A co-crystal of lutein and adipic acid, and a preparation method and use thereof

Abstract

The application discloses a lutein and adipic acid co-crystal and a preparation method and application thereof, wherein a stoichiometric ratio of lutein and adipic acid in the co-crystal is 1:1. The preparation method of the co-crystal disclosed by the application has the advantages of low cost, environmental friendliness, easy control and good reproducibility. Moreover, compared with lutein itself, the co-crystal disclosed by the application has more excellent chemical stability, greatly improves the application convenience of lutein, saves the cost in the storage, transportation and use process, and can further widen the application range of lutein.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of lutein, in particular to a lutein and adipic acid co-crystal, a preparation method and application thereof. BACKGROUND

[0002] Lutein, also known as "plant lutein", is a natural pigment widely existing in vegetables, flowers, fruits and some algae. Lutein is the main pigment in the macular region of the human eye retina, can filter blue light, prevent retinal damage, and has a positive effect on maintaining eye health and protecting vision. In recent years, a large number of studies have shown that lutein also has the effects of antioxidant, free radical scavenging, anticancer and antitumor. Lutein is a natural carotenoid, which has bright color, strong coloring power, good antioxidant property, safety and no toxicity, and rich nutritional value, and is widely used in food, health products, cosmetics, medicine, tobacco and poultry feed and other fields. In 1995, the U.S. FDA approved lutein as a food nutrient supplement and colorant. In China, lutein is also listed in GB2760-1996 as a food additive.

[0003] However, lutein is a fat-soluble pigment with high unsaturation and is easily oxidized, which limits the application of lutein as a nutritional fortifier and natural pigment in food. Studies have found that lutein is very sensitive to temperature, light, oxygen, reducing agents and oxidizing agents, and therefore lutein crystals should be stored at low temperature, in the dark and in a vacuum. At present, the main method for improving the stability of lutein is microencapsulation. However, the lutein content in the encapsulated powder is very low (the lutein content in the commercially available encapsulated powder is generally 5% and 10%). At the same time, the encapsulation process is relatively complex and involves high-energy and high-cost production processes such as high-temperature emulsification and spray drying. Therefore, it is the goal of people to obtain a lutein product with convenient use, high content, chemical stability, simple process and low cost. SUMMARY

[0004] In order to improve the stability of lutein product, the present application attempts to form a co-crystal with lutein and a variety of compounds through a large number of experiments. The results show that by adding edible adipic acid as a ligand, a stable co-crystal can be formed, so as to change the intermolecular interaction and spatial arrangement of lutein molecules at the molecular level, enhance the stability of lutein molecules to oxygen and temperature, and further improve the chemical stability and broaden the application field. Therefore, the present application determines to use lutein and adipic acid to prepare a co-crystal to solve the above technical problems, thereby completing the present application.

[0005] The lutein co-crystal with more excellent stability can further broaden the application range of lutein. Therefore, the lutein and adipic acid co-crystal described in the present application has strong practical application value.

[0006] One of the objectives of this invention is to provide a eutectic of lutein and adipic acid.

[0007] The second objective of this invention is to provide a method for preparing the eutectic of lutein and adipic acid.

[0008] A third objective of the present invention is to provide a composition comprising the above-mentioned eutectic of lutein and adipic acid.

[0009] The fourth objective of this invention is to provide a use of the above-mentioned eutectic of lutein and adipic acid or the composition thereof in the preparation of products, wherein the products are selected from health products, food, cosmetics, pharmaceuticals, pharmaceutical excipients and feed.

[0010] According to one aspect of the present invention, a eutectic of lutein and adipic acid is provided, wherein the stoichiometric ratio of lutein to adipic acid in the eutectic is 1:1.

[0011] Specifically, the X-ray powder diffraction pattern of the lutein-adipic acid cocrystal exhibits characteristic peaks at 2θ angles of 3.4°±0.2°, 12.2°±0.2°, 13.6°±0.2°, 15.7°±0.2°, 16.6°±0.2°, and 17.8°±0.2°; more specifically, it also exhibits characteristic peaks at 2θ angles of 3.4°±0.2°, 12.2°±0.2°, 13.6°±0.2°, 15.7°±0.2°, 16.6°±0.2°, 17.8°±0.2°, 18.2±0.2°, and 21.5±0.2°; particularly, the lutein-adipic acid cocrystal exhibits essentially the following characteristics. Figure 1 The X-ray powder diffraction pattern shown is shown.

[0012] Specifically, the eutectic of lutein and adipic acid was determined by differential scanning calorimetry (DSC). When the temperature increased at a rate of 10 °C / min, its DSC spectrum showed a characteristic endothermic peak at approximately 187 ± 2 °C. Preferably, it has essentially the following characteristics: Figure 2 The differential scanning calorimetry (DSC) spectrum is shown.

[0013] In particular, the infrared spectrum of the lutein-adipic acid cocrystal is at approximately 3446 cm⁻¹. -1 1723cm -1 , and 963cm -1 It has a characteristic peak at 3023 cm⁻¹; in particular, it also has a characteristic peak at 302 -1 2957cm -1 2865cm -1 1567cm -1 1411cm -1 12778cm -1 1190cm-1 preferably, having characteristic peaks substantially as shown in the infrared spectrum. Figure 3

[0014] According to a second aspect of the present application, the present application provides a method for preparing the co-crystal of lutein and adipic acid, which is one of the following methods:

[0015] Method one: recrystallizing lutein and adipic acid with a molar ratio of 1:1 in a solvent, precipitating and drying to obtain the co-crystal of lutein and adipic acid;

[0016] Method two: ball-milling lutein and adipic acid with a molar ratio of 1:1 in a solvent for more than 10 minutes, and drying the obtained solid to obtain the co-crystal of lutein and adipic acid.

[0017] In particular, in the method one, lutein and adipic acid can be stirred and suspended in a solvent, for example at 10-40℃, for example for 5-30 hours, precipitated (for example filtered) and dried to obtain the co-crystal of lutein and adipic acid.

[0018] In particular, in the method two, lutein and adipic acid can be ball-milled in a solvent for more than 10 minutes, for example for 30 minutes to 2 hours, and the obtained solid can be dried (for example dried in vacuum, for example at room temperature for 10-15 hours) to obtain the co-crystal of lutein and adipic acid.

[0019] The solvents are respectively selected from solvents having a certain solubility to the raw materials and not causing deterioration of the raw materials. Preferably, the solvents are respectively one or more selected from water, alcohols, ketones, esters, alkanes, aromatic hydrocarbons and halogenated alkanes; more preferably, the solvents are respectively one or more selected from methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl tert-butyl ether, n-hexane and n-heptane.

[0020] The preparation method of the present application is simple in operation, easy to control in crystallization process, high in crystallinity, good in reproducibility, and stable in obtaining the co-crystal of lutein and adipic acid.

[0021] In a third aspect, the present application provides a lutein composition comprising the co-crystal of lutein and adipic acid as described above.

[0022] ​In some embodiments, the lutein composition can contain an excess of lutein and / or an excess of adipic acid in addition to the lutein and adipic acid co-crystal of the present application, and other excipients. That is, the molar ratio of lutein to adipic acid in the lutein composition is not particularly limited, as long as the lutein composition contains the lutein and adipic acid co-crystal described above or the raw materials thereof can produce the lutein and adipic acid co-crystal described above. For example, the stoichiometric ratio of lutein to adipic acid in the lutein composition can be 10:1 to 1:10, in which a part of the components exist in the form of the lutein and adipic acid co-crystal and the other part of the components exist in the free form. Preferably, the lutein is entirely formed into the co-crystal to overcome the defect of poor stability of lutein; or the lutein composition consists essentially of the lutein and adipic acid co-crystal. The other excipients are not particularly limited and can vary depending on the application purpose. For example, when applied to a medicine, the excipients can be pharmaceutically acceptable excipients; when applied to a health product, the excipients can be health product acceptable excipients; when applied to a food, the excipients can be food acceptable excipients; when applied to a cosmetic, the excipients can be cosmetic acceptable excipients; and when applied to a feed, the excipients can be feed acceptable excipients.

[0023] In some embodiments, the stoichiometric ratio of lutein to adipic acid in the lutein composition can be 1:10, 1:5, 1:2, 2:1, 5:1, or 10:1.

[0024] When the stoichiometric ratio of lutein to adipic acid in the lutein composition is 1:2, the X-ray powder diffraction pattern of the composition has characteristic peaks at 2θ angles of about 3.4°±0.2°, 12.2°±0.2°, 13.5°±0.2°, 15.7°±0.2°, 16.7°±0.2°, and 17.8°±0.2°. The lutein and adipic acid co-crystal of the present application has the characteristic peaks, thereby confirming that the composition contains the co-crystal of the present application.

[0025] The lutein composition having a stoichiometric ratio of lutein to adipic acid of 1:2 has an X-ray powder diffraction pattern substantially as shown in FIG. 2. Figure 4

[0026] In yet other embodiments, the stoichiometric ratio of lutein to adipic acid in the lutein composition is 2:1.

[0027] ​The X-ray powder diffraction pattern of the lutein composition having a stoichiometric ratio of lutein to adipic acid of 2: 1 has characteristic peaks at about 3.4°±0.2°, 12.3°±0.2°, 13.5°±0.2°, 15.8°±0.2°, 16.7°±0.2°, 17.7°±0.2° in terms of 2 theta angle. It has the characteristic peaks of the lutein and adipic acid co-crystal of the present application, thereby confirming that the crystal form of the co-crystal in the composition is identical to that of the co-crystal of the present application.

[0028] The lutein composition having a stoichiometric ratio of lutein to adipic acid of 1:2 has an X-ray powder diffraction pattern substantially as shown in Figure 5

[0029] In still other embodiments, the stoichiometric ratio of lutein to adipic acid in the lutein composition is 1:5.

[0030] The X-ray powder diffraction pattern of the lutein composition having a stoichiometric ratio of lutein to adipic acid of 2: 1 has characteristic peaks at about 3.3°±0.2°, 12.1°±0.2°, 13.5°±0.2°, 15.8°±0.2°, 16.6°±0.2°, 17.7°±0.2° in terms of 2 theta angle. It has the characteristic peaks of the lutein and adipic acid co-crystal of the present application, thereby confirming that the crystal form of the co-crystal in the composition is identical to that of the co-crystal of the present application.

[0031] The lutein composition having a stoichiometric ratio of lutein to adipic acid of 1:5 has an X-ray powder diffraction pattern substantially as shown in Figure 6

[0032] In still other embodiments, the stoichiometric ratio of lutein to adipic acid in the lutein composition is 5: 1.

[0033] The X-ray powder diffraction pattern of the lutein composition having a stoichiometric ratio of lutein to adipic acid of 5: 1 has characteristic peaks at about 3.4°±0.2°, 12.2°±0.2°, 13.5°±0.2°, 15.8°±0.2°, 16.5°±0.2°, 17.5°±0.2° in terms of 2 theta angle. It has the characteristic peaks of the lutein and adipic acid co-crystal of the present application, thereby confirming that the crystal form of the co-crystal in the composition is identical to that of the co-crystal of the present application.

[0034] The lutein composition having a stoichiometric ratio of lutein to adipic acid of 5: 1 has an X-ray powder diffraction pattern substantially as shown in Figure 7

[0035] In still other embodiments, the stoichiometric ratio of lutein to adipic acid in the lutein composition is 1:10.

[0036] ​​​The X-ray powder diffraction pattern of the lutein composition having a stoichiometric ratio of lutein to adipic acid of 1:10 has characteristic peaks at about 3.3°±0.2°, 12.0°±0.2°, 13.5°±0.2°, 15.8°±0.2°, 16.6°±0.2°, 17.7°±0.2° in terms of 2 theta angle. It has the characteristic peaks of the lutein-adipic acid co-crystal of the present application, thereby confirming that the crystal form of the co-crystal in the composition is identical to that of the co-crystal of the present application.

[0037] The lutein composition having a stoichiometric ratio of lutein to adipic acid of 1:10 has an X-ray powder diffraction pattern substantially as shown in Figure 8

[0038] In still another embodiment, the stoichiometric ratio of lutein to adipic acid in the lutein composition is 10:1.

[0039] The X-ray powder diffraction pattern of the lutein composition having a stoichiometric ratio of lutein to adipic acid of 10:1 has characteristic peaks at about 3.3°±0.2°, 12.2°±0.2°, 13.5°±0.2°, 15.6°±0.2°, 16.5°±0.2°, 17.5°±0.2° in terms of 2 theta angle. It has the characteristic peaks of the lutein-adipic acid co-crystal of the present application, thereby confirming that the crystal form of the co-crystal in the composition is identical to that of the co-crystal of the present application.

[0040] The lutein composition having a stoichiometric ratio of lutein to adipic acid of 10:1 has an X-ray powder diffraction pattern substantially as shown in Figure 9

[0041] In still another aspect, the present application provides a lutein product comprising the lutein-adipic acid co-crystal or the above-mentioned lutein composition, the product being selected from the group consisting of health foods, foods, cosmetics, pharmaceuticals, pharmaceutical excipients, and feed.

[0042] In still another aspect, the present application provides the use of the lutein-adipic acid co-crystal or the above-mentioned lutein composition for the preparation of a lutein product, the product being selected from the group consisting of health foods, foods, cosmetics, pharmaceuticals, pharmaceutical excipients, and feed.

[0043] ​​The product can further include other suitable raw materials required for the product, for example, food products can include food main materials and food acceptable edible food additives such as sweeteners, flavorings, preservatives, fragrances, colorants, etc.; cosmetic products can include cosmetic main materials and additives acceptable for cosmetics such as solvents, fragrances, preservatives, essences, colorants, etc.; pharmaceutical products can include pharmaceutically active ingredients and pharmaceutically acceptable excipients such as carriers, diluents, adjuvants, colorants, etc.; and feed products can include feed main materials such as soybean meal, hay, etc., and feed acceptable feed additives such as sweeteners, flavorings, preservatives, fragrances, colorants, etc., but the present application is not limited thereto.

[0044] The above product is prepared by adding the co-crystal of lutein and adipic acid according to the present application or the lutein composition according to the present application. The product can be prepared according to its conventional method except for adding the co-crystal of lutein and adipic acid according to the present application or the lutein composition according to the present application.

[0045] The present application has been described in detail above, but the above embodiments are merely illustrative in nature and are not intended to limit the present application. Furthermore, the present text is not limited by any theory described in the foregoing prior art or summary of the invention or in the following examples.

[0046] Unless explicitly stated otherwise, numerical ranges in the entire application document include any sub-ranges therein and any numerical values therein that increment by the smallest sub-unit of the given value. Unless explicitly stated otherwise, numerical values in the entire application document represent an approximate measure or limit of a range that includes minor deviations from the given value and embodiments having about the value mentioned and having the exact value mentioned. Except for the working examples provided at the end of the detailed description, all numerical values of parameters (e.g., amounts or conditions) in the present application document (including the appended claims) should be understood, in all instances, to be modified in all instances by the term "about" whether or not "about" actually appears before the numerical value. "About" means that the stated numerical value is permitted to be slightly inaccurate (some close to exact; approximately or reasonably close to the value; approximate). If the inaccuracy provided by "about" is not understood in this ordinary sense in the art, "about" as used herein means at least the variations that can be produced by ordinary methods of measuring and using these parameters. For example, "about" can include variations of less than or equal to 10%, less than or equal to 5%, less than or equal to 4%, less than or equal to 3%, less than or equal to 2%, less than or equal to 1%, or less than or equal to 0.5%, and in certain aspects, less than or equal to 0.1%.

[0047] Unless specifically stated otherwise, the use of the terms "comprise", "comprising", "contain", "containing", "include", "including", "have", "having", or other similar words in the specification is intended to indicate that the mentioned element is present, but not excluding the presence of other elements. In addition, the use of the terms "comprise", "comprising", "contain", "containing", "include", "including", "have", "having" should be interpreted as specifically disclosing the presence of the stated elements, but not to the exclusion of other elements. "Consisting essentially of" means that the listed elements are present, but other elements can be present, provided that the other elements do not materially alter the basic and novel characteristics of the claimed composition or method.

[0048] Compared with the prior art, the present application has the following advantages:

[0049] The present application provides a stable co-crystal of lutein and adipic acid. Compared with lutein itself, the co-crystal has significantly improved chemical stability and higher melting point. The preparation method of the co-crystal disclosed in the present application is simple, has the advantages of low cost, environmental friendliness, easy control and good reproducibility. Moreover, the co-crystal disclosed in the present application has more excellent chemical stability, greatly improves the convenience of use of lutein, saves the cost in the process of storage, transportation and use, and can further broaden the application range of lutein. Therefore, the co-crystal of lutein and adipic acid has strong practical application value. BRIEF DESCRIPTION OF DRAWINGS

[0050] Figure 1 is the X-ray powder diffraction (XRPD) pattern of the co-crystal of lutein and adipic acid prepared in Example 1;

[0051] Figure 2 is the differential scanning calorimetry (DSC) pattern of the co-crystal of lutein and adipic acid prepared in Example 1;

[0052] Figure 3 is the infrared spectrum (IR) pattern of the co-crystal of lutein and adipic acid prepared in Example 1;

[0053] Figure 4 is the X-ray powder diffraction (XRPD) pattern of the mixture containing the co-crystal of lutein and adipic acid (lutein: adipic acid = 1:2) prepared in Example 5;

[0054] Figure 5 is the X-ray powder diffraction (XRPD) pattern of the mixture containing the co-crystal of lutein and adipic acid (lutein: adipic acid = 2:1) prepared in Example 6;

[0055] Figure 6is an X-ray powder diffraction (XRPD) pattern of a mixture containing a co-crystal of lutein and adipic acid (lutein: adipic acid = 1:5) prepared in Example 7;

[0056] Figure 7 is an X-ray powder diffraction (XRPD) pattern of a mixture containing a co-crystal of lutein and adipic acid (lutein: adipic acid = 5:1) prepared in Example 8;

[0057] Figure 8 is an X-ray powder diffraction (XRPD) pattern of a mixture containing a co-crystal of lutein and adipic acid (lutein: adipic acid = 1:10) prepared in Example 9;

[0058] Figure 9 is an X-ray powder diffraction (XRPD) pattern of a mixture containing a co-crystal of lutein and adipic acid (lutein: adipic acid = 10:1) prepared in Example 10. DETAILED DESCRIPTION

[0059] In order to make the objectives, technical solutions and advantages of the present application clearer, further detailed description will be given below in combination with the drawings and examples. It should be understood that the specific examples described herein are only used to explain the present application, and are not used to limit the present application.

[0060] In the present application, the X-ray powder diffraction pattern is obtained by using a Bruker D8 Advanced X-ray co-crystal diffractometer. The instrument uses Cu-Ka irradiation The scanning range is from 3° to 40° in the 2θ interval, and the scanning speed is 5° / min.

[0061] The differential scanning calorimetry uses a TA DSC Q2000 device, and the heating speed is 10 K / min.

[0062] The Fourier transform infrared spectrometer uses Thermo Scientific Nicolet 6700.

[0063] The ball milling uses a Jingxin JX-2G planetary ball mill.

[0064] The liquid chromatography uses an Agilent 1260 Infinity HPLC.

[0065] Except for special instructions, the raw materials, reagents, equipment, methods, etc. used in the present application are conventional raw materials, reagents, equipment, methods in the art.

[0066] Example 1

[0067] Example 1

[0068] This co-crystal was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results are shown in Figures 1-3, respectively. Figures 1-3

[0069] Wherein, the peak values of the X-ray powder diffraction pattern of the co-crystal of lutein and adipic acid obtained above are shown in Table 1:

[0070] Table 1. Position and intensity of peaks

[0071]

[0072]

[0073] Example 2

[0074] Example 2

[0075] This co-crystal was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results are substantially consistent with those of Example 1. Figures 1-3

[0076] Example 3

[0077] Example 3

[0078] This co-crystal was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results are substantially consistent with those of Example 1. Figures 1-3

[0079] Example 4

[0080] Example 4

[0081] ​​​The co-crystal was characterized by solid state methods such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and infrared (IR) spectroscopy. The results were substantially consistent with Figures 1-3

[0082] Example 5

[0083] Example 5

[0084] The mixture was characterized by X-ray powder diffraction (XRPD) and the results are shown in Figure 5. Figure 4

[0085] The peak values of the X-ray powder diffraction pattern of the lutein composition obtained above with a stoichiometric ratio of lutein to adipic acid of 1 :2 are shown in Table 2:

[0086] Table 2. Peak position and intensity

[0087] Position (2Θ) Relative intensity (%) 3.40 21.0 6.79 7.2 12.21 8.0 13.13 14.1 13.45 22.9 15.74 3.3 16.74 28.8 17.80 36.2 18.32 24.9 19.20 6.8 21.55 100 23.89 23.3 25.38 19.5 28.82 26.6 26.85 10.7 31.23 9.8

[0088] Example 6

[0089] Example 6

[0090] The mixture was characterized by X-ray powder diffraction (XRPD) and the results are shown in Figure 6. Figure 5

[0091] The peak values of the X-ray powder diffraction pattern of the lutein composition obtained above with a stoichiometric ratio of lutein to adipic acid of 2:1 are shown in Table 3:

[0092] Table 3. Peak position and intensity

[0093] Position (2Θ) Relative intensity (%) 3.42 96.6 6.75 33.5 8.39 35.4 12.30 28.1 13.13 65.0 13.49 76.4 14.15 22.4 15.77 31.6 16.70 87.5 17.74 100 18.28 74.5 19.08 54.8 19.90 46.4 20.71 71.9 21.47 81.4 22.33 16.0 23.31 28.5 23.87 68.8 25.30 28.9 26.68 33.5

[0094] Example 7

[0095] Example 7

[0096] The mixture was characterized by X-ray powder diffraction (XRPD) and the results are shown in Figure 7.​​​Figure 6 X-ray powder diffraction pattern of the lutein composition obtained above with a stoichiometric ratio of lutein to adipic acid of 1 :5 is shown in Table 4:

[0097] X-ray powder diffraction pattern of the lutein composition obtained above with a stoichiometric ratio of lutein to adipic acid of 1 :5 is shown in Table 4:

[0098] Table 4. Position and intensity of peaks

[0099] Position (2Θ) Relative intensity (%) 3.32 4.0 12.13 2.1 12.95 8.5 13.47 5.0 15.77 2.0 16.64 7.3 17.68 9.4 18.26 7.9 19.12 3.1 20.95 2.6 21.49 100 23.37 2.8 23.87 5.0 24.66 3.0 25.30 16.8 25.80 43.8 26.82 3.9 31.15 17.2 33.50 2.0 35.77 2.5 37.25 3.5 38.35 5.3

[0100] Example 8

[0101] Example 8

[0102] This mixture was characterized by X-ray powder diffraction (XRPD) and the results are shown in Figure 8. Figure 7

[0103] X-ray powder diffraction pattern of the lutein composition obtained above with a stoichiometric ratio of lutein to adipic acid of 5: 1 is shown in Table 5:

[0104] Table 5. Position and intensity of peaks

[0105] Position (2Θ) Relative intensity (%) 3.36 44.3 6.01 13.9 6.71 8.1 10.62 13.9 11.68 33.6 12.16 12.9 13.53 46.7 14.97 100 15.79 3.0 16.46 77.1 17.52 54.4 18.14 73.1 20.79 17.0 23.81 26.0 25.12 18.7 26.00 15.7

[0106] Example 9

[0107] Example 9

[0108] This mixture was characterized by X-ray powder diffraction (XRPD) and the results are shown in Figure 9. Figure 8

[0109] X-ray powder diffraction pattern of the lutein composition obtained above with a stoichiometric ratio of lutein to adipic acid of 1 :10 is shown in Table 6:

[0110] Table 6. Position and intensity of peaks

[0111] Position (2Θ) Relative intensity (%) 3.32 1.9 12.04 1.2 12.97 9.6 13.47 3.3 15.77 1.1 16.60 4.9 17.67 5.6 18.26 5.2 18.92 2.3 20.97 2.2 21.51 100 23.29 1.8 23.83 2.8 24.74 1.5 25.32 16.4 25.83 38.8 26.84 4.8 29.83 1.3 31.17 23.0 33.54 1.7 25.40 1.7 35.77 3.1 37.27 3.8 38.37 5.5

[0112] Example 10

[0113] ​​Example 1 Hexanedioic acid (0.146 g) and lutein (5.69 g) (1 :10 molar ratio) were added to a ball mill jar, 2 mL of acetone was added, and the mixture was ball milled for 1 hour and the solid was dried in a vacuum oven at room temperature for 12 hours to obtain a mixture containing lutein and hexanedioic acid co-crystals.

[0114] This mixture was characterized by X-ray powder diffraction (XRPD) and the results are shown in Figure 1. Figure 9

[0115] The peak values of the X-ray powder diffraction pattern of the lutein composition obtained from the 10:1 stoichiometric ratio of lutein and hexanedioic acid are shown in Table 7:

[0116] Table 7. List of selected peaks

[0117] Position (2Θ) Relative intensity (%) 3.34 29.2 6.02 7.7 10.00 10.5 10.66 14.3 11.74 31.1 12.18 4.0 13.00 15.4 13.47 29.2 15.01 100 15.59 1.1 16.50 30.9 16.95 11.9 17.50 27.9 18.02 46.2 20.38 9.5 20.77 10.0 23.85 11.4 24.96 19.1 26.02 13.8

[0118] Experimental Example (Comparison of the stability of lutein itself and lutein co-crystals according to the present application)

[0119] The stability of commercially available lutein crystals (purchased from Chengguang Bio) and lutein co-crystals containing lutein and hexanedioic acid obtained in Examples 1 and 3 was compared with lutein itself in the context that the person skilled in the art can prove.

[0120] The commercially available lutein crystals and the lutein co-crystals containing lutein and hexanedioic acid obtained in Examples 1 and 3 and the mixtures containing lutein co-crystals and hexanedioic acid obtained in Examples 5-10 were compared in terms of stability. The commercially available lutein crystals and the lutein co-crystals containing lutein and hexanedioic acid obtained in Examples 1 and 3 and the mixtures containing lutein co-crystals and hexanedioic acid obtained in Examples 5-10 were stored at 40°C / 75% relative humidity in the open air and protected from light. The lutein content was analyzed by HPLC. The results are shown in Table 8.

[0121] Table 8. Stability of lutein under accelerated conditions (40°C / 75% relative humidity, open air)

[0122] 0 days 3 days 5 days 7 days Lutein commercial crystal 100.0％ 75.4％ 55.2％ 38.1％ Lutein co-crystal (Example 1) 100.0％ 101.1％ 100.3％ 97.7％ Lutein co-crystal (Example 3) 100.0％ 99.5％ 98.7％ 97.0％ Composition containing lutein co-crystal (Example 5) 100.0％ 96.8％ 93.8％ 90.8％ Composition containing lutein co-crystal (Example 6) 100.0％ 90.8％ 85.3％ 79.7％ Composition containing lutein co-crystal (Example 7) 100.0％ 97.3％ 95.2％ 89.0％ Composition containing lutein co-crystal (Example 8) 100.0％ 98.4％ 97.2％ 93.5％ Composition containing lutein co-crystal (Example 9) 100.0％ 96.7％ 93.8％ 88.1％ Composition containing lutein co-crystal (Example 10) 100.0％ 96.3％ 94.5％ 91.5％

[0123] As shown by the above results, the lutein co-crystals disclosed in the present application have superior stability compared to commercially available lutein crystals, and can remain stable for a longer period of time under high temperature and high humidity conditions without special protection from oxygen. The stability of the composition containing the lutein co-crystals is slightly lower than that of the lutein co-crystals themselves, but is still much higher than that of the commercially available lutein crystals.

[0124] Comparative Example 1

[0125] ​Into a ball mill jar, 0.118 g succinic acid and 0.569 g lutein were added, 1 mL of acetone or ethyl acetate was added, ball milled for 1 hour, and the solid was dried in a vacuum oven at room temperature for 12 hours to obtain a yellow powder.

[0126] This powder was tested by X-ray powder diffraction (XRPD) and found that no co-crystal was formed.

[0127] Comparative Example 2

[0128] Into a ball mill jar, 0.132 g glutaric acid and 0.569 g lutein were added, 1 mL of acetone or ethyl acetate was added, ball milled for 1 hour, and the solid was dried in a vacuum oven at room temperature for 12 hours to obtain a yellow powder.

[0129] This powder was tested by X-ray powder diffraction (XRPD) and found that no co-crystal was formed.

[0130] Comparative Example 3

[0131] Into a ball mill jar, 0.160 g pimelic acid and 0.569 g lutein were added, 1 mL of acetone or ethyl acetate was added, ball milled for 1 hour, and the solid was dried in a vacuum oven at room temperature for 12 hours to obtain a yellow powder.

[0132] This powder was tested by X-ray powder diffraction (XRPD) and found that no co-crystal was formed.

[0133] Comparative Example 4

[0134] Into a ball mill jar, 0.174 g suberic acid and 0.569 g lutein were added, 1 mL of acetone or ethyl acetate was added, ball milled for 1 hour, and the solid was dried in a vacuum oven at room temperature for 12 hours to obtain a yellow powder.

[0135] This powder was tested by X-ray powder diffraction (XRPD) and found that no co-crystal was formed.

[0136] From the above, it can be seen that when succinic acid, glutaric acid, pimelic acid, and suberic acid are used, they cannot form co-crystals with lutein to improve the stability of lutein.

Claims

1. A co-crystal of lutein and adipic acid, wherein, The stoichiometric ratio of lutein to adipic acid in the co-crystal is 1:1, wherein the co-crystal has characteristic peaks at 2θ angles of 3.4°±0.2°, 12.2°±0.2°, 13.6°±0.2°, 15.7°±0.2°, 16.6°±0.2°, and 17.8°±0.2° in the X-ray powder diffraction pattern.

2. The co-crystal of lutein and adipic acid according to claim 1, wherein, The co-crystal has characteristic peaks at 2θ angles of 3.4°±0.2°, 12.2°±0.2°, 13.6°±0.2°, 15.7°±0.2°, 16.6°±0.2°, 17.8°±0.2°, 18.2±0.2°, and 21.5±0.2° in the X-ray powder diffraction pattern.

3. The co-crystal of lutein and adipic acid according to claim 1, wherein, The co-crystal of lutein and adipic acid has an X-ray powder diffraction pattern substantially as shown in FIG.

1.

4. The co-crystal of lutein and adipic acid according to claim 1, wherein, The co-crystal has a characteristic endothermic peak at 187±2°C in the differential scanning calorimetry spectrum when the temperature is raised at a rate of 10°C / min.

5. The co-crystal of lutein and adipic acid according to claim 1, wherein, The co-crystal has a differential scanning calorimetry spectrum substantially as shown in FIG. 2 when the temperature is raised at a rate of 10°C / min.

6. The co-crystal of lutein and adipic acid according to claim 1, wherein, The co-crystal has characteristic peaks in the infrared spectrum at 3446 cm -1 , 1723 cm -1 , and 963 cm -1 .

7. The co-crystal of lutein and adipic acid according to claim 6, wherein The infrared spectrum of said co-crystal also has characteristic peaks at 3023 cm -1 , 2957 cm -1 , 2865 cm -1 , 1567 cm -1 , 1411 cm -1 , 1277 8 cm -1 , 1190 cm -1 .

8. The co-crystal of lutein and adipic acid according to claim 1, wherein, The co-crystal has an infrared spectrum substantially as shown in FIG.

3.

9. A method for preparing the co-crystal of lutein and adipic acid according to any one of claims 1 to 8, which is Method I or Method II: Method I: recrystallizing lutein and adipic acid in a solvent at a molar ratio of 1:1, precipitating and drying to obtain the co-crystal of lutein and adipic acid; Method II: ball-milling lutein and adipic acid in a solvent at a molar ratio of 1:1 for more than 10 minutes, and drying the obtained solid to obtain the co-crystal of lutein and adipic acid.

10. The method according to claim 9, wherein, in Method I, lutein and adipic acid are stirred and suspended in a solvent at 10-40°C for 5-30 hours, precipitated and dried to obtain the co-crystal of lutein and adipic acid; in Method II, lutein and adipic acid are ball-milled in a solvent for more than 10 minutes, and the obtained solid is dried to obtain the co-crystal of lutein and adipic acid.

11. The method according to claim 9, wherein, the solvent is one or more selected from water, alcohols, ketones, esters, alkanes, aromatic hydrocarbons, and halogenated alkanes, respectively.

12. The method of claim 9, wherein, the solvent is one or more selected from methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, methyl tert-butyl ether, n-hexane, and n-heptane, respectively.

13. A lutein composition comprising the co-crystal of lutein and adipic acid according to any one of claims 1 to 8.

14. The lutein composition according to claim 13, wherein, In the lutein composition, the stoichiometric ratio of lutein to adipic acid is 10:1 to 1:

10.

15. The lutein composition of claim 13, wherein, In the lutein composition, the stoichiometric ratio of lutein to adipic acid is 1:2; or In the lutein composition, the stoichiometric ratio of lutein to adipic acid is 2:1; or In the lutein composition, the stoichiometric ratio of lutein to adipic acid is 1:5; or In the lutein composition, the stoichiometric ratio of lutein to adipic acid is 5:1; or In the lutein composition, the stoichiometric ratio of lutein to adipic acid is 1 :10; or In the lutein composition, the stoichiometric ratio of lutein to adipic acid is 10:

1.

16. A lutein product comprising the lutein-adipic acid co-crystal according to any one of claims 1 to 8 or the lutein composition according to any one of claims 13 to 15, said product being selected from the group consisting of nutraceuticals, foodstuffs, cosmetics, pharmaceuticals, pharmaceutical excipients and feedstuffs.

17. Use of the lutein-adipic acid co-crystal according to any one of claims 1 to 8 or the lutein composition according to any one of claims 13 to 15 for the manufacture of a lutein product, said product being selected from the group consisting of nutraceuticals, foodstuffs, cosmetics, pharmaceuticals, pharmaceutical excipients and feedstuffs.

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