°C, pterostilbene (2.29 g, 8.9 mmol) was added, and the mixture was stirred at this temperature until a clear solution was obtained. It was allowed to stand at room temperature for 24 hours, during which time crystals separated. It was filtered, washed with a water:methanol mixture (3 mL, 1:3), and dried in an oven at 40-45°C under vacuum. Yield: 3.1 g, mp: 130-133°C. PXRD: 13.20 (100%), 15.35 (16.1%), 16.50 (11.8%), 17.90 (3.3%), 19.88 (13.3%), 20.83 (3.9%), 22.06 (5.0%), 23.05 (1.3%), 23.88 (4.1%), 25.60 (14.9%), 36.03 (1.2%), 42.05 (1.2%), and 72.67 (7.7%) ± 0.2° 2θ.

[0142] Example 13: Preparation of methylliberin and pterostilbene cocrystal: polymorphic form-IV To a stirred solution of methylliberin (2.0 g, 8.9 mmol) in formic acid (3 mL) at 65-70°C, pterostilbene (2.29 g, 8.9 mmol) was added, and the mixture was stirred at the same temperature until a clear solution was obtained. It was allowed to stand at room temperature for 24 hours, during which time crystals separated. It was filtered, washed with a water:methanol mixture (3 mL, 1:3), and dried in an oven at 40-45°C under vacuum. Yield: 3.84 g; mp: 130-133°C. PXRD: 12.00 (43.4%), 12.48 (91.5%), 13.63 (84.8%), 15.32 (11.0%), 16.77 (24.7%), 18.34 (10.9%), 19.02 (11.1%), 20.22 (20.4%), 21.44 (16.9%), 22.32 (14.8%), 23.34 (3.9%), 24.24 (10.5%) %), 25.84(100%), 27.48(81.2%), 33.31(2.7%), 34.78(5.1%), 35.01(4.9%), 36.44(3.5%), 38.10(8.2%), 40.78(1.5%), 43.12(4.9%), 46.52(2.7%), 47.75(1.7%), 49.85(1.4%)±0.2° 2θ.

[0143] Example 14: Preparation of caffeine and pterostilbene cocrystal: polymorphic form-I. To a stirred solution of caffeine (5.0 g, 25.7 mmol) in a mixture of water (10 mL) and methanol (30 mL) at 65-70°C, pterostilbene (6.6 g, 25.7 mmol) was added and the mixture was stirred until a clear solution was obtained. It was allowed to stand at room temperature for 15 hours, during which time crystals separated. It was filtered, washed with a water:methanol mixture (3 mL, 1:1.5), and dried under vacuum in an oven at 40-45°C. Yield: 10.8 g, mp: 116-120°C. PXRD: 11.90 (28.6%), 15.03 (100%), 16.81 (51.2%), 19.06 (53.5%), 21.65 (44.4%), 25.81 (94.2%), 26.35 (91.04%), 28.16 (10.4%), 29.54 (6.7%), 31.32 (4.8%), 32.52 (10.3%), 35.74 (3.6%), 36.99 (3.8%), 39.36 (3.7%), 40.93 (7.3%), 43.66 (5.7%), 45.45 (3.6%), 49.83 (2.1%), 72.74 (8.5%) and 88.35 (3.3%) ± 0.2° 2θ.

[0144] Example 15: Preparation of caffeine and pterostilbene cocrystal: polymorphic form-II. To a stirred solution of caffeine (2.0 g, 10.29 mmol) in formic acid (3 mL) at 75-80°C, pterostilbene (2.63 g, 10.29 mmol) was added, and the mixture was stirred until a clear solution was obtained. It was allowed to stand at room temperature for 15 hours, during which time crystals separated. It was filtered and dried under vacuum in an oven at 40-45°C. Yield: 3.2 g, mp: 116-127°C. PXRD: 12.83 (2.19%), 17.04 (5.43%), 19.41 (5.24%), 22.25 (6.28%), 26.31 (100%), 28.67 (3.8%), 30.04 (1.6%), 32.96 (2.3%), 41.34 (1.1%), and 53.94 (1.7%) ± 0.2° 2θ.

[0145] Example 16: Preparation of caffeine and pterostilbene cocrystal: polymorphic form-III. To a stirred solution of caffeine (2.0 g, 10.29 mmol) in acetic acid (4 mL) at 75-80°C, pterostilbene (2.63 g, 10.29 mmol) was added, and the mixture was stirred until a clear solution was obtained. It was allowed to stand at room temperature for 15 hours, during which time crystals separated. It was filtered and dried under vacuum in an oven at 40-45°C. Yield: 2.73 g, mp: 115-122°C. PXRD 10.53 (18.3%), 12.18 (4.9%), 14.01 (23.04%), 15.56 (25.3%), 17.22 (21.0%), 19.35 (16.7%), 22.13 (13.7%), 24.02 (4.3%), 26.51 (100%), 28.57 (20.4%), 30.22 (4.0%), 31.82 (4.1%), 36.23 (1.1%), 43.3 (1.8%), 46.52 (1.1%), 53.52 (1.1%) and 72.72 (2.2%) ± 0.2° 2θ.

[0146] Example 17: Preparation of caffeine and pterostilbene cocrystal: polymorphic form-IV. To a stirred solution of caffeine (2.0 g, 10.3 mmol) in a mixture of water (3 mL) and ethanol (10 mL) at 75-80°C, pterostilbene (2.64 g, 10.3 mmol) was added, and the mixture was stirred until a clear solution was obtained. It was allowed to stand at room temperature for 15 hours, during which time crystals separated. It was filtered, washed with a water:ethanol mixture (3 mL, 1:1.5), and dried under vacuum in an oven at 40-45°C. Yield: 3.9 g, mp: 119-122°C. PXRD10.49(100%), 12.24(18.5%), 13.92(35.3%), 14.18(53.8%), 15.49(41.5%), 15.60(63.8%), 17.08(36.3%), 19.3(24.9%), 19.5(60.2%), 22.13(35.6%), 23.77(12.7%), 26.06(79.5%), 26.7( 94.8%), 28.51(17.7%), 30.00(13.0%), 32.48(10.0%), 36.36(10.3%), 38.15(12.0%), 40.00(8.1 %), 41.28(10.4%), 43.26(7.5%), 46.34(14.8%), 50.19(8.5%), 53.95(9.2%), 56.00(5.7%)±0.2° 2θ.

[0147] Example 18: Debittering Study The results were recorded by individual panelists for each form, indicating their preference (like) and dislike (dislike) for consumption as tabulated below: The sensory test results showed a clear preference for the cocrystals of the present invention over pure theacrine, theobromine, methylliberine, caffeine, paraxanthine, and theophylline by all eight panelists, as the bitter taste of theacrine, theobromine, methylliberine, caffeine, paraxanthine, and theophylline is completely masked in the cocrystal form.

[0148] [Table 1]

[0149] As is evident from the above, a clear preference was shown by the panelists for the co-crystals of methylxanthine compounds over the pure methylxanthines, which conclusively indicates that the coformers pterostilbene and resveratrol de-bitter the methylxanthines.

[0150] Example 19: Co-crystal dissolution studies The dissolution data of various methylxanthine cocrystals with the pterostilbene / resveratrol system are expressed using zero-order kinetics, first-order kinetics, and diffusion kinetics, as illustrated in Figures 1 to 5. From the data, the dissolution patterns of the different cocrystal systems can be summarized as follows:

[0151] Zero-order kinetics: In all cases, curve plots of % dissolution as a function of time show that the dissolution rate does not follow zero-order kinetics, which means that the dissolution rate is independent of the amount of available active ingredient.

[0152] Solubility and release rate of active ingredients: From the figures below (1.A; 2.A; 3.A; and 4.A), it is clear that the methylxanthines, i.e., theacrine, methylliberine, caffeine, paraxanthine, and theophylline, in the form of cocrystals have lower solubility, slower release rate, and are therefore more bioavailable when compared to their pure forms. In the case of theobromine, the cocrystals provided improved solubility leading to better bioavailability compared to pure theobromine. The dissolution patterns of various cocrystal systems after a certain time in the graph are summarized below:

[0153] [Table 2]

[0154] While the present invention has been described in detail in the foregoing for purposes of illustration, it is to be understood that such details are for that purpose only and that modifications may be made therein by those skilled in the art without departing from the spirit and scope of the invention except as may be limited by the claims.

Claims

1. Co-crystals of methylxanthines with stilbenoids as coformers, and polymorphic forms thereof, which exhibit a pleasant taste and lack the bitter taste of methylxanthines.

2. 2. The cocrystal of claim 1, wherein the methylxanthine is selected from the group consisting of theacrine, theobromine, methylliberine, caffeine, paraxanthine, and theophylline, alone or in mixtures thereof.

3. 2. The co-crystal of claim 1, wherein the stilbenoid is selected from pterostilbene or resveratrol.

4. 4. The co-crystal of claim 1 or 3, wherein the debittering agent is pterostilbene and resveratrol.

5. 5. The co-crystal of any one of claims 1 to 4, which exhibits various polymorphs.

6. 6. The co-crystal of any one of claims 1 to 5, wherein the methylxanthine and the stilbenoid are in a ratio of 1:4 to 4:

1.

7. a methylxanthine selected from theacrine, theobromine, methylliberine, caffeine, paraxanthine or theophylline or a mixture thereof, together with a coformer selected from pterostilbene or resveratrol in a ratio of 1:4 to 4:1; 7. The co-crystal of any one of claims 1 to 6, wherein the co-crystal and its polymorphs exhibit a pleasant taste and lack the bitter taste of methylxanthines.

8. 8. The co-crystal of claim 7, wherein the methylxanthine and the stilbenoid are preferably in a ratio of 1:

1.

9. (a) Theacrine: Pterostilbene; (b) Theobromine: Pterostilbene; (c) Methylliberine: Pterostilbene; (d) Paraxanthine: Pterostilbene (e) Caffeine: Pterostilbene and (f) Theophylline: Resveratrol; 8. The co-crystal of claim 7, comprising:

10. Along with DSC showing a sharp endotherm at 146.22°C 1 10. The co-crystal of claim 9, comprising theacrine:pterostilbene (1:1), characterized by HNMR (400 MHz, dmso-d6): δ 3.19 (3H, s), 3.39 (3H, s), 3.52 (3H, s), 3.63 (3H, s), 3.76 (6H, s), 6.36 (1H, s), 6.70 (2H, s), 6.76 (2H, d, J = 8.4 Hz), 6.93 (1H, d, J = 16.4 Hz), 7.15 (1H, d, J = 16.4 Hz), 7.41 (2H, d, J = 8.4 Hz), 9.59 (1H, s);

11. Along with the DSC showing a sharp endotherm at 93.0°C 1 10. The co-crystal of claim 9, comprising theobromine:pterostilbene (1:1), characterized by HNMR (400 MHz, dmso-d6): δ 3.33 (3H, s), 3.76 (6H, s), 3.84 (3H, s), 6.36 (1H, t, J = 2.4 Hz), 6.71 (2H, t, J = 2.4 Hz), 6.77 (2H, d, J = 8.8 Hz), 6.94 (1H, d, J = 16.4 Hz), 7.15 (1H, d, J = 16.4 Hz), 7.41 (2H, d, J = 8.8 Hz), 7.97 (1H, s), 9.60 (1H, s), 11.12 (1H, s);

12. Along with DSC showing a sharp endotherm at 132.54℃ 1 10. The co-crystal of claim 9, comprising methylliberine:pterostilbene (1:1), characterized by HNMR (400 MHz, dmso-d6): δ 3.21 (3H, s), 3.31 (3H, s), 3.40 (3H, s), 3.76 (6H, s), 4.01 (3H, s), 6.36 (1H, t, J = 2 Hz), 6.71 (2H, d, J = 1.6 Hz), 6.76 (2H, d, J = 8.8 Hz), 6.93 (1H, d, J = 16.8 Hz), 7.15 (1H, d, J = 16.8 Hz), 7.41 (2H, d, J = 8.8 Hz), 9.59 (1H, s);

13. Along with a sharp endotherm at 117.30°C in DSC 1 10. The co-crystal of claim 9, comprising caffeine:pterostilbene (1:1), characterized by HNMR (400 MHz, DMSO-d): δ 3.20 (3H, s), 3.40 (3H, s), 3.76 (6H, s), 3.86 (3H, s), 6.36 (1H, t, J = 2.0 Hz), 6.71 (2H, d, J = 2.0 Hz), 6.76 (2H, d, J = 8.8 Hz), 6.93 (1H, d, J = 16.4 Hz), 7.15 (1H, d, J = 16.4 Hz), 7.41 (2H, d, J = 8.4 Hz), 7.99 (1H, s), 9.59 (1H, s);

14. 1 HNMR (400 MHz, dmso-d6): δ 3.17 (3H, s), 3.76 (6H, s), 3.85 (3H, s), 6.36 (1H, s), 6.71 (2H, s), 6.76 (2H, d, J = 8.4 Hz), 6.94 (1H, PXRD: 11.31 (12.8%), 15.88 (71.8%), 19.86 (18.7%), 21.28 (26.0%), 22.52 (33.6%), 24.9 (83.2%), 26.96 (100%), 29.00 (12.3%), 29.21 (19.3%), 30.41 (14.3%), 32.45 (9.9%), 38.8 (6.5%), 40.68 (5.2%), 44.84 (4.9%), 50.55 (3.6%), 55.48 (4.4%) ±0.2° 2θ. DSC: Sharp endotherm observed at 204.17°C 10. The cocrystal of claim 9, comprising paraxanthine:pterostilbene (1:1), characterized by:

15. Along with a DSC showing a sharp endotherm at 201.95°C 1 10. The co-crystal of claim 9, comprising theophylline:resveratrol (1:1), characterized by HNMR (400 MHz, dmso-d6): δ 3.24 (3H, s), 3.44 (3H, s), 6.12 (1H, t, J = 2 Hz), 6.39 (2H, d, J = 2 Hz), 6.75 (2H, d, J = 8.4 Hz), 6.81 (1H, d, J = 16.4 Hz), 6.92 (1H, d, J = 16.4 Hz), 7.38 (2H, d, J = 8.4 Hz), 8.04 (1H, s), 9.21 (2H, s), 9.54 (1H, s), 13.57 (1H, s);

16. Approximately 12.78(100%), 14.18(90.2%), 14.69(17.9%), 15.55(19.0%), 17.45(11.8%), 19.04(9.1%), 22.28(12.0%), 23.46(14.4%), 27.90(5.0%) , 28.80(5.6%), 29.50(7.3%), 31.50(7.6%), 33.04(10.1%), 38.90(14.2%), 41.02(6.1%), 41.93(4.7%), 53.16(4.5%), 72.73(8.4%)±0.2° 2θ.

10. The co-crystal of claim 9, comprising theacrine:pterostilbene co-crystal polymorph Form I, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at

17. Approximately 10.98(4.8%), 13.06(33.6%), 14.45(65.4%), 15.09(38.5%), 15.85(32.3%), 17.71(6.5%), 19.18(13.9%), 20. 21(28.7%), 21.44(6.8%), 22.58(11.1%), 23.73(9.5%), 26.40(59.7%), 27.21(100%), 28.29(10.0%), 29.12(2.

10. The cocrystal of claim 9, comprising theacrine:pterostilbene cocrystal polymorph Form II, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at 72.69 (2.5%), 73.73 (1%), 74.71 (2.7%), 75.00 (1.4%), 76.38 (1.8%), 77.41 (1.2%), 78.05 (1.7%), 79.61 (2.8%), 80.71 (2.4%), 82.69 (2.5%), 84.00 (1.4%), 85.00 (1.4%), 86.38 (1.8%), 87.41 (1.2%), 88.05 (1.7%), 84.61 (2.8%), 85.46 (2.4%), and 86.00 (2.5%) ± 0.2 degrees 2θ.

18. Approximately 12.90 (64.2%), 14.32 (100%), 15.64 (13.3%), 17.45 (8.2%), 19.17 (6.6%), 21.69 (10.5%), 22.38 (7.9%), 23.58 (10.0%), 25.07 (7.0%), 26.19 (6.1%), 26.98 (9.6%), 28.86 (1.9%), 29.59 (2.8%), 31.58 (2.7%), 33.12 (3.7%), 38.98 (7%), 41.10 (1.4%), 43.62 (1.1%), 47.80 (1.0%), and 72.70 (2.7%) ± 0.2°.

10. The co-crystal of claim 9, comprising theacrine:pterostilbene co-crystal polymorph Form III, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at 2θ.

19. Approximately 12.98(100%), 14.38(97.8%), 15.72(18.6%), 17.66(14.9%), 19.38(10.3%), 21.72(7.5%), 22.47(9.1%), 2 3.69(12.8%), 25.14(8.1%), 26.16(11.6%), 27.00(17.2%), 28.03(2.5%), 29.69(4.4%), 30.83(1.1%), 31.66 10. The cocrystal of claim 9, comprising theacrine:pterostilbene cocrystal polymorph Form IV, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at 47.30 (1.1%), 47.95 (1.9%), 49.04 (1.0%), 53.36 (1.5%), 72.68 (3.3%), and 88.31 (1.0%) ± 0.2 degrees 2θ.

20. 10. The cocrystal of claim 9, comprising theacrine:pterostilbene cocrystal polymorph Form V, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at about 12.83 (17.0%), 14.33 (100%), 15.72 (18.8%), 19.15 (3.5%), 20.06 (3.5%), 22.10 (8.8%), 23.55 (6.5%), 27.17 (5.8%), 31.73 (4.8%), 33.71 (2.0%), 37.88 (1.4%), 39.19 (6.2%), 41.07 (1.4%), 41.54 (2.2%), 43.86 (1.0%) ± 0.2 degrees 2θ.

21. Approximately 11.75 (30.21), 13.38 (63.19), 15.3 (77.89), 17.31 (10.20%), 19.35 (95.4%), 23.46 (44.32%), 26.98 (10 0%), 29.35(14.13%), 31.65(6.50%), 34.30(2.19%), 35.93(6.20%), 39.15(5.40%), 40.67(3.61%), 42.08( 10. The co-crystal of claim 9, comprising the theobromine:pterostilbene co-crystal polymorph Form I, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at: 44.61 (2.87%), 48.89 (2.4%), 50.06 (2.9%), 52.53 (2.36%), 55.83 (2.22%), 72.73 (6.96%), 88.42 (2.35%).

22. Approximately 12.25(87.7%), 13.33(100%), 15.52(24.8%), 16.44(6.6%), 17.98(6.0%), 19.99(16.5%), 21.12(8.6%), 21.99(5.2%), 23.93(4.5%), 25.44(6.6%), 27.05(11.1%), 28.76(3.9%), 34.75(3.8%), 37.81(5.8%), 40.49(3.0%), 42.78(4.9%), 44.64(3.9%), 72.73(5.8%)±0.2° 10. The cocrystal of claim 9, comprising methylliberin:pterostilbene cocrystal Form I, characterized by an X-ray powder diffraction pattern with one or more peaks at 2θ.

23. Approximately 12.43(68.3%), 13.49(100%), 15.65(11.9%), 16.60(11%), 18.12(4.6%), 20.13( 15.3%), 21.30(7.2%), 22.16(6.2%), 23.34(1.5%), 24.08(4.4%), 25.69(17%), 26 10. The cocrystal of claim 9, comprising methylliberine:pterostilbene cocrystal Form II, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at: 0.91 (16.8%), 27.31 (22.4%), 29.91 (1.3%), 30.82 (1.2%), 31.29 (1.6%), 34.51 (1.3%), 36.24 (1.4%), 37.94 (3.7%), 42.82 (1.0%), 44.67 (1.1%), 72.70 (2.5%) ± 0.2° 2θ.

24. 10. The cocrystal of claim 9, comprising methylliberine:pterostilbene cocrystal Form III, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at about 13.20 (100%), 15.35 (16.1%), 16.50 (11.8%), 17.90 (3.2%), 19.88 (13.3%), 20.83 (3.9%), 22.06 (5.0%), 23.05 (1.3%), 23.88 (4.1%), 25.60 (14.9%), 36.03 (1.1%), 42.05 (1.2%), and 72.67 (7.7%) ± 0.2 degrees 2θ.

25. Approximately 12.00 (43.3%), 12.48 (91.5%), 13.63 (84.8%), 15.32 (11.0%), 16.77 (24.7%), 18.34 (10.8 %), 19.02(11.1%), 20.22(20.4%), 21.44(16.9%), 22.32(14.8%), 23.34(3.9%), 24.24(10.

10. The cocrystal of claim 9, comprising methylliberine:pterostilbene cocrystal Form IV, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at: 25.84 (100%), 27.48 (81.2%), 33.31 (2.7%), 34.78 (5.1%), 35.01 (4.9%), 36.44 (3.5%), 38.10 (8.2%), 40.78 (1.5%), 43.12 (4.9%), 46.52 (2.7%), 47.75 (1.7%), 49.85 (1.4%) ± 0.2 degrees 2θ.

26. 11.90 (28.6%), 15.03 (100%), 16.81 (51.2%), 19.06 (53.5%), 21.65 (44.4%), 25.81 (94.2%), 26.35 (91.04%), 28.16 (10.4%), 29.54 (6.7%), 31.32 (4.8%), 32.52 (10.3%), 35.74 (3.6%), 36.99 (3.8%), 39.36 (3.7%), 40.93 (7.3%), 43.66 (5.7%), 45.45 (3.6%), 49.83 (2.1%), 72.74 (8.5%) and 88.35 (3.3%) ±0.2° 10. The co-crystal of claim 9, comprising caffeine:pterostilbene co-crystal Form I, characterized by an X-ray powder diffraction pattern with one or more peaks at 2θ.

27. 10. The co-crystal of claim 9, comprising caffeine:pterostilbene co-crystal polymorph Form II, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at about 12.83 (2.19%), 17.04 (5.43%), 19.41 (5.24%), 22.25 (6.28%), 26.31 (100%), 28.67 (3.8%), 30.04 (1.6%), 32.96 (2.3%), 41.34 (1.1%), and 53.94 (1.7%) ± 0.2 degrees 2θ.

28. 10. The co-crystal of claim 9, comprising caffeine:pterostilbene co-crystal polymorph Form III, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at about 10.53 (18.3%), 12.18 (4.9%), 14.01 (23.04%), 15.56 (25.3%), 17.22 (21.0%), 19.35 (16.7%), 22.13 (13.7%), 24.02 (4.3%), 26.51 (100%), 28.57 (20.4%), 30.22 (4.0%), 31.82 (4.1%), 36.23 (1.1%), 43.3 (1.8%), 46.52 (1.1%), 53.52 (1.1%), and 72.72 (2.2%) ± 0.2 degrees 2θ.

29. Approximately 12.00 (43.3%), 12.48 (91.5%), 13.63 (84.8%), 15.32 (11.0%), 16.77 (24.7%), 18.34 (10.8 %), 19.02(11.1%), 20.22(20.4%), 21.44(16.9%), 22.32(14.8%), 23.34(3.9%), 24.24(10.

10. The co-crystal of claim 9, comprising caffeine:pterostilbene cocrystal polymorph Form IV, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at: 25.84 (100%), 27.48 (81.2%), 33.31 (2.7%), 34.78 (5.1%), 35.01 (4.9%), 36.44 (3.5%), 38.10 (8.2%), 40.78 (1.5%), 43.12 (4.9%), 46.52 (2.7%), 47.75 (1.7%), 49.85 (1.4%) ± 0.2 degrees 2θ.

30. 10. The cocrystal of claim 9, comprising paraxanthine:pterostilbene cocrystal, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensity at about PXRD: 11.31 (12.8%), 15.88 (71.8%), 19.86 (18.7%), 21.28 (26.0%), 22.52 (33.6%), 24.9 (83.2%), 26.96 (100%), 29.00 (12.3%), 29.21 (19.3%), 30.41 (14.3%), 32.45 (9.9%), 38.8 (6.5%), 40.68 (5.2%), 44.84 (4.9%), 50.55 (3.6%), 55.48 (4.4%) ± 0.2 degrees 2θ.

31. About PXRD: 10.30(9.4%), 12.40(30.7%), 13.81(100%), 15.21(9.4%), 16.27(14.1%), 17.21(4.5%), 19.22( 21.1%), 20.76(13.0%), 22.30(8.4%), 23.52(8.4%), 24.84(47.9%), 25.36(33.6%), 26.64(7.4%) 10. The cocrystal of claim 9, comprising theophylline:resveratrol cocrystal, characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at 28.26 (8.6%), 30.68 (8.9%), 32.88 (3.3%), 34.96 (1.1%), 36.46 (1.5%), 37.61 (1.1%), 38.45 (2.0%), 39.84 (1.4%), 42.16 (2.3%), 45.91 (1.3%), 52.26 (1.3%), 72.73 (4.1%), and 88.35 (1.2%) ± 0.2 degrees 2θ.

32. (a) dissolving a coformer selected from stilbenoids in a solvent at 35-55°C to obtain a clear solution, followed by adding a methylxanthine; (b) stirring the above mixture at a temperature of 40-60°C to obtain a clear solution; (c) gradually cooling the solution to room temperature and maintaining said temperature for a period of 10 to 20 hours to allow precipitation of the co-crystals; and (d) allowing the formed co-crystals to settle and separate, followed by filtration, washing and drying 10. A process for the preparation of the co-crystal and polymorphs thereof of any one of claims 1 to 9, comprising:

33. 33. The process according to claim 32, wherein the solvent for the process is selected from C1 to C5 alcohols, water, acids selected from formic acid, acetic acid, propanoic acid, butyric acid; ethers; esters; ketones, etc., alone or in mixtures thereof.

34. 10. A method for the preparation of co-crystals according to any one of claims 1 to 9, wherein the co-crystals are prepared by mechanically grinding a mixture of a co-former selected from methylxanthines and stilbenoids to obtain the desired co-crystals.

35. 35. The method of claim 34, wherein the mechanical milling may be carried out in the presence or absence of a solvent.

36. 36. The method according to any one of claims 32 to 35, wherein the methylxanthine is selected from theacrine, theobromine, methylliberine, caffeine, paraxanthine and theophylline, alone or in mixtures thereof; and the stilbenoid is selected from pterostilbene or resveratrol, preferably in a 1:1 ratio.

37. 37. A method for masking the bitter taste of methylxanthines, comprising the formation of a co-crystal or a polymorph thereof with a coformer by the method of any one of claims 32 to 36.

38. 10. A dietary supplement or pharmaceutical composition comprising an effective amount of a co-crystal of a methylxanthine with a coformer selected from stilbenoids or a polymorph thereof according to any one of claims 1 to 9, and one or more acceptable excipients.

39. 39. The composition of claim 38, wherein the methylxanthine is selected from theacrine, theobromine, methylliberine, caffeine, paraxanthine, theophylline, etc., alone or in mixture; and the stilbenoid is selected from pterostilbene or resveratrol.

40. 39. The composition of claim 38, wherein the excipient is selected from one or more of binders, fillers, lubricants, emulsifiers, suspending agents, sweeteners, preservatives, buffers, wetting agents, disintegrants, diluents, binders, flavoring agents, coloring agents, suitable polymeric foaming agents, additives, and mixtures thereof.

41. 41. The composition of claim 40, wherein the additive is selected from the group consisting of microcrystalline cellulose, lactose, sucrose, fructose, glucose, dextrose, dibasic calcium phosphate, calcium sulfate, cellulose, methylcellulose, cellulose derivatives, kaolin, mannitol, lactitol, maltitol, xylitol, sorbitol, sugar alcohols, dry starch, dextrin, maltodextrin, polysaccharides, and mixtures thereof.

42. 10. A dietary supplement or pharmaceutical dosage form comprising a co-crystal of a methylxanthine with a coformer selected from stilbenoids or a polymorph thereof according to any one of claims 1 to 9.

43. 43. A dietary supplement or pharmaceutical dosage form as claimed in claim 42, wherein the methylxanthine is selected from the group consisting of theacrine, theobromine, methylliberine, caffeine, paraxanthine and theophylline, alone or in mixtures thereof; and the stilbenoid is selected from pterostilbene or resveratrol.

44. 41. The dietary supplement or pharmaceutical dosage form of claim 40, wherein the dosage form is an oral dosage form selected from the group consisting of a tablet, a capsule, a powder, a suspension, and a lozenge.

45. 10. A pharmaceutical composition for dermatological use comprising an effective amount of a cocrystal of a methylxanthine with a coformer selected from stilbenoids or a polymorph thereof according to any one of claims 1 to 9 and one or more acceptable excipients.

Images