Eutectic of azelaic acid and ligustrazine and preparation method thereof

Abstract

The invention discloses an azelaic acid and ligustrazine eutectic crystal and a preparation method thereof, and belongs to the technical field of eutectic crystals, and the preparation method is characterized by comprising the following steps: uniformly mixing azelaic acid and ligustrazine according to a specific feeding ratio, transferring into a closed reactor, placing in a certain atmosphere condition, ensuring a water-free and oxygen-free environment, and carrying out constant-temperature stirring at 70-115 DEG C, so as to obtain the azelaic acid and ligustrazine eutectic crystal. The stirring time is 1-10 hours, cooling to room temperature to obtain a solid product, and grinding the solid product to obtain a white solid product, namely the azelaic acid / ligustrazine eutectic crystal. According to the eutectic system, the water solubility of the azelaic acid can be remarkably improved, and meanwhile through the synergistic effect of the azelaic acid and ligustrazine, the permeability, antibacterial activity, oxidation resistance and other effects of the azelaic acid are remarkably improved.

Description

Technical Field

[0001] This invention relates to a cocrystal of azelaic acid and tetramethylpyrazine and its preparation method, and relates to the field of pharmaceutical cocrystal technology. Background Technology

[0002] Azelaic acid (AzA) is a natural dicarboxylic acid that is effective in treating acne, but its extremely low solubility and stability severely limit its application prospects. In practical applications, it is usually prepared as a 10%–20% concentration gel or cream, but this high-concentration formulation has certain irritant properties, which may cause skin burning, redness, and other symptoms, making it unsuitable for sensitive skin. Moreover, azelaic acid in high-concentration formulations has poor stability and is prone to precipitation, resulting in limited skin penetration.

[0003] To address the water solubility issue of azelaic acid, existing technologies have employed various modifications and physicochemical property optimizations. Patent CN 114181072 A discloses a preparation process for ultrafine azelaic acid, which improves its water solubility to some extent. However, the preparation of ultrafine powder increases the cost of azelaic acid raw materials and fails to achieve a significant increase in azelaic acid solubility. Patent CN 113248364A discloses a method for increasing the water solubility of azelaic acid by compounding it with alkaline substances (such as theophylline, echinocoline, carnitine, etc.) to form a salt. However, this preparation process requires a large amount of organic solvent and is quite complex. Patent CN 112624918A discloses a method for preparing a eutectic of azelaic acid and an organic base. The preparation of the solid eutectic is carried out in an organic solvent under inert gas conditions. Subsequent steps include membrane filtration, recrystallization, and removal of organic solvents to obtain the target eutectic. This process is complex, and the patent does not specify the exact solubility increase value for azelaic acid. Patent CN108187070A discloses a method for preparing azelaic acid-cyclodextrin inclusion complexes via cyclodextrin inclusion and spray drying. Although this method increases the solubility of azelaic acid to some extent, the process is relatively complex, and it requires a large amount of cyclodextrin, which makes the inclusion system sticky and unpleasant to the skin during use. Patent CN 110669226A discloses a method for preparing a polyethylene glycol / propylene glycol / azelaic acid supramolecular system. This method uses propylene glycol and polyethylene glycol as solvents to first dissolve azelaic acid, and then adds the dissolved system to a large amount of water while it is still hot. Propylene glycol and polyethylene glycol are commonly used solvents and solubilizers in cosmetic formulations. This method is essentially a thermal dissolution of azelaic acid under the solubilization of conventional alcohols and polyethylene glycol.

[0004] Cocrystals are crystal structures formed by two or more molecules bonded together in a specific stoichiometric ratio through weak interactions such as hydrogen bonds, electrostatic attraction, and hydrophobic interactions. Among these, hydrogen bonds play a crucial role in cocrystal formation due to their high directionality, specificity, and strong stability. Without altering the molecular structure of the active pharmaceutical ingredient, cocrystals can significantly improve its physicochemical properties, including solubility, stability, and transdermal permeability, thereby enhancing drug bioavailability. By selecting suitable cocrystal ligands to construct cocrystal systems with azelaic acid, it is hoped that both solubility and permeability can be improved, while significantly enhancing the drug's efficacy.

[0005] Tetramethylpyrazine (TMP) is an active alkaloid extracted from the traditional Chinese medicine Ligusticum chuanxiong. Its main pharmacological effects include vasodilation, improved microcirculation, antioxidant activity, anti-inflammation, and neuroprotection. Studies have shown that tetramethylpyrazine can effectively scavenge free radicals, inhibit lipid peroxidation, and slow down the cellular aging process. In the cosmetics industry, tetramethylpyrazine is widely used in anti-aging, whitening, and dark circle-reducing skincare products due to its excellent antioxidant and blood circulation-promoting properties. Tetramethylpyrazine can enhance skin metabolism, improve dull skin tone, and has the potential to soothe sensitivity and strengthen the skin barrier function, gradually becoming one of the important representatives of natural plant active ingredients.

[0006] Therefore, the preparation of an azelaic acid eutectic system by organically combining tetramethylpyrazine and azelaic acid using eutectic technology can improve its water solubility and achieve synergistic effects, which has extremely high practical and economic value. Summary of the Invention

[0007] To address the aforementioned issues, this invention utilizes tetramethylpyrazine and azelaic acid to prepare a cocrystal, resulting in a tetramethylpyrazine-azelaic acid cocrystal with significantly improved antibacterial, antioxidant, and transdermal permeability properties. This aims to resolve the problems of low water solubility and poor stability of azelaic acid in existing technologies.

[0008] The first objective of this invention is to provide a method for preparing tetramethylpyrazine-azelic acid eutectic, comprising the steps of:

[0009] Azelaic acid and tetramethylpyrazine were mixed in a molar ratio of 1-3:1-3, heated, cooled, and ground to prepare a tetramethylpyrazine-azelaic acid eutectic.

[0010] In one embodiment, heating is performed at 70–115°C with stirring for 1–10 hours;

[0011] Optionally, heating is performed at 80–95°C with stirring for 1–4 hours.

[0012] In one embodiment, the mixture is placed under sealed conditions for reaction;

[0013] Alternatively, the sealed conditions may be air, argon, or carbon dioxide.

[0014] A second object of the present invention is to provide a tetramethylpyrazine-azelic acid eutectic prepared by any of the methods described above.

[0015] A third objective of this invention is to provide the application of the above-mentioned tetramethylpyrazine-azelic acid eutectic in the preparation of antibacterial and antioxidant products.

[0016] In one embodiment, the product includes cosmetics and pharmaceuticals.

[0017] The fourth objective of this invention is to provide a method for simultaneously improving the antibacterial, antioxidant, and transdermal permeability of azelaic acid, using tetramethylpyrazine and azelaic acid to prepare a eutectic, comprising the steps of:

[0018] Azelaic acid and tetramethylpyrazine were mixed in a molar ratio of 1-3:1-3, heated, cooled, and ground to prepare a tetramethylpyrazine-azelaic acid eutectic.

[0019] Optionally, heating is performed at 70–115°C with stirring for 1–10 hours;

[0020] Optionally, heating is performed at 80–95°C with stirring for 1–4 hours;

[0021] Alternatively, the sealed conditions may be air, argon, or carbon dioxide.

[0022] The fifth object of the present invention is to provide a daily chemical product containing the above-mentioned tetramethylpyrazine-azelic acid eutectic.

[0023] Optionally, the daily chemical products include shampoo, facial cleanser, and cosmetics.

[0024] The sixth object of the present invention is to provide an antibacterial and antioxidant medicine containing the above-mentioned tetramethylpyrazine-azelic acid eutectic.

[0025] A seventh object of the present invention is to provide the use of any of the above-described methods or the above-described tetramethylpyrazine-azelic acid eutectic in the preparation of pharmaceuticals or cosmetics.

[0026] Optionally, the dosage forms of the medicine include tinctures, liniments, lotions, oils, ointments, creams, gels, sprays, and film-forming agents;

[0027] Optionally, the cosmetics include serums, lotions, and creams.

[0028] Beneficial effects of the present invention

[0029] (1) The azelaic acid / tetramethylpyrazine eutectic system prepared by the present invention significantly improves the water solubility of azelaic acid, up to about 5 times.

[0030] (2) The azelaic acid / tetramethylpyrazine eutectic system prepared by the present invention significantly improves the physicochemical properties of azelaic acid, including solubility, stability and transdermal performance, without changing the molecular structure of the active pharmaceutical ingredient, thereby improving the bioavailability of the drug and playing a synergistic role.

[0031] (3) The azelaic acid / tetramethylpyrazine eutectic system prepared by the present invention has good stability, is not easy to decompose, and is easy to store and transport.

[0032] (4) The azelaic acid / tetramethylpyrazine eutectic system prepared by this invention has a green and pollution-free preparation process, is simple, is suitable for industrial promotion, and the product can be directly used as a raw material for drugs or cosmetics. Attached Figure Description

[0033] Figure 1 This is a Gaussian plot of the azelaic acid / tetramethylpyrazine eutectic system in Example 1.

[0034] Figure 2 The image shows the infrared spectrum of the azelaic acid / tetramethylpyrazine eutectic system in Example 1.

[0035] Figure 3 This is a differential scanning calorimeter of the azelaic acid / tetramethylpyrazine eutectic system in Example 1.

[0036] Figure 4 The powder X-ray diffraction pattern of the azelaic acid / tetramethylpyrazine eutectic system in Example 1 is shown below.

[0037] Figure 5 This is a graph showing the antibacterial activity of the azelaic acid / tetramethylpyrazine eutectic system in Example 1.

[0038] Figure 6 This is a graph showing the antioxidant properties of the azelaic acid / tetramethylpyrazine eutectic system in Example 1.

[0039] Figure 7 This is a permeability test diagram of the azelaic acid / ligustrazine eutectic system in Example 1 of this invention. Detailed Implementation

[0040] To make the objectives, technical solutions, and advantages of this invention clearer and more explicit, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

[0041] The technical problem to be solved by the present invention is to provide a eutectic of azelaic acid and tetramethylpyrazine and its preparation method, in order to address the shortcomings of the prior art and solve the problems of low water solubility and poor stability of azelaic acid in the prior art.

[0042] A eutectic of azelaic acid and tetramethylpyrazine and its preparation method, comprising the following steps:

[0043] Azelaic acid and tetramethylpyrazine were mixed evenly according to a specific feeding ratio, transferred to a closed reactor, and placed under specific atmospheric conditions to ensure anhydrous and oxygen-free environment. The mixture was stirred at a constant temperature within the range of 70–115℃ for 1–10 hours. After cooling to room temperature, a solid product was obtained. This solid product was then ground to obtain a white solid product, namely the azelaic acid / tetramethylpyrazine eutectic. This eutectic system significantly improves the water solubility of azelaic acid, and through synergistic effects with tetramethylpyrazine, significantly enhances the permeability, antibacterial properties, and antioxidant effects of azelaic acid.

[0044] In this invention, the molar ratio of azelaic acid to tetramethylpyrazine is preferably 3:1 to 1:3, more preferably 2:1 to 1:2, and most preferably 1:1 to 1:2; specifically, in the embodiments of this invention, it can be 1:1, 1:1.5 or 1:2.

[0045] In this invention, the specific atmosphere is air, argon, or carbon dioxide; specifically, in the embodiments of this invention, it can be air, argon, or carbon dioxide.

[0046] In this invention, the stirring and heating temperature is preferably 70-115°C, more preferably 70-100°C, and most preferably 80-95°C; specifically, in the embodiments of this invention, it can be 80°C, 90°C, or 95°C.

[0047] In this invention, the heating time is preferably 1 to 10 hours, more preferably 1 to 5 hours, and most preferably 2 to 4 hours; specifically, in the embodiments of this invention, it can be 2 hours, 3 hours, or 4 hours.

[0048] In this invention, the obtained azelaic acid eutectic system was characterized and tested using infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction, and Gaussian calculation analysis was performed simultaneously.

[0049] The resulting azelaic acid eutectic system was subjected to antibacterial, antioxidant, and in vitro skin penetration tests using a Franz diffusion cell. Raw materials used in the examples:

[0050] Azelaic acid was purchased from Shanghai Haohong Biomedical Technology Co., Ltd.

[0051] Ligustrazine was purchased from Shanghai Haohong Biomedical Technology Co., Ltd.

[0052] Test method:

[0053] Gaussian molecular simulations were performed using Gaussian16. The M06-2X function was used for geometry optimization, and the standard 6-31G(d,p) basis set was employed. Resonant frequencies were calculated for all rest points to confirm their local minima. Single-point energies were calculated at the M06-2X / 6-311+G(d,p) level. Electrostatic potential (ESP), non-covalent index (NCI), and atoms in the molecule (AIM) analyses were observed using Multiwfn software and visualized using the VMD software package.

[0054] The Fourier transform infrared spectroscopy test parameters are as follows: Machine specifications: FTS6000; Machine manufacturer: Bio-ard, USA; Experimental parameters: Scan range 500–4000 cm⁻¹ -1 The resolution is 4cm. -1 .

[0055] The differential scanning calorimetry (DSC) parameters are as follows: Machine specifications: DSC-8000 model; Machine manufacturer: PE Corporation, USA; Experimental parameters: Nitrogen atmosphere, flow rate 50 mL / min, temperature range 30–115 °C, heating rate 10 °C / min.

[0056] The powder X-ray diffraction test parameters are as follows: machine specifications: D8 type, manufacturer: Bruker AXS GmbH, Germany, experimental parameters: degree range of 5 to 50°, scanning speed of 2° / min.

[0057] The antibacterial activity of azelaic acid, tetramethylpyrazine, and AzA / TMP cocrystal against *Propionibacterium acnes* was determined by agar diffusion method. The AzA / TMP cocrystal was diluted to 100 mg / mL with DMSO, and azelaic acid and tetramethylpyrazine were diluted to equal concentrations of each component in the AzA / TMP (58.02 mg of azelaic acid and 41.98 mg of tetramethylpyrazine per 100 mg of AzA / TMP). Wells were uniformly punched in solid culture medium, and an appropriate amount of bacterial suspension was added, followed by the three test drugs and DMSO as a control. After incubation at 37°C under anaerobic conditions for 48 h, the diameter of the inhibition zone was measured.

[0058] The antioxidant properties of the cocrystal were verified by testing its scavenging efficiency against DPPH and ABTS+ free radicals. Azelaic acid, tetramethylpyrazine, and AzA / TMP cocrystal were diluted with methanol to 10 mg / mL as the test drug solution. The scavenging rates of the three drug solutions against DPPH and ABTS+ free radicals were tested according to the method in GB / T39100-2020.

[0059] In vitro skin penetration tests were performed using a Franz diffusion cell. Undamaged, clean porcine skin was placed on the cell with the stratum corneum facing upwards. Azelaic acid, azelaic acid-tetramethylpyrazine equimolar physical mixture, and AzA / TMP eutectic were diluted with propylene glycol to ensure azelaic acid concentration of 10 mg / mL in each system. The receiving chamber was filled with physiological saline, and 2 mL of each drug solution was added to the diffusion cell. The mixture was continuously stirred at a constant temperature (37±0.1℃), and 1 mL of the receiving solution was collected at 2, 4, 6, 12, and 24 hours, with an equal volume of fresh receiving solution added. The collected samples were filtered through a 0.45 μm microporous filter and then subjected to HPLC analysis. The cumulative drug penetration was calculated using the following formula:

[0060]

[0061] Where Q is the cumulative transdermal penetration of the drug per unit area (μg / cm²). 2 V is the volume of the receiving cell (7 mL); A is the diffusion area (3 cm²). 2 Cn represents the drug concentration (μg / mL) measured at the nth sampling point; Vi is the sampling volume (1 mL).

[0062] To further illustrate the present invention, the following describes in detail, with reference to embodiments, a eutectic of azelaic acid and tetramethylpyrazine and its preparation method.

[0063] Example 1: A method for preparing azelaic acid and tetramethylpyrazine eutectic

[0064] 1. A method for preparing azelaic acid and tetramethylpyrazine eutectic, comprising the following steps:

[0065] Weigh out 0.01 mol of azelaic acid and 0.01 mol of tetramethylpyrazine, mix them evenly, transfer them to a closed reactor, and place them under an argon atmosphere. Stir and heat at 95°C for 3 hours, cool to room temperature, and grind to obtain a white solid product (tetramethylpyrazine-azelaic acid eutectic system; i.e., AzA / TMP).

[0066] 2. Property testing

[0067] (1) Solubility

[0068] The solubility of the prepared AzA / TMP in water at room temperature was determined by high performance liquid chromatography (HPLC), reaching 14.7 mg / mL, which is about 5 times higher than that of azelaic acid, and it also has good stability.

[0069] (2) Eutectic structure

[0070] Figure 1The Gaussian calculation results of the AzA / TMP eutectic in Example 1 are shown in (a) and (b), respectively. The electrostatic potential analysis diagram and the molecular interaction force analysis diagram are shown. It can be seen that the carboxyl group in azelaic acid and the nitrogen atom in tetramethylpyrazine molecule form hydrogen bonds with a small dipole moment (μ = 2.07D), indicating that the structure has low polarity and the eutectic system has good stability.

[0071] Figure 2 The infrared spectrum of the AzA / TMP eutectic in Example 1 is shown in the 3500–3200 cm⁻¹ range. -1 The absorption peak in the range corresponds to the absorption peak of the hydroxyl group (hydrogen bond), at 1385 cm⁻¹. -1 The peak at this location is the stretching vibration peak of C=N. In the eutectic system corresponding to Example 1, a significant shift in certain characteristic peaks can be observed, with the C=O diffraction peak shifting from 1690 cm⁻¹. -1 Offset to 1708cm -1 The stretching vibration peak of C=N also increased from 1385 cm⁻¹ -1 Offset to 1463cm -1 This demonstrates that hydrogen bonds are formed between the carboxyl group of azelaic acid and the nitrogen atom of tetramethylpyrazine, and the intermolecular interaction forces in the system cause the shift of the infrared absorption peak.

[0072] Figure 3 and Figure 4 The figures show the DSC and PXRD patterns of the AzA / TMP eutectic in Example 1. Azelaic acid and tetramethylpyrazine exhibited single melting peaks at 106.5°C and 82°C, respectively, while the melting point of the corresponding AzA-TMP eutectic system in Example 1 was 60.2°C. The presence of a single melting point different from the raw material components indicates the formation of the eutectic system. PXRD results further confirmed the formation of the eutectic. The AzA-TMP eutectic in Example 1 showed novel characteristic diffraction peaks at positions 9.78°, 10.53°, 22.39°, and 28.66°, while the intensity of some characteristic diffraction peaks of azelaic acid and tetramethylpyrazine was significantly reduced or disappeared. This indicates that the eutectic system was not a physical mixture, but rather formed a new crystal structure.

[0073] (3) Antibacterial effect

[0074] The antibacterial effect of the AzA / TMP co-crystal in Example 1 against Propionibacterium acnes was evaluated using the agar diffusion method. The test results are as follows: Figure 5 As shown.

[0075] The results showed that ligustrazine and the solvent control group did not exhibit antibacterial activity, while both the AzA-TMP system and azelaic acid effectively inhibited the growth of Propionibacterium acnes. The inhibition zone diameter of the AzA-TMP system was 24.6 mm, which was larger than the inhibition zone of an equal amount of AzA (16.7 mm), demonstrating that the formation of the eutectic system enhanced the antibacterial performance.

[0076] (4) Antioxidant properties

[0077] Antioxidant test results as follows Figure 6 As shown, under the same concentration (10 mg / mL) conditions, the scavenging rates of the azelaic acid, tetramethylpyrazine and AzA-TMP co-crystal system for DPPH free radicals were 68%, 72% and 78%, respectively, and the scavenging rates for ABTS+ free radicals were 57%, 63% and 70%, respectively.

[0078] It is evident that both azelaic acid and tetramethylpyrazine exhibit strong antioxidant properties and can effectively scavenge free radicals. After forming the AzA-TMP eutectic system, the free radical scavenging rate is higher than that of the two component raw materials, demonstrating a synergistic effect of "1+1>2".

[0079] (5) Permeability test

[0080] Permeability test results as follows Figure 7 As shown, the permeability of azelaic acid and the physical mixture group was not significantly different, with cumulative permeability of 20.98% and 23.38% respectively after 12 hours, proving that tetramethylpyrazine does not show a significant permeation-enhancing effect on azelaic acid or the permeation-enhancing effect is extremely low; however, when a eutectic system is formed, the permeability of the AzA-TMP eutectic system increases to 38.79%, which is much higher than that of the azelaic acid system alone. At the same time, it has a better continuous transdermal delivery ability compared with azelaic acid, and can still maintain a strong continuous permeation ability after 12 hours.

[0081] Example 2: A method for preparing azelaic acid and tetramethylpyrazine eutectic

[0082] A method for preparing azelaic acid and tetramethylpyrazine eutectic includes the following steps:

[0083] Weigh out 0.01 mol of azelaic acid and 0.015 mol of tetramethylpyrazine, mix them evenly, transfer them to a closed reactor, place them under air conditions, and heat them at a constant temperature of 90°C for 2 hours with stirring. After cooling to room temperature and grinding, a white solid product is obtained.

[0084] Example 3: A method for preparing azelaic acid and tetramethylpyrazine eutectic

[0085] A method for preparing azelaic acid and tetramethylpyrazine eutectic includes the following steps:

[0086] Weigh out 0.01 mol of azelaic acid and 0.02 mol of tetramethylpyrazine, mix them evenly, transfer them to a closed reactor, place them under carbon dioxide conditions, and heat them at a constant temperature of 80°C for 4 hours with stirring. After cooling to room temperature and grinding, a white solid product is obtained.

[0087] Comparative Example 1: Changing the ratio of azelaic acid to tetramethylpyrazine

[0088] (1) Based on Example 1, the amount of azelaic acid was changed to 0.04 mol, and the remaining steps were the same as in Example 1.

[0089] The results showed that after increasing the amount of azelaic acid, the two components did not completely melt during the entire heating process. Subsequent tests revealed that a high-purity eutectic system could not be obtained, and there was an excess of azelaic acid.

[0090] (2) Based on Example 1, the amount of ligustrazine was changed to 0.04 mol, and the remaining steps were the same as in Example 1.

[0091] The results showed that after increasing the amount of tetramethylpyrazine, the two components did not completely melt during the entire heating process. Subsequent tests revealed that a high-purity eutectic system could not be obtained, and there was an excess of azelaic acid.

[0092] Comparative Example 2: Changing the heating temperature

[0093] (1) Based on Example 1, the heating temperature was changed to 60°C, and the remaining steps were the same as in Example 1.

[0094] The results showed that after lowering the heating temperature, the two components did not completely melt during the entire heating process. Subsequent tests revealed that a high-purity eutectic system could not be obtained, and the system's self-assembly was incomplete.

[0095] (2) Based on Example 1, the heating temperature was changed to 120°C, and the remaining steps were the same as in Example 1.

[0096] The results show that when the heating temperature is increased, a large number of components will volatilize and sublimate during the entire heating process, and high-purity eutectic cannot be obtained.

[0097] Comparative Example 3: Changing the heating time

[0098] (1) Based on Example 1, the heating time was changed to 0.5h, and the remaining steps were the same as in Example 1.

[0099] The results showed that after shortening the heating time, the two components did not completely melt during the entire heating process. Subsequent tests revealed that a high-purity eutectic system could not be obtained, and the system's self-assembly was incomplete.

[0100] (2) Based on Example 1, the heating time was changed to 12h, and the remaining steps were the same as in Example 1.

[0101] The results showed that extending the heating time resulted in a large amount of crystals volatilizing and sublimating, making it impossible to obtain a high-purity eutectic system.

[0102] Comparative Example 4: Changing the ligand

[0103] (1) Based on Example 1, arginine was used to replace ligustrazine, and the remaining steps were the same as in Example 1.

[0104] (2) Based on Example 1, theophylline was used to replace ligustrazine, and the remaining steps were the same as in Example 1.

[0105] (3) Based on Example 1, matrine was used instead of ligustrazine, and the remaining steps were the same as in Example 1.

[0106] (4) Based on Example 1, pyrazine was used to replace ligustrazine, and the remaining steps were the same as in Example 1.

[0107] The results are shown in Table 1.

[0108] Table 1 Performance Testing

[0109]

[0110] Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Anyone skilled in the art can make various modifications and alterations without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be determined by the claims.

Claims

1. A method for preparing tetramethylpyrazine-azelic acid eutectic, characterized in that, Including the following steps: Azelaic acid and tetramethylpyrazine were mixed in a molar ratio of 1-3:1-3, heated, cooled, and ground to prepare a tetramethylpyrazine-azelaic acid eutectic.

2. The method according to claim 1, characterized in that, Heating is performed at 70–115℃ with stirring for 1–10 hours; Optionally, heating is performed at 80–95°C with stirring for 1–4 hours.

3. The method according to claim 1, characterized in that, After mixing, the mixture is placed under sealed conditions for reaction. Alternatively, the sealed conditions may be air, argon, or carbon dioxide.

4. The tetramethylpyrazine-azelate eutectic prepared by the method according to any one of claims 1 to 3.

5. The application of the tetramethylpyrazine-azelic acid eutectic as described in claim 4 in the preparation of antibacterial and antioxidant products.

6. The application according to claim 5, characterized in that, The products include cosmetics and pharmaceuticals.

7. A method for simultaneously improving the antibacterial, antioxidant, and transdermal permeability of azelaic acid, characterized in that, The preparation of the eutectic using tetramethylpyrazine and azelaic acid includes the following steps: Azelaic acid and tetramethylpyrazine were mixed in a molar ratio of 1-3:1-3, heated, cooled, and ground to prepare a tetramethylpyrazine-azelaic acid eutectic. Optionally, heating is performed at 70–115°C with stirring for 1–10 hours; Optionally, heating is performed at 80–95°C with stirring for 1–4 hours; Alternatively, the sealed conditions may be air, argon, or carbon dioxide.

8. A daily chemical product, characterized in that, The daily chemical product contains the tetramethylpyrazine-azelaic acid eutectic as described in claim 4; Optionally, the daily chemical products include shampoo, facial cleanser, and cosmetics.

9. An antibacterial and antioxidant drug, characterized in that, The drug contains the tetramethylpyrazine-azelic acid eutectic as described in claim 4.

10. The application of the method according to any one of claims 1 to 3, the method according to any one of claims 7 to 9, or the tetramethylpyrazine-azelic acid eutectic according to claim 4 in the preparation of pharmaceuticals or cosmetics; Optionally, the dosage forms of the medicine include tinctures, liniments, lotions, oils, ointments, creams, gels, sprays, and film-forming agents; Optionally, the cosmetics include serums, lotions, and creams.

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