Salicylic acid ionic liquid pure aqueous solution preparation, preparation method and application thereof

Abstract

The present invention relates to the field of ionic liquid and biomedical technology, and in particular, to a salicylic acid ionic liquid pure aqueous solution preparation, a preparation method thereof and its application. The salicylic acid ionic liquid pure aqueous solution preparation is an aqueous solution of salicylic acid-γ-aminobutyric acid ionic liquid, and its structural formula is: #imgabs0# wherein n is any integer between 2 and 4, salicylic acid is an active pharmaceutical ingredient and constitutes the anion part of the salicylic acid-γ-aminobutyric acid ionic liquid, γ-aminobutyric acid is a counterion, the molar ratio of salicylic acid to γ ​​amino acid is (1:2)-(1:4), and the molar fraction of water is above 0.9. The embodiment of the present invention provides a salicylic acid ionic liquid pure aqueous solution preparation that can completely replace and eliminate traditional organic solvents, so as to improve the solubility and bioavailability of salicylic acid, reduce the skin irritation of topical salicylic acid, and the cumulative irritation effect associated with traditional organic solvents, and improve the compliance of patient treatment.

Description

Technical Field

[0001] The invention relates to the technical field of ionic liquids and biomedicine, and in particular to a salicylic acid ionic liquid pure aqueous solution preparation, a preparation method thereof and an application thereof. Background Art

[0002] Acne vulgaris is the most common chronic skin disease in adolescents, with an incidence rate of nearly 100%. Although only a few patients choose to go to the hospital for treatment, acne vulgaris has accounted for more than one-third of the outpatient visits to dermatology. In recent years, the prevalence of adult women has also increased. Among adults with an average age of 42, the incidence of acne in women is 23.7%, and in men it is 29.9% (Gollnick HP, Zouboulis CC. Not all acne is acne vulgaris. Dtsch Arztebl Int. 2014 Apr 25; 111 (17): 301-12.).

[0003] Salicylic acid is the most widely used OTC acne treatment drug in the world. However, salicylic acid is a poorly soluble active pharmaceutical ingredient (API). The conventional preparation is to dissolve salicylic acid in 70% ethanol to make a tincture or disperse it in vaseline to make an ointment (Chen Xinqian et al., ed., "New Pharmacology", People's Medical Publishing House, 18th edition, 2018). Since topical application of salicylic acid and traditional organic solvents may cause significant skin irritation, the resulting cumulative irritation effect further increases the skin adverse reactions of salicylic acid and reduces compliance with drug treatment.

[0004] Ionic liquids are organic liquids composed entirely of anions and cations, which are liquid at room temperature. Anions and cations are bound together by electrostatic forces, van der Waals forces, and hydrogen bonds rather than covalent bonds, thereby changing the physicochemical properties of the API without changing its pharmacological activity.

[0005] As is known to all, the main obstacles to the industrial application of ionic liquids are high viscosity, low air and water stability. For example, CN 102190589 A discloses an amino acid ionic liquid for food and medical use, which is an amino acid ionic liquid obtained by a one-step reaction of 22 α-amino acids as cations or anions and almost all inorganic or organic acids and bases as counterions. The specific synthesis steps are: take 100 ml of water in a three-necked flask, mix the amino acid with the inorganic or organic acid and base in an equimolar ratio, react for 10 hours under intense electromagnetic stirring at 80°C, then dehydrate by rotary evaporation under vacuum conditions, and then vacuum dry at 100°C for 48 hours, or directly spray dry to obtain an anhydrous amino acid ionic liquid. This is a typical laboratory synthesis method of early amino acid ionic liquids. This amino acid ionic liquid synthesized under vacuum conditions has the general characteristics of high viscosity and instability to air and water. It is limited to small tests (100 ml level) under laboratory conditions and difficult to apply on a large scale (Zhang Suojiang, Liu Xiaomin, Yao Xiaoqian, etc. Frontiers, progress and applications of ionic liquids [J]. Chinese Science (Series B: Chemistry), 2009, 39(10): 1134-1144.).

[0006] Or CN 109908018 B discloses a γ-aminobutyric acid ionic liquid and its preparation method and application, wherein the preparation method is to add an organic acid or base to a solution containing γ-aminobutyric acid under low oxygen (nitrogen atmosphere or inert gas atmosphere) and light-proof conditions for neutralization reaction to obtain a γ-aminobutyric acid ionic liquid. The molar ratio of γ-aminobutyric acid to salicylic acid or other acid or base is 1:1, and the reaction time is 9 to 16 hours under vacuum conditions, followed by recrystallization, separation and purification, suction filtration, and vacuum drying to obtain an anhydrous γ-aminobutyric acid ionic liquid. Obviously, the obtained amino acid ionic liquid is unstable to air and water, and is also limited to small tests under laboratory conditions, and does not have the conditions for large-scale production. The same inventor of the patent improved it, and CN 110200843 B disclosed a chitosan-encapsulated γ-aminobutyric acid salicylic acid and its preparation method and application. The chitosan was used to further encapsulate the same γ-aminobutyric acid ionic liquid prepared in CN 109908018 B to increase its water solubility. However, even after encapsulation, organic solvents such as PEG-26 glyceryl ether, PEG-60 hydrogenated castor oil, dipropylene glycol, glycerol, etc. are still required for solubilization to prepare the final usable preparation. It cannot reduce or replace traditional organic solvents, and makes the preparation process more complicated and generates more energy consumption and waste.

[0007] Among them, γ-aminobutyric acid is a natural non-protein amino acid and has the common properties of all amino acids. Since amino acid molecules contain amino groups and carboxyl groups, they exist in the form of dissociated zwitterions in aqueous solution: the amino group is protonated to ammonium cations (- +NH3), and the carboxyl group loses a proton to dissociate into a carboxyl anion (-COO - ). Therefore, amino acids are ideal ionic liquid components. However, various amino acid ionic liquids synthesized under existing technical conditions are limited to small-scale tests under laboratory conditions, are unstable to water and air, and do not have large-scale synthesis conditions and practical commercial value.

[0008] Hiroyuki Ohno and others used 20 kinds of natural amino acids as raw materials, and prepared a series of amino acid ionic liquids by neutralization reaction with imidazole quaternary ammonium base; the team led by Professor Kou Yuan also prepared a series of amino acid chiral ionic liquids, which were generated by direct reaction of natural amino acids with equimolar amounts of strong acids in water in one step. However, this type of ionic liquid has a high melting point and high viscosity. To this end, they first esterified the amino acids, and then obtained an amino acid lipid ionic liquid through anion exchange, which has high thermal stability, but it is still limited to the level of academic exchanges and has never been able to achieve industrial application (Liu Baoyou et al., "Ionic Liquids-Research on Preparation, Properties and Application Technology", China Petrochemical Press, 1st edition, 2021).

[0009] It can be seen that the existing technologies have not been able to break through the bottleneck of high viscosity and instability to water and air of amino acid ionic liquids, and are limited to synthesizing anhydrous amino acid ionic liquids under laboratory conditions. In practical applications, they cannot completely replace traditional organic solvents. In the field of biomedicine, the cumulative irritation effect associated with API and organic solvents cannot be avoided.

[0010] In view of this, the present invention is proposed. Summary of the invention

[0011] The purpose of the present invention is to provide a salicylic acid ionic liquid pure water solution preparation, a preparation method thereof and an application thereof. The embodiment of the present invention provides a salicylic acid ionic liquid pure water solution preparation that can completely replace / eliminate traditional organic solvents, so as to improve the solubility and bioavailability of salicylic acid, reduce the skin irritation of salicylic acid itself, reduce the additional damage and environmental hazards caused by organic solvents, and eliminate the cumulative irritation effect of salicylic acid and traditional organic solvents in skin applications.

[0012] In order to solve the technical bottleneck of high viscosity of ionic liquids, first of all, the inventors adopted the technical route of synthesizing hydrated ionic liquids from scratch. This is because the viscosity of ionic liquids decreases with increasing temperature and water content. At a specific temperature, the viscosity of ionic liquids decreases linearly with increasing water content, but when the water content exceeds 0.5 mole fraction, the electrostatic balance between anions and cations changes due to the influence of water polarity and solvent effect, making the ionic liquid unstable; secondly, in order to solve the technical bottleneck of amino acid ionic liquids to water, including instability to air, the inventors proposed a new strategy of entropy enthalpy compensation according to the second law of thermodynamics, by adjusting the molar ratio of ion pairs (Example) or adding small molecule soluble solutes (Comparative Example 4), so as to produce entropy changes and enthalpy changes that are conducive to the process in the direction of the product, to increase the yield and stability of the product.

[0013] The present invention is achieved in that:

[0014] In a first aspect, the present invention provides a salicylic acid ionic liquid pure aqueous solution preparation, wherein the salicylic acid ionic liquid pure aqueous solution preparation is an aqueous solution of salicylic acid-γ-aminobutyric acid ionic liquid; the structural formula of the salicylic acid-γ-aminobutyric acid ionic liquid is as follows:

[0015]

[0016] Wherein, salicylic acid is an active pharmaceutical ingredient (API) and the anion part of the salicylic acid-γ-aminobutyric acid ionic liquid, and the γ amino acid is used as the cation part of the salicylic acid-γ-aminobutyric acid ionic liquid; n is any integer between 2 and 4, and the molar fraction of water is greater than 0.9;

[0017] The molar ratio of salicylic acid to gamma amino acid is (1:2)-(1:4).

[0018] In an optional embodiment, the molar ratio of salicylic acid to gamma amino acid is (1:2)-(1:3).

[0019] In an optional embodiment, the mass concentration of salicylic acid in the salicylic acid ionic liquid pure aqueous solution preparation is 0.1 wt%-10.0 wt%.

[0020] In an optional embodiment, the mass concentration of salicylic acid in the salicylic acid ionic liquid pure aqueous solution preparation is 0.5 wt%-5.0 wt%.

[0021] In an optional embodiment, the salicylic acid ionic liquid pure aqueous solution preparation does not contain any organic solvent;

[0022] Preferably, the salicylic acid-γ-aminobutyric acid ionic liquid is a hydrated ionic liquid.

[0023] In a second aspect, the present invention provides a method for preparing the salicylic acid ionic liquid pure aqueous solution preparation described in the aforementioned embodiment, comprising: mixing and dissolving salicylic acid raw material, γ amino acid raw material and water through in-situ synthesis in a one-step method.

[0024] In an alternative embodiment, the mixed dissolution is performed under non-vacuum conditions.

[0025] In an optional embodiment, the mixed dissolution conditions include: 30-50° C., and time of 10-30 min.

[0026] In a third aspect, the present invention provides a use of the salicylic acid ionic liquid pure aqueous solution preparation described in the aforementioned embodiment directly as a skin external preparation.

[0027] In an alternative embodiment, the active ingredient of the external skin preparation includes only the salicylic acid ionic liquid pure aqueous solution preparation.

[0028] The present invention has the following beneficial effects: (1) The present invention adopts a technical route of synthesizing hydrated ionic liquids from scratch, and when the molar ratio of salicylic acid to γ-aminobutyric acid is 1:2 to 1:4, the obtained salicylic acid-γ-aminobutyric acid ionic liquid has the characteristics of low viscosity and is stable to water and air, which changes the high viscosity and instability of amino acid ionic liquids prepared by the prior art, and creates basic conditions for the industrial application of amino acid ionic liquids;

[0029] (2) The salicylic acid-γ-aminobutyric acid ionic liquid provided in the embodiment of the present invention is only combined by ions and hydrogen bonds rather than covalent bonds, and therefore only changes the physicochemical properties of the active pharmaceutical ingredient salicylic acid without changing its pharmacological activity. The salicylic acid and γ-aminobutyric acid that make up the ionic liquid are both safe and effective active pharmaceutical ingredients, non-toxic and harmless, and therefore suitable for use in biopharmaceutical preparations. In addition, the obtained salicylic acid-γ-aminobutyric acid hydrated ionic liquid can be directly used as a salicylic acid ionic liquid pure aqueous solution preparation, and has good stability, spreadability, and comfort at a salicylic acid concentration that is clinically effective in dermatology;

[0030] (3) More importantly, the preparation process of the pure aqueous solution of salicylic acid ionic liquid does not require esterification, additional organic solvent solubilization, inert gas environment, special equipment and conditions. It only uses water as solvent and is a one-step, in-situ synthesis at room temperature and pressure. The process is simple, convenient and energy-saving, which significantly reduces the production cost and can meet the needs of large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments are briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without creative work.

[0032] Figure 1 A schematic diagram showing that the reaction enthalpy of the salicylic acid-γ-aminobutyric acid ionic liquid provided in an embodiment of the present invention decreases as the molar ratio of γ-aminobutyric acid increases;

[0033] Figure 2 A schematic diagram of hydrogen bonding introduced by adding free or unpaired ion γ-aminobutyric acid to an ionic liquid provided in an embodiment of the present invention;

[0034] Figure 3 This is a schematic diagram of hydrogen bonding introduced by adding a small molecule soluble solute into the ionic liquid provided in the comparative example of the present invention. DETAILED DESCRIPTION

[0035] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0036] Amino acids are natural products with abundant sources, are non-toxic and harmless, and have zwitterionic properties. Therefore, in the field of biomedicine, using amino acids as counterions to prepare salicylic acid ionic liquid solutions is a feasible technical solution. In view of the high viscosity and low stability commonly found in amino acid ionic liquids prepared by prior art, the inventors adopted the technical route of de novo synthesis of hydrated ionic liquids and the entropy enthalpy compensation strategy to improve the stability of amino acid ionic liquids, and finally obtained a low-viscosity, stable salicylic acid-γ-aminobutyric acid ionic liquid, which successfully converted the poorly soluble salicylic acid into a soluble salicylic acid ionic liquid without the need for additional organic solvent solubilization, and is therefore called a salicylic acid ionic liquid pure aqueous solution preparation, thereby avoiding the threats of traditional organic solvents to the environment and health, as well as the cumulative irritation effects associated with organic solvents.

[0037] In the first aspect, an embodiment of the present invention provides a salicylic acid ionic liquid pure water solution preparation, wherein the salicylic acid ionic liquid pure water solution preparation is an aqueous solution of salicylic acid-γ-aminobutyric acid ionic liquid; it is composed of salicylic acid-γ-aminobutyric acid hydrated ionic liquid, and its structural formula is SA[GA], wherein SA represents salicylic acid, which is an active pharmaceutical ingredient (API) and serves as the anion part of the ionic liquid; [GA] represents γ-aminobutyric acid as the cationic part. The structural formula of the salicylic acid-γ-aminobutyric acid ionic liquid is as follows:

[0038] Among them, n is 2-4, that is, the molar ratio of salicylic acid and γ-aminobutyric acid is (1:2)-(1:4), for example, 1:2, 1:2.5, 1:3, 1:3.5 and 1:4, etc., any value between (1:2)-(1:4) or a range value between any two values, preferably (1:2)-(1:3).

[0039] The above molar ratio of salicylic acid to γ-aminobutyric acid is based on computational chemistry methods and experimental results. According to the second law of thermodynamics and the Gibbs equation ΔG=ΔH-TΔS, enthalpy represents the heat of reaction or heat of solution, and entropy is a measure of the disorder of the system. Almost all reactions in solvents should lead to entropy-enthalpy compensation behavior. For reactions without gas participation, the total number of moles of substances in the reactants usually increases, the disorder of the system increases, and corresponding entropy changes and enthalpy changes occur. Therefore, in theory, favorable entropy-enthalpy compensation can be generated by increasing the total molar amount of the reactants, so that the reaction proceeds in a direction that is favorable to the product. Experiments have shown that increasing the molar amount of the counterion γ-aminobutyric acid or adding additional small molecule soluble solutes are beneficial to the process proceeding in the direction of the product, and the resulting product is more stable. Since adjusting the molar ratio of the ion pairs themselves is more conducive to the preparation of pure salicylic acid ionic liquid pure aqueous solution preparations, it is preferred to increase the stability of the ionic liquid by adjusting the molar ratio of the ion pairs.

[0040] The salicylic acid-γ-aminobutyric acid ionic liquid provided in the embodiment of the present invention is combined only by ion action and hydrogen bond action rather than covalent bond, and therefore only the physicochemical properties of the active pharmaceutical ingredient salicylic acid are changed without changing its pharmacological activity.

[0041] The mass concentration of salicylic acid in the pure salicylic acid ionic liquid pure water solution preparation is 0.1wt%-10.0wt%, for example, 0.1wt%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% and any value between 0.1wt%-10.0wt% or a range between any two values, for example, preferably 0.5wt%-5.0wt%.

[0042] Furthermore, the above pure salicylic acid ionic liquid aqueous solution preparation does not contain any organic solvent, which significantly reduces the cumulative irritation effect of salicylic acid preparations and traditional organic solvents, and has good stability, spreadability, comfort and compliance at a clinically effective API concentration in dermatology.

[0043] In a second aspect, the present invention provides a method for preparing the salicylic acid ionic liquid pure aqueous solution preparation described in the aforementioned embodiment, namely, a one-step in-situ synthesis of salicylic acid-γ-aminobutyric acid hydrated ionic liquid using a de novo synthesis route of hydrated ionic liquid, specifically comprising: mixing and dissolving a salicylic acid raw material, a γ-amino acid raw material and water.

[0044] The molar fraction of water content in the salicylic acid ionic liquid pure water solution preparation is above 0.9. Therefore, the obtained salicylic acid ionic liquid pure water solution preparation has low viscosity, thus creatively breaking through the limitation of high viscosity that makes ionic liquid difficult to apply industrially.

[0045] The preparation process of the salicylic acid ionic liquid pure aqueous solution preparation does not require esterification, purification, dehydration, additional organic solvents, or an inert gas environment. It is synthesized in situ in a one-step process at room temperature and pressure using only water as a solvent. No special equipment or conditions are required. The process is simple and convenient, and the production cost is significantly reduced, which can meet the needs of large-scale industrial production.

[0046] Specifically, the synthesis is carried out under non-vacuum conditions, that is, mixed dissolution is carried out under normal temperature and pressure and conventional stirring. The mixed dissolution conditions include: 30-50° C., and the time is 10-30 minutes.

[0047] In a third aspect, the present invention provides a use of the salicylic acid ionic liquid pure aqueous solution preparation described in the aforementioned embodiment directly as a skin external preparation.

[0048] The active ingredient of the external skin preparation includes only the salicylic acid ionic liquid pure aqueous solution preparation.

[0049] However, it is understandable that the skin topical preparation may also include other active pharmaceutical ingredients, such as other active pharmaceutical ingredients soluble in the salicylic acid-γ-aminobutyric acid hydrated ionic liquid, such as niacinamide, ascorbic acid, adenosine triphosphate (ATP), sodium salicylate and sodium hyaluronate, etc., and may also include medicinal plant compounds such as chlorogenic acid, plant tannins and seaweed polysaccharides, etc., to expand the indication range of salicylic acid ionic liquid pure aqueous solution preparations or improve the efficacy or reduce adverse drug reactions.

[0050] In summary, the present invention provides a new method for increasing the molar amount of the active ingredient itself in the reactant to produce a favorable enthalpy drop, thereby obtaining a stable salicylic acid-γ-aminobutyric acid ionic liquid; since the preparation process of the ionic liquid adopts a hydrated ionic liquid synthesis route, it is a hydrated ionic liquid obtained with water as a solvent and has a high water content, and thus has a natural low viscosity. In addition, due to the solvent effect of the ionic liquid, no additional organic solvent solubilization is required, and the cumulative skin irritation effect associated with organic solvents can be significantly eliminated. Moreover, no special environment and equipment are required, and large-scale production conditions are met.

[0051] The features and performance of the present invention are further described in detail below in conjunction with the embodiments.

[0052] Examples 1-7 and Comparative Examples 1-5

[0053] Examples 1-7 and Comparative Examples 1-5 respectively provide a method for preparing a salicylic acid ionic liquid pure aqueous solution preparation. Specifically, salicylic acid and γ-amino acid are added to a small amount of water in sequence according to the composition molar ratio (mol) and concentration (wt / %) in Table 1, and stirred for 10-30 minutes at 30-50°C until completely dissolved, and water is added to a total liquid volume of 100wt% or a molar fraction (xi) of 1, thereby obtaining salicylic acid-γ-aminobutyric acid hydrated ionic liquids of Examples 1-7 and Comparative Examples 1-3.

[0054] Among them, the preparation method of comparative examples 4 and 5 is as follows: salicylic acid and γ-amino acid are added to a small amount of water in sequence according to the composition molar ratio (mol) and concentration (wt / %) in Table 1, and stirred conventionally for 10-30 minutes at 30-50° C. until completely dissolved, and then an equal molar amount of sodium salicylate is added, and conventionally stirred until completely dissolved, and then water is added to a total liquid volume of 100wt% or a molar fraction (xi) of 1, to obtain salicylic acid-γ-aminobutyric acid hydrated ionic liquids of comparative examples 4 and 5.

[0055] Furthermore, the physicochemical parameters and cold and heat resistance of the salicylic acid-γ-aminobutyric acid hydrated ionic liquids obtained in Examples 1-7 and Comparative Examples 1-5 were measured. The measurement results are shown in Table 1.

[0056] Method for determination of physicochemical parameters: pH is determined by direct measurement with a pH meter, and the test temperature is 25-30°C.

[0057] Cold resistance test method: Pre-adjust the refrigerator to (0±1℃), place a bottle of sample in the refrigerator. Take it out after 24 hours, return it to room temperature and observe it visually. If there is no obvious difference in properties before the test, it is considered stable.

[0058] Method for determination of physicochemical parameters: pH is determined by direct measurement with a pH meter, and the test temperature is 25-30°C.

[0059] Cold resistance test method: Pre-adjust the refrigerator to (0±1℃), place a bottle of sample in the refrigerator. Take it out after 24 hours, return it to room temperature and observe visually. If there is no obvious difference in properties from before the test, it is considered stable.

[0060] According to Table 1, the cold resistance test results show that there is no obvious difference in properties between Examples 1-7 after returning to room temperature and before the test. It can be seen that when the molar ratio of salicylic acid to γ-aminobutyric acid is 1:2-1:4, a stable salicylic acid-γ-aminobutyric acid hydrated ionic liquid can be obtained, and a stable salicylic acid ionic liquid pure aqueous solution preparation can be directly obtained without additional organic solvent solubilization.

[0061] In Example 6, when the concentration of salicylic acid further reaches 10 wt %, the obtained ionic liquid appears slightly yellowish.

[0062] According to Table 1, the cold resistance test results show that comparative examples 1-3 have obvious precipitation and precipitation after returning to room temperature. It can be seen that when the molar ratio of salicylic acid to γ-aminobutyric acid is 1:1, the obtained ionic liquid is unstable, and even when the salicylic acid concentration is as low as 0.5wt%, the obtained ionic liquid is also unstable.

[0063] Furthermore, since the ionic liquids obtained in Comparative Examples 1-3 are unstable, in order to verify whether the addition of small molecule soluble solutes can affect the stability of the ionic liquids, an equimolar amount of sodium salicylate was added in Comparative Example 4, and the obtained ionic liquids showed good stability according to the cold resistance test results. It is suggested that adding soluble solutes is helpful to improve the stability of salicylic acid-γ-aminobutyric acid hydrated ionic liquids.

[0064] Furthermore, in Comparative Example 5, when the concentration of salicylic acid was increased to 2 wt %, the obtained ionic liquid precipitated and crystallized when left standing at room temperature, indicating that the addition of small molecule soluble solutes had limited effect on the stability of the ionic liquid.

[0065] Table 1 Composition and physicochemical properties of Examples 1-7 and Comparative Examples 1-5

[0066]

[0067] Wherein, molar ratio (mol) is rounded to the nearest integer;

[0068] Wherein, xi represents the water content (molar fraction), Cv represents the molar heat capacity (unit: cal / mol-k), ΔS represents the entropy change (unit: cal / mol-k), ΔH represents the enthalpy change (unit: kJ / mol), and ΔG represents the Gibbs free energy change (unit: au).

[0069] Molecular simulation experiments

[0070] According to the second law of thermodynamics, spontaneous processes always proceed in the direction of decreasing the energy of the system. According to the Gibbs equation: ΔG = ΔH-TΔS, using the Gibbs free energy change as a thermodynamic criterion, the direction and limit of the process can be predicted under specific conditions.

[0071] According to the second law of thermodynamics, the thermal effect of an isobaric reaction is Q = ΔH, that is, during an isobaric reaction, all the heat absorbed by the system is used to change the enthalpy of the system. Since entropy change mainly affects the disorder of the system, entropy change has little effect in reactions without gas participation. The thermal effect of the reaction is equal to the enthalpy change of the reaction, and the enthalpy drop is conducive to the reaction proceeding in the direction of the product. Therefore, changing the factors that affect the enthalpy change can change the yield and stability of the product.

[0072] The results of the molecular simulation experiment are shown in Table 1. The experimental data show that the Gibbs free energy change (ΔG < 0) of the reaction when the molar ratio of salicylic acid to γ-aminobutyric acid ranges from 1:1 to 1:4 can determine that the process of generating salicylic acid-γ-aminobutyric acid ionic liquid can proceed spontaneously; as the molar ratio of γ-aminobutyric acid increases, the enthalpy change (ΔH) of the reaction further decreases ( Figure 1 ), which is conducive to the reaction proceeding towards the product.

[0073] Furthermore, increasing the molar ratio of γ-aminobutyric acid did not result in an increase in entropy, indicating that no old bonds were broken or new bonds were formed, but the introduction of hydrogen bonds increased the stability of the system. In other words, the stabilizing effect of the increased number of free ions or unpaired ions on the ionic liquid mainly depends on the contribution of enthalpy, and the entropy drop is the result of entropy-enthalpy compensation. The introduction of hydrogen bonds increased the solubility and stability of salicylic acid-γ-aminobutyric acid ionic liquids (see Figure 2 ), without changing the chemical structure of salicylic acid;

[0074] Furthermore, the results of molecular simulation experiments show that the introduction of free or unpaired ions leads to a decrease in entropy, indicating that the process of generating salicylic acid-γ-aminobutyric acid ionic liquid is an exothermic reaction, and heating is unfavorable, and the reaction temperature should not be too high. Exothermic reactions can generally be carried out at room temperature, which is consistent with the experimental results. This result is consistent with the general characteristics of ionic liquids, that is, they are liquid near room temperature and are called room temperature ionic liquids. Therefore, the results of molecular simulation experiments at least indirectly prove that the embodiment of the present invention obtains a salicylic acid ionic liquid solution;

[0075] Furthermore, the molar heat capacity of different molar ratios was compared. The experimental data showed that when the molar ratio of salicylic acid to γ-aminobutyric acid was 1:1, the molar heat capacity of the product was significantly lower than that of salicylic acid to γ-aminobutyric acid at 1:2 to 1:4, indicating that the thermodynamic stability of the product increased with the increase of the molar ratio of γ-aminobutyric acid;

[0076] Furthermore, molecular simulation experimental data showed that on the basis of a 1:1 molar ratio of salicylic acid to γ-aminobutyric acid, adding a small molecule soluble solute sodium salicylate introduced hydrogen bond formation to increase the solubility and stability of the product ( Figure 3 ), the enthalpy change (ΔH) of the reaction is further reduced, which is conducive to the reaction proceeding in the direction of the product. In contrast, the enthalpy drop generated by increasing the small molecule soluble solute is less than the enthalpy drop generated by adjusting the molar ratio of the ion pair itself (see Table 1, comparison between Comparative Example 4 and the embodiment). Although the effect of small molecule soluble solute on enthalpy is limited, it is also feasible in the preparation of low concentration salicylic acid preparations.

[0077] In summary, as the molar ratio (molar amount) of γ-aminobutyric acid increases, the introduction of free and unpaired ions into the system leads to an enthalpy drop, indicating that the reaction is an enthalpy-driven process, and the enthalpy drop is conducive to the process proceeding in the direction of the product. The molecular simulation experimental data are consistent with the experimental results, indicating that by changing the molar ratio of ion pairs to increase free or unpaired ions, a favorable entropy enthalpy compensation can be achieved, so that the process proceeds in the direction that is conducive to the product, and the resulting product is more stable.

[0078] The above description is only the preferred embodiment of the present invention and is not intended to limit the present invention. The embodiments of the present invention and the comparative examples can constitute the scope of the present invention. For those skilled in the art, the present invention can have various changes and variations. Any modification, equivalent replacement, improvement, etc. made within the principles, spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A salicylic acid ionic liquid pure aqueous solution preparation, characterized in that: The salicylic acid ionic liquid pure aqueous solution preparation is an aqueous solution of salicylic acid-γ-aminobutyric acid ionic liquid; the structural formula of salicylic acid-γ-aminobutyric acid ionic liquid is as follows: Among them, salicylic acid is an active pharmaceutical ingredient and constitutes the anion part of the salicylic acid-γ-aminobutyric acid ionic liquid, γ-aminobutyric acid is a counterion, n is any integer between 2-4, the molar ratio of salicylic acid to γ-aminobutyric acid is (1:2)-(1:4), and the molar fraction of water is greater than 0.

9.

2. The salicylic acid ionic liquid pure aqueous solution preparation according to claim 1, characterized in that: The molar ratio of salicylic acid to gamma amino acid is (1:2)-(1:3).

3. The salicylic acid ionic liquid pure aqueous solution preparation according to claim 1 or 2, characterized in that: The mass concentration of salicylic acid in the salicylic acid ionic liquid pure aqueous solution preparation is 0.1 wt %-10.0 wt %.

4. The salicylic acid ionic liquid pure aqueous solution preparation according to claim 1 or 2, characterized in that: The mass concentration of salicylic acid in the salicylic acid ionic liquid pure aqueous solution preparation is 0.5wt%-5.0wt%.

5. The salicylic acid ionic liquid pure aqueous solution preparation according to claim 1 or 2, characterized in that: The salicylic acid ionic liquid pure aqueous solution preparation does not contain any organic solvent.

6. The salicylic acid ionic liquid pure aqueous solution preparation according to claim 1 or 2, characterized in that: The salicylic acid-γ-aminobutyric acid ionic liquid is a hydrated ionic liquid.

7. A method for preparing the salicylic acid ionic liquid pure aqueous solution preparation according to claim 1, characterized in that: include: The salicylic acid raw material, the gamma amino acid raw material and water are mixed and dissolved to perform in-situ synthesis in a one-step method.

8. The preparation method according to claim 7, characterized in that: The mixing and dissolution is carried out under non-vacuum conditions.

9. The preparation method according to claim 7, characterized in that: The mixed dissolution conditions include: 30-50°C, and the time is 10-30 minutes.

10. Use of the salicylic acid ionic liquid pure aqueous solution preparation according to claim 1 in preparing a preparation for direct external use on the skin.

11. The use according to claim 10, characterized in that: The active ingredient of the external skin preparation includes only the salicylic acid ionic liquid pure aqueous solution preparation.

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