A ligustrazine succinic acid co-crystal, a preparation method and application thereof

Abstract

The application provides a tetramethylpyrazine succinic acid co-crystal as well as a preparation method and application thereof, and belongs to the technical field of co-crystal manufacturing. 12 H 18 N2O4, and the molar ratio of tetramethylpyrazine and succinic acid in the tetramethylpyrazine succinic acid co-crystal is 1:1. The tetramethylpyrazine succinic acid co-crystal has good fat solubility, so that the succinic acid in the co-crystal can also better play a role in deep target points.

Description

Technical Field

[0001] This application relates to the field of eutectic manufacturing technology, and more specifically, to a tetramethylpyrazine succinic acid eutectic, its preparation method, and its application. Background Technology

[0002] Succinic acid is a natural dicarboxylic acid widely found in traditional Chinese medicines such as amber and jujube. It possesses sedative and antioxidant physiological activities, and can inhibit the release of key inflammatory factors (such as TNF-α and IL-6), thereby reducing skin inflammation. Furthermore, succinic acid is an important intermediate in the mitochondrial energy cycle (tricarboxylic acid cycle). Supplementing with succinic acid helps optimize cellular energy metabolism, making cells more vibrant. When cellular energy is sufficient, the skin's self-repair ability and collagen synthesis are enhanced, thus better resisting external damage and playing an antioxidant and anti-aging role.

[0003] However, succinic acid has a short ethylene chain (-CH2-CH2-) in its backbone and a hydrophilic carboxyl group (-COOH) at each end of the molecule, making it highly water-soluble but poorly lipid-soluble. Poor lipid solubility means that the active ingredient has difficulty penetrating the stratum corneum of the skin, resulting in it mostly remaining on the skin surface and failing to reach deeper target sites to exert its effect, thus leading to low bioavailability. Therefore, there is an urgent need to develop a succinic acid product with good lipid solubility, so that succinic acid can also exert its effects at deeper target sites. Summary of the Invention

[0004] The purpose of this application is to provide a tetramethylpyrazine succinic acid cocrystal, its preparation method and application. The tetramethylpyrazine succinic acid cocrystal has good lipophilicity, so that the succinic acid therein can also play a better role at deep target sites.

[0005] The embodiments of this application are implemented as follows: In a first aspect, embodiments of this application provide a tetramethylpyrazine succinic acid eutectic, the structural formula of which is shown in Formula I:

[0006] Formula I; The molecular formula of the tetramethylpyrazine succinic acid eutectic is C1. 12 H 18 N2O4, and in the tetramethylpyrazine-succinic acid eutectic, the molar ratio of tetramethylpyrazine to succinic acid is 1:1.

[0007] In the above technical solution, tetramethylpyrazine and succinic acid can form a eutectic in a molar ratio of 1:1. Specifically, the molecular structure of tetramethylpyrazine is a pyrazine ring, and the two nitrogen atoms on its nitrogen-containing aromatic heterocycle have a tendency to accept protons. The carboxyl groups at both ends of succinic acid readily donate protons, so that the two can combine to form hydrogen bonds and form a structurally stable eutectic structure through hydrogen bonds. In addition, in the tetramethylpyrazine-succinic acid eutectic, besides hydrogen bonds, there are also other non-covalent bond interactions such as van der Waals forces inside the eutectic. This causes the highly polar carboxyl groups on the succinic acid molecule to be wrapped by tetramethylpyrazine, so that the polarity of the entire eutectic molecule decreases, while the contribution of the lipophilicity of the aromatic ring structure of tetramethylpyrazine increases relatively, thereby increasing the lipophilicity of the entire tetramethylpyrazine-succinic acid eutectic. Correspondingly, the succinic acid in it can reach the deep target site and play a better role.

[0008] In some alternative embodiments, the tetramethylpyrazine succinic acid eutectic is triclinic with space group P-1 and cell parameters a=4.8713(4) Å, b=7.9365(7) Å, c=8.9107(8) Å, α=95.107(4)°, β=105.339(5)°, γ=100.078(4)°, Z=1, and cell volume V=323.76(5) Å. 3 .

[0009] In some alternative embodiments, the X-ray powder diffraction pattern of the tetramethylpyrazine succinic acid cocrystal exhibits characteristic peaks at 2θ angles of 14.40±0.2°, 23.71±0.2°, 31.06±0.2°, and 41.77±0.2°.

[0010] Secondly, embodiments of this application provide a method for preparing tetramethylpyrazine succinic acid eutectic, comprising the following steps: A. Ligustrazine and succinic acid are mixed in a solvent, wherein the sum of the masses of ligustrazine and succinic acid is m1, the mass of the solvent is m2, and 1 ≤ m2 / m1, to obtain a mixed solution; the mixed solution is stirred at 60℃~75℃ for 2~4 h, and then the reaction solution is subjected to crystallization treatment, solid-liquid separation treatment, and drying treatment in sequence to obtain ligustrazine-succinic acid eutectic; or B. Ligustrazine and succinic acid are mixed in a solvent, wherein the molar ratio of ligustrazine and succinic acid is 1:1, the sum of the masses of ligustrazine and succinic acid is m3, the mass of the solvent is m4, and 0.6 ≤ m4 / m3, to obtain a mixed solution; the mixed solution is stirred at 60℃~75℃ for 3~6 h, and then the reaction solution is subjected to crystallization treatment, solid-liquid separation treatment, and drying treatment in sequence to obtain ligustrazine-succinic acid eutectic.

[0011] In the above technical solution, high-purity tetramethylpyrazine succinic acid cocrystal can be prepared by either step A or step B. In step A, limiting m2 / m1 within the above range allows tetramethylpyrazine and succinic acid to be completely dissolved in the solvent, and then the reaction is carried out according to the above reaction temperature and time, so that high-purity tetramethylpyrazine succinic acid cocrystal can be prepared without limiting the molar ratio of tetramethylpyrazine and succinic acid. In step B, by limiting the molar ratio of tetramethylpyrazine and succinic acid to 1:1 and limiting m4 / m3 within the above range and carrying out the reaction according to the above reaction temperature and time, high-purity and high-yield tetramethylpyrazine succinic acid cocrystal can also be prepared under the condition of less solvent consumption.

[0012] In some alternative embodiments, in step A, the molar ratio of tetramethylpyrazine to succinic acid is (1~1.5):(1~1.5), or / and, 1≤m2 / m1≤10.

[0013] In the above technical solution, in step A, the molar ratio of tetramethylpyrazine and succinic acid is limited to the above range so that the molar ratio of the two is closer to 1:1, which can prepare high-purity tetramethylpyrazine-succinic acid eutectic with a higher yield; further limiting m2 / m1 to the above range, that is, limiting the upper limit of the amount of solvent to a suitable range, also helps to improve the yield of tetramethylpyrazine-succinic acid eutectic.

[0014] In some alternative implementations, in step B, 0.8 ≤ m4 / m3.

[0015] In the above technical solution, in step B, m4 / m3 is further limited to the above range, that is, the lower limit of the amount of solvent is limited to a more suitable range, so that high purity and high yield of tetramethylpyrazine succinic acid eutectic can be prepared more efficiently with less solvent.

[0016] In some alternative embodiments, in steps A and B, the stirring speed is 200 rpm to 800 rpm; or / and, in steps A and B, the crystallization treatment includes: first lowering the temperature of the reaction solution to 20°C to 30°C, and then lowering the temperature of the reaction solution to 0°C to 5°C and maintaining the temperature for crystallization for 10 h to 24 h.

[0017] In the above technical solution, limiting the stirring speed within the aforementioned range provides a suitable stirring speed. A suitable stirring speed provides a suitable heat transfer efficiency for the mixed solution and also allows the mixed solution to have a relatively stable temperature, thereby enabling tetramethylpyrazine and succinic acid to react more efficiently and thoroughly to form a eutectic. The crystallization treatment is carried out in stages according to the above steps, which enables the tetramethylpyrazine-succinic acid eutectic to precipitate more uniformly and thoroughly, thereby obtaining tetramethylpyrazine-succinic acid eutectic with a relatively uniform particle size in high yield.

[0018] In some alternative implementations, the heat preservation crystallization is carried out under stirring conditions, with a stirring speed of 50 rpm to 200 rpm.

[0019] In the above technical solution, the heat preservation crystallization is carried out under stirring conditions and the stirring speed is limited to the above range, which can prepare tetramethylpyrazine succinic acid eutectic with a suitable and uniform particle size.

[0020] In some alternative embodiments, in steps A and B, the solvent is selected from at least one of water, ethanol, methanol, ethyl acetate, acetonitrile, isopropanol, n-propanol, and acetone.

[0021] The above technical solutions have a wide range of applicable solvents, providing a variety of feasible solutions, which facilitates adaptive selection according to actual needs.

[0022] Thirdly, embodiments of this application provide the application of tetramethylpyrazine succinic acid cocrystal as provided in the first aspect embodiment or the tetramethylpyrazine succinic acid cocrystal prepared by the preparation method provided in the second aspect embodiment in the preparation of skin care products, cosmetics, food or pharmaceuticals. Attached Figure Description

[0023] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of this application and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0024] Figure 1 This is a schematic diagram of a single crystal of the tetramethylpyrazine succinic acid eutectic obtained in Example 1 of this application; Figure 2 The 1H NMR spectrum of the tetramethylpyrazine succinic acid eutectic obtained in Example 1 of this application; Figure 3 The infrared comparison images are of the tetramethylpyrazine succinic acid eutectic obtained in Example 1 of this application and various monomers. Figure 4 This is a comparison of the powder XRD patterns of the tetramethylpyrazine succinic acid eutectic obtained in Example 1 of this application with various monomers; Figure 5 This is a comparison chart of thermogravimetric analysis of the tetramethylpyrazine succinic acid eutectic obtained in Example 1 of this application with various monomers. Detailed Implementation

[0025] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions in the embodiments of this application will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0026] It should be noted that the terms "and / or" in this application, such as "feature 1 and / or feature 2", all refer to the three cases of "feature 1" alone, "feature 2" alone, and "feature 1" plus "feature 2".

[0027] In addition, in the description of this application, unless otherwise stated, "one or more" means two or more; the range of "numerical value a to numerical value b" includes the two endpoints "a" and "b"; and "unit of measurement" in "numerical value a to numerical value b + unit of measurement" represents the "unit of measurement" of both "numerical value a" and "numerical value b".

[0028] Cocrystallization technology is an innovative development strategy to improve the physicochemical properties and bioavailability of active ingredients. This technology does not change the original chemical structure of the compound, but optimizes its physicochemical properties through physical means, such as reducing irritation, improving solubility, enhancing stability, and improving bioavailability. This method can play a synergistic role in treatment and reduce toxicity and enhance efficacy.

[0029] However, the formation of eutectics is unpredictable. Even two compounds with extremely similar structures may react with the same ligand to form completely different products. For example, salicylic acid and nicotinamide form a eutectic, while 4-methoxysalicylic acid and nicotinamide form an ionic salt. This means that even a slight difference in a single substituent can lead to entirely different products when combined with the same ligand. Therefore, selecting a suitable ligand capable of forming a eutectic for improving the performance of the modified material is extremely difficult.

[0030] Based on this, the inventors have made an innovative discovery that using tetramethylpyrazine as a ligand for succinic acid can react with succinic acid to form a eutectic. This eutectic product has both good lipophilicity and superior efficacy.

[0031] The following is a detailed description of a tetramethylpyrazine succinic acid eutectic, its preparation method, and its application, based on embodiments of this application.

[0032] In a first aspect, embodiments of this application provide a tetramethylpyrazine succinic acid eutectic, the structural formula of which is shown in Formula I:

[0033] Formula I; The molecular formula of the tetramethylpyrazine succinic acid eutectic is C1. 12 H 18 N2O4, and in the tetramethylpyrazine-succinic acid eutectic, the molar ratio of tetramethylpyrazine to succinic acid is 1:1.

[0034] In this application, tetramethylpyrazine and succinic acid can form a co-crystal in a molar ratio of 1:1. Specifically, the molecular structure of tetramethylpyrazine is a pyrazine ring, and the two nitrogen atoms on its nitrogen-containing aromatic heterocycle have a tendency to accept protons. The carboxyl groups at both ends of succinic acid readily donate protons, so that the two can combine to form hydrogen bonds and form a structurally stable co-crystal structure through hydrogen bonds. In addition to hydrogen bonds, there are other non-covalent bond interactions such as van der Waals forces in the tetramethylpyrazine-succinic acid co-crystal. This causes the highly polar carboxyl groups on the succinic acid molecule to be wrapped by tetramethylpyrazine, so that the polarity of the entire co-crystal molecule decreases, while the contribution of the lipophilicity of the aromatic ring structure of tetramethylpyrazine increases relatively, thereby increasing the lipophilicity of the entire tetramethylpyrazine-succinic acid co-crystal. Correspondingly, the succinic acid in it can reach the deep target site and play a better role.

[0035] As an example, the tetramethylpyrazine succinic acid eutectic is triclinic with space group P-1 and cell parameters a=4.8713(4) Å, b=7.9365(7) Å, c=8.9107(8) Å, α=95.107(4)°, β=105.339(5)°, γ=100.078(4)°, Z=1, and cell volume V=323.76(5) Å. 3 .

[0036] As an example, the X-ray powder diffraction pattern of the tetramethylpyrazine succinic acid eutectic has characteristic peaks at 2θ angles of 14.40±0.2°, 23.71±0.2°, 31.06±0.2° and 41.77±0.2°.

[0037] Secondly, embodiments of this application provide a method for preparing tetramethylpyrazine succinic acid eutectic, comprising the following steps: A. Ligustrazine and succinic acid are mixed in a solvent, wherein the sum of the masses of ligustrazine and succinic acid is m1, and the mass of the solvent is m2, where 1 ≤ m2 / m1 (e.g., but not limited to any one of the ratios 1, 2, 4, 6, 8, 10, 15, and 20, or any range between the two), to obtain a mixed solution; the mixed solution is stirred at 60℃~75℃ (e.g., but not limited to any one of the temperatures 60℃, 62℃, 64℃, 66℃, 68℃, 70℃, 72℃, 74℃, and 75℃, or any range between the two) for 2~4 h (e.g., but not limited to any one of the durations 2 h, 2.5 h, 3 h, 3.5 h, and 4 h, or any range between the two), and then the reaction solution is subjected to crystallization treatment, solid-liquid separation treatment, and drying treatment in sequence to obtain ligustrazine-succinic acid eutectic; or, B. Ligustrazine and succinic acid are mixed in a solvent, wherein the molar ratio of ligustrazine to succinic acid is 1:1, the sum of the masses of ligustrazine and succinic acid is m3, the mass of the solvent is m4, and 0.6 ≤ m4 / m3 (e.g., but not limited to any one of 0.6, 0.7, 0.8, 0.9, and 0.95 or any range between any two) to obtain a mixed solution. The mixed solution is stirred at 60℃~75℃ (e.g., but not limited to any one of 60℃, 62℃, 64℃, 66℃, 68℃, 70℃, 72℃, 74℃, and 75℃ or any range between any two) for 3~6 h (e.g., but not limited to any one of 3 h, 4 h, 5 h, and 6 h or any range between any two). Then, the reaction solution is subjected to crystallization treatment, solid-liquid separation treatment, and drying treatment in sequence to obtain ligustrazine-succinic acid eutectic.

[0038] In this application, high-purity tetramethylpyrazine succinic acid cocrystals can be prepared according to either step A or step B. In step A, limiting m2 / m1 within the above-mentioned range allows tetramethylpyrazine and succinic acid to be completely dissolved in the solvent, and then the reaction is carried out according to the above-mentioned reaction temperature and time, so that high-purity tetramethylpyrazine succinic acid cocrystals can be prepared without limiting the molar ratio of tetramethylpyrazine and succinic acid. In step B, by limiting the molar ratio of tetramethylpyrazine and succinic acid to 1:1 and limiting m4 / m3 within the above-mentioned range and carrying out the reaction according to the above-mentioned reaction temperature and time, high-purity and high-yield tetramethylpyrazine succinic acid cocrystals can also be prepared under conditions of less solvent consumption.

[0039] It should be noted that step A is usually used without considering solvent costs, and its characteristic is that the molar ratio of tetramethylpyrazine to succinic acid is not limited to 1:1. Step B, on the other hand, has a lower lower limit for the amount of solvent used, and can be used when strict control of solvent costs is required, such as in large-scale industrial mass production. It can significantly reduce manufacturing costs and reduce the huge pressure on the environment caused by the use of large amounts of solvent. However, step B requires strict control of the molar ratio of tetramethylpyrazine to succinic acid to 1:1, otherwise it will be difficult for tetramethylpyrazine and succinic acid to react completely, so that what is obtained after crystallization is a mixture of eutectic and monomer raw materials instead of high-purity tetramethylpyrazine-succinic acid eutectic.

[0040] It should be noted that the minimum stirring time in step B is 3 hours. This is because when the solvent volume is low (e.g., m4 / m3 is 0.6), step A is a staged reaction, thus requiring a longer time. Specifically, the reaction process is as follows: most of the equimolar amounts of tetramethylpyrazine and succinic acid preferentially dissolve and react in the solvent. Since the mixed solution is saturated, some of the eutectic will precipitate. At this point, the remaining small portion of equimolar amounts of tetramethylpyrazine and succinic acid can also dissolve and react normally in the solvent to form the eutectic. Therefore, even with a small amount of solvent, high-purity and high-yield tetramethylpyrazine-succinic acid eutectic can be prepared.

[0041] It should be noted that the temperature of the stirring reaction is limited to the above range in order to provide suitable energy for the reaction so that tetramethylpyrazine and succinic acid can react to form a eutectic.

[0042] As an example, in steps A and B, the stirring speed is 200 rpm to 800 rpm, for example, but not limited to any one of 200 rpm, 300 rpm, 400 rpm, 500 rpm, 600 rpm, 700 rpm and 800 rpm or any range between two speeds.

[0043] In this embodiment, limiting the stirring speed within the above-mentioned range can provide a more suitable stirring speed. A suitable stirring speed can provide a more suitable heat transfer efficiency for the mixed solution and also make the mixed solution have a more stable temperature, thereby enabling tetramethylpyrazine and succinic acid to react more efficiently and thoroughly to form a eutectic.

[0044] As an example, in step A, the molar ratio of tetramethylpyrazine to succinic acid is (1~1.5):(1~1.5), for example, but not limited to any one of the molar ratios of 1:1, 1:1.25, 1:1.5, 1.25:1, 1.25:1.5, 1.5:1 and 1.5:1.25 or any range between the two.

[0045] In this embodiment, in step A, the molar ratio of tetramethylpyrazine and succinic acid is limited to the above range so that the molar ratio of the two is closer to 1:1, and high-purity tetramethylpyrazine-succinic acid eutectic can be prepared with a higher yield.

[0046] As an example, 1 ≤ m2 / m1 ≤ 10, for example, but not limited to point values ​​of any one of the ratios 1, 2, 4, 6, 8 and 10, or range values ​​between any two.

[0047] In this embodiment, limiting m2 / m1 to the above range, that is, limiting the upper limit of the amount of solvent to a suitable range, also helps to improve the yield of tetramethylpyrazine succinic acid eutectic.

[0048] As an example, in step B, 0.8 ≤ m4 / m3, for example, but not limited to, any point value or range between any two of the ratios of 0.8, 0.85, 0.9, 0.95, and 0.99.

[0049] In this embodiment, in step B, m4 / m3 is limited to the above range, that is, the lower limit of the amount of solvent is limited to a more suitable range, so that high purity and high yield of tetramethylpyrazine succinic acid eutectic can be prepared more efficiently with less solvent.

[0050] As an example, in steps A and B, the crystallization process includes: first lowering the temperature of the reaction solution to 20°C to 30°C (e.g., but not limited to any one of 20°C, 22°C, 24°C, 26°C, 28°C, and 30°C, or any range between two), and then lowering the temperature of the reaction solution to 0°C to 5°C (e.g., but not limited to any one of 0°C, 1°C, 2°C, 3°C, 4°C, and 5°C, or any range between two) and maintaining the temperature for crystallization for 10 h to 24 h (e.g., but not limited to any one of 10 h, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h, and 24 h, or any range between two).

[0051] In this embodiment, the crystallization process is carried out in stages according to the above steps, which enables the tetramethylpyrazine succinic acid eutectic to precipitate more uniformly and thoroughly, thereby obtaining tetramethylpyrazine succinic acid eutectic with relatively uniform particle size in high yield.

[0052] As an example, the heat preservation crystallization is carried out under stirring conditions, and the stirring speed is 50 rpm to 200 rpm, for example, but not limited to any one of 50 rpm, 100 rpm, 150 rpm and 200 rpm or any range between two of them.

[0053] In this embodiment, the heat preservation crystallization is carried out under stirring conditions and the stirring speed is limited to the above-mentioned range, so as to prepare tetramethylpyrazine succinic acid eutectic with a suitable and uniform particle size.

[0054] As an example, in the step of lowering the temperature of the reaction solution to 20°C to 30°C, the cooling rate is 0.5°C / min to 2°C / min, for example, but not limited to any one of 0.5°C / min, 1°C / min, 1.5°C / min and 2°C / min or any range between two of them.

[0055] In this embodiment, limiting the cooling rate within the above-mentioned range enables the tetramethylpyrazine succinic acid eutectic to precipitate more uniformly.

[0056] As an example, in steps A and B, the solvent is selected from at least one of water, ethanol, methanol, ethyl acetate, acetonitrile, isopropanol, n-propanol, and acetone.

[0057] In this embodiment, a wide variety of solvents are applicable, providing numerous feasible solutions and facilitating adaptive selection based on actual needs.

[0058] As an example, in the drying process, the drying method is vacuum drying, the drying temperature is 40℃~50℃ (e.g., but not limited to any one of 40℃, 42℃, 44℃, 46℃, 48℃ and 50℃ or any range between two), and the drying time is 6 h~24 h (e.g., but not limited to any one of 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h and 24 h or any range between two).

[0059] As an example, in steps A and B, the step of adding tetramethylpyrazine and succinic acid to the solvent for mixing is carried out under stirring and heating conditions, wherein the stirring speed is 200 rpm to 800 rpm and the processing temperature is 25℃ to 75℃.

[0060] In this embodiment, the mixing step is carried out under stirring and heating conditions, which can accelerate the dissolution efficiency of tetramethylpyrazine and succinic acid in the solvent.

[0061] It should be noted that for the preparation of tetramethylpyrazine succinic acid eutectic, any process or step not specifically described or limited can be carried out in accordance with conventional processes in this field.

[0062] Thirdly, embodiments of this application provide the application of tetramethylpyrazine succinic acid cocrystal as provided in the first aspect embodiment or the tetramethylpyrazine succinic acid cocrystal prepared by the preparation method provided in the second aspect embodiment in the preparation of skin care products, cosmetics, food or pharmaceuticals.

[0063] It should be noted that when tetramethylpyrazine succinic acid cocrystal is used as a functional component, there are no restrictions on the type of product it corresponds to, and there are no restrictions on the specific dosage standard during the preparation of the corresponding product. It can be added according to actual needs and the dosage standard of different products.

[0064] The features and performance of this application will be further described in detail below with reference to the embodiments.

[0065] Example 1 This application provides a method for preparing tetramethylpyrazine succinic acid eutectic, which is carried out according to method A and includes the following steps: 13.6 g of tetramethylpyrazine (0.1 mol) and 11.8 g of succinic acid (0.1 mol) were added to ethanol (m2 / m1 = 1) and stirred at 50°C and 500 rpm to obtain a clear mixed solution. The temperature of the mixed solution was then raised to 70°C and kept at 500 rpm for 3 h to obtain a reaction solution containing tetramethylpyrazine succinic acid eutectic.

[0066] The reaction solution was then removed and cooled to 25°C at a rate of 1°C / min. The temperature was then lowered to 0°C and kept at 100 rpm for 12 hours to allow crystals to crystallize. The crystals were then filtered and dried in a vacuum drying oven at 50°C for 10 hours to obtain the product.

[0067] The product mass was measured to be 22.52 g, and the yield was calculated to be 88.7%. The melting point of the product was measured to be 137.3℃ (the melting point of succinic acid is 191℃ and the melting point of tetramethylpyrazine is 89.6℃, meaning that the melting points of the product are different from those of succinic acid and tetramethylpyrazine alone), indicating that a high-purity tetramethylpyrazine-succinic acid eutectic was prepared.

[0068] Example 2 This application provides a method for preparing tetramethylpyrazine succinic acid eutectic, which is carried out according to method A and includes the following steps: 13.6 g of tetramethylpyrazine (0.1 mol) and 11.8 g of succinic acid (0.1 mol) were added to ethanol (m2 / m1 = 1.6) and stirred at 50°C and 500 rpm to obtain a clear mixed solution. The temperature of the mixed solution was then raised to 70°C and kept at 500 rpm for 3 h to obtain a reaction solution containing tetramethylpyrazine succinic acid eutectic.

[0069] The reaction solution was then removed and cooled to 25°C at a rate of 1°C / min. The temperature was then lowered to 0°C and kept at 100 rpm for 12 hours to allow crystals to crystallize. The crystals were then filtered and dried in a vacuum drying oven at 50°C for 10 hours to obtain the product.

[0070] The product mass was measured to be 22.49 g, and the yield was calculated to be 88.5%. The melting point of the product was measured to be 137.3℃ (the melting point of succinic acid is 191℃ and the melting point of tetramethylpyrazine is 89.6℃, meaning that the melting points of the product are different from those of succinic acid and tetramethylpyrazine alone), indicating that a high-purity tetramethylpyrazine-succinic acid eutectic was prepared.

[0071] Example 3 This application provides a method for preparing tetramethylpyrazine succinic acid eutectic, which is carried out according to method A and includes the following steps: 13.6 g of tetramethylpyrazine (0.1 mol) and 11.8 g of succinic acid (0.1 mol) were added to water (m2 / m1 = 6) and stirred at 60°C and 700 rpm to obtain a clear mixed solution. The temperature of the mixed solution was then raised to 75°C and kept at 700 rpm for 4 h to obtain a reaction solution containing tetramethylpyrazine succinic acid eutectic.

[0072] The reaction solution was then removed and cooled to 25°C at a rate of 1°C / min. The temperature was then lowered to 5°C and kept at 100 rpm for 16 h to allow crystals to crystallize. The crystals were then filtered and dried in a vacuum drying oven at 50°C for 12 h to obtain the product.

[0073] The product mass was measured to be 21.18 g, and the yield was calculated to be 83.4%. The melting point of the product was also measured to be 137.2℃ (the melting point of succinic acid is 191℃, and the melting point of tetramethylpyrazine is 89.6℃, meaning the melting points of the product are different from those of succinic acid and tetramethylpyrazine alone), indicating that a high-purity tetramethylpyrazine-succinic acid eutectic was prepared.

[0074] Example 4 This application provides a method for preparing tetramethylpyrazine succinic acid eutectic, which is carried out according to method A and includes the following steps: 27.2 g of tetramethylpyrazine (0.2 mol) and 11.8 g of succinic acid (0.1 mol) were added to ethanol (m2 / m1 = 2) and stirred at 60°C and 600 rpm to obtain a clear mixed solution. The temperature of the mixed solution was then raised to 75°C and kept at 700 rpm for 2 h to obtain a reaction solution containing tetramethylpyrazine succinic acid eutectic.

[0075] The reaction solution was then removed and cooled to 25°C at a rate of 1°C / min. The temperature was then lowered to 5°C and kept at 100 rpm for 20 h to allow crystals to crystallize. The crystals were then filtered and dried in a vacuum drying oven at 50°C for 12 h to obtain the product.

[0076] The product mass was measured to be 23.02 g, and the yield was calculated to be 59.0%. The melting point of the product was measured to be 137.2℃ (the melting point of succinic acid is 191℃ and the melting point of tetramethylpyrazine is 89.6℃, meaning that the melting points of the product are different from those of succinic acid and tetramethylpyrazine alone), indicating that a high-purity tetramethylpyrazine-succinic acid eutectic was prepared.

[0077] Example 5 This application provides a method for preparing tetramethylpyrazine succinic acid eutectic, which is carried out according to method A and includes the following steps: 13.6 g of tetramethylpyrazine (0.1 mol) and 23.6 g of succinic acid (0.2 mol) were added to water (m2 / m1 = 4) and stirred at 50°C and 600 rpm to obtain a clear mixed solution. The temperature of the mixed solution was then raised to 75°C and kept at 700 rpm for 3 h to obtain a reaction solution containing tetramethylpyrazine succinic acid eutectic.

[0078] The reaction solution was then removed and cooled to 25°C at a rate of 1°C / min. It was then cooled to 0°C and kept at 100 rpm for 14 h to crystallize. The crystals were then filtered and dried in a vacuum drying oven at 50°C for 12 h to obtain the product.

[0079] The product mass was measured to be 22.75 g, and the yield was calculated to be 58.3%. The melting point of the product was measured to be 137.2℃ (the melting point of succinic acid is 191℃ and the melting point of tetramethylpyrazine is 89.6℃, meaning that the melting points of the product are different from those of succinic acid and tetramethylpyrazine alone), indicating that a high-purity tetramethylpyrazine-succinic acid eutectic was prepared.

[0080] Example 6 This application provides a method for preparing tetramethylpyrazine succinic acid eutectic, which differs from Example 1 only in that the amount of tetramethylpyrazine is adjusted from 0.1 mol to 0.15 mol, while the amount of succinic acid remains at 0.1 mol.

[0081] The product mass was measured to be 22.64 g, and the yield was calculated to be 70.3%. The melting point of the product was measured to be 137.3℃ (the melting point of succinic acid is 191℃ and the melting point of tetramethylpyrazine is 89.6℃, meaning that the melting points of the product are different from those of succinic acid and tetramethylpyrazine alone), indicating that a high-purity tetramethylpyrazine-succinic acid eutectic was prepared.

[0082] Example 7 This application provides a method for preparing tetramethylpyrazine succinic acid eutectic, which differs from Example 1 only in that the amount of tetramethylpyrazine is adjusted from 0.1 mol to 0.2 mol, while the amount of succinic acid remains at 0.1 mol.

[0083] The product mass was measured to be 22.79 g, and the yield was calculated to be 58.4%. The melting point of the product was also measured to be 137.3℃ (the melting point of succinic acid is 191℃, and the melting point of tetramethylpyrazine is 89.6℃, meaning the melting points of the product are different from those of succinic acid and tetramethylpyrazine alone), indicating that a high-purity tetramethylpyrazine-succinic acid eutectic was prepared.

[0084] Example 8 This application provides a method for preparing tetramethylpyrazine succinic acid eutectic, which differs from Example 1 only in that the amount of tetramethylpyrazine remains 0.1 mol, and the amount of succinic acid is adjusted from 0.1 mol to 0.15 mol.

[0085] The product mass was measured to be 22.47 g, and the yield was calculated to be 71.8%. The melting point of the product was measured to be 137.3℃ (the melting point of succinic acid is 191℃ and the melting point of tetramethylpyrazine is 89.6℃, meaning that the melting points of the product are different from those of succinic acid and tetramethylpyrazine alone), indicating that a high-purity tetramethylpyrazine-succinic acid eutectic was prepared.

[0086] Example 9 This application provides a method for preparing tetramethylpyrazine-succinic acid cocrystal, which differs from Example 1 only in that the tetramethylpyrazine content remains 0.1 mol, while the succinic acid content is adjusted from 0.1 mol to 0.2 mol. After testing, the product mass was 21.83 g, and the calculated yield was 58.7%. Simultaneously, the melting point of the product was measured to be 137.3℃ (the melting point of succinic acid is 191℃, and the melting point of tetramethylpyrazine is 89.6℃, meaning the melting points of the product are different from those of succinic acid and tetramethylpyrazine alone), indicating that a high-purity tetramethylpyrazine-succinic acid cocrystal was prepared.

[0087] As can be seen from Examples 1 to 9, high-purity tetramethylpyrazine succinic acid eutectic can be prepared by following process A; wherein, when the molar ratio of tetramethylpyrazine to succinic acid satisfies (1~1.5):(1~1.5), the former can prepare high-purity tetramethylpyrazine succinic acid eutectic with a higher yield compared to when it is not in this range.

[0088] Example 10 This application provides a method for preparing tetramethylpyrazine succinic acid eutectic, which is carried out according to method B and includes the following steps: 13.6 g of tetramethylpyrazine (0.1 mol) and 11.8 g of succinic acid (0.1 mol) were added to ethanol (m4 / m3 = 0.8) and stirred at 50°C and 600 rpm to obtain a mixed solution in a suspension state. The mixed solution could not be completely dissolved because the amount of solvent was small, so a small portion of equimolar amounts of tetramethylpyrazine and succinic acid could not be dissolved.

[0089] The temperature of the mixed solution was then raised to 70°C and kept at 600 rpm for 3 h to obtain a suspension containing tetramethylpyrazine and succinic acid eutectic. The reaction solution could not be completely dissolved because the eutectic was partially precipitated due to saturation of the reaction solution. This also explains why the remaining small amount of tetramethylpyrazine and succinic acid in equal molar amounts could dissolve and react normally in the later stage of the reaction.

[0090] The reaction solution was then removed and cooled to 25°C at a rate of 1°C / min. The temperature was then lowered to 0°C and kept at 100 rpm for 12 hours to allow crystals to crystallize. The crystals were then filtered and dried in a vacuum drying oven at 50°C for 10 hours to obtain the product.

[0091] The product mass was measured to be 22.53 g, and the yield was calculated to be 88.7%. The melting point of the product was measured to be 137.3℃ (the melting point of succinic acid is 191℃ and the melting point of tetramethylpyrazine is 89.6℃, meaning that the melting points of the product are different from those of succinic acid and tetramethylpyrazine alone), indicating that a high-purity tetramethylpyrazine-succinic acid eutectic was prepared.

[0092] Example 11 This application provides a method for preparing tetramethylpyrazine succinic acid eutectic, which differs from Example 10 only in that the m4 / m3 ratio is 0.6.

[0093] The product mass was measured to be 22.61 g, and the yield was calculated to be 89.0%. The melting point of the product was also measured to be 137.3℃ (the melting point of succinic acid is 191℃, and the melting point of tetramethylpyrazine is 89.6℃, meaning the melting points of the product are different from those of succinic acid and tetramethylpyrazine alone), indicating that a high-purity tetramethylpyrazine-succinic acid eutectic was prepared.

[0094] Comparative Example 1 This application provides a comparative example of a method for preparing tetramethylpyrazine succinic acid eutectic, which differs from Example 10 only in that the m4 / m3 ratio is 0.5.

[0095] After testing, the melting point of the product was found to be 89.6~191℃ (the melting point of succinic acid is 191℃ and the melting point of tetramethylpyrazine is 89.6℃), which means that the product exhibits multi-stage melting, indicating that the prepared product is impure and the raw materials have not reacted completely.

[0096] Comparative Example 2 This application provides a comparative method for preparing tetramethylpyrazine succinic acid eutectic, which differs from Example 10 only in that the amount of tetramethylpyrazine remains 0.1 mol, and the amount of succinic acid is adjusted from 0.1 mol to 0.2 mol.

[0097] After testing, the melting point of the product was found to be 137~191℃ (the melting point of succinic acid is 191℃ and the melting point of tetramethylpyrazine is 89.6℃). This indicates that the product exhibits multi-stage melting, suggesting that the prepared product is impure, the raw materials did not react completely, and there is an excessive amount of undissolved succinic acid doping.

[0098] Comparative Example 3 This application provides a comparative example of a method for preparing tetramethylpyrazine succinic acid eutectic, which differs from Example 10 only in that the temperature of the mixed solution is raised to 70°C and the reaction is maintained at 600 rpm for 2 h.

[0099] After testing, the melting point of the product was found to be 89.6~191℃ (the melting point of succinic acid is 191℃ and the melting point of tetramethylpyrazine is 89.6℃), which means that the product exhibits multi-stage melting, indicating that the prepared product is impure and the raw materials have not reacted completely.

[0100] As can be seen from Examples 10-11, by following process B, high-purity tetramethylpyrazine succinic acid eutectic can be prepared in high yield.

[0101] As can be seen from the comparison between Example 10 and Comparative Examples 1-3, only by limiting the ratio of m4 / m3, the molar ratio of tetramethylpyrazine and succinic acid, and the reaction time, can high-purity and high-yield tetramethylpyrazine-succinic acid eutectic be prepared with a small amount of solvent.

[0102] Experimental Example 1 Qualitative analysis of tetramethylpyrazine succinic acid eutectic Test method: X-ray single-crystal diffraction was performed on the tetramethylpyrazine succinic acid eutectic obtained in Example 1. The specific test results are shown in Table 1, and the crystal schematic diagram is shown in [reference needed]. Figure 1 .

[0103] Table 1

[0104] See Figure 1 It can be seen that there is no proton transfer between tetramethylpyrazine and succinic acid, which proves that the two form a eutectic.

[0105] Experimental Example 2 1H NMR spectrum ( 1 H-NMR characterization Test method: The tetramethylpyrazine succinic acid cocrystal obtained in Example 1 was subjected to 1H NMR spectroscopy (NMR spectroscopy). 1 Characterization was performed using H-NMR, and MeOD was used as the test solvent in the experiment.

[0106] See Figure 2 The four hydrogen atoms of succinic acid and the twelve hydrogen atoms of tetramethyl methacrylate can be clearly seen in the 1H NMR spectrum. 1 ¹H NMR (400 MHz, MeOD), δ 2.56 (d, J = 1.6 Hz, 4H), δ 2.45 (d, J = 1.6 Hz, 12H); the remaining peaks were small amounts of residual water and deuterated reagent peaks, with no obvious impurity peaks observed. This indicates that in the tetramethylpyrazine-succinic acid eutectic, tetramethylpyrazine and succinic acid exist in a molar ratio of 1:1.

[0107] Experimental Example 3 Infrared spectroscopy characterization Test methods: Infrared spectroscopy was performed on tetramethylpyrazine, succinic acid, and the tetramethylpyrazine-succinic acid cocrystal obtained in Example 1. The test parameter was transmittance, and the test wavenumber was 400 cm⁻¹. -1 ~4000cm -1 The test mode was tablet compression.

[0108] See Figure 3 It is known that when succinic acid and tetramethylpyrazine form a eutectic, intermolecular hydrogen bonds are generated, causing a shift in the stretching vibration peak. Specifically, the peak of succinic acid alone shifts between 2500-3300 cm⁻¹. -1 There are multiple stretching vibration peaks, while ligustrazine alone has a peak at 2985 cm⁻¹. -1 The presence of stretching vibration peaks indicates that a eutectic structure was successfully prepared after the two materials formed a eutectic structure.

[0109] Test Example 4 X-ray powder diffraction (XRD) testing Test method: Powder X-ray diffraction tests were performed on the physical mixture of tetramethylpyrazine, succinic acid, the tetramethylpyrazine and succinic acid, and the tetramethylpyrazine-succinic acid eutectic prepared in Example 1. The data results of each sample were then compared and analyzed.

[0110] See Figure 4 It can be seen that the characteristic peaks of succinic acid are at 2θ angles of 16.17°, 18.96°, 20.08°, 26.22°, 31.62°, and 38.51°, while the characteristic peaks of tetramethylpyrazine are at 2θ angles of 10.22°, 13.09°, 15.24°, 16.55°, 21.11°, 22.41°, 24.83°, and 27.43°. After physical mixing of the two in a certain proportion, no new characteristic peaks appeared in the XRD pattern compared to the monomers. However, after the formation of the eutectic, the XRD pattern changed significantly. The characteristic peaks of the monomers were weakened or disappeared to some extent after the reaction of tetramethylpyrazine and succinic acid (specifically, characteristic peaks were observed at 2θ angles of 14.4°, 16.17°, 23.71°, 26.22°, 31.06°, 32.37° and 41.77°). Furthermore, strong new characteristic peaks appeared at 14.4°, 23.71°, 31.06° and 41.77°, indicating that a crystalline substance different from the monomer was produced after the reaction of tetramethylpyrazine and succinic acid, indicating that tetramethylpyrazine-succinic acid eutectic was successfully prepared.

[0111] Experimental Example 5 Thermogravimetric analysis (TG) test Test methods: Thermogravimetric analysis (TG) was performed on tetramethylpyrazine, succinic acid, and the tetramethylpyrazine-succinic acid eutectic prepared in Example 1.

[0112] See Figure 5 It can be seen that succinic acid has a melting point of 191℃ and a decomposition temperature of 239.5℃; tetramethylpyrazine has a melting point of 89.6℃ and a decomposition temperature of 163.9℃; and tetramethylpyrazine-succinic acid eutectic has a melting point of 137.3℃ and a decomposition temperature of 181.3℃. That is, the melting point of the tetramethylpyrazine-succinic acid eutectic is significantly different from the melting points of the two monomers, indicating that the tetramethylpyrazine-succinic acid eutectic was successfully prepared.

[0113] Experimental Example 6 Material fat solubility test (1) Experimental principle Octyl alcohol has an 8-carbon hydrophobic alkyl chain structure, which is chemically similar to the fatty acid chains that make up the phospholipid bilayer of cell membranes. This structure effectively mimics the hydrophobic interactions encountered when molecules enter the lipid environment. Simultaneously, it possesses a polar hydroxyl group (-OH), which allows it to form hydrogen bonds with water molecules, much like the hydrophilic head of phospholipid molecules. This enables the octanol-water system to simulate the water-lipid interface encountered by molecules crossing cell membranes. Therefore, the solubility of a substance in octanol can be used to evaluate its lipid solubility, thereby assessing its membrane permeability.

[0114] (2) Instruments and equipment Microbalance, temperature-controlled shaker, high-performance liquid chromatography, stoppered glass bottle, 0.45 μm organic filter membrane.

[0115] (3) Testing process Excess succinic acid and the tetramethylpyrazine succinic acid cocrystal prepared in Example 1 were added to equal masses of n-octanol and placed in a shaker at 25°C with a speed of 200 r / min to ensure thorough shaking for 24 h. After shaking, the solution was filtered through a 0.45 μm organic filter membrane to obtain a saturated filtrate, which was then sent for analysis by high-performance liquid chromatography.

[0116] (4) Test results High-performance liquid chromatography (HPLC) analysis showed that the saturated solubility of succinic acid in n-octanol was 7.37 mg / mL, while the saturated solubility of succinic acid in the tetramethylpyrazine-succinic acid cocrystal was 9.44 mg / mL. After the formation of the cocrystal, the lipophilicity of succinic acid increased by 1.3 times, demonstrating that the formation of the cocrystal between tetramethylpyrazine and succinic acid helps to improve its lipophilicity, thereby enhancing its transdermal penetration ability.

[0117] Experimental Example 7 5α-reductase inhibition ability test (1) Experimental principle Sebum secretion is closely related to sebaceous gland function, which in turn is closely related to androgen regulation. 5α-reductase is a membrane protease located on microsomes and the cell nucleus. Using the reduced coenzyme NADPH as a hydrogen donor, it catalyzes the conversion of testosterone to dihydrotestosterone (DHT), which induces excessive sebum secretion from the sebaceous glands. Inhibiting 5α-reductase activity can reduce DHT production, thereby lowering sebaceous gland lipid secretion levels.

[0118] Through experimental design, the enzyme activity of 5α-reductase in the test sample was lower than that in the negative control (physiological saline), indicating that the catalytic rate of 5α-reductase in the negative control (physiological saline) was significantly faster than that in the test sample. Therefore, the test sample had a certain inhibitory effect on 5α-reductase, thus achieving the oil control effect.

[0119] (2) Experimental methods Dissolve the sample in purified water to prepare a test solution of the specified concentration. Add 20 µL each of the sample solution and the negative control (physiological saline) to the enzyme reaction system for catalytic incubation. Measure the absorbance at 340 nm using a UV spectrophotometer, and calculate the enzyme activity by taking the average absorbance value, thereby calculating the inhibition rate.

[0120] (3) Test results Table 2

[0121] *Statistical method: Analysis is performed using the t-test, with a test level α=0.05; P≥0.05 indicates no statistical difference; 0.01<P<0.05 indicates a significant difference; P≤0.01 indicates a very significant difference; P≤0.001 indicates an extremely significant difference.

[0122] As can be seen from Table 2, compared with the NC group, the physical mixture of tetramethylpyrazine and succinic acid, the tetramethylpyrazine-succinic acid co-crystal, tetramethylpyrazine and succinic acid at test concentrations of 5% and 1%, tetramethylpyrazine at a test concentration of 0.54%, and succinic acid at a test concentration of 0.46%, all have better enzyme activity than the NC group, and have the effect of inhibiting 5α-reductase.

[0123] At the same test concentration, the inhibition rate of 1% tetramethylpyrazine-succinic acid co-crystal on 5α-reductase is higher than that of 1% tetramethylpyrazine + succinic acid (physical mixture), tetramethylpyrazine, and succinic acid, with significance. The inhibition rate of 5% tetramethylpyrazine-succinic acid co-crystal on 5α-reductase is higher than that of 1% tetramethylpyrazine + succinic acid (physical mixture), tetramethylpyrazine, and succinic acid, with significance.

[0124] In the tetramethylpyrazine-succinic acid co-crystal, succinic acid accounts for 46% and tetramethylpyrazine accounts for 54%, and the inhibition rate of 1% tetramethylpyrazine-succinic acid co-crystal on 5α-reductase is still higher than that of 0.54% tetramethylpyrazine and 0.46% succinic acid, with significance. The above data proves that the formation of the tetramethylpyrazine-succinic acid co-crystal can increase the inhibition rate of the monomers on 5α-reductase, thereby improving its oil control level.

[0125] Test Example 8 Antibacterial Performance Test against Cutibacterium acnes (1) Experimental Principle Cutibacterium acnes overproliferates in blocked hair follicles, and its metabolites (such as free fatty acids and CAMP factors) can trigger the outbreak of inflammatory factors such as IL-1α and IL-6 by activating TLR2 / 4 receptors and NLRP3 inflammasomes, leading to rupture of the hair follicle wall and infiltration of immune cells, transforming comedones into red and swollen pustules, and exacerbating tissue damage and scar formation. The agar dilution method is to add different doses of antibacterial drugs to a fixed amount of agar that has been melted and cooled to about 50°C, prepare plates containing antibacterial drugs of different decreasing concentrations, inoculate the test bacteria, observe the bacterial growth after incubation, and take the lowest drug concentration contained in the agar plate that inhibits bacterial growth as the MIC.

[0126] (2) Experimental Method Disinfection Technical Specification (2002 Edition) 2.1.8.3 Agar dilution method for determination of the minimum inhibitory concentration (MIC) of antibacterial agents.

[0127] (3) Result Determination The endpoint of the test is determined by placing the plate on a dark, non-reflective surface. The minimum drug concentration that inhibits bacterial growth is defined as the MIC. The advantage of this method is that it allows for the simultaneous determination of the MIC of multiple bacterial strains on a single plate, providing reliable results and facilitating the detection of contaminating bacteria.

[0128] (4) Test results Table 3

[0129] Referring to Table 3, even at a very high concentration (50 mg / mL), tetramethylpyrazine alone still failed to achieve an antibacterial effect. Compared to succinic acid, the succinic acid content in the tetramethylpyrazine-succinic acid cocrystal was 46%. When the concentration of the cocrystal was 10 mg / mL, the antibacterial concentration based on succinic acid was 4.6 mg / mL, which was lower than the minimum inhibitory concentration of succinic acid alone (5 mg / mL). This proves that after tetramethylpyrazine and succinic acid formed a cocrystal, the antibacterial effect of succinic acid was not reduced due to the presence of tetramethylpyrazine; on the contrary, it helped to enhance its antibacterial and acne-removing effects.

[0130] The embodiments described above are some, but not all, of the embodiments of this application. The detailed description of the embodiments of this application is not intended to limit the scope of the claimed application, but merely to illustrate selected embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this application without inventive effort are within the scope of protection of this application.

Claims

1. A tetramethylpyrazine succinic acid eutectic, characterized in that, The structural formula of the tetramethylpyrazine succinic acid eutectic is shown in Formula I: Formula I; The molecular formula of the tetramethylpyrazine succinic acid eutectic is C2. 12 H 18 N2O4, and in the tetramethylpyrazine succinic acid eutectic, the molar ratio of tetramethylpyrazine to succinic acid is 1:1; The tetramethylpyrazine succinic acid eutectic is triclinic with space group P-1 and cell parameters a=4.8713(4) Å, b=7.9365(7) Å, c=8.9107(8) Å, α=95.107(4)°, β=105.339(5)°, γ=100.078(4)°, Z=1, and cell volume V=323.76(5) Å. 3 ; The X-ray powder diffraction pattern of the tetramethylpyrazine succinic acid eutectic exhibits characteristic peaks at 2θ angles of 14.40±0.2°, 23.71±0.2°, 31.06±0.2°, and 41.77±0.2°.

2. A method for preparing tetramethylpyrazine succinic acid eutectic, characterized in that, Includes the following steps: A. Ligustrazine and succinic acid are added to a solvent and mixed, wherein the sum of the masses of ligustrazine and succinic acid is m1, the mass of the solvent is m2, and 1 ≤ m2 / m1, to obtain a mixed solution; the mixed solution is stirred at 60℃~75℃ for 2~4 h, and then the reaction solution is subjected to crystallization treatment, solid-liquid separation treatment and drying treatment in sequence to obtain ligustrazine-succinic acid eutectic; or, B. Ligustrazine and succinic acid are added to a solvent and mixed, wherein the molar ratio of ligustrazine to succinic acid is 1:1, the sum of the masses of ligustrazine and succinic acid is m3, the mass of the solvent is m4, and 0.6 ≤ m4 / m3, to obtain a mixed solution; the mixed solution is stirred at 60℃~75℃ for 3~6 h, and then the reaction solution is subjected to crystallization treatment, solid-liquid separation treatment and drying treatment in sequence to obtain ligustrazine-succinic acid eutectic.

3. The method for preparing tetramethylpyrazine succinic acid eutectic according to claim 2, characterized in that, In step A, the molar ratio of tetramethylpyrazine to succinic acid is (1~1.5):(1~1.5), or / and, 1≤m2 / m1≤10.

4. The method for preparing tetramethylpyrazine succinic acid eutectic according to claim 2, characterized in that, In step B, 0.8 ≤ m4 / m3.

5. The method for preparing the tetramethylpyrazine succinic acid eutectic according to any one of claims 2 to 4, characterized in that, In steps A and B, the stirring speed is 200 rpm to 800 rpm. or / and, In steps A and B, the crystallization treatment includes: first lowering the temperature of the reaction solution to 20℃~30℃, and then lowering the temperature of the reaction solution to 0℃~5℃ and keeping it at that temperature for 10 h~24 h to allow crystallization to occur.

6. The method for preparing tetramethylpyrazine succinic acid eutectic according to claim 5, characterized in that, The heat preservation and crystallization process is carried out under stirring conditions, with a stirring speed of 50 rpm to 200 rpm.

7. The method for preparing tetramethylpyrazine succinic acid eutectic according to any one of claims 2 to 4, characterized in that, In steps A and B, the solvent is selected from at least one of water, ethanol, methanol, ethyl acetate, acetonitrile, isopropanol, n-propanol, and acetone.

8. The use of the tetramethylpyrazine succinic acid eutectic as described in claim 1 or the tetramethylpyrazine succinic acid eutectic prepared by any one of the preparation methods described in claims 2 to 7 in the preparation of skin care products or cosmetics.

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