Lithium ion eutectic and preparation method and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to a lithium ion eutectic crystal and a preparation method and application thereof. Wherein the lithium ion eutectic comprises antioxidant, lithium and proline in a molar ratio of 1: 1: 1; the antioxidant has a cinnamic acid structure, a cinnamic acid derivative structure or a phenolic acid structure containing benzoic acid. The lithium ion eutectic can improve the antioxidant activity of the antioxidant component and increase the solubility of the antioxidant component in water. In addition, lithium in the co-crystal can also improve the release characteristic of the medicine in vivo, and the clinical application value of the antioxidant component is further improved.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a lithium ion eutectic, a preparation method thereof and an application thereof. Background Art

[0002] Pharmaceutical cocrystals are a new type of crystals formed by the active pharmaceutical ingredient (API) and the cocrystal ligand (CCF) at a fixed stoichiometric ratio through non-covalent bonds. Studies have shown that it can improve the physical and chemical properties of drugs without changing their molecular structure, so it has attracted more and more attention in the modification of raw materials.

[0003] Currently, lithium is mainly used clinically to treat mental health problems, such as mania, Alzheimer's disease, and to prevent patients from developing suicidal tendencies.

[0004] The antioxidant activity of drugs also plays an important role in neurodegenerative diseases. Common natural product ingredients with antioxidant activity include vitamin C, vitamin E, polyphenolic compounds, carotenoids and coenzyme Q10. These ingredients have shown the potential to protect nerve cells, slow down the aging process and reduce the risk of cancer in clinical studies. In the study of neurodegenerative diseases, the efficacy of antioxidants is particularly significant. Oxidative stress is considered to be an important pathogenesis of diseases such as Alzheimer's disease and Parkinson's disease. Antioxidants can play a neuroprotective role by reducing oxidative damage, protecting nerve cells and improving mitochondrial function.

[0005] At present, there are no reported cases of preparing ionic cocrystals with natural ingredients with antioxidant activity and lithium salts. If the two are combined, it is expected that the efficacy of the drug will be further improved. Summary of the invention

[0006] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a lithium ion eutectic, a preparation method and application thereof, aiming to improve the antioxidant properties of drug components.

[0007] In order to achieve the above object, the present invention adopts the following technical solutions:

[0008] A first aspect of the present invention provides a lithium ion eutectic, which includes an antioxidant, lithium and proline in a molar ratio of 1:1:1; the antioxidant has a cinnamic acid structure, a cinnamic acid derivative structure or a phenolic acid structure containing benzoic acid.

[0009] In the lithium ion eutectic, the antioxidant is p-coumaric acid or vanillic acid.

[0010] The lithium ion eutectic, wherein when the lithium ion eutectic is p-coumaric acid-lithium-L-proline eutectic, the powder X-ray diffraction pattern of the p-coumaric acid-lithium-L-proline eutectic includes the following characteristic peaks: 6.66°, 10.80°, 13.14°, 13.36°, 17.38°, 18.80°, 19.82°, 21.18°, 21.88°, 23.00°, 23.62°, 25.14°, 26.50°, 27.44°, 29.22°, and 35.14°.

[0011] The lithium ion eutectic, wherein, when the lithium ion eutectic is a vanillic acid-lithium-L-proline eutectic, the powder X-ray diffraction pattern of the vanillic acid-lithium-L-proline eutectic includes the following characteristic peaks: 15.96°, 16.32°, 16.72°, 17.56°, 19.20°, 20.04°, 22.12°, 22.88°, and 23.56°.

[0012] A second aspect of the present invention provides a method for preparing a eutectic, which is used to prepare the lithium ion eutectic as described above, comprising the following steps: heating and dissolving lithium hydroxide, an antioxidant, and proline in a solvent, slowly volatilizing the solvent, crystallizing, filtering and drying to obtain the lithium ion eutectic.

[0013] The method for preparing the eutectic is characterized in that the molar ratio of the lithium hydroxide, the antioxidant and L-proline is (1-2):(1-2):(1-2).

[0014] The method for preparing the eutectic, wherein the temperature of the heating and dissolving is 60 to 90° C., and the time is 15 to 90 minutes.

[0015] The method for preparing the eutectic, wherein the solvent includes at least one of water, methanol, ethanol, acetonitrile, dimethyl sulfoxide, isopropanol, 3-methyl-1-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, 1-pentanol, 1-propanol, 2-propanol, and chloroform.

[0016] The third aspect of the present invention provides the use of the above-mentioned lithium ion eutectic in the preparation of lithium salt drugs.

[0017] The fourth aspect of the present invention provides a method for improving the antioxidant activity of an antioxidant, wherein the antioxidant has a cinnamic acid structure, a cinnamic acid derivative structure or a phenolic acid structure containing benzoic acid, comprising the following steps: preparing the antioxidant as a lithium ion eutectic as described above.

[0018] Beneficial effects: The first aspect of the present invention provides a lithium ion eutectic, which can effectively improve the antioxidant activity of antioxidants by forming a eutectic with lithium and proline, so that the antioxidants can more effectively combat oxidative stress when used to treat diseases.

[0019] A second aspect of the present invention provides a method for preparing a eutectic, which is used to prepare the lithium ion eutectic as described above. The preparation method has simple process steps and good controllability, and can well ensure the quality of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is the crystal structure of p-coumaric acid-lithium-L-proline ion cocrystal.

[0021] Figure 2 This is the crystal structure of the vanillic acid-lithium-L-proline ion cocrystal.

[0022] Figure 3 This is the powder diffraction pattern of p-coumaric acid-lithium-L-proline ion cocrystal.

[0023] Figure 4 This is the powder diffraction pattern of vanillic acid-lithium-L-proline ion cocrystal.

[0024] Figure 5 These are the results of the solubility tests of p-coumaric acid and vanillic acid in water.

[0025] Figure 6 The results are for the determination of the solubility of p-coumaric acid and vanillic acid in water in the cocrystal.

[0026] Figure 7 These are the experimental results of DPPH scavenging of p-coumaric acid, vanillic acid and the corresponding lithium ion cocrystals.

[0027] Figure 8 These are the experimental results of ABTS scavenging of p-coumaric acid, vanillic acid and the corresponding lithium ion cocrystals.

[0028] Fig. 9 These are the experimental results of iron ion scavenging of p-coumaric acid, vanillic acid and the corresponding lithium ion eutectics. DETAILED DESCRIPTION

[0029] The present invention provides a lithium ion eutectic, a preparation method and application thereof. In order to make the purpose, technical solution and effect of the present invention clearer and more specific, the present invention is further described in detail with reference to the accompanying drawings and examples. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0030] A first aspect of the present invention provides a lithium ion eutectic, which includes an antioxidant, lithium and proline in a molar ratio of 1:1:1; the antioxidant has a cinnamic acid structure, a cinnamic acid derivative structure or a phenolic acid structure containing benzoic acid.

[0031] Ionic eutectics can be used as drug delivery carriers to enhance the stability and bioavailability of drugs. In the present invention, the combination of antioxidants and lithium can improve the release characteristics of drugs in the body, thereby improving their efficacy. Lithium has been widely used to treat bipolar disorder, and its neuroprotective effect has also been confirmed in studies of neurodegenerative diseases. By combining lithium with antioxidants, it is expected that the neuroprotective effect of lithium will be enhanced and neurodegenerative diseases will be slowed down. In addition, the synergistic effect of lithium and antioxidants can help to more effectively combat oxidative stress, especially in the prevention and treatment of aging and related diseases.

[0032] Preferably, the antioxidant is p-coumaric acid or vanillic acid. Among them, p-coumaric acid has anti-inflammatory, anti-tumor activity, cardiovascular protection, neuroprotection and antimicrobial activity in addition to its antioxidant properties. Coumaric acid has anti-inflammatory, analgesic, anti-cancer activity, cardiovascular protection, neuroprotection and antimicrobial activity in addition to its antioxidant properties. In addition, coumaric acid also shows potential in the treatment of metabolic diseases (such as diabetes and obesity) and cardiovascular diseases.

[0033] In the present invention, the antioxidant activity of p-coumaric acid or vanillic acid can be improved by forming a cocrystal with lithium and proline. In addition, p-coumaric acid and vanillic acid both have problems such as poor water solubility, which will seriously affect their clinical application. After the cocrystal is formed, the solubility of p-coumaric acid or vanillic acid in water is also significantly improved.

[0034] A second aspect of the present invention provides a method for preparing a eutectic, which is used to prepare the lithium ion eutectic as described above, comprising the following steps: heating and dissolving lithium hydroxide, an antioxidant, and proline in a solvent, slowly volatilizing the solvent, crystallizing, filtering and drying to obtain the lithium ion eutectic.

[0035] Preferably, the molar ratio of lithium hydroxide, antioxidant and L-proline is (1-2):(1-2):(1-2).

[0036] Preferably, the temperature of the heating and dissolving is 60 to 90° C., and the time is 15 to 90 minutes.

[0037] Preferably, the solvent includes at least one of water, methanol, ethanol, acetonitrile, dimethyl sulfoxide, isopropanol, 3-methyl-1-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, 1-pentanol, 1-propanol, 2-propanol, and chloroform.

[0038] The third aspect of the present invention provides the use of the above-mentioned lithium ion eutectic in the preparation of lithium salt drugs.

[0039] A fourth aspect of the present invention provides a method for improving the antioxidant activity of an antioxidant, comprising the following steps: preparing the antioxidant into the lithium ion eutectic as described above.

[0040] Example 1

[0041] A p-coumaric acid-lithium-L-proline ion eutectic, the preparation method of which comprises the following steps:

[0042] Place p-coumaric acid, lithium hydroxide and L-proline in a molar ratio of 1:1:1 in a round-bottom flask, add an appropriate amount of 50% methanol solution, heat in a 60°C water bath for 1 hour, transfer the solution to a beaker, and slowly evaporate the solvent at room temperature to obtain light yellow crystals.

[0043] Example 2

[0044] A p-coumaric acid-lithium-L-proline ion eutectic, the preparation method of which comprises the following steps:

[0045] Place p-coumaric acid, lithium hydroxide and L-proline in a molar ratio of 1:1:1 in a round-bottom flask, add an appropriate amount of 80% methanol solution, dissolve by ultrasonication, and slowly evaporate the solvent at room temperature to obtain light yellow crystals.

[0046] Example 3

[0047] A vanillic acid-lithium-L-proline ion eutectic, the preparation method of which comprises the following steps:

[0048] Lithium hydroxide, vanillic acid and L-proline in a molar ratio of 1:1:1 were placed in a round-bottom flask, and an appropriate amount of distilled water was added. After heating under reflux at 90°C in a water bath with stirring for 1 hour, the reaction solution was transferred to a beaker, allowed to stand at room temperature to precipitate crystals, which were filtered and dried to obtain colorless crystals.

[0049] Example 4

[0050] A vanillic acid-lithium-L-proline ion eutectic, the preparation method of which comprises the following steps:

[0051] Lithium hydroxide, vanillic acid and L-proline in a molar ratio of 1:1:1 were placed in a round-bottom flask, and an appropriate amount of 30% ethanol was added to dissolve. After heating under reflux in a 60°C water bath with stirring for 1 hour, the reaction solution was transferred to a beaker, and colorless crystals precipitated after standing at room temperature, which were filtered and dried.

[0052] Example 5

[0053] A vanillic acid-lithium-L-proline ion eutectic, the preparation method of which comprises the following steps:

[0054] Lithium hydroxide, vanillic acid and L-proline in a molar ratio of 1:1:1 were placed in a beaker, and an appropriate amount of 50% ethanol was added. After ultrasonic dissolution, the reaction solution was transferred to a beaker, and colorless crystals were precipitated after standing at room temperature, which were filtered and dried.

[0055] The lithium ion eutectic prepared in the above examples was characterized and its performance was measured.

[0056] 1. The lithium ion eutectic prepared above was tested using a single crystal X-ray diffractometer D8 QUEST ECO, with a test temperature of 293 (2) K, using CuKa radiation, collecting data in ω scanning mode and performing Lp correction. The structure was analyzed using the direct method, and the difference Fourier method was used to find all non-hydrogen atoms. The hydrogen atoms on all carbon and nitrogen were obtained by theoretical hydrogenation. The structure was refined using the least squares method to obtain the crystal structure of the light yellow crystals of Example 1-2 (p-coumaric acid-lithium-L-proline ion eutectic) and the colorless crystals of Example 3-5 (vanillic acid-lithium-L-proline ion eutectic). The crystal structure of the light yellow crystals of Example 1-2 is as follows: Figure 1 The crystal structure of the colorless crystals of Example 3-5 is shown in Figure 2 shown.

[0057] 2. The light yellow crystals of Example 1-2 and the colorless crystals of Example 3-5 were measured by X-ray powder diffractometer to obtain a powder diffraction pattern. The measurement conditions are as follows: the scanning range is 0-50°, the scanning rate is 8° / min, the emission target is Cu Kα, the voltage and current are 40 kV and 100 mA respectively. The X-ray diffraction pattern of the obtained co-crystal is compared with the X-ray diffraction patterns of the two raw materials. The results are as follows: Figure 3 and Figure 4 shown.

[0058] See also Figure 3 ,The results showed that the p-coumaric acid-lithium-L-proline ion cocrystal had characteristic peaks at 6.66°, 10.80°, 13.14°, 13.36°, 17.38°, 18.80°, 19.82°, 21.18°, 21.88°, 23.00°, 23.62°, 25.14°, 26.50°, 27.44°, 29.22°, and 35.14°.

[0059] See also Figure 4 ,The results showed that the vanillic acid-lithium-L-proline ion cocrystal had characteristic peaks at 15.96°, 16.32°, 16.72°, 17.56°, 19.20°, 20.04°, 22.12°, 22.88°, and 23.56°.

[0060] 3. The antioxidants used and their solubility in the cocrystals were determined by high performance liquid chromatography. Figures 5 and 6 As shown, the results show that in the present invention, the preparation of cocrystals can greatly improve the solubility of the antioxidant components p-coumaric acid and vanillic acid in water. Among them, the solubility of p-coumaric acid in the cocrystal is more than 440 times that of the p-coumaric acid raw material; the solubility of vanillic acid in the cocrystal is more than 80 times that of the vanillic acid raw material.

[0061] 4. The antioxidant activity of the antioxidant ingredients used and the prepared lithium ion eutectic was evaluated using in vitro antioxidant methods, DPPH, ABTS and iron ion scavenging test methods. The results are as follows: Figures 7 to 9 shown.

[0062] Among them, in the DPPH scavenging experiment, the IC of p-coumaric acid 50 is 2.3898 mg / ml, while the IC of p-coumaric acid-lithium-L-proline ion cocrystal is 50 is 0.9571mg / ml; IC of vanillic acid 50 is 0.17 mg / ml, while the IC of vanillic acid-lithium-L-proline ion cocrystal is 50 0.038mg / ml;

[0063] In the ABTS scavenging experiment, the IC of p-coumaric acid 50 is 0.0201 mg / ml, while the IC of p-coumaric acid-lithium-L-proline ion cocrystal is 50 is 0.0075mg / ml; IC of vanillic acid 50 is 0.0506 mg / ml, while the IC of vanillic acid-lithium-L-proline ion cocrystal is 50 0.0013mg / ml;

[0064] In the iron ion scavenging experiment, the IC of p-coumaric acid 50 is 0.434 mg / ml, while the IC of p-coumaric acid-lithium-L-proline ion cocrystal is 50 is 0.163mg / ml; IC of vanillic acid 50 is 0.252 mg / ml, while the IC of vanillic acid-lithium-L-proline ion cocrystal is 50 0.041mg / ml;

[0065] The other two components of the eutectic, lithium and L-proline, do not have antioxidant activity. Therefore, the data measured in the experiment can reflect the antioxidant activity of the antioxidant after the eutectic is formed. 50 From the above, we can see that the IC values ​​of the two ionic cocrystals in three antioxidant experiments are 50Both are smaller than the original ligand, indicating that the antioxidant capacity of p-coumaric acid and vanillic acid has been significantly improved after forming cocrystal.

[0066] It is understandable that those skilled in the art can make equivalent substitutions or changes based on the technical solution and inventive concept of the present invention, and all these changes or substitutions should fall within the protection scope of the claims attached to the present invention.

Claims

1. A lithium ion eutectic, characterized in that: The invention comprises an antioxidant, lithium and proline in a molar ratio of 1:1:1; the antioxidant has a cinnamic acid structure, a cinnamic acid derivative structure or a phenolic acid structure containing benzoic acid.

2. The lithium ion eutectic according to claim 1, characterized in that The antioxidant is p-coumaric acid or vanillic acid.

3. The lithium ion eutectic according to claim 1, characterized in that When the lithium ion eutectic is a p-coumaric acid-lithium-L-proline eutectic, the powder X-ray diffraction pattern of the p-coumaric acid-lithium-L-proline eutectic includes the following characteristic peaks: 6.66°, 10.80°, 13.14°, 13.36°, 17.38°, 18.80°, 19.82°, 21.18°, 21.88°, 23.00°, 23.62°, 25.14°, 26.50°, 27.44°, 29.22°, and 35.14°.

4. The lithium ion eutectic according to claim 1, characterized in that When the lithium ion co-crystal is a vanillic acid-lithium-L-proline co-crystal, the powder X-ray diffraction pattern of the vanillic acid-lithium-L-proline co-crystal includes the following characteristic peaks: 15.96°、16.32°、16.72°、17.56°、19.20°、20.04°、22.12°、22.88°、23.56°。 5. A method for preparing a eutectic, characterized in that: The method for preparing the lithium ion eutectic as described in any one of claims 1 to 4 comprises the following steps: heating and dissolving lithium hydroxide, antioxidant and proline in a solvent, slowly volatilizing the solvent, crystallizing, filtering and drying to obtain the lithium ion eutectic.

6. The method for preparing a eutectic according to claim 5, characterized in that: The molar ratio of the lithium hydroxide, antioxidant and L-proline is (1-2):(1-2):(1-2).

7. The method for preparing a eutectic according to claim 5, characterized in that: The temperature of the heating dissolution is 60-90° C. and the time is 15-90 min.

8. The method for preparing a eutectic according to claim 5, characterized in that: The solvent includes at least one of water, methanol, ethanol, acetonitrile, dimethyl sulfoxide, isopropanol, 3-methyl-1-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, 1-pentanol, 1-propanol, 2-propanol, and chloroform.

9. Use of the lithium ion eutectic according to any one of claims 1 to 4 in the preparation of lithium salt drugs.

10. A method for improving the antioxidant activity of antioxidants, characterized in that: The antioxidant has a cinnamic acid structure, a cinnamic acid derivative structure or a phenolic acid structure containing benzoic acid, and comprises the following steps: preparing the antioxidant into the lithium ion eutectic as claimed in claim 1.

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