Lithium ion eutectic, method of making and use thereof

Abstract

The present application relates to the technical field of medicine, in particular to a lithium ion co-crystal, a preparation method and application thereof. The lithium ion co-crystal comprises an antioxidant, lithium and proline with 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 co-crystal can improve the antioxidant activity of the antioxidant component and increase the solubility of the antioxidant component in water. In addition, the lithium in the co-crystal can also improve the release characteristics of the drug in the body, further improving the clinical application value of the antioxidant component.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a lithium-ion eutectic, its preparation method and application. Background Technology

[0002] Drug cocrystals are a novel type of crystal formed by the non-covalent bonding of an active pharmaceutical ingredient (API) and a cocrystal ligand (CCF) in a fixed stoichiometric ratio. Studies have shown that they can improve the physicochemical properties of drugs without altering their molecular structure, and therefore are attracting increasing attention for the modification of active pharmaceutical ingredients (APIs).

[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] In neurodegenerative diseases, the antioxidant activity of drugs plays a crucial role. Common natural antioxidants include vitamin C, vitamin E, polyphenols, carotenoids, and coenzyme Q10. These components have shown potential in clinical studies to protect nerve cells, slow the aging process, and reduce cancer risk. In research on neurodegenerative diseases, the efficacy of antioxidants is particularly significant. Oxidative stress is considered a key pathogenic mechanism in diseases such as Alzheimer's and Parkinson's. Antioxidants can play a neuroprotective role by reducing oxidative damage, protecting nerve cells, and improving mitochondrial function.

[0005] Currently, there are no reported cases of preparing ionic cocrystals by combining natural ingredients with antioxidant activity and lithium salts. If the two are combined, it is expected to further improve the efficacy of the drug. Summary of the Invention

[0006] In view of the shortcomings of the prior art, the purpose of this invention is to provide a lithium-ion eutectic, its preparation method and application, which aims to improve the antioxidant properties of drug components.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

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

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

[0010] The lithium-ion eutectic, wherein 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°, 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°, 23.56°.

[0012] The 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, antioxidant, and proline in a solvent, slowly evaporating the solvent, crystallizing, filtering and drying to obtain the lithium-ion eutectic.

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

[0014] In the method for preparing the eutectic, the heating and dissolution temperature is 60–90°C and the time is 15–90 min.

[0015] The method for preparing the eutectic, wherein the solvent includes at least one selected from 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 this invention provides the application of the lithium-ion eutectic described above 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 into 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 eutectic with antioxidants, lithium and proline, so that antioxidants can more effectively combat oxidative stress when applied to treat diseases.

[0019] The 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, good controllability, and can well ensure the quality of the product. Attached Figure Description

[0020] Figure 1 The crystal structure of the p-coumaric acid-lithium-L-proline ion eutectic is shown.

[0021] Figure 2 It has a crystal structure of vanillic acid-lithium-L-proline ion eutectic.

[0022] Figure 3 The powder diffraction pattern of the coumaric acid-lithium-L-proline ion eutectic is shown.

[0023] Figure 4 Powder diffraction pattern of vanillic acid-lithium-L-proline ion eutectic.

[0024] Figure 5 The results show the water solubility of coumaric acid and vanillic acid.

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

[0026] Figure 7 The results show the DPPH removal experiments on coumaric acid, vanillic acid, and the corresponding lithium ion eutectics.

[0027] Figure 8 The results are from ABTS removal experiments on coumaric acid, vanillic acid, and the corresponding lithium-ion eutectics.

[0028] Figure 9 The results show the iron ion removal experiments on coumaric acid, vanillic acid, and the corresponding lithium ion eutectics. Detailed Implementation

[0029] This invention provides a lithium-ion eutectic, its preparation method, and its application. To make the objectives, technical solutions, and effects of this invention clearer and more explicit, the invention is further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only for explaining the invention and are not intended to limit the invention.

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

[0031] Ion eutectics can be used as drug delivery carriers, enhancing drug stability and bioavailability. In this invention, the conjugation of antioxidants with lithium can improve the drug's release characteristics in vivo, thereby enhancing its efficacy. Lithium has been widely used to treat bipolar disorder, and its neuroprotective effects have been confirmed in studies of neurodegenerative diseases. By conjugating lithium with antioxidants, it is expected to enhance the neuroprotective effects of lithium and slow the progression of neurodegenerative diseases. Furthermore, the synergistic effect of lithium and antioxidants can help combat oxidative stress more effectively, particularly 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, in addition to its antioxidant properties, also possesses anti-inflammatory, antitumor, cardiovascular protective, neuroprotective, and antimicrobial activities. Furthermore, coumaric acid shows potential in the treatment of metabolic diseases (such as diabetes and obesity) and cardiovascular diseases.

[0033] In this invention, the antioxidant activity of p-coumaric acid or vanillic acid can be improved by forming a eutectic with lithium and proline. Furthermore, both p-coumaric acid and vanillic acid suffer from poor water solubility, which severely affects their clinical application; however, the solubility of p-coumaric acid or vanillic acid in water is significantly improved after forming the eutectic.

[0034] The 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, antioxidant, and proline in a solvent, slowly evaporating 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 heating and melting temperature is 60–90°C, and the time is 15–90 min.

[0037] Preferably, the solvent includes at least one selected from 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 this invention provides the application of the lithium-ion eutectic described above 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 a lithium-ion eutectic as described above.

[0040] Example 1

[0041] A coumaric acid-lithium-L-proline ion eutectic is prepared by the following steps:

[0042] Coumaric acid, lithium hydroxide, and L-proline in a molar ratio of 1:1:1 were placed in a round-bottom flask, and an appropriate amount of 50% methanol solution was added. The mixture was heated in a water bath at 60°C for 1 hour, and then the solution was transferred to a beaker. The solvent was slowly evaporated at room temperature to obtain pale yellow crystals.

[0043] Example 2

[0044] A coumaric acid-lithium-L-proline ion eutectic is prepared by the following steps:

[0045] Coumaric acid, lithium hydroxide, and L-proline in a molar ratio of 1:1:1 were placed in a round-bottom flask, and an appropriate amount of 80% methanol solution was added. After sonication to dissolve the mixture, the solvent was slowly evaporated at room temperature to obtain pale yellow crystals.

[0046] Example 3

[0047] A vanillic acid-lithium-L-proline ion eutectic is prepared by 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. The mixture was heated under reflux in a water bath at 90°C with stirring for 1 hour. The reaction solution was then transferred to a beaker and allowed to stand at room temperature to precipitate crystals. After filtration and drying, colorless crystals were obtained.

[0049] Example 4

[0050] A vanillic acid-lithium-L-proline ion eutectic is prepared by 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 them. The mixture was heated under reflux in a water bath at 60°C and stirred for 1 hour. The reaction solution was then transferred to a beaker, and after standing at room temperature, colorless crystals precipitated. The crystals were then filtered and dried.

[0052] Example 5

[0053] A vanillic acid-lithium-L-proline ion eutectic is prepared by 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 sonication to dissolve, the reaction solution was transferred to a beaker and allowed to stand at room temperature to precipitate colorless crystals. The crystals were then 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 obtained above was detected using a single-crystal X-ray diffractometer D8 QUEST ECO at a test temperature of 293(2) K. CuKa radiation was used, and data was collected in ω-scan mode with Lp correction. The structure was analyzed using the direct method, and all non-hydrogen atoms were identified using the difference Fourier method. All hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation. The structure was refined using the least squares method to obtain the crystal structures of the pale yellow crystals (coumaric acid-lithium-L-proline ion eutectic) of Examples 1-2 and the colorless crystals (vanillic acid-lithium-L-proline ion eutectic) of Examples 3-5. The crystal structures of the pale yellow crystals of Examples 1-2 are as follows: Figure 1 As shown. The crystal structures of the colorless crystals in Examples 3-5 are as follows. Figure 2 As shown.

[0057] 2. The pale yellow crystals of Examples 1-2 and the pale yellow crystals of Examples 3-5 were measured using an X-ray powder diffractometer to obtain powder diffraction patterns. The measurement conditions were as follows: scanning range of 0–50°, scanning rate of 8° / min, emission target of Cu Kα, voltage and current of 40 kV and 100 mA, respectively. The obtained X-ray diffraction patterns of the eutectic were compared with the X-ray diffraction patterns of the two raw materials, and the results are as follows. Figure 3 and Figure 4 As shown.

[0058] Please see Figure 3 The results showed that the p-coumaric acid-lithium-L-proline ion eutectic 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] Please see Figure 4 The results showed that the vanillic acid-lithium-L-proline ion eutectic 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 eutectic were determined using high-performance liquid chromatography (HPLC). For example... Figures 5 to 6 As shown, the results indicate that the preparation of the cocrystal in this invention can significantly improve the solubility of the antioxidant components coumaric acid and vanillic acid in water. Specifically, the solubility of coumaric acid in the cocrystal is more than 440 times that of the 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 components used and the prepared lithium-ion eutectic was evaluated using in vitro antioxidant methods, DPPH, ABTS, and iron ion scavenging assays. The results are as follows: Figures 7 to 9 As shown.

[0062] In the DPPH scavenging experiment, the IC50 for coumaric acid was... 50 The concentration was 2.3898 mg / ml, while the IC50 for the coumaric acid-lithium-L-proline ion cocrystal was... 50 The concentration was 0.9571 mg / ml; the IC50 of vanillic acid was... 50 The concentration was 0.17 mg / ml, while the IC50 of the vanillic acid-lithium-L-proline ion cocrystal was... 50 It is 0.038 mg / ml;

[0063] In the ABTS scavenging experiment, the IC50 for coumaric acid was... 50 The concentration was 0.0201 mg / ml, while the IC50 for the coumaric acid-lithium-L-proline ion cocrystal was... 50 The concentration was 0.0075 mg / ml; the IC50 of vanillic acid was... 50 The concentration was 0.0506 mg / ml, while the IC50 of the vanillic acid-lithium-L-proline ion co-crystal was 0.0506 mg / ml. 50 It is 0.0013 mg / ml;

[0064] In the iron ion scavenging experiment, the IC50 value for coumaric acid was... 50 The concentration was 0.434 mg / ml, while the IC50 for the coumaric acid-lithium-L-proline ion cocrystal was... 50 The concentration was 0.163 mg / ml; the IC50 of vanillic acid was... 50 The concentration was 0.252 mg / ml, while the IC50 of the vanillic acid-lithium-L-proline ion co-crystal was... 50 It was 0.041 mg / ml;

[0065] The other two components of the eutectic, lithium and L-proline, do not possess antioxidant activity. Therefore, the data measured in the experiment can reflect the antioxidant activity of the antioxidants after the formation of the eutectic. The IC50 values ​​derived from the experimental results... 50 Let's look at the IC50 values ​​of the two ionic eutectic in three antioxidant experiments. 50Both are smaller than the original ligand, indicating that the antioxidant capacity of p-coumaric acid and vanillic acid is significantly improved after forming a eutectic.

[0066] It is understood that those skilled in the art can make equivalent substitutions or modifications to the technical solution and inventive concept of the present invention, and all such substitutions or modifications should fall within the protection scope of the appended claims.

Claims

1. A lithium-ion eutectic, characterized in that, It is composed of an antioxidant, lithium, and proline in a molar ratio of 1:1:1; the antioxidant is p-coumaric acid or vanillic acid; the lithium-ion eutectic is a p-coumaric acid-lithium-L-proline eutectic or a vanillic acid-lithium-L-proline eutectic. 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°, 35.14°; 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°、23.56°。 2. A method for preparing a eutectic, characterized in that, The method for preparing the lithium-ion eutectic as described in claim 1 comprises the following steps: heating and dissolving lithium hydroxide, antioxidant, and proline in a solvent, slowly evaporating the solvent, crystallizing, filtering and drying to obtain the lithium-ion eutectic.

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

4. The method for preparing the eutectic according to claim 2, characterized in that, The heating and melting temperature is 60–90°C, and the time is 15–90 min.

5. The method for preparing the eutectic according to claim 2, 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.

6. The application of the lithium-ion eutectic as described in claim 1 in the preparation of antioxidant drugs.

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