阅读说明：本技术 一种2-羟基苄胺-丁二酸的盐及其制备方法 (Salt of 2-hydroxybenzylamine-succinic acid and preparation method thereof ) 是由 陈巍 李九龙 纪旭 李唱 侯宝红 周丽娜 谢闯 龚俊波 鲍颖 张美景 于 2021-01-22 设计创作，主要内容包括：本发明涉及一种2-羟基苄胺-丁二酸的盐及制备方法,2-羟基苄胺-丁二酸的盐中2-羟基苄胺和丁二酸的摩尔比为1:1；结构式如下；将2-羟基苄胺和丁二酸混合后,加入溶剂,采用液体辅助研磨或浆液混悬或溶剂挥发析晶的方法,经干燥后获得2-羟基苄胺和丁二酸的盐。2-羟基苄胺-丁二酸的盐的差示扫描量热分析谱图在143℃～153℃有特征熔融峰。其晶胞参数为轴角α＝90°,β＝90°,γ＝90°。2-羟基苄胺-丁二酸盐的形成显著提高了2-羟基苄胺的水溶性。制备方法简单易行、结晶过程易于控制具有良好的工业化前景。(The invention relates to a salt of 2-hydroxybenzylamine-succinic acid and a preparation method thereof, wherein the molar ratio of 2-hydroxybenzylamine to succinic acid in the salt of 2-hydroxybenzylamine-succinic acid is 1: 1; the structural formula is as follows; mixing 2-hydroxybenzylamine and succinic acid, adding a solvent, adopting a liquid auxiliary grinding or slurry suspension or solvent volatilization crystallization method, and drying to obtain the salt of 2-hydroxybenzylamine and succinic acid. The differential scanning calorimetry analysis spectrogram of the salt of the 2-hydroxybenzylamine-succinic acid has a characteristic melting peak at the temperature of 143-153 ℃. Having a cell parameter of The axial angle α is 90 °, β is 90 °, and γ is 90 °. The formation of 2-hydroxybenzylamine-succinate significantly improves the water solubility of 2-hydroxybenzylamine. The preparation method is simple and easy to implement, and the crystallization process is easy to control, so that the method has a good industrial prospect.)

1. A salt of 2-hydroxybenzylamine-succinic acid is characterized in that the molar ratio of 2-hydroxybenzylamine to succinic acid in the salt of 2-hydroxybenzylamine-succinic acid is 1: 1; the structural formula is as follows:

2. the salt of claim 1, wherein the salt of 2-hydroxybenzylamine-succinic acid has an X-ray powder diffraction pattern having characteristic peaks at angles of 2 θ of 6.4 ° ± 0.2 °, 9.1 ° ± 0.2 °, 11.7 ° ± 0.2 °, 12.3 ° ± 0.2 °, 14.9 ° ± 0.2 °, 18.4 ° ± 0.2 °, 19.3 ° ± 0.2 °, 19.9 ° ± 0.2 °, 21.9 ° ± 0.2 °, 23.1 ° ± 0.2 °, 23.7 ° ± 0.2 °, 24.5 ° ± 0.2, 25.5 ° ± 0.2, 26.6 ° ± 0.2 °, 27.8 ° ± 0.2 °, 28.5 ° ± 0.2 °, 29.4 ° ± 0.2 °, 30.2 ° ± 0.2 °.

3. The salt of claim 1, wherein the salt of 2-hydroxybenzylamine-succinic acid has a differential scanning calorimetry spectrum with a characteristic melting peak at 143-153 ℃.

4. The salt of claim 1, wherein the salt of 2-hydroxybenzylamine-succinic acid has an infrared spectrum of 3292 ± 1, 1682 ± 1, 1593 ± 1, 1457 ± 1, 1342 ± 1, 1251 ± 1, 1200 ± 1, 1126 ± 1, 1068 ± 1, 967 ± 1, 763 ± 1, 651 ± 1, 620 ± 1, 456 ± 1cm^-1Has characteristic peaks.

5. The salt of claim 1, wherein the salt of 2-hydroxybenzylamine-succinic acid is orthorhombic, the space group is Pbcn, and the unit cell parameter isThe axial angle α is 90 °, β is 90 °, and γ is 90 °.

6. A process for the preparation of a salt of 2-hydroxybenzylamine-succinic acid according to claim 1, characterized in that 2-hydroxybenzylamine-succinic acid is mixed, added with a solvent, dried to obtain a salt of 2-hydroxybenzylamine-succinic acid by liquid-assisted grinding or slurry suspension or solvent evaporation crystallization.

7. The method of claim 6, wherein the liquid-assisted milling is carried out by adding a solvent dropwise to a mixture of 2-hydroxybenzylamine and succinic acid, and milling the mixture in a vibratory ball mill; wherein, the mol ratio of the 2-hydroxybenzylamine to the succinic acid is 1:1, the solvent is selected from one of methanol, ethanol or acetonitrile, the dosage ratio of the total mass of the corresponding 2-hydroxybenzylamine and succinic acid mixture to the solvent is 4.8-12.1g/mL, and the grinding conditions are as follows: the frequency is 6-10 times/second, and the time duration is 20-60 minutes.

8. The method according to claim 6, wherein the slurry suspension is prepared by mixing 2-hydroxybenzylamine and succinic acid, suspending in a solvent, and filtering; wherein the mol ratio of the 2-hydroxybenzylamine to the succinic acid is 1:1, the solvent is selected from one of methanol, ethanol or acetonitrile, the dosage ratio of the total mass of the corresponding mixture of the 2-hydroxybenzylamine and the succinic acid to the solvent is 0.09-0.20g/mL, and the suspension time is 12-24 hours.

9. The method as claimed in claim 6, wherein the solvent is evaporated and crystallized by completely dissolving a mixture of 2-hydroxybenzylamine and succinic acid in the solvent and evaporating until crystals are precipitated; wherein, the mol ratio of the 2-hydroxybenzylamine to the succinic acid is 1:1, the solvent is acetonitrile, the volume of the added solvent is required to completely dissolve the mixture of the 2-hydroxybenzylamine and the succinic acid, and the volatilization time of the solvent is based on crystal precipitation.

10. The method of claim 6, wherein the drying conditions are: drying by blowing at 40-60 deg.C for 8-12 hr.

Technical Field

The invention belongs to the field of compound salification, and particularly relates to a salt of 2-hydroxybenzylamine-succinic acid and a preparation method thereof.

Background

The improvement of the physicochemical properties of poorly soluble drugs is an important step in the process of drug development. As an important branch of the crystal engineering field, the salification of the medicine can effectively improve the solubility, dissolution rate, stability, bioavailability and the like of the medicine on the basis of not changing the chemical properties of active components of the medicine.

The low bioavailability of a plurality of active pharmaceutical ingredients caused by low water solubility is a main restriction factor for the development of a new preparation, the problem can be well solved by a salifying method, more than half of the medicaments on the market are sold in a salified form at present, and the research on salification of the medicaments is increased year by year. For example, CN110804017A discloses a method for preparing salts of two sulfonylurea compounds and metformin, which have greatly improved solubility compared with the sulfonylurea compounds: the solubility of the gliquidone single product in pure water is 0.018mg/ml, and the solubility of the gliquidone-metformin salt in the pure water is 10.611 mg/ml; the solubility of the glibenclamide single product in pure water is less than 0.001mg/ml, and the solubility of the glibenclamide-metformin salt in the pure water is 16.783 mg/ml. However, the study of drug salts still faces difficulties and challenges, such as the requirement that the target drug must have a dissociable group, the salt forming agent (acid or base) must be safe for the human body, the salt forming agent requires extensive experimental screening, etc.

2-hydroxybenzylamine (C)₇H₉NO, molecular weight 123.15, CAS number 932-30-9, structure as in Table 1) (2-Hydroxybenzylamine, 2-HOBA), also known as salicylamine, is an effective scavenger of gamma-aldone (gamma-KA). Gamma-ketoaldehyde is a highly reactive lipid aldehyde generated in the processes of prostaglandin formation and arachidonic acid oxidation, and the lipid aldehyde can rapidly form an adduct with protein and lipid, and the adduct can cause partial protein function loss and cell oxidative stress, and cause symptoms of hypertension, arteriosclerosis, senile dementia and the like. Since 2-hydroxybenzylamine (2-HOBA) eliminates gamma-ketoaldehyde at a rate faster than the rate at which gamma-ketoaldehyde forms these adducts, cells and tissues can be protected from damage, 2-HOBA has a preventive and therapeutic effect on the above-mentioned common diseases and is an emerging nutritional medicine. However, 2-HOBA, a BCS class II drug, is poorly water soluble and therefore is designed for salt synthesis to improve water solubility.

Currently, only 2-HOBA-acetate is reported in 2-HOBA, related researches mostly focus on the aspect of the drug toxicology of 2-HOBA, and few researches are reported on the salification of the compound. In 2018, Fuller et al reported pharmacological evaluation of 2-hydroxybenzimine acetate In vitro safety In Food Chem Toxicol 2018,121,541-548, which demonstrated that 2-HOBA is a nutritional supplement. In 2019, Pitchford et al for the First time demonstrated that 2-HOBA-acetate is safe and well tolerated in healthy human volunteers in the First-in-human student assessment safety, tolerability, and pharmacokinetics of 2-hydroxybenzimidone acetate, a selective di-carboxylic electrolyte scavenger, in health volnters (BMC pharmacy. Toxicol.2019,20,6.) articles, making it a good candidate for a continuously developing nutritional supplement. Therefore, the application of 2-HOBA drugs in the aspect of medicine has great development potential, but no report on the aspect of improving the water solubility is provided.

Disclosure of Invention

2-hydroxybenzylamine (2-HOBA) contains an amino synthon unit in a molecule, amino has certain alkalinity, and-NH 3 is formed after proton transfer⁺Ionic, quaternary ammonium cations can form charge-assisted strong hydrogen bonding interactions with the carbonyl group of carboxylic acids, and thus 2-HOBA is expected to form salts with carboxylic acid compounds. Through screening, the salt of 2-HOBA and succinic acid (the structures are shown in table 1) is prepared, the water solubility of the 2-HOBA is obviously improved, and a foundation is laid for the further development and application of the 2-HOBA.

The invention aims to overcome the problem of poor water solubility of 2-HOBA in the prior art.

The technical scheme of the invention is as follows:

succinic acid is used as (C)₄H₆O₄Molecular weight 118.09, CAS number 110-15-6, structure as shown in Table 1) ligand forms salt with 2-HOBA, and the obtained salt has higher water solubility than 2-HOBA. In addition, the salt also has the advantages of simple preparation method, low production cost and the like, and is suitable for being applied to the production and application process of pharmaceutical preparations.

Table 1 Compound structural formula

In order to achieve the purpose, the invention is specifically realized by the following technical scheme:

the molar ratio of the 2-hydroxybenzylamine to the succinic acid in the 2-hydroxybenzylamine-succinic acid salt is 1: 1; the structural formula is as follows:

the X-ray powder diffraction pattern of the salt of 2-hydroxybenzylamine-succinic acid has characteristic peaks at 2 theta angles of 6.4 degrees +/-0.2 degrees, 9.1 degrees +/-0.2 degrees, 11.7 degrees +/-0.2 degrees, 12.3 degrees +/-0.2 degrees, 14.9 degrees +/-0.2 degrees, 18.4 degrees +/-0.2 degrees, 19.3 degrees +/-0.2 degrees, 19.9 degrees +/-0.2 degrees, 21.9 degrees +/-0.2 degrees, 23.1 degrees +/-0.2 degrees, 23.7 degrees +/-0.2 degrees, 24.5 degrees +/-0.2 degrees, 25.5 degrees +/-0.2 degrees, 26.6 degrees +/-0.2 degrees, 27.8 degrees +/-0.2 degrees, 28.5 degrees +/-0.2 degrees, 29.4 degrees +/-0.2 degrees and 30.2 degrees. The powder X-ray diffraction pattern is shown in figure 1.

The differential scanning calorimetry analysis spectrogram of the 2-hydroxybenzylamine-succinic acid salt has a characteristic melting peak at 143-153 ℃, as shown in figure 2, and the melting point range is related to the crystallinity of the medicament.

The infrared spectrum of the salt of 2-hydroxybenzylamine-succinic acid has characteristic peaks at 3292 + -1, 1682 + -1, 1593 + -1, 1457 + -1, 1342 + -1, 1251 + -1, 1200 + -1, 1126 + -1, 1068 + -1, 967 + -1, 763 + -1, 651 + -1, 620 + -1 and 456 + -1, as shown in figure 3.

The salt of 2-hydroxybenzylamine-succinic acid is an orthorhombic system, the space group is Pbcn, and the unit cell parameter is The axial angle α is 90 °, β is 90 °, and γ is 90 °. The structural formula is shown in figure 4.

According to another aspect of the present invention, there is provided a process for preparing a salt of 2-HOBA and succinic acid, comprising mixing 2-HOBA and succinic acid, adding a solvent, drying to obtain a salt of 2-HOBA and succinic acid by liquid-assisted milling or slurry suspension or solvent evaporation crystallization.

The method for preparing the salt of 2-hydroxybenzylamine-succinic acid is characterized in that the liquid auxiliary grinding method is to drop a mixture of 2-HOBA and succinic acid into a solvent and grind the mixture in a vibration ball mill. The mol ratio of the 2-HOBA and the succinic acid is 1:1, the solvent is selected from one of methanol, ethanol or acetonitrile, the dosage ratio of the total mass of the corresponding 2-HOBA and succinic acid mixture to the solvent is 4.8-12.1g/mL, and the grinding conditions are as follows: the frequency is 6-10 times/second, and the time duration is 20-60 minutes.

The method for preparing the salt of 2-hydroxybenzylamine-succinic acid is characterized in that the slurry suspension method comprises the steps of mixing 2-HOBA and succinic acid, suspending in a solvent and filtering. The mol ratio of the 2-HOBA and the succinic acid is 1:1, the solvent is selected from one of methanol, ethanol or acetonitrile, the dosage ratio of the total mass of the corresponding 2-HOBA and succinic acid mixture to the solvent is 0.09-0.20g/mL, and the suspension time is 12-24 hours.

The method for preparing the salt of 2-hydroxybenzylamine-succinic acid is characterized in that the solvent volatilization method is that a mixture of 2-HOBA and succinic acid is completely dissolved in the solvent and volatilized until crystals are separated out. The molar ratio of the 2-HOBA to the succinic acid is 1:1, the solvent is acetonitrile (methanol and ethanol are not applicable in the method), the volume of the added solvent is required to be completely dissolved in the mixture of the 2-HOBA and the succinic acid, and the volatilization time of the solvent is based on crystal precipitation.

The method for preparing the salt of 22-hydroxybenzylamine-succinic acid comprises the following drying conditions: drying by blowing at 40-60 deg.C for 8-12 hr.

The yield of the method for preparing the salt of 2-hydroxybenzylamine-succinic acid is over 50 percent and can reach over 99.0 percent at most. Based on moles of salt obtained versus moles of 2-HOBA starting material used.

High performance liquid chromatography is adopted to detect the solubility of the 2-HOBA and the obtained 2-hydroxybenzylamine-succinic acid salt in pure water. Adding excessive 2-HOBA or 2-hydroxybenzylamine-succinic acid salt product into 10mL of water, stirring at 25 ℃ for 12h, standing for 12h, taking supernatant, filtering and diluting the supernatant by a polytetrafluoroethylene filter membrane, and detecting the concentration by high performance liquid chromatography to obtain 10.7199g/L of the solubility of the 2-HOBA raw material, wherein the solubility (calculated by the 2-HOBA component) of the 2-HOBA in the obtained 2-hydroxybenzylamine-succinic acid salt is 97.8731 g/L. It is thus seen that the water solubility of the obtained salt of 22-hydroxybenzylamine-succinic acid is significantly improved.

A powder property tester is adopted to carry out comparative test on the fluidity and bulk density of the 2-hydroxybenzylamine-succinic acid salt and the 2-HOBA raw material, and the bulk density of the raw material is as follows: 0.436-0.440g/mL and an angle of repose of 38.6-38.8 degrees. The bulk density of the salt of 2-HOBA and succinic acid was: 0.450-0.454g/mL, and an angle of repose of 39.9-40.1 degrees. The bulk density of the salt of 2-hydroxybenzylamine-succinic acid is increased to a certain degree, and the fluidity is improved to a certain degree.

In conclusion, compared with 2-HOBA, the 2-hydroxybenzylamine-succinic acid salt disclosed by the invention has higher water solubility, slightly increased bulk density and enhanced fluidity, and is beneficial to subsequent storage and transportation. The method has the advantages of simple process, strong operability, low equipment requirement, short production period, suitability for industrial production, and capability of preparing the salt of 2-HOBA and succinic acid for industrial production according to requirements.

Drawings

FIG. 1 is a PXRD spectrum of the salt of 2-hydroxybenzylamine-succinic acid prepared in example 1 and the two starting materials used in all examples, with diffraction intensity on the ordinate in units of counts; the abscissa is diffraction angle 2 θ, in degrees (°);

FIG. 2 is a DSC spectra of the salt of 2-hydroxybenzylamine-succinic acid prepared in example 1 and the two starting materials used in all examples, with the ordinate being the heat flux emitted per mass of material, in (W/g), with an upward exotherm; the abscissa is temperature, in degrees centigrade (° c);

fig. 3 is an infrared spectrum of the salt of 2-hydroxybenzylamine-succinic acid prepared in example 1 and two raw materials used in all examples, with transmittance on the ordinate in (%); the abscissa is the wave number in degrees Celsius (cm)^-1)；

FIG. 4 is a structural diagram of the salt of 22-hydroxybenzylamine-succinic acid in example 1, with the molecular formula C₁₁H₁₅NO₅。

Detailed Description

For the purpose of enhancing the understanding of the present invention, the present invention will be described in further detail with reference to the following embodiments and the accompanying drawings, which are only used for explaining the present invention and are not to be construed as limiting the scope of the present invention.

The detection instrument and the method comprise the following steps:

single crystal X-rayThe line diffraction measurement is performed by using a X-ray surface detection diffractometer Rapid-Rigaku II, MoK alpha target ray wavelength 7.103X 10^-10m are scanned. Integration and scaling of intensity data is done using SAINT program. The structure was resolved by a direct method using SHELXS-XT. And refining by using SHELXL-XL through a full matrix least square method, wherein the hydrogen atom refining process is obtained by isotropic calculation processing.

Powder X-ray diffraction Using an X-ray diffractometer model D/max-2500 of Japan science (Rigaku) with a radiation source of The scan range is 2-40 ° (2 θ), the scan step is 0.02 °, and the rate is 8 °/min. The power supply was set at 40kV, 100 mA.

DSC was performed in a Mettler DSC 1 system (STARe, Mettler, Switzerland). Samples weighing 3-5mg were heated in a standard aluminum pan at a ramp rate of 10 deg.C/min under a nitrogen flow of 50 mL/min.

Infrared spectra were collected on an ALPHA II infrared instrument (Bruker, Germany). Each sample was at 4000-400cm^-1In the spectral range of 4cm^-1Is scanned. At least 16 scans were collected and averaged.

The liquid chromatography is carried out by using Agilent extended C18 chromatographic column (250X 4.6mm, 5 μm) and detecting at 25 deg.C and 275nm ultraviolet detection wavelength. The mobile phase was acetonitrile, water and acetic acid (v: v: v ═ 70:30:1) at a flow rate of 1.0 mL/min. The observed retention time of 2-HOBA was 2.044 min.

Example 1:

a liquid assisted milling method is used. Adding 0.123g of 2-HOBA and 0.118g of succinic acid into a sample tube of a vibration ball mill, adding 50 mu L of ethanol by using a liquid transfer gun, grinding at the frequency of 6 times/second, taking out after 60 minutes, drying in an air-blast drying oven at the temperature of 40 ℃ for 12 hours to obtain the salt of 2-hydroxybenzylamine-succinic acid, wherein the yield is 99%. The PXRD pattern of the product is shown in FIG. 1The characteristic peak (2 θ, ± 0.2 °) is: 6.4 degrees +/-0.2 degrees, 9.1 degrees +/-0.2 degrees, 11.7 degrees +/-0.2 degrees, 12.3 degrees +/-0.2 degrees, 14.9 degrees +/-0.2 degrees, 18.4 degrees +/-0.2 degrees, 19.3 degrees +/-0.2 degrees, 19.9 degrees +/-0.2 degrees, 21.9 degrees +/-0.2 degrees, 23.1 degrees +/-0.2 degrees, 23.7 degrees +/-0.2 degrees, 24.5 degrees +/-0.2 degrees, 25.5 degrees +/-0.2 degrees, 26.6 degrees +/-0.2 degrees, 27.8 degrees +/-0.2 degrees, 28.5 degrees +/-0.2 degrees, 29.4 degrees +/-0.2 degrees and 30.2 degrees +/-0.2 degrees, and is consistent with the fitting result of a single crystal structure; the DSC spectrum is shown in figure 2, and the characteristic values are as follows: melting start point 145.4 ℃, peak 148.2 ℃; the infrared spectrum is shown in FIG. 3, and can be determined at 3292 + -1, 1682 + -1, 1593 + -1, 1457 + -1, 1342 + -1, 1251 + -1, 1200 + -1, 1126 + -1, 1068 + -1, 967 + -1, 763 + -1, 651 + -1, 620 + -1, 456 + -1 cm^-1Has characteristic peaks. The solubility in water at 25 ℃ was 97.8731g/L (based on the 2-HOBA fraction). The bulk density was 0.450g/mL, and the angle of repose was 39.9 °.

Example 2:

a liquid assisted milling method is used. Adding 0.123g of 2-HOBA and 0.118g of succinic acid into a sample tube of a vibration ball mill, adding 20 mu L of methanol by using a liquid transfer gun, grinding at the frequency of 8 times/second, taking out after 50 minutes, drying in an air-blast drying oven at the temperature of 40 ℃ for 12 hours to obtain the salt of 2-hydroxybenzylamine-succinic acid with the yield of 99%. The PXRD pattern, DSC pattern and infrared pattern of the product are similar to those of example 1. The solubility was 97.8731g/L (based on the 2-HOBA fraction). The bulk density was 0.452g/mL, and the angle of repose was 40.0 °.

Example 3:

a liquid assisted milling method is used. Adding 0.123g of 2-HOBA and 0.118g of succinic acid into a sample tube of a vibration ball mill, adding 50 mu L of acetonitrile by using a liquid transfer gun, grinding at the frequency of 10 times/second, taking out after 20 minutes, drying in an air-blast drying oven at the temperature of 40 ℃ for 12 hours to obtain the salt of 2-hydroxybenzylamine-succinic acid with the yield of 99%. The PXRD pattern, DSC pattern and infrared pattern of the product are similar to those of example 1. The solubility was 97.8731g/L (based on the 2-HOBA fraction). The bulk density was 0.454g/mL, and the angle of repose was 40.1 °.

Example 4:

a slurry suspension method is used. Weighing 0.984g of 2-HOBA, adding 0.944g of succinic acid, adding 10ml of ethanol, stirring at room temperature for 12 hours, filtering, and drying in an air-blast drying oven at 40 ℃ for 12 hours to obtain the salt of 2-hydroxybenzylamine-succinic acid with the yield of 99%. The PXRD pattern, DSC pattern and infrared pattern of the product are similar to those of example 1. The solubility was 97.8731g/L (based on the 2-HOBA fraction). The bulk density was 0.451g/mL, and the angle of repose was 39.9 °.

Example 5:

a slurry suspension method is used. Weighing 0.984g of 2-HOBA, adding 0.944g of succinic acid, adding 10ml of methanol, stirring at room temperature for 12 hours, filtering, and drying in an air-blast drying oven at 40 ℃ for 12 hours to obtain the salt of 2-hydroxybenzylamine-succinic acid with the yield of 99%. The PXRD pattern, DSC pattern and infrared pattern of the product are similar to those of example 1. The solubility was 97.8731g/L (based on the 2-HOBA fraction). The bulk density was 0.453g/mL, and the angle of repose was 40.0 ℃.

Example 6:

a slurry suspension method is used. Weighing 0.984g of 2-HOBA, adding 0.944g of succinic acid, adding 20ml of acetonitrile, stirring at room temperature for 24 hours, filtering, and drying in an air-blast drying oven at the temperature of 40 ℃ for 12 hours to obtain the salt of 2-hydroxybenzylamine-succinic acid with the yield of 99%. The PXRD pattern, DSC pattern and infrared pattern of the product are similar to those of example 1. The solubility was 97.8731g/L (based on the 2-HOBA fraction). The bulk density was 0.451g/mL, and the angle of repose was 40.1 °.

Example 7:

a method of solvent evaporation is used. Weighing 49.2mg of 2-HOBA, adding 47.2mg of succinic acid, adding 4mL of acetonitrile, volatilizing at room temperature after dissolving, filtering, and drying in a forced air drying oven at 60 ℃ for 8 hours to obtain the salt of 2-hydroxybenzylamine-succinic acid, wherein the yield is 50.3%. The PXRD pattern, DSC pattern and infrared pattern of the product are similar to those of example 1. The solubility was 97.8731g/L (based on the 2-HOBA fraction). The bulk density was 0.453g/mL, and the angle of repose was 40.1 °.

Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.