Novel methylxanthine-based co-crystals, their polymorphs and methods thereof

Abstract

The present invention relates to co-crystals of methylxanthines and stilbenes as co-formations, their polymorphs and methods of preparation thereof. The debitterizing of methylxanthines is carried out by co-crystallization using stilbenes as co-formates. The invention also relates to the preparation of the polymorphic forms of the debittered co-crystals and their use in nutraceuticals and pharmaceutical compositions.

Description

Technical Field

[0001] The present invention relates to co-crystals of methylxanthines with stilbenes as coformers, their polymorphs and methods for their preparation. The debittering of methylxanthines is carried out by co-crystals using stilbenes as coformers. The present invention also relates to the preparation of polymorphs of the debittered co-crystals and their use in nutraceuticals and pharmaceutical compositions.

[0002] Background and Prior Art

[0003] Methylxanthines such as caffeine, theophylline, theobromine, methylcaproline, theophylline, paraxanthine are purine alkaloids that are said to have similar neuroenergetic effects. These are found in the seeds and leaves of various coffee (Coffea) species. Initially, caffeine accumulates in the young leaves of coffee trees, but as it grows into adult leaves, it is gradually replaced by theophylline, theobromine and methylcaproline.

[0004] Pterostilbene, chemically known as trans-3,5-dimethoxy-4'-hydroxystilbene, is a naturally occurring stilbene found in nature, such as many tree barks and various berries (including grapes), as well as plants commonly used in traditional folk medicine and structurally related to resveratrol. It is considered a nutraceutical with potential antioxidant, anticancer, anti-inflammatory, pro-apoptotic, anti-tumor, cytoprotective properties, and has also been reported to reduce plasma glucose levels and also reduce the LDL / HDL cholesterol ratio. Pterostilbene is reported to exert its antioxidant activity by scavenging reactive oxygen species (ROS) after administration, thereby preventing oxidative stress and ROS-induced cell damage.

[0005] US2009 / 0069444 describes the use of pterostilbene for improving oxidative stress and improving working memory and compositions comprising pterostilbene. As pterostilbene is believed to have health benefits; the consumption of foods containing this compound, such as berries and grapes, has increased.

[0006] WO 2011097372A3 discloses co-crystals of pterostilbene, including pterostilbene:caffeine co-crystals, pterostilbene:carbamazepine co-crystals, pterostilbene:glutaric acid co-crystals and pterostilbene:piperazine co-crystals.

[0007] 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 theophyllines, wherein the alkaline uric acid structure has been partially or fully methylated at the 2, 3 or 4 positions; and b) at least one aqueous buffer solution having a pH range of about 1.5-9.0.

[0008] EP3068240A1 discloses a dietary supplement comprising theophylline and optionally other active ingredients that modulate the effects of theophylline.

[0009] US20210100266 discloses an energy supplement composition comprising caffeine and methylcafrine.

[0010] Although methylxanthines are known to have very good health benefits, their use is limited due to their bitter taste and there is a need to mask the bitterness or to make these nutraceuticals edible by debittering them to improve palatability. Unacceptable palatability is a major problem in the development of nutraceuticals as it often hinders patient compliance. Therefore, masking the bitterness of methylxanthines is a major goal in the development of nutraceuticals and is widely considered a key aspect of modern drug development.

[0011] Co-crystallization of two or more pure nutraceutical compounds by crystal engineering to create a novel functional material with improved taste and bioavailability has great industrial significance for both the pharmaceutical and food industries. Therefore, there is still a need in the art to provide a composition comprising methylxanthines that has a good taste, is not bitter, and has improved bioavailability.

[0012] Purpose of the Invention

[0013] Therefore, an object of the present invention is to provide co-crystals of methylxanthines and stilbenes which have a good taste and are free from bitterness.

[0014] Another object of the present invention is to provide co-crystals of methylxanthines using stilbenes, more particularly pterostilbene and resveratrol as crystal formers for taste masking of methylxanthines.

[0015] A further object of the present invention is to provide a method for preparing co-crystals of methylxanthines using stilbenes, more particularly pterostilbene and resveratrol as crystal formers and compositions comprising the same.

[0016] A further object of the present invention is to provide a method for preparing polymorphic forms of co-crystals of methylxanthines with pterostilbene and resveratrol. Summary of the invention

[0017] According to the above object, the present invention provides co-crystals of methylxanthines and stilbenes as coformers and polymorphs thereof, wherein the co-crystals exhibit a pleasant taste and do not have the bitter taste of methylxanthines.

[0018] The methylxanthines are selected from the group consisting of theophylline, theobromine, methylcaproline, caffeine, paraxanthine and theophylline.

[0019] The stilbenes are selected from hydroxy derivatives of styrene, preferably pterostilbene and resveratrol.

[0020] In a preferred aspect, the present invention provides a debittered co-crystal of methylxanthines and stilbenes, comprising

[0021] (a) Theophylline: Pterostilbene

[0022] (b) Theobromine: Pterostilbene

[0023] (c) Methyl macrocaffeine: Pterostilbene

[0024] (d) Paraxanthine: Pterostilbene

[0025] (e) Caffeine: Pterostilbene and

[0026] (f) Theophylline: Resveratrol

[0027] The co-crystal exhibits a pleasant taste and does not contain the bitter taste of methylxanthines.

[0028] In another aspect, the methylxanthine and the coformer are present in the co-crystal in a molar ratio of 1:4 to 4:1, preferably 1:1.

[0029] In yet another aspect, the present invention provides novel co-crystals of theophylline and pterostilbene having co-crystal polymorphs Form 1, Form II, Form III, Form IV and Form V and methods for preparing the same.

[0030] Therefore, the present invention provides a crystalline theophylline: pterostilbene cocrystal polymorph I, which is characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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.

[0031] According to another aspect, the present invention provides a crystalline theophylline: pterostilbene cocrystal polymorph II, which is characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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 (2.7%), 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.

[0032] In another aspect, the present invention provides a crystalline theophylline: pterostilbene cocrystal polymorph III, which is characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: 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°2θ.

[0033] In yet another aspect, the present invention provides a crystalline theophylline: pterostilbene cocrystal polymorph IV, which is characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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(1.1%), 47.95(1.9%), 49.04(1.0%), 53.36(1.5%), 72.68(3.3%) and 88.31(1.0%) ±0.2°2θ.

[0034] On the other hand, the present invention provides a crystalline theophylline: pterostilbene cocrystal polymorph V, which is characterized by an X-ray powder diffraction pattern having one or more peaks and 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°2θ.

[0035] In yet another aspect, the present invention provides a crystalline theobromine: pterostilbene cocrystal polymorph I characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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 (2.2%), 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.

[0036] In yet another aspect, the present invention provides methyl macrocarpaline and pterostilbene cocrystal polymorphs Form 1, Form II, Form III and Form IV and methods for preparing the same.

[0037] In another aspect, the present invention provides a crystalline methyl macrocarpacine: pterostilbene cocrystal polymorph I characterized by an X-ray powder diffraction pattern having one or more peaks at: about 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°2θ.

[0038] In another aspect, the present invention provides a crystalline methyl macrocarpaline: pterostilbene cocrystal polymorph II characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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%), 26.91(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.

[0039] In another aspect, the present invention provides a crystalline methylcaproline: pterostilbene cocrystal polymorph 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° 2θ.

[0040] In another aspect, the present invention provides a crystalline methyl macrocarpacine: pterostilbene cocrystal polymorph IV characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at: about 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(10.5%), 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.

[0041] In yet another aspect, the present invention provides novel polymorphic forms Form 1, Form II, Form III and Form IV of caffeine and pterostilbene co-crystals and methods for preparing the same.

[0042] Therefore, the present invention provides a crystalline caffeine: pterostilbene cocrystal polymorph I, which is characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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.

[0043] In another aspect, the present invention provides a crystalline caffeine: pterostilbene cocrystal polymorph II characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at: approximately 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.

[0044] In another aspect, the present invention provides a crystalline caffeine: pterostilbene cocrystal polymorph III characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at: approximately 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.

[0045] In another aspect, the present invention provides a crystalline caffeine: pterostilbene cocrystal polymorph IV characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at: about 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.

[0046] In yet another aspect, the present invention provides a novel co-crystal of paraxanthine and pterostilbene and a method for preparing the same.

[0047] Therefore, 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°2θ.

[0048] In yet another aspect, the present invention provides novel co-crystals of theophylline:resveratrol and methods for preparing the same.

[0049] Thus, the co-crystal of theophylline:resveratrol is characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at about 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.

[0050] In one aspect, the present invention provides a method for preparing the debittered co-crystals of methylxanthines and polymorphs thereof, the method comprising:

[0051] (a) dissolving the coformer in a solvent at 35-55° C. to obtain a clear solution, followed by adding a methylxanthine;

[0052] (b) stirring the mixture at a temperature of 40-60° C. to obtain a clear solution;

[0053] (c) gradually cooling the solution to ambient temperature and maintaining the temperature for a period of 10-20 hours to allow co-crystallization; and

[0054] (d) isolating the co-crystals formed upon standing, followed by filtration, washing and drying.

[0055] The solvent of the method is selected from water, C1-C5 alcohol, lower organic acid such as formic acid, acetic acid, propionic acid, butyric acid, ether, ester, ketone, or a mixture thereof.

[0056] In an alternative aspect, a method of preparing the debittered co-crystal comprises mechanically grinding a mixture of methylxanthines and stilbenes in a molar ratio of 1:4 to 4:1, preferably 1:1 to obtain the desired co-crystal.

[0057] In another aspect, the present invention provides a method for masking the bitter taste of methylxanthines, the method comprising:

[0058] (a) dissolving the coformer in a solvent at 35-55° C. to obtain a clear solution, followed by adding a methylxanthine;

[0059] (b) stirring the mixture at a temperature of 40-60° C. to obtain a clear solution;

[0060] (c) gradually cooling the solution to ambient temperature and maintaining the temperature for a period of 10-20 hours to allow co-crystallization; and

[0061] (d) isolating the co-crystals formed upon standing, followed by filtration, washing and drying.

[0062] In yet another aspect, a method of masking the bitter taste of methylxanthines selected from theophylline, theobromine, methylcrocorine, caffeine, paraxanthine or theophylline comprises mechanically grinding a mixture of methylxanthines and pterostilbene or resveratrol in a molar ratio of 1:4 to 4:1, preferably 1:1 to obtain the desired debittered co-crystals.

[0063] In one aspect, mechanical grinding is performed in the presence or absence of a solvent. In yet another aspect, the coformer is slurried in an alcohol solvent or a mixture of an alcohol solvent and water or in an organic acid.

[0064] In yet another aspect, the present invention provides a nutraceutical / pharmaceutical composition comprising co-crystals of theophylline, theobromine, methylcaproline, caffeine, paraxanthine and theophylline and polymorphs thereof with one or more suitable carriers, wherein a coformer selected from pterostilbene or resveratrol masks the bitter taste of methylxanthines by blocking the receptors responsible for taste. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1. Depicts dissolution data for different theophylline-pterostilbene cocrystal systems plotted according to the 0th order equation (1.A.), the 1st order equation (1.B.), and the Higuchi square root equation (1.C.).

[0066] Figure 2. Dissolution data of different methylcaproline-pterostilbene cocrystal systems plotted according to the 0th order equation (2.A.), the 1st order equation (2.B.) and the Higgins square root equation (2.C.).

[0067] Figure 3. Dissolution data of different caffeine-pterostilbene cocrystal systems plotted according to the 0th order equation (3.A.), the 1st order equation (3.B.), and the Higgins square root equation (3.C.).

[0068] Figure 4. Dissolution data of theophylline-resveratrol cocrystal system plotted according to the 0th order equation (4.A.), the 1st order equation (4.B.), and the Higgins square root equation (4.C.).

[0069] Figure 5. Dissolution data of theobromine-pterostilbene cocrystal system plotted according to the 0th order equation.

[0070] Figure 6. Change in the % availability of active ingredient over time in various cocrystal systems. DETAILED DESCRIPTION

[0071] 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.

[0072] Pterostilbene, resveratrol, theophylline, theobromine, methylcroftan, paraxanthine, caffeine and theophylline used in the present invention are commercially available synthetic compounds.

[0073] The terms "coformer," "cocrystal," "nutraceutical," and "drug" are used in this application with the same meanings as used in the scientific literature.

[0074] Taste assessment is an increasingly important aspect in the development of any oral dosage form. Bitterness is the most problematic due to its intuitive association with toxicity. Various taste masking techniques exist to suppress bitterness, such as polymer coating, co-crystal formation or complexation with cyclodextrins.

[0075] The present inventors surprisingly found that when methylxanthines such as theophylline, theobromine, methylcaffeine, caffeine and paraxanthine are prepared into co-crystals using pterostilbene, or when theophylline is prepared into co-crystals using resveratrol, the bitterness of theophylline, theobromine, methylcaffeine, paraxanthine, caffeine and theophylline is completely reduced or eliminated.

[0076] In an embodiment, the present invention relates to co-crystals of methylxanthines with stilbenes as coformers, wherein the co-crystals exhibit a pleasant taste and lack the bitter taste of methylxanthines.

[0077] The methylxanthines are selected from the group consisting of theophylline, theobromine, methylcrocaffeine, paraxanthine, caffeine and theophylline.

[0078] In an embodiment, the present invention relates to co-crystals derived from coformers of methylxanthines selected from theophylline, theobromine, methylcrocarpine, paraxanthine, caffeine and theophylline, alone or in mixtures thereof, and selected from stilbenes, and their polymorphs;

[0079] The co-crystal exhibits a pleasant taste and does not contain the bitter taste of methylxanthines.

[0080] The stilbenes are selected from hydroxy derivatives of styrene, preferably pterostilbene and resveratrol.

[0081] In an embodiment, the present invention relates to co-crystals of methylxanthines and stilbenes as coformers, and polymorphs thereof, comprising:

[0082] (a) Theophylline: Pterostilbene

[0083] (b) Theobromine: Pterostilbene

[0084] (c) Methyl macrocaffeine: Pterostilbene

[0085] (d) Paraxanthine: Pterostilbene

[0086] (e) Caffeine: Pterostilbene and

[0087] (f) Theophylline: Resveratrol

[0088] The co-crystal exhibits a pleasant taste and does not contain the bitter taste of methylxanthines.

[0089] The methylxanthine and the coformer are present in the co-crystal in a molar ratio of 1:4 to 4:1, in particular in a ratio of 1:1.

[0090] In one embodiment, the cocrystal of theophylline: pterostilbene (1:1) is prepared by 1 HNMR (400MHz, dmso-d6) characterization: δ3.19 (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).

[0091] In another embodiment, the cocrystal of theobromine: pterostilbene (1:1) is prepared by1 HNMR (400MHz, dmso-d6) characterization: δ3.33 (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).

[0092] The cocrystal of methylcaproline: pterostilbene (1:1) was prepared by 1 HNMR (400MHz, dmso-d6) characterization: δ3.21 (3H, s), 3.31 (3H, s), 3.40 (3H, s), 3.76 (6H, s), 4.01 (3H, s), 6.36 (1H, t, J = 2Hz), 6.71 (2H, d, J = 1.6Hz), 6.76 (2H, d, J = 8.8Hz), 6.93 (1H, d, J = 16.8Hz), 7.15 (1H, d, J = 16.8Hz), 7.41 (2H, d, J = 8.8Hz), 9.59 (1H, s).

[0093] The cocrystal of caffeine: pterostilbene (1:1) was obtained by 1 HNMR (400MHz, DMSO-d6) characterization: δ3.20 (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).

[0094] The cocrystal of paraxanthine: pterostilbene (1:1) was prepared by 1 HNMR (400MHz, DMSO-d6) characterization: δ3.17 (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).

[0095] Theophylline:resveratrol (1:1) cocrystals were prepared by 1 HNMR (400MHz, dmso-d6) characterization: δ3.24 (3H, s), 3.44 (3H, s), 6.12 (1H, t, J = 2Hz), 6.39 (2H, d, J = 2Hz), 6.75 (2H, d, J = 8.4Hz), 6.81 (1H, d, J = 16.4Hz), 6.92 (1H, d, J = 16.4Hz), 7.38 (2H, d, J = 8.4Hz), 8.04, (1H, s) 9.21 (2H, s), 9.54 (1H, s), 13.57 (1H, s).

[0096] According to the same content, the present invention provides a method for debittering methylxanthines, which method comprises co-crystallizing methylxanthines with pterostilbene or with resveratrol in a ratio of 1:4 to 4:1, preferably a ratio of 1:1.

[0097] The co-crystallization process can be carried out with or without the use of a solvent.

[0098] In one aspect, the present invention provides a method for preparing co-crystals of methylxanthines and coformers and their polymorphs, the method comprising:

[0099] (a) dissolving the coformer in a solvent at 35-55° C. to obtain a clear solution, followed by adding a methylxanthine;

[0100] (b) stirring the mixture at a temperature of 40-60° C. to obtain a clear solution;

[0101] (c) gradually cooling the solution to ambient temperature and maintaining the temperature for a period of 10-20 hours to allow co-crystallization; and

[0102] (d) isolating the co-crystals formed upon standing, followed by filtration, washing and drying.

[0103] The solvent of the method is selected from water, C1-C5 alcohol, lower organic acid such as formic acid, acetic acid, propionic acid, butyric acid, ether, ester, ketone, or a mixture thereof.

[0104] In an alternative embodiment, the method for preparing debittered methylxanthines comprises mechanically grinding a mixture of methylxanthines and stilbenes in a molar ratio of 1:4 to 4:1, preferably 1:1.

[0105] In another embodiment, the present invention provides a method for masking the bitter taste of methylxanthines, comprising:

[0106] (a) dissolving a methylxanthine selected from theophylline, theobromine, methylcaproline, caffeine, paraxanthine or theophylline in a suitable solvent or solvent mixture, and then adding a coformer selected from pterostilbene or resveratrol in a molar ratio of 1:4 to 4:1, preferably 1:1;

[0107] (b) stirring the mixture until a clear solution is obtained;

[0108] (c) allowing the solution of step (a) to stand, isolating the co-crystals thus formed, followed by filtering, washing and drying to obtain the desired co-crystals.

[0109] In yet another embodiment, the method of masking the bitter taste of methylxanthines selected from theophylline, theobromine, methylcrocorine, caffeine, paraxanthine or theophylline comprises mechanically grinding a mixture of methylxanthines and pterostilbene or resveratrol in a molar ratio of 1:4 to 4:1, preferably a ratio of 1:1 to obtain the desired co-crystal.

[0110] Thus, in one embodiment, the present invention relates to a method for masking the bitter taste of theophylline by forming a co-crystal with pterostilbene as a coformer, the method involving dissolving theophylline and pterostilbene in a suitable solvent at a molar ratio of 1:4 to 4:1, preferably a ratio of 1: 1. In an alternative embodiment, the present invention discloses a method for masking the bitter taste of theophylline by forming a co-crystal with pterostilbene as a coformer, the method comprising mechanically grinding theophylline and pterostilbene at a molar ratio of 1:4 to 4:1, preferably a ratio of 1:1.

[0111] In another embodiment, the present invention discloses a method for masking the bitter taste of theobromine by forming co-crystals with pterostilbene as a coformer, the method involves dissolving theobromine and pterostilbene in a suitable solvent in a molar ratio of 1:4 to 4:1, preferably a ratio of 1: 1. In an alternative embodiment, the present invention relates to a method for masking the bitter taste of theobromine by forming co-crystals with pterostilbene as a coformer, the method comprises mechanically grinding theobromine and pterostilbene in a molar ratio of 1:4 to 4:1, preferably a ratio of 1:1.

[0112] In yet another embodiment, the present invention discloses a method for masking the bitter taste of methyl caffeine by forming a co-crystal with pterostilbene as a coformer, the method involving dissolving methyl caffeine and pterostilbene in a suitable solvent at a molar ratio of 1:4 to 4:1, preferably a ratio of 1:1. In an alternative embodiment, the present invention discloses a method for masking the bitter taste of methyl caffeine by forming a co-crystal with pterostilbene as a coformer, the method comprising mechanically grinding methyl caffeine and pterostilbene at a molar ratio of 1:4 to 4:1, preferably a ratio of 1:1.

[0113] In yet another embodiment, the present invention relates to a method for masking the bitter taste of caffeine by forming a novel polymorph of co-crystals with pterostilbene as a coformer, the method involving dissolving caffeine and pterostilbene in a suitable solvent in a molar ratio of 1:4 to 4:1, preferably 1:1. In an alternative embodiment, the present invention provides a method for masking the bitter taste of caffeine by forming a co-crystal with pterostilbene as a coformer, the method comprising mechanically grinding caffeine and pterostilbene in a molar ratio of 1:4 to 4:1, preferably a ratio of 1:1.

[0114] 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, the method involving dissolving paraxanthine and pterostilbene in a suitable solvent in a molar ratio of 1:4 to 4:1, preferably a ratio of 1:1. 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, the method comprising mechanically grinding paraxanthine and pterostilbene in a molar ratio of 1:4 to 4:1, preferably a ratio of 1:1.

[0115] In yet another embodiment, the present invention relates to a method for masking the bitter taste of theophylline by forming co-crystals with resveratrol as a coformer, the method involves dissolving theophylline and resveratrol in a suitable solvent in a molar ratio of 1:4 to 4:1, preferably a ratio of 1: 1. In an alternative embodiment, the present invention discloses a method for masking the bitter taste of theophylline by forming co-crystals with resveratrol as a coformer, the method comprising mechanically grinding theophylline and resveratrol in a molar ratio of 1:4 to 4:1, preferably a ratio of 1:1.

[0116] The solvent used in the process is selected from C1-C5 alcohols; water; acids such as formic acid, acetic acid, propionic acid, butyric acid; ethers, esters, ketones, etc., alone or in mixtures thereof.

[0117] In another embodiment, mechanical grinding is carried out in the presence or absence of a solvent. When a solvent is used, the solvent is selected from C1-C5 alcohols; water; acids such as formic acid, acetic acid, propionic acid, butyric acid; ethers, esters, ketones, etc., alone or in mixtures thereof.

[0118] In yet another embodiment, theophylline, theobromine, methylcrocodile caffeine, paraxanthine, caffeine, theophylline, pterostilbene and resveratrol used in the present invention are chemically synthesized compounds.

[0119] In yet another embodiment, the present invention provides a novel co-crystal of theophylline and pterostilbene.

[0120] In another embodiment, the present invention provides a process for preparing co-crystals of theophylline and pterostilbene in a 1:1 ratio and various polymorphic forms thereof.

[0121] In additional embodiments, the present invention provides polymorphic forms I, II, III, IV, and V of theophylline and pterostilbene cocrystals and methods for preparing the same.

[0122] Therefore, the present invention provides a crystalline theophylline: pterostilbene cocrystal polymorph I, which is characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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.

[0123] In another embodiment, the present invention discloses a crystalline theophylline: pterostilbene cocrystal polymorph II, which is characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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 (2.7%), 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.

[0124] In another embodiment, the present invention relates to a crystalline theophylline: pterostilbene cocrystal polymorph III, which is characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: 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°2θ.

[0125] According to another embodiment, the present invention discloses a crystalline theophylline: pterostilbene cocrystal polymorph IV, which is characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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(1.1%), 47.95(1.9%), 49.04(1.0%), 53.36(1.5%), 72.68(3.3%) and 88.31(1.0%) ±0.2°2θ.

[0126] In another embodiment, the present invention is directed to crystalline theophylline: pterostilbene cocrystal polymorph V, which is 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° 2θ.

[0127] In another embodiment, the present invention is directed to a crystalline theobromine: pterostilbene cocrystal characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at about 11.75 (30.21%), 13.38 (63.19%), 15.37 (7.89%), 17.31 (10.18%), 19.35 (95.4%), 23.46 (44.32%), 26.98 (100%), 29.35 (14.13%), 31 .65(6.47%), 34.30(2.19%), 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.

[0128] In another embodiment, the present invention provides a novel co-crystal of methyl macrocarpamine and pterostilbene. Therefore, in another embodiment, the present invention provides methyl macrocarpamine and pterostilbene co-crystal polymorphs 1, II, III and IV and methods for preparing the same.

[0129] According to another aspect, the present invention provides a crystalline methyl macrocarpacine: pterostilbene cocrystal polymorph I characterized by an X-ray powder diffraction pattern having one or more peaks at: about 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°2θ.

[0130] In another embodiment, the present invention discloses a crystalline methylcaproline: pterostilbene cocrystal polymorph II characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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%), 23.3 4(1.5%), 24.08(4.4%), 25.69(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.

[0131] In another embodiment, the present invention discloses a crystalline methylcaproline:pterostilbene cocrystal polymorph 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° 2θ.

[0132] In another embodiment, the present invention discloses a crystalline methyl macrocarpacine: pterostilbene cocrystal polymorph IV characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at about 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(10.5%), 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.

[0133] In additional embodiments, the present invention discloses novel polymorphs Form 1, Form II, Form III and Form IV of caffeine and pterostilbene co-crystals and methods for their preparation.

[0134] The polymorphs of the co-crystals of methylxanthines of the present invention are functionally similar to the co-crystals and mask the bitter taste of methylxanthines.

[0135] Therefore, the present invention relates to crystalline caffeine: pterostilbene cocrystal polymorph I, which is characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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.

[0136] In another embodiment, the present invention discloses a crystalline caffeine: pterostilbene cocrystal polymorph 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° 2θ,

[0137] In another embodiment, the present invention discloses a crystalline caffeine: pterostilbene cocrystal polymorph 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° 2θ.

[0138] According to another aspect, the present invention provides a crystalline caffeine: pterostilbene cocrystal polymorph IV characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at: about 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.

[0139] In another embodiment, the present invention discloses novel co-crystals of paraxanthine and pterostilbene.

[0140] Therefore, the co-crystal of paraxanthine and pterostilbene in a ratio of 1:1 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.

[0141] In another embodiment, the present invention discloses a novel co-crystal of theophylline and resveratrol. Therefore, the co-crystal of theophylline and resveratrol in a ratio of 1:1 is characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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.

[0142] These polymorphs are reliably characterized by the peak positions in the X-ray diffraction pattern, which produces a fingerprint of the crystalline form and enables it to be distinguished from all other crystalline and amorphous forms of theophylline or theophylline or theobromine or caffeine or paraxanthine and pterostilbene. The 2θ values ​​are measured with an accuracy within ±0.2 degrees. All powder diffraction patterns were measured on a PANalytical X'Pert3 X-ray powder diffractometer equipped with a copper-K-alpha radiation source.

[0143] In an embodiment, the present invention discloses a composition comprising an effective amount of a co-crystal of a coformer of a methylxanthine selected from theophylline, theobromine, methylcaproline, caffeine, paraxanthine and theophylline and a stilbene selected from theophylline or a polymorph thereof and one or more excipients.

[0144] The excipient is selected from one or more of the following: binders, fillers, lubricants, emulsifiers, suspending agents, sweeteners, preservatives, buffers, wetting agents, disintegrants, diluents, flavoring agents, colorants, suitable polymer effervescent agents, additives and mixtures thereof.

[0145] The additive is selected from the group consisting of microcrystalline cellulose, lactose, sucrose, fructose, glucose, dextrose, calcium hydrogen phosphate, calcium sulfate, cellulose, methyl cellulose, cellulose derivatives, kaolin, mannitol, lactitol, maltitol, xylitol, sorbitol, sugar alcohols, dry starch, dextrin, maltodextrin, polysaccharides and mixtures thereof.

[0146] In yet another embodiment, the present invention relates to a nutraceutical or pharmaceutical dosage form comprising a co-crystal of a coformer of a methylxanthine selected from theophylline, theobromine, methylcrocarpine, caffeine, paraxanthine and theophylline and a stilbene selected from theophylline or a polymorph thereof.

[0147] In another embodiment, the present invention relates to a pharmaceutical composition for dermatological use, comprising an effective amount of a co-crystal of a coformer of a methylxanthine selected from theophylline, theobromine, methylcaproline, caffeine, paraxanthine and theophylline and a stilbene selected from theophylline or a polymorph thereof and one or more excipients.

[0148] The nutraceutical or pharmaceutical dosage form, wherein the dosage form is an oral dosage form selected from the group consisting of tablets, capsules, powders, suspensions and lozenges.

[0149] The coformer selected from pterostilbene or resveratrol used in the present invention masks the bitter taste of methylxanthines by blocking the receptors responsible for taste perception.

[0150] Taste is the sensation achieved when a nutraceutical or a drug is placed in the mouth. Preference tests provide information on whether the tester likes or dislikes the product. Taste evaluation tests are designed by using statistical tools to minimize or reduce the bias in responses within and between human volunteers. For sensory analysis, one of the important parts is testing the taste buds of healthy volunteers.

[0151] Smell, taste and texture are the three main components that affect the palatability of a product. Palatability refers to the voluntary acceptance and consumption of a pharmaceutical composition, which can be measured by acceptance, preference and consumption tests, and when a substance has a voluntary acceptance rate of 90% or more among the test subjects; the product is considered palatable.

[0152] Therefore, round table evaluations were performed every six days by a group of eight panelists. The panelists were asked to take water and unsalted crackers to cleanse their palates before the test.

[0153] On the first day, all panelists took theophylline and equal concentrations (quantities) of theophylline: pterostilbene cocrystals for sensory analysis.

[0154] On the second day, all panelists took theobromine and an equal concentration (amount) of theobromine:pterostilbene co-crystal for sensory analysis.

[0155] On the third day, all panelists took caffeine and an equal concentration (amount) of caffeine:pterostilbene cocrystal for sensory analysis.

[0156] On the fourth day, all panelists were given caffeine and an equal concentration (amount) of caffeine:pterostilbene co-crystal for sensory analysis.

[0157] On the fifth day, all panelists were given paraxanthine and an equal concentration (amount) of paraxanthine:pterostilbene co-crystal for sensory analysis.

[0158] On the sixth day, all panelists took theophylline and equal concentrations (amounts) of theophylline:resveratrol co-crystals for sensory analysis.

[0159] The results were recorded by each panelist in their own form, indicating their preference (like) and dislike (dislike) for taking. The results of the sensory test showed that all eight panelists had a clear preference for the co-crystals of the present invention compared to pure theophylline, theobromine, methyl-caffeine, caffeine, paraxanthine and theophylline, because the bitter taste of theophylline, theobromine, methyl-caffeine, caffeine, paraxanthine and theophylline was completely masked in the co-crystal form. The results are provided in Table 1 below.

[0160] As is evident from the table below, the panelists showed a clear preference for the co-crystallized methylxanthines compared to the pure methylxanthines, which ultimately suggests that pterostilbene and resveratrol de-bitter the methylxanthines by masking their bitter taste.

[0161] In other embodiments, the co-crystal compositions of the present invention produce various health benefits based on the dosage form, such as improved memory, alertness, concentration, relaxation, enhanced energy and endurance.

[0162] Furthermore, the crystal formers, namely pterostilbene and resveratrol, are safe and tested nutraceuticals and thus synergistically improve the nutraceutical effects of theophylline, theobromine, methylcrocarpine, caffeine, paraxanthine and theophylline.

[0163] In an embodiment, dissolution studies of co-crystals of methylxanthines with the coformers pterostilbene and resveratrol were evaluated. It was observed that in all cases, the dissolution rate did not follow zero-order kinetics, which means that the dissolution rate was independent of the available amount of active ingredient. Compared to its pure form, the co-crystals had lower solubility, slower release rate, and therefore higher bioavailability (Figures 1 to 6).

[0164] experiment:

[0165] The following examples, including preferred embodiments, will serve to illustrate the practice of the invention, it being understood that the details shown are exemplary and for purposes of illustrative discussion of preferred embodiments of the invention.

[0166] General method for eutectic synthesis:

[0167] A general synthetic method for preparing novel co-crystals, the process includes adding the co-former (pterostilbene or resveratrol) to a suitable solvent and dissolving at 45-50°C to obtain a clear solution, followed by adding methylxanthines (theophylline, theobromine, methylcaproline, paraxanthine, caffeine and theophylline). Stirring is continued for 30 min at 45-50°C to obtain a clear solution. The reaction mass is gradually cooled to ambient temperature and maintained at the same temperature for 12-18 hours to crystallize the corresponding co-crystals. Suitable solvents that can be applied to synthesize co-crystals are selected from the group including: C1-5 alcohols, water, formic acid, acetic acid, propionic acid, butyric acid; ethers, esters, ketones, etc. alone or in mixtures thereof. The following additional techniques can also be used to prepare the methylxanthine co-crystals of the present invention; neat grinding, solvent drip grinding, reactive crystallization, anti-solvent addition, cooling crystallization and slow solvent evaporation.

[0168] Example:

[0169] Example-1: Preparation of theophylline: Pterostilbene (1:1) cocrystal (Form I): To a stirred solution of theophylline (5.0 g, 22.3 mmol) in a mixture of water (20 mL) and methanol (30 mL) was added pterostilbene (5.72 g, 22.3 mmol) at 65-70°C and the mixture was stirred until it became a clear solution. It was allowed to stand at room temperature for 24 h, during which time crystals were separated. It was filtered, washed with a water: methanol mixture (3 mL, 1:1.5) and dried in a vacuum oven at 40-45°C. Yield: 9.82 g, mp: 143-145°C. 1HNMR(400MHz,dmso-d6): δ3.19(3H,s),3.39(3H,s),3.52(3H,s),3.63(3H,s),3.76(6H,s),6.36(1H,s),6.70(2 H, 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.

[0170] Example-2: Preparation of Theobromine: Pterostilbene (1:1) Co-crystal: 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 h. It was dried in an oven at 40-45°C under vacuum. 1HNMR (400MHz, dmso-d6): δ3.33(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). 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%), 35.9 3 (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.

[0171] Example-3: Preparation of Methyl Macrocaffeine: Pterostilbene (1:1) Cocrystal (Form I): To a stirred solution of methyl macrocaffeine (5.80 g, 25.9 mmol) in a mixture of water (10 mL) and methanol (30 mL) was added pterostilbene (6.63 g, 25.9 mmol) at 65-70°C and the mixture was stirred at the same temperature until it became a clear solution. It was warmed to room temperature and allowed to stand at room temperature for 24 h, during which time crystals were 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 (400MHz, dmso-d6): δ3.21(3H,s),3.31(3H,s),3.40(3H,s),3.76(6H,s),4.01(3H,s),6.36(1H,t,J=2Hz),6.71(2H ,d,J=1.6Hz), 6.76(2H,d,J=8.8Hz), 6.93(1H,d,J=16.8Hz), 7.15(1H,d,J=16.8Hz), 7.41(2H,d,J=8.8Hz), 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.

[0172] 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) was added resveratrol (0.63 g, 2.8 mmol) at 80-83°C and the mixture was stirred at the same temperature until it became clear. The clear solution was allowed to stand at room temperature for 24 h, during which time crystals were separated. It was filtered, washed with water:ethanol mixture (3 mL, (1:3)) and dried in a vacuum oven at 40-45°C. Yield: 0.79 g, mp: 201-216°C. 1HNMR (400MHz, dmso-d6): δ3.24(3H,s), 3.44(3H,s), 6.12(1H,t,J=2Hz), 6.39(2H,d,J=2Hz), 6.75(2H,d,J=8.4Hz), 6.8 1(1H,d,J=16.4Hz), 6.92(1H,d,J=16.4Hz), 7.38(2H,d,J=8.4Hz), 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.

[0173] 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) was added pterostilbene (6.6 g, 25.7 mmol) at 65-70°C and the mixture was stirred until it became a clear solution. It was allowed to stand at room temperature for 15 h, during which time crystals separated. It was filtered, washed with a water:methanol mixture (3 mL, 1:1.5) and dried in a vacuum oven at 40-45°C. Yield: 10.8 g, mp: 116-120°C. 1HNMR (400MHz, DMSO-d6): δ3.20(3H,s),3.40(3H,s),3.76(6H,s),3.86(3H,s),6.36(1H,t,J=2.0Hz),6.71(2H,d,J=2.0Hz ), 6.76 (2H, d, J = 8.8Hz), 6.93 (1H, d, J = 16.4Hz), 7.15 (1H, d, J = 16.4Hz), 7.41 (2H, d, J = 8.4Hz), 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%), 2 5.81 (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.

[0174] 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 h. It was dried in a vacuum oven at 40-45°C. Yield (0.120 g), mp: 193.4-207.8°C. 1 HNMR (400MHz, dmso-d6): δ 1HNMR (400MHz, DMSO-d6): δ3.17(3H,s),3.76(6H,s),3.85(3H,s),6.36(1H,s),6.71(2H,s),6.76(2H,d,J=8.4Hz),6.94 (1H,d,J=16.8Hz),7.15(1H,d,J=16.4Hz),7.41(2H,d,J=8.0Hz),7.92(1H,s),9.59(1H,s),11.84(1H,s),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.

[0175] Polymorph

[0176] Example 7: Preparation of theophylline and pterostilbene cocrystal: polymorph II

[0177] At 65-70°C, pterostilbene (2.29 g, 8.9 mmol) was added to a stirred solution of theophylline (2.0 g, 8.9 mmol) in a mixture of water (3 mL) and ethanol (10 mL), and the mixture was stirred continuously until it became a clear solution. It was allowed to stand at room temperature for 24 h, during which time crystals were separated. It was filtered, washed with a water: ethanol mixture (3 mL, 1:3) and dried in a vacuum oven at 40-45°C. 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.

[0178] Example 8: Preparation of theophylline and pterostilbene cocrystal: polymorph III

[0179] At 65-70°C, pterostilbene (2.29 g, 8.9 mmol) was added to a stirred solution of theophylline (2.0 g, 8.9 mmol) in a mixture of water (4 mL) and acetone (4 mL), and the mixture was stirred continuously until it became a clear solution. It was allowed to stand at room temperature for 24 h, during which time crystals were separated. It was filtered, washed with a water: acetone mixture (3 mL, 1: 1) and dried in a vacuum oven at 40-45°C. 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.

[0180] Example 9: Preparation of theophylline and pterostilbene cocrystal: polymorph IV.

[0181] To a stirred solution of theophylline (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 it became a clear solution. It was allowed to stand at room temperature for 24 h, during which time crystals were separated. It was filtered, washed with a water: isopropanol mixture (3 mL, 1:2.5) and dried in a vacuum oven at 40-45°C. 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%), 31.6 6(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.

[0182] Example 10: Preparation of theophylline and pterostilbene cocrystal: polymorph-V.

[0183] Pterostilbene (2.29 g, 8.9 mol) was added to a stirred solution of theophylline (2.0 g, 8.9 mol) in formic acid (3 mL) at 65-70°C and the mixture was stirred continuously until it became a clear solution. It was allowed to stand at room temperature for 24 h, during which time crystals were separated. It was filtered and washed with water and dried in a vacuum oven at 40-45°C. 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.

[0184] Example 11: Preparation of methyl macrocarpine and pterostilbene cocrystal: polymorph-II. To a stirred solution of methyl macrocarpine (2.0 g, 8.9 mmol) in a mixture of water (3 mL) and ethanol (10 mL) was added pterostilbene (2.29 g, 8.9 mmol) at 65-70°C and the mixture was stirred until it became a clear solution. It was allowed to stand at room temperature for 24 h, during which time the crystals were separated. It was filtered, washed with a water:methanol mixture (3 mL, 1:3) and dried in an oven under vacuum at 40-45°C. 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%), 20.1 3(15.4%), 21.30(7.2%), 22.16(6.3%), 23.34(1.6%), 24.08(4.4%), 25.69(17.1%), 26.91(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.

[0185] Example 12: Preparation of methyl macrocarpaline and pterostilbene (1:1) co-crystal: polymorph-III.

[0186] To a stirred solution of methyl macrocarpaline (2.0 g, 8.9 mmol) in a mixture of water (4 mL) and acetone (4 mL) was added pterostilbene (2.29 g, 8.9 mmol) at 65-70°C and the mixture was stirred at this temperature until it became a clear solution. It was left to stand at room temperature for 24 h, during which time crystals separated. It was filtered, washed with a water:methanol mixture (3 mL, 1:3) and dried in an oven under vacuum at 40-45°C. 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.

[0187] Example 13: Preparation of Methylcaproline and Pterostilbene Cocrystal: Polymorph IV

[0188] To a stirred solution of methyl macrocarpaline (2.0 g, 8.9 mmol) in formic acid (3 mL) was added pterostilbene (2.29 g, 8.9 mmol) at 65-70°C and the mixture was stirred at the same temperature until it became a clear solution. It was allowed to stand at room temperature for 24 h, during which time crystals separated. It was filtered, washed with a water:methanol mixture (3 mL, 1:3) and dried in an oven under vacuum at 40-45°C. 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%), 3 8.10 (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.

[0189] Example 14: Preparation of caffeine and pterostilbene co-crystal: polymorph-I.

[0190] 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 it became a clear solution. It was allowed to stand at room temperature for 15 h, during which time crystals separated. It was filtered, washed with a water: methanol mixture (3 mL, 1:1.5) and dried in a vacuum 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.

[0191] Example 15: Preparation of caffeine and pterostilbene co-crystal: polymorph-II.

[0192] To a stirred solution of caffeine (2.0 g, 10.29 mmol) in formic acid (3 mL) was added pterostilbene (2.63 g, 10.29 mmol) at 75-80°C and the mixture was stirred until it became a clear solution. It was allowed to stand at room temperature for 15 h, during which time crystals separated. It was filtered and dried in an oven under vacuum 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.

[0193] Example 16: Preparation of Caffeine and Pterostilbene Cocrystal: Polymorph-III. To a stirred solution of caffeine (2.0 g, 10.29 mmol) in acetic acid (4 mL) was added pterostilbene (2.63 g, 10.29 mmol) at 75-80°C and the mixture was stirred until it became a clear solution. It was allowed to stand at room temperature for 15 h, during which time crystals separated. It was filtered and dried in an oven under vacuum 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.

[0194] Example 17: Preparation of caffeine and pterostilbene co-crystal: polymorph-IV.

[0195] 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 it became a clear solution. It was allowed to stand at room temperature for 15 h, during which time crystals separated. It was filtered, washed with a water:ethanol mixture (3 mL, 1:1.5) and dried in an oven under vacuum at 40-45°C. Yield: 3.9 g, mp: 119-122°C. PXRD 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.

[0196] Example 18: Debittering Study

[0197] The results were recorded by each panelist in their own form, indicating their preference (like) or dislike (dislike) for taking, as shown in the table below. The results of the sensory test showed that all eight panelists had a clear preference for the co-crystals of the present invention compared to pure theophylline, theobromine, methyl-caffeine, caffeine, paraxanthine and theophylline, because the bitter taste of theophylline, theobromine, methyl-caffeine, caffeine, paraxanthine and theophylline was completely masked in the co-crystal form.

[0198]

[0199] Note: Theophylline (TC); Theobromine (TB); Methylcaproline (ML); Caffeine (CA), Paraxanthine (PX); Theophylline (TP); Pterostilbene (PB); Resveratrol (RS)

[0200] As is evident from the above, the panelists expressed a clear preference for cocrystals of methylxanthines compared to pure methylxanthines, which ultimately suggests that the coformers pterostilbene and resveratrol debitter the methylxanthines.

[0201] Example 19: Dissolution study of eutectic

[0202] The dissolution data of various methylxanthine cocrystals and pterostilbene / resveratrol systems are represented using 0th-order reaction rates, 1st-order reaction rates, and diffusion kinetics, as shown in Figures 1 to 5. Based on the data, the dissolution patterns of different cocrystal systems are summarized as follows:

[0203] Zero Order Kinetics: In all cases, the plots of % Dissolution versus time indicate that the dissolution rate does not follow zero order kinetics, meaning that the dissolution rate is independent of the available amount of active ingredient.

[0204] Solubility and release rate of active ingredients: From the following Figure (1.A ; 2.A; 3.A and 4.A) it is apparent that the methylxanthines, i.e. theophylline, methylcaproline, caffeine, paraxanthine and theophylline, in cocrystal form, have lower solubility, slower release rate and therefore higher bioavailability when compared to their pure forms. In the case of theobromine, the cocrystals provide improved solubility compared to pure theobromine, leading to better bioavailability. The dissolution patterns of the various cocrystal systems after a certain period of time are summarized in the figure as follows:

[0205]

[0206] Although the present invention has been described in detail above for purposes of illustration, it should be understood that such details are for that purpose only and variations may be made therein by those skilled in the art without departing from the spirit and scope of the present invention, unless it may be limited by the claims.

Claims

1. Cocrystals of methylxanthines and stilbenes as coformers and polymorphs thereof, wherein: The co-crystals exhibit a pleasant taste and lack the bitter taste of methylxanthines.

2. The eutectic according to claim 1, wherein The methylxanthines are selected from theophylline, theobromine, methyl caffeine, caffeine, paraxanthine or theophylline, etc., alone or in a mixture thereof.

3. The eutectic according to claim 1, wherein The stilbenes are selected from pterostilbene or resveratrol.

4. The eutectic according to claim 1 and 3, wherein The debittering agents are pterostilbene and resveratrol.

5. The co-crystal according to claim 1, wherein: The co-crystals exhibit various polymorphic forms.

6. The eutectic according to claims 1 to 5, wherein: The ratio of the methylxanthines to the stilbenes is 1:4 to 4:

1.

7. A co-crystal according to any one of claims 1 to 6, comprising a coformer of a methylxanthine selected from theophylline, theobromine, methylcrocorine, caffeine, paraxanthine or theophylline or a mixture thereof and selected from pterostilbene or resveratrol in a ratio of 1:4 to 4:1; in, The co-crystal and its polymorphs exhibit a pleasant taste and are free of the bitter taste of methylxanthines.

8. The eutectic according to claim 7, wherein: The ratio of the methylxanthines to the stilbenes is preferably 1:

1.

9. The eutectic of claim 7, comprising: (a) Theophylline: Pterostilbene; (b) Theobromine: Pterostilbene; (c) Methyl macrocarpon: pterostilbene; (d) Paraxanthine: Pterostilbene (e) Caffeine: Pterostilbene and (f) Theophylline: Resveratrol; The co-crystal exhibits a pleasant taste and does not contain the bitter taste of methylxanthines.

10. The co-crystal according to claim 9, comprising theophylline: pterostilbene (1:1), 1 HNMR (400MHz, dmso-d6) characterization: δ3.19 (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); DSC showed a sharp endotherm at 146.22°C.

11. The co-crystal of claim 9, comprising theobromine: pterostilbene (1:1), 1 HNMR (400MHz, dmso-d6) characterization: δ3.33 (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); DSC showed a sharp endotherm at 93.0°C.

12. The co-crystal according to claim 9, comprising methyl caffeine: pterostilbene (1:1), 1 HNMR (400MHz, dmso-d6) characterization: δ3.21 (3H, s), 3.31 (3H, s), 3.40 (3H, s), 3.76 (6H, s), 4.01 (3H, s), 6.36 (1H, t, J = 2Hz), 6.71 (2H, d, J = 1.6Hz), 6.76 (2H, d, J = 8.8Hz), 6.93 (1H, d, J = 16.8Hz), 7.15 (1H, d, J = 16.8Hz), 7.41 (2H, d, J = 8.8Hz), 9.59 (1H, s); DSC showed a sharp endotherm at 132.54°C.

13. The co-crystal of claim 9, comprising caffeine: pterostilbene (1:1), 1 HNMR (400MHz, DMSO-d6) characterization: δ3.20 (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); DSC showed a sharp endotherm at 117.30 °C.

14. The co-crystal of claim 9, comprising paraxanthine: pterostilbene (1:1), 1 HNMR (400MHz, dmso-d6) characterization: δ3.17 (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), 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.

15. The co-crystal of claim 9, comprising theophylline:resveratrol (1:1), 1 HNMR (400MHz, dmso-d6) characterization: δ3.24 (3H, s), 3.44 (3H, s), 6.12 (1H, t, J = 2Hz), 6.39 (2H, d, J = 2Hz), 6.75 (2H, d, J = 8.4Hz), 6.81 (1H, d, J = 16.4Hz), 6.92 (1H, d, J = 16.4Hz), 7.38 (2H, d, J = 8.4Hz), 8.04, (1H, s) 9.21 (2H, s), 9.54 (1H, s), 13.57 (1H, s); DSC showed a sharp endotherm at 201.95℃.

16. The co-crystal of claim 9, comprising theophylline: pterostilbene co-crystal polymorph I, characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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.

17. The co-crystal of claim 9, comprising theophylline: pterostilbene co-crystal polymorph II, characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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 (1 3.9%), 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 (2.7%), 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.

18. The cocrystal of claim 9, comprising theophylline: pterostilbene cocrystal polymorph III, characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: 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° 2θ.

19. The cocrystal of claim 9, comprising theophylline: pterostilbene cocrystal polymorph IV, characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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(1.1%), 47.95(1.9%), 49.04(1.0%), 53.36(1.5%), 72.68(3.3%) and 88.31(1.0%) ±0.2°2θ.

20. The cocrystal of claim 9, comprising theophylline: pterostilbene cocrystal polymorph 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° 2θ.

21. The cocrystal of claim 9, comprising theobromine: pterostilbene cocrystal polymorph I characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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 (100%), 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(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％)。 22. The cocrystal of claim 9, comprising methyl caffeine: pterostilbene cocrystal Form I characterized by an X-ray powder diffraction pattern having one or more peaks at about 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°2θ.

23. The cocrystal of claim 9, comprising methyl caffeine: pterostilbene cocrystal Form II characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at: about 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%), 26.91(16.8%), 27.31(22.4%), 29.91(1.3%), 30.82(1.2%), 31.2 9(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. The cocrystal of claim 9, comprising methyl macrocarpaline: 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° 2θ.

25. The cocrystal of claim 9, comprising methyl caffeine: pterostilbene cocrystal Form IV characterized by an X-ray powder diffraction pattern having one or more peaks and relative intensities at about 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(10.5％)、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.

26. The cocrystal of claim 9, comprising caffeine: pterostilbene cocrystal Form I characterized by an X-ray powder diffraction pattern having one or more peaks at: 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.

27. The co-crystal of claim 9, comprising caffeine: pterostilbene cocrystal polymorph 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° 2θ.

28. The cocrystal of claim 9, comprising caffeine: pterostilbene cocrystal polymorph 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° 2θ.

29. The cocrystal of claim 9, comprising caffeine: pterostilbene cocrystal polymorph IV characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at about 12.00 (43.3%), 12.48 (91.5%), 13.63 (84.8%), 15.32 (11.0%), 16.77 (24.7%), 18.34 (10.8%), 1 9.02 (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.

30. The co-crystal of claim 9, comprising a paraxanthine: pterostilbene co-crystal characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities 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°2θ.

31. The co-crystal of claim 9, comprising a theophylline:resveratrol co-crystal characterized by an X-ray powder diffraction pattern having one or more peaks with relative intensities at 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%), 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.

32. A method for preparing the co-crystal and polymorphs thereof according to claims 1-9, the method comprising: (a) dissolving a coformer selected from stilbenes 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 ambient temperature and maintaining the temperature for a period of 10-20 hours to allow the eutectic to precipitate; and (d) isolating the co-crystals formed upon standing, followed by filtering, washing and drying.

33. The method of claim 32, wherein: The solvent used in the method is selected from C1-C5 alcohol, water, acid selected from formic acid, acetic acid, propionic acid, butyric acid; ether; ester; ketone, etc., alone or in mixtures thereof.

34. A method for preparing the co-crystal according to claims 1-9, wherein: The co-crystals may be prepared by mechanically grinding a mixture of methylxanthines and coformers selected from stilbenes to obtain the desired co-crystals.

35. The method of claim 34, wherein: The mechanical grinding can be performed in the presence or absence of a solvent.

36. The method according to any one of claims 32 to 35, wherein: The methylxanthines are selected from theophylline, theobromine, methylcaproline, caffeine, paraxanthine and theophylline, etc., alone or in a mixture thereof; the stilbenes are selected from pterostilbene or resveratrol, preferably in a 1:1 ratio.

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

38. A nutraceutical or pharmaceutical composition comprising an effective amount of a co-crystal of a coformer of a methylxanthine and a stilbene selected from claims 1 to 9 or a polymorph thereof and one or more acceptable excipients.

39. The composition according to claim 38, wherein The methylxanthines are selected from the methylxanthines selected from theophylline, theobromine, methylcaproline, caffeine, paraxanthine and theophylline, etc., alone or in mixtures thereof; the stilbenes are selected from pterostilbene or resveratrol.

40. The composition according to claim 38, wherein The excipient is selected from one or more of the following: binders, fillers, lubricants, emulsifiers, suspending agents, sweeteners, preservatives, buffers, wetting agents, disintegrants, diluents, binders, flavoring agents, colorants, suitable polymer effervescent agents, one or more of additives, and mixtures thereof.

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

42. A nutraceutical or pharmaceutical dosage form comprising a co-crystal of a coformer of a methylxanthine selected from stilbenes as claimed in claims 1 to 9 or a polymorph thereof.

43. The nutritional product or pharmaceutical dosage form of claim 42, wherein: The methylxanthines are selected from theophylline, theobromine, methylcaproline, caffeine, paraxanthine and theophylline, etc., alone or in a mixture thereof; the stilbenes are selected from pterostilbene or resveratrol.

44. The nutritional product or pharmaceutical dosage form of claim 40, wherein: The dosage form is an oral dosage form selected from the group consisting of tablets, capsules, powders, suspensions and lozenges.

45. A pharmaceutical composition for use in dermatology, comprising an effective amount of a co-crystal of a coformer of a methylxanthine and a stilbene selected from claims 1 to 9 or a polymorph thereof and one or more acceptable excipients.

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