阅读说明：本技术 绿原酸钠水合物及其应用 (Chlorogenic acid sodium hydrate and application thereof ) 是由 邹德超 陈先红 于 2020-06-12 设计创作，主要内容包括：本发明为绿原酸钠水合物及其应用,提供了一种绿原酸钠一水合物。与现有技术相比,本发明提供的绿原酸钠一水合物具有较高的稳定性、较高的纯度及溶解度,可减小注射给药体积,并且其在水中的pH值近中性,可降低注射给药局部的刺激性,更加适合开发成注射剂。(The invention provides a sodium chlorogenic acid hydrate and application thereof, and provides a sodium chlorogenic acid hydrate. Compared with the prior art, the sodium chlorogenic acid monohydrate provided by the invention has higher stability, higher purity and solubility, can reduce the injection administration volume, has a pH value in water close to neutrality, can reduce the local irritation of injection administration, and is more suitable for being developed into an injection.)

1. A sodium chlorogenic acid monohydrate.

2. The sodium chlorogenic acid monohydrate according to claim 1, characterized in that, with Cu-ka as radiation source, it has characteristic peaks at diffraction angles 2 Θ of X-ray powder diffraction of 6.883 ± 0.1 °, 13.208 ± 0.1 °, 13.858 ± 0.1 °, 14.850 ± 0.1 °, 18.803 ± 0.1 °, 19.437 ± 0.1 °, 20.831 ± 0.1 °, 22.221 ± 0.1 ° and 23.337 ± 0.1 °.

3. The sodium chlorogenic acid monohydrate according to claim 1, characterized in that, with Cu-K α as a radiation source, it has a relative intensity of characteristic peaks at 14.850 ± 0.1 ° in X-ray powder diffraction at diffraction angle 2 θ of 100%; the relative intensity of characteristic peaks at 6.883 +/-0.1 degrees is not lower than 60 percent; the relative intensity of characteristic peaks at 13.858 +/-0.1 degrees is not lower than 10 percent; the relative loudness of characteristic peaks at 19.437 +/-0.1 degrees is not lower than 10 percent; the relative intensity of the characteristic peak at 23.337 + -0.1 deg. is not lower than 10%.

4. The sodium chlorogenic acid monohydrate according to claim 1, characterized in that the characteristic peaks of X-ray powder diffraction 2 θ of the sodium chlorogenic acid monohydrate include at least three of the following with Cu-K α as radiation source:

5. the sodium chlorogenic acid monohydrate according to claim 1, characterized in that when Cu-K α is used as radiation source, it has the X-ray powder diffraction pattern shown in fig. 1.

6. The sodium chlorogenic acid monohydrate according to claim 1, characterized in that it comprises two endothermic peaks and one exothermic peak by differential scanning calorimetry; the endothermic peak is positioned at 130-135 ℃ and 240-245 ℃; the exothermic peak is located at 245-250 ℃.

7. The sodium chlorogenic acid monohydrate according to claim 6, wherein the endothermic peak-to-peak values are 133.72 ℃ and 242.94 ℃; the peak exotherm was 247.36 ℃.

8. A method for preparing sodium chlorogenic acid monohydrate, which is characterized by comprising the following steps:

dissolving chlorogenic acid in alcohol solvent, adding sodium acetate, stirring to react and separate out solid to obtain chlorogenic acid sodium monohydrate.

9. The preparation method of claim 8, wherein the mass-to-volume ratio of the chlorogenic acid to the alcoholic solvent is 1 g: (10-30) ml; the temperature of stirring reaction is 0-50 ℃; the stirring reaction time is 1-5 h.

10. An injection comprising the sodium chlorogenic acid monohydrate according to any one of claims 1 to 7 or the sodium chlorogenic acid monohydrate prepared according to claim 8 or 9.

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a chlorogenic acid sodium hydrate and application thereof.

Background

Chlorogenic acid (also known as caffeotannic acid or caffeotannic acid) is a depside formed by the condensation of caffeic acid (caffeic acid) and quinic acid (quinic acid), which is a product of aerobic respiratory metabolism of plants. Chlorogenic acid has a chemical name of 5-O-caffeoylquinic acid (5-O-caffeoylquinic acid),the molecular formula is as follows: c₁₆H₁₈O₉Molecular weight: 354.31, the structural formula is shown below.

Chlorogenic acid is an important bioactive substance, and the prior art discloses that chlorogenic acid has multiple purposes: including anti-tumor, treating autoimmune diseases, anti-oxidation, anti-aging, anti-musculoskeletal aging, protecting cardiovascular: treatment of cardiomyopathy and the like; although chlorogenic acid has good pharmacological activity, the prepared injection needs to be stable under a slightly acidic condition due to poor stability of chlorogenic acid. Chinese patent CN201310366945.0 discloses a preparation method of a freeze-dried powder injection, which mainly comprises chlorogenic acid, a bracket and an antioxidant, wherein phosphate is used as a buffer solution, the pH value is 3-3.5 and is low, and the solubility of the chlorogenic acid in water is only about 2%, so that the injection volume of the preparation is large and the irritation is high during clinical tests.

Disclosure of Invention

In view of the above, the technical problem to be solved by the present invention is to provide a chlorogenic acid sodium hydrate and an application thereof, the chlorogenic acid sodium hydrate provided by the present invention has characteristics of good stability, high solubility, reduced injection administration volume, small irritation, and greatly expanded clinical applications of chlorogenic acid.

The invention provides a sodium chlorogenic acid monohydrate. Compared with chlorogenic acid, the sodium chlorogenic acid monohydrate has higher stability and solubility, the pH value in water is nearly neutral, the injection administration volume can be smaller, the local irritation of injection administration is reduced, and the sodium chlorogenic acid monohydrate is more suitable for being developed into an injection.

Preferably, the sodium chlorogenic acid monohydrate has a characteristic peak at a diffraction angle 2 theta of X-ray powder diffraction at least 3 of 6.883 + -0.1 DEG, 13.208 + -0.1 DEG, 13.858 + -0.1 DEG, 14.850 + -0.1 DEG, 18.803 + -0.1 DEG, 19.437 + -0.1 DEG, 20.831 + -0.1 DEG, 22.221 + -0.1 DEG and 23.337 + -0.1 DEG by using Cu-K alpha as a radiation source.

Preferably, the relative intensity of a characteristic peak of the sodium chlorogenic acid monohydrate at a diffraction angle 2 theta of 14.850 +/-0.1 DEG in an X-ray powder diffraction manner is 100 percent by taking Cu-K alpha as a radiation source; the relative intensity of characteristic peaks at 6.883 +/-0.1 degrees is not lower than 60 percent; the relative intensity of characteristic peaks at 13.858 +/-0.1 degrees is not lower than 10 percent; the relative loudness of characteristic peaks at 19.437 +/-0.1 degrees is not lower than 10 percent; the relative intensity of the characteristic peak at 23.337 + -0.1 deg. is not lower than 10%.

Preferably, with Cu-K α as a radiation source, the characteristic peaks of X-ray powder diffraction 2 θ of the sodium chlorogenic acid monohydrate include at least three of the following:

preferably, the sodium chlorogenic acid monohydrate has an X-ray powder diffraction pattern shown in figure 1 by taking Cu-K alpha as a radiation source.

Preferably, the sodium chlorogenic acid monohydrate comprises two endothermic peaks and one exothermic peak by differential scanning calorimetry analysis; the endothermic peak is positioned at 130-135 ℃ and 240-245 ℃; the exothermic peak is located at 245-250 ℃.

Preferably, the endothermic peak value is between 133.72 ℃ and 242.94 ℃; the peak exotherm was 247.36 ℃.

The invention also provides a preparation method of the sodium chlorogenic acid monohydrate, which comprises the following steps: :

dissolving chlorogenic acid in alcohol solvent, adding sodium acetate, stirring to react and separate out solid to obtain chlorogenic acid sodium monohydrate.

Preferably, the mass volume ratio of the chlorogenic acid to the alcohol solvent is 1 g: (10-30) ml; the temperature of stirring reaction is 0-50 ℃; the stirring reaction time is 1-5 h.

The invention also provides an injection, which comprises the sodium chlorogenic acid monohydrate.

The invention provides a sodium chlorogenic acid monohydrate. Compared with the prior art, the sodium chlorogenic acid monohydrate provided by the invention has higher stability, higher purity and solubility, can reduce the injection administration volume, has a pH value in water close to neutrality, can reduce the local irritation of injection administration, and is more suitable for being developed into an injection.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of sodium chlorogenic acid monohydrate prepared in example 1 of the present invention;

FIG. 2 is a DSC of sodium chlorogenic acid monohydrate prepared in example 1 of this invention;

FIG. 3 is a TG spectrum of sodium chlorogenic acid monohydrate prepared in example 1 of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The invention provides a chlorogenic acid sodium monohydrate, namely a monohydrate of chlorogenic acid sodium salt. The chlorogenic acid sodium monohydrate has good stability, high purity and good reproducibility.

According to the present invention, the sodium chlorogenic acid monohydrate has diffraction angle 2 θ of X-ray powder diffraction having characteristic peaks at least 3 of 6.883 + -0.1 °, 13.208 + -0.1 °, 13.858 + -0.1 °, 14.850 + -0.1 °, 18.803 + -0.1 °, 19.437 + -0.1 °, 20.831 + -0.1 °, 22.221 + -0.1 ° and 23.337 + -0.1 ° with Cu-K α as a radiation source, that is, sodium chlorogenic acid monohydrate can be represented by any composition of 3 or more of the above-mentioned characteristic peaks.

Preferably, the relative intensity of a characteristic peak of the sodium chlorogenic acid monohydrate at a diffraction angle 2 theta of 14.850 +/-0.1 DEG in an X-ray powder diffraction manner is 100 percent by taking Cu-K alpha as a radiation source; the relative intensity of the characteristic peak at 6.883 ± 0.1 ° is preferably not less than 60%, more preferably not less than 65%; the relative intensity of the characteristic peak at 13.858 ± 0.1 ° is preferably not less than 10%, more preferably not less than 11%; the relative intensity of the characteristic peak at 19.437 ± 0.1 ° is preferably not less than 10%, more preferably not less than 12%, still more preferably not less than 13%; the relative intensity of the characteristic peak at 23.337. + -. 0.1 ℃ is preferably not less than 10%, more preferably not less than 12%, still more preferably not less than 13%.

More preferably, with Cu-K α as the radiation source, the characteristic peaks of X-ray powder diffraction 2 θ of the sodium chlorogenic acid monohydrate include at least three of the following:

still preferably, the sodium chlorogenic acid monohydrate has an X-ray powder diffraction pattern shown in fig. 1 with Cu-K α as a radiation source.

According to the invention, said sodium chlorogenic acid monohydrate comprises two endothermic peaks and one exothermic peak by Differential Scanning Calorimetry (DSC) analysis; the endothermic peak is positioned at 130-135 ℃ and 240-245 ℃; the peak value of the endothermic peak is preferably 133.72 ℃ and 242.94 ℃; the exothermic peak is positioned at 245-250 ℃; the peak value of the exothermic peak is preferably 247.36 ℃; the programmed heating rate during differential scanning calorimetry is preferably 5-15K/min, more preferably 8-12K/min, and still more preferably 10K/min.

According to the invention, the sodium chlorogenic acid monohydrate is preferably lost by weight by 4.2% to 4.6%, more preferably 4.3% to 4.5%, and even more preferably 4.344% before 100 ℃ by thermogravimetric analysis; the heating rate of the thermogravimetric analysis is preferably 5-10K/min, and more preferably 5K/min.

The invention also provides a preparation method of the chlorogenic acid sodium monohydrate, which comprises the following steps: dissolving chlorogenic acid in alcohol solvent, adding sodium acetate, stirring to react and separate out solid to obtain chlorogenic acid sodium monohydrate.

In the present invention, the sources of all raw materials are not particularly limited, and they may be commercially available.

Dissolving chlorogenic acid in alcohol solvent; the alcohol solvent is preferably one or more of methanol, ethanol, n-propanol and isopropanol, more preferably one or two of methanol, ethanol, n-propanol and isopropanol, and still more preferably methanol and/or ethanol; the mass volume ratio of the chlorogenic acid to the alcohol solvent is preferably 1 g: (10-30) ml, more preferably 1 g: (15-25) ml, more preferably 1 g: (15-22.5) ml; the temperature of chlorogenic acid when dissolved in the alcohol solvent is preferably 0-50 ℃, more preferably 10-40 ℃, and even more preferably 20-30 ℃.

Then adding sodium acetate; the sodium acetate is preferably solid sodium acetate; the mass ratio of the sodium acetate to the chlorogenic acid is preferably (1-5): (10-20), more preferably (1.3-4.6): (10-20); in some embodiments provided herein, the mass ratio of sodium acetate to chlorogenic acid is preferably 1.3: 10; in other embodiments provided herein, the mass ratio of sodium acetate to chlorogenic acid is preferably 4.6: 20.

stirring and reacting; the temperature of the stirring reaction is preferably 0-50 ℃, more preferably 10-40 ℃, and further preferably 20-30 ℃; the stirring reaction time is preferably 1-5 h, and more preferably 2-3 h.

After the reaction is stirred, a solid is separated out, and preferably, the solid product is obtained by filtration or centrifugal separation.

The solid product obtained is preferably washed with an alcoholic solvent; the alcohol solvent is preferably one or more of methanol, ethanol, n-propanol and isopropanol, more preferably one or two of methanol, ethanol, n-propanol and isopropanol, and still more preferably methanol and/or ethanol.

Washing, preferably drying to obtain chlorogenic acid sodium monohydrate; the drying temperature is preferably 30 ℃ to 70 ℃, and more preferably 40 ℃ to 50 ℃.

The sodium chlorogenic acid monohydrate provided by the present invention can be administered in the form of a crystalline or amorphous product. They can be obtained, for example, in the form of solid plugs, powders or films by processes such as precipitation, crystallization, freeze drying, spray drying or evaporation drying. Microwave or radio frequency drying may be used to achieve the above objectives.

The invention also provides an injection, which comprises the sodium chlorogenic acid monohydrate; compared with chlorogenic acid, the solubility of the sodium chlorogenic acid monohydrate provided by the invention is greatly improved to be more than 140mg/ml, the pH value in water is nearly neutral (when 100mg/ml is reached, the pH value is 6.7), the injection administration volume can be reduced, the local irritation of injection administration is reduced, and the sodium chlorogenic acid monohydrate is more suitable for being developed into injections.

The invention also provides a pharmaceutical preparation, which comprises the sodium chlorogenic acid monohydrate and pharmaceutically acceptable auxiliary materials. The pharmaceutical formulation of the present invention may comprise sodium chlorogenic acid monohydrate alone or in combination with other drugs.

The term "pharmaceutically acceptable excipient" is meant to include any and all solvents, diluents or other liquid excipients, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like as appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, e.w. maetin (Mack Publishing co., Easton, Pa.,1980) discloses various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, e.g., any other component that produces no biological effect or interacts in a deleterious manner with a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.

Some examples of materials capable of serving as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; buffer substances, for example: a phosphate salt; glycine; sorbic acid or potassium sorbate; a mixture of partial glyceride esters of saturated vegetable fatty acids; water; salts or electrolytes, for example: disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salt; colloidal silicon dioxide; magnesium trisilicate; polyvinylpyrrolidone; a polyacrylate; sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; pyrogen-free water; isotonic saline; ethanol; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preserving and anti-oxidizing agents may also be present in the composition, according to the judgment of the person skilled in the art.

The sodium chlorogenic acid monohydrate provided by the invention can be prepared into a conventional pharmaceutical preparation according to a conventional preparation method; the dosage forms of the pharmaceutical preparation comprise capsules, tablets, pills, granules, emulsions, floating agents, injections, drops, freeze-dried powder injections and the like.

The sodium chlorogenic acid monohydrate is combined with a common carrier or diluent and can be administered orally, parenterally or topically.

Oral administration should include swallowing, so that the compound is able to enter the gastrointestinal tract, or buccal or sublingual administration, so that the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid and liquid formulations, solid formulations such as tablets; capsules containing particles, liquids or powders; lozenges (including liquid-filled lozenges); chewable tablets; composite particles and nanoparticles; gelling; a solid solution; a liposome; films (including mucoadhesives); an egg agent; a spray; liquid preparations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers for soft or hard gelatin capsules and typically comprise a carrier such as water, EtOH, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil, together with one or more emulsifying and/or suspending agents. Liquid formulations may also be prepared by formulating a solid from, for example, a sachet.

The compounds disclosed herein are also useful in fast dissolving, fast disintegrating dosage forms.

For tablet dosage forms, a disintegrant is typically included in addition to the drug. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose, polyvinyl polypyrrolidone, polyvinyl pyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate.

Binders are commonly used to impart cohesive properties to the tablet. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

The tablets also optionally contain surfactants such as sodium lauryl sulfate and polysorbate vinegar 80, and glidants such as silicon dioxide and talc.

Tablets also typically contain lubricating agents such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Other ingredients may include preservatives, antioxidants, fragrances and colorants.

In the present invention, the term parenteral administration includes intravenous, intramuscular, subcutaneous, intranasal, intrarectal, intravaginal or intraperitoneal administration. Formulations for parenteral administration are typically aqueous solutions containing excipients such as salts, carbohydrates and buffers (preferably at a pH of 3-9), but for some applications are more suitably formulated as sterile, anhydrous solutions or in dry form for use in conjunction with a suitable vehicle such as sterile, pyrogen-free water. Preparation of a parenteral formulation may be conveniently accomplished by lyophilization under sterile conditions using conventional pharmaceutical techniques well known to those skilled in the art.

Sodium chlorogenic acid monohydrate in the present invention can also be administered topically, either to the skin or mucosa, either transdermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, emulsions, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, tampons, fibers, bandages and microemulsions, and liposomes may also be used. Typical carriers include alcohols, water, mineral oil, liquid paraffin, white petrolatum, glycerin, and propylene glycol. Typical formulations may also contain penetration enhancers.

In the present invention, the administration form of sodium chlorogenic acid monohydrate is preferably injection administration or oral administration.

The preparation type of the injection administration is preferably injection or freeze-dried powder injection; the solvent of the injection and the double solvent used for the freeze-dried powder injection are aqueous soluble and non-aqueous solvents which are well known by the technical personnel in the field. The aqueous solvent is most commonly water for injection, and can also be 0.9% sodium chloride solution or other suitable aqueous solution; the non-aqueous solvent is usually vegetable oil, mainly soybean oil for injection and other non-aqueous solvents such as ethanol, propylene glycol, polyethylene glycol and glycerol.

The invention also provides application of the sodium chlorogenic acid monohydrate, and the effect of the chlorogenic acid serving as a medicine and a health-care product in the aspects of resisting tumors, treating autoimmune diseases, resisting oxidation, resisting aging, resisting muscular skeletal aging, protecting cardiovascular system, increasing bone marrow cells, treating thrombocytopenia and anemia, treating spleen hematopoietic stem cell injury, treating myelofibrosis, treating urticaria, treating psoriasis, treating osteopetrosis, promoting fibroblast proliferation, protecting liver, treating epilepsy, treating bone marrow infection, treating amyotrophic lateral sclerosis, treating Parkinson's disease, resisting viruses, resisting bacteria and the like is proved.

Therefore, the invention also provides the application of the sodium chlorogenic acid monohydrate in preparing the medicaments or health-care products for resisting oxidation, removing free radicals, improving central excitation, expanding blood vessels, protecting liver and gallbladder, resisting HIV (acquired immune deficiency syndrome) or resisting bacteria and diminishing inflammation.

The invention also provides the application of the sodium chlorogenic acid monohydrate in preparing the medicines for treating and/or preventing tumors, inflammatory diseases or autoimmune diseases.

The tumor of the invention comprises solid tumor and non-solid tumor; tumors described in the present invention include, but are not limited to, melanoma, pancreatic cancer, colorectal cancer, lung cancer, liver cancer, gastric cancer, laryngeal cancer, nasopharyngeal cancer, esophageal cancer, multiple myeloma, lymphoma, leukemia, bladder cancer, prostate cancer, bile duct cancer, cervical cancer, ovarian cancer, breast cancer, endometrial cancer, skin cancer, and the like.

The autoimmune diseases described in the present invention include, but are not limited to, systemic lupus erythematosus, psoriasis, rheumatoid arthritis, scleroderma, and the like.

In order to further illustrate the present invention, the following examples are provided to describe a chlorogenic acid sodium hydrate and its application in detail.

The reagents used in the following examples are all commercially available.

The detection device used in the present invention is as follows:

powder X-ray diffraction analysis:

rigaku D/max-2550 powder X-ray diffractometer in Japan, test conditions: Cu-Kalpha radiation, 150mA tube flow, 40kV tube pressure, 8 degrees/minute scanning speed and 0.02 step length.

Differential Scanning Calorimetry (DSC)

Mettler DSC1 thermal analyzer, Switzerland, onset temperature 30 ℃; the termination temperature is 250 ℃; the heating rate is 10K/min.

Thermogravimetric analysis (TG)

Testing an instrument: switzerland Mettler TGA/DSC1 thermal analyzer, parameter settings: the starting temperature is 30 ℃; the termination temperature is 500 ℃; the heating rate is 5K/min.

Example 1

Adding 20.0g of chlorogenic acid, 400mL of ethanol and 50mL of methanol into a reaction bottle, stirring at 20-30 ℃ for dissolving, adding 4.6g of sodium acetate solid, stirring at 20-30 ℃ for 3h, filtering, washing a filter cake with 100mL of ethanol, and drying at 40 ℃ under reduced pressure to obtain 18.0g of off-white powder, namely sodium chlorogenic acid monohydrate.

The sodium chlorogenic acid monohydrate obtained in example 1 was analyzed by X-ray powder diffraction to obtain an X-ray powder diffraction pattern thereof, as shown in fig. 1.

The sodium chlorogenic acid monohydrate obtained in example 1 was subjected to DSC analysis, and the DSC spectrum thereof was shown in fig. 2. As can be seen from FIG. 2, sodium chlorogenic acid monohydrate exhibits two endothermic peaks and one exothermic Peak in DSC, wherein the Peak of endothermic Peak is 133.72 deg.C, 242.94 deg.C, and the Peak of exothermic Peak is 247.36 deg.C.

TG analysis was performed on the sodium chlorogenic acid monohydrate obtained in example 1 to obtain a TG spectrum thereof, as shown in fig. 3. As can be seen from fig. 3, the weight loss was 4.344% before 100 ℃, and the moisture content measurement result was 5.26%, thereby indicating that the sample contained one molecule of crystal water and the theoretical moisture content was 4.56%.

The sodium chlorogenic acid monohydrate obtained in example 1 was dissolved in water to prepare a 100mg/ml aqueous solution, and the pH thereof was measured to be 6.7.

Determination of solubility of chlorogenic acid and sodium chlorogenic acid monohydrate in water (25 ℃), weighing a certain amount of raw materials, adding a certain amount of water, inspecting the volume of the completely dissolved solvent, and calculating the dissolution concentration, the results are shown in the following table:

as can be seen from the above table, the solubility of chlorogenic acid sodium salt monohydrate is improved by 9 times (as C) compared with chlorogenic acid₁₆H₁₈O₉Meter).

The sodium chlorogenic acid monohydrate obtained in example 1 was subjected to an influence factor test with reference to the pharmaceutical stability guideline (2015 edition chinese pharmacopoeia general rule 9001), in order to consider its stability, and the obtained results are shown in table 1.

Table 1 stability test results for sodium chlorogenic acid monohydrate

The test result shows that the sodium chlorogenic acid monohydrate has stable physicochemical properties, and the crystal form of related substances is not changed in influencing factor tests.

Example 2

Adding 10.0g of chlorogenic acid and 150mL of ethanol into a reaction bottle, stirring and dissolving at 20-30 ℃, adding 1.3g of sodium acetate solid, stirring at 20-30 ℃ for 4 hours, filtering, washing a filter cake with 50mL of ethanol, and drying at 50 ℃ under reduced pressure to obtain 17.6g of white powder, namely sodium chlorogenic acid monohydrate.

According to the invention, Cu-Kalpha is used as a radiation source, and the diffraction angle 2 theta of the X-ray powder diffraction of the sodium chlorogenic acid monohydrate has characteristic peaks at 6.851 degrees, 13.162 degrees, 13.836 degrees, 14.817 +/-0.1 degrees, 18.732 degrees, 19.413 degrees, 20.808 degrees, 22.205 degrees and 23.309 degrees, and has the same characteristic peak and consistent crystal form with the sodium chlorogenic acid monohydrate in the first embodiment.

Comparative example 1

Putting 10.0g of chlorogenic acid and 200.0ml of ethanol into a 500ml three-necked flask, stirring to dissolve the chlorogenic acid and the ethanol clearly, slowly dropwise adding a sodium acetate (2.31g, 1.0 eq)/methanol (25.0ml) solution, and separating out a solid in the solution for 20 min. After dripping, a large amount of solid is separated out in the system. Cooling the system to 0 ℃, keeping the temperature and stirring for 40 min. The system is stirred smoothly, the filtration is carried out, the filter cake is washed by 30.0ml of ethanol, and the filter cake still has swelling phenomenon. The product was dried under vacuum at 40 ℃ for 7 h. 10.86g of brown hard granular product is obtained. The method still has swelling phenomenon, and is abandoned.

Example 3: stimulation test of intramuscular injection of sodium chlorogenic acid monohydrate to rabbits

1. Preparation of solution to be tested

Preparing a chlorogenic acid solution: adding chlorogenic acid 150mg into mannitol 400mg, dissolving with injectable water, diluting to 10mL, filtering, and sterilizing to obtain chlorogenic acid 15 mg/mL.

Preparing a sodium chlorogenic acid monohydrate solution: taking 150mg (calculated by chlorogenic acid) of the chlorogenic acid sodium monohydrate obtained in the example 1, adding 400mg of mannitol, adding water for injection to dissolve, fixing the volume to 10mL, and filtering and sterilizing to obtain 15mg/mL chlorogenic acid monohydrate.

2. Test procedure

Taking 3 female big-ear white rabbits, adopting a same-body left-right self-contrast method, and injecting 15mg/ml sodium chlorogenic acid monohydrate into the left muscle of each of the 3 animals, and injecting 15mg/ml chlorogenic acid injection into the right muscle of the animals. The administration is carried out 1 time per day for 7 days, and the injection volume is 0.3 ml.

3. Test results

The test results are shown in table 2, and the results show that the intramuscular injection administration irritation of the chlorogenic acid sodium monohydrate is smaller than that of the chlorogenic acid.

TABLE 2 histopathological observations of the local stimulation test

Note: "-": no significant abnormality (No significant abnormality); "+": mild lesions (Slight); "2+": mild lesions (Mild); "3+": moderate lesions (Moderate); "4+": severe lesions (Severe).