Crystal form IV of chlorogenic acid and preparation method and pharmaceutical composition thereof

Abstract

The invention discloses a crystal form IV of chlorogenic acid as well as a preparation method and a pharmaceutical composition thereof, relates to the technical field of pharmaceutical solid chemistry, and aims to solve the technical problems that an existing chlorogenic acid product is easy to absorb moisture, deliquesce, deform and mildew in the process of process production, transportation and storage. According to the crystal form IV of the chlorogenic acid, a powder diffraction pattern of the crystal form IV obtained by utilizing an X-ray powder diffraction method of Cu K alpha has the following characteristic peaks at a 2 theta value: 4.53 degrees + / -0.2 degrees, 9.14 degrees + / -0.2 degrees, 16.02 degrees + / -0.2 degrees, 16.48 degrees + / -0.2 degrees, 17.12 degrees + / -0.2 degrees, 17.46 degrees + / -0.2 degrees, 20.16 degrees + / -0.2 degrees, 20.90 degrees + / -0.2 degrees, 24.66 degrees + / -0.2 degrees, 25.51 degrees + / -0.2 degrees and 28.97 degrees + / -0.2 degrees. The technical scheme of the invention is used for providing the crystal form IV of chlorogenic acid and the preparation method thereof.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical solid chemistry, and in particular to a chlorogenic acid crystal form IV and a preparation method and a pharmaceutical composition thereof. Background Art

[0002] Polymorphism refers to the phenomenon that a solid substance forms a solid state with different physical and chemical properties in two or more different spatial arrangements. In the field of drug research, polymorphism includes multi-component crystal forms such as organic solvates and hydrates. Drug polymorphism is widely present in the process of drug development and is an inherent characteristic of small organic molecules. Polymorphism is not only controlled by intrinsic factors such as the spatial structure and functional group properties of the molecule itself, and the interactions between molecules and molecules, but also by factors such as drug synthesis process design, crystallization and purification conditions, formulation excipient selection, formulation process route and granulation method, as well as storage conditions, packaging materials, etc. Different crystal forms have different colors, melting points, solubility, hygroscopicity, dissolution properties, chemical stability, reactivity, mechanical stability, etc. These physical and chemical properties or processability sometimes directly affect the safety and effectiveness of the drug. Therefore, crystal form research and control has become an important research content in the process of drug research and development.

[0003] The chemical name of chlorogenic acid is: 1,3,4,5-tetrahydroxycyclohexanecarboxylic acid-(3,4-dihydroxycinnamate), and its structural formula is as follows: Fig. 9 As shown. Chlorogenic acid has a wide range of biological activities. Modern scientific research on the biological activity of chlorogenic acid has penetrated into many fields such as food, health care, medicine and daily chemical industry. Chlorogenic acid is an important biologically active substance with antibacterial, antiviral, white blood cell increase, liver protection and choleretic, anti-tumor, blood pressure lowering, blood lipid lowering, free radical scavenging and central nervous system excitation. The hygroscopicity of different crystalline forms of chlorogenic acid will be significantly different. Too much hygroscopicity will cause the product to easily produce problems such as moisture absorption, deliquescence, deformation and mold during process production, transportation and storage. The hygroscopicity of several existing chlorogenic acid crystals is not ideal and cannot solve the above problems. Summary of the invention

[0004] In order to solve the technical problem that the existing chlorogenic acid crystal form has high hygroscopicity, which causes the chlorogenic acid product to easily absorb moisture, deliquescence, deform and mold during the process of production, transportation and storage, the present invention provides a chlorogenic acid crystal form IV and a preparation method and a pharmaceutical composition thereof. In view of this, the present invention is implemented by the following technical scheme.

[0005] In the first aspect, the present invention provides a crystalline form IV of chlorogenic acid, and the crystalline form IV powder diffraction pattern obtained by the Cu Kα X-ray powder diffraction method has the following characteristic peaks at 2θ values: 4.53°±0.2°, 9.14°±0.2°, 16.02°±0.2°, 16.48°±0.2°, 17.12°±0.2°, 17.46°±0.2°, 20.16°±0.2°, 20.90°±0.2°, 24.66°±0.2°, 25.51°±0.2° and 28.97°±0.2°.

[0006] Compared with the prior art, the crystalline form IV of chlorogenic acid of the present invention has high crystallinity, low hygroscopicity, and a regular crystal morphology, which solves the technical problem that the existing crystalline form of chlorogenic acid has high hygroscopicity, which causes chlorogenic acid products to easily absorb moisture, deliquescence, deform and mold during process production, transportation and storage.

[0007] Furthermore, the crystalline form IV powder diffraction pattern of chlorogenic acid of the present invention has the following characteristic peaks at 2θ values: 13.78°±0.2°, 14.11°±0.2°, 14.63°±0.2°, 15.23°±0.2°, 18.40°±0.2°, 18.90°±0.2°, 20.49°±0.2°, 21.55°±0.2°, 22.64°±0.2°, 23.03°±0.2°, 23.90°±0.2°, 28.11°±0.2°, 28.64°±0.2°, 31.32°±0.2°, 32.46°±0.2°, 33.56°±0.2°, 35.80°±0.2°, 36.24°±0.2°, 36.63°±0.2°, 38.20°±0.2° and 39.29°±0.2°.

[0008] Furthermore, in the thermal analysis spectrum obtained by performing differential scanning calorimetry analysis on the crystalline form IV of chlorogenic acid of the present invention, the crystalline form IV has a characteristic endothermic peak at 200-212°C.

[0009] In a second aspect, the present invention provides a method for preparing the crystalline form IV of chlorogenic acid, which is applied to the crystalline form IV of chlorogenic acid, and comprises the following preparation steps:

[0010] dissolving chlorogenic acid in a good solvent to obtain a chlorogenic acid solution;

[0011] The chlorogenic acid solution is added to a first container, and a poor solvent for chlorogenic acid is added to a second container; the first container is opened and placed in the second container, and the second container is sealed, and then allowed to stand at room temperature until solids precipitate, and filtered to obtain the crystalline form IV of the chlorogenic acid.

[0012] Compared with the prior art, the beneficial effects of the preparation method of the crystalline form IV of chlorogenic acid of the present invention are the same as the beneficial effects of the crystalline form IV of chlorogenic acid mentioned above, which will not be repeated here.

[0013] Furthermore, in the method for preparing the crystalline form IV of chlorogenic acid of the present invention, the good solvent is isopropanol and methyl ethyl ketone, and the poor solvent is n-heptane.

[0014] In a third aspect, the present invention further provides a method for preparing the crystalline form IV of chlorogenic acid, which is applied to the crystalline form IV of chlorogenic acid, and comprises the following preparation steps:

[0015] The chlorogenic acid is dissolved in an organic solvent to obtain a chlorogenic acid solution, and the chlorogenic acid solution is evaporated and dried at a temperature of 40 to 65° C. to obtain the crystalline form IV of the chlorogenic acid; wherein the mass ratio of the chlorogenic acid to the organic solvent is 1:(30 to 60).

[0016] Compared with the prior art, the beneficial effects of the preparation method of the crystalline form IV of chlorogenic acid of the present invention are the same as the beneficial effects of the crystalline form IV of chlorogenic acid mentioned above, which will not be repeated here.

[0017] Furthermore, in the method for preparing the crystalline form IV of chlorogenic acid of the present invention, the organic solvent comprises a single solvent or a mixed solvent, and the single solvent comprises: ethyl ketone, isopropanol;

[0018] The mixed solvent includes: methanol / methyl isobutyl ketone, ethanol / isopropyl acetate, isopropyl alcohol / ethyl ether, isoamyl alcohol / methyl tert-butyl ether, isoamyl alcohol / toluene, isoamyl alcohol / methyl isobutyl ketone, isoamyl alcohol / n-hexane, acetone / acetonitrile, acetone / methyl tert-butyl ether, acetone / toluene, acetone / methyl isobutyl ketone, acetone / isopropyl acetate, methyl ethyl ketone / acetonitrile, methyl ethyl ketone / nitromethane, methyl ethyl ketone / methyl tert-butyl ether, methyl ethyl ketone / toluene, and methyl ethyl ketone / methyl isobutyl ketone.

[0019] In a fourth aspect, the present invention provides a pharmaceutical composition, comprising the above-mentioned crystalline form IV of chlorogenic acid, and a pharmaceutically acceptable carrier.

[0020] Compared with the prior art, the beneficial effects of the pharmaceutical composition of the present invention are the same as those of the above-mentioned crystalline form IV of chlorogenic acid, which will not be described in detail here.

[0021] In a fifth aspect, the present invention provides an application of chlorogenic acid crystal form IV in antibacterial, antiviral, antioxidant, free radical scavenging, anti-aging, anti-musculoskeletal aging, mutation inhibition and anti-tumor, as well as cardiovascular protection. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The drawings described herein are used to provide a further understanding of the present invention and constitute a part of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0023] Figure 1 This is an X-ray powder diffraction (XRPD) pattern of the crystalline form IV of chlorogenic acid according to an embodiment of the present invention;

[0024] Figure 2 This is a thermogravimetric analysis (TG) diagram of the crystalline form IV of chlorogenic acid according to an embodiment of the present invention;

[0025] Figure 3 is a differential scanning calorimetry (DSC) diagram of the crystalline form IV of chlorogenic acid according to an embodiment of the present invention;

[0026] Figure 4 This is an infrared spectrum (IR) of the crystalline form IV of chlorogenic acid according to an embodiment of the present invention;

[0027] Figure 5 This is a hygroscopicity (DVS) diagram of the crystalline form IV of chlorogenic acid according to an embodiment of the present invention;

[0028] Figure 6 This is a Raman spectrum (Raman) of the crystalline form IV of chlorogenic acid according to an embodiment of the present invention;

[0029] Figure 7 This is a schematic diagram of a polarized photograph of the crystalline form IV of chlorogenic acid according to an embodiment of the present invention;

[0030] Figure 8 It is a schematic diagram comparing the hygroscopicity of the crystalline form IV of chlorogenic acid according to an embodiment of the present invention and the existing crystalline form;

[0031] Fig. 9 It is the structural formula of chlorogenic acid. DETAILED DESCRIPTION

[0032] In order to make the technical problems, technical solutions and beneficial effects to be solved by the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0033] The chemical name of chlorogenic acid is 1,3,4,5-tetrahydroxycyclohexanecarboxylic acid-(3,4-dihydroxycinnamate), which has a wide range of biological activities. Modern scientific research on the biological activity of chlorogenic acid has penetrated into many fields such as food, health care, medicine and daily chemical industry. Chlorogenic acid is an important biologically active substance with antibacterial, antiviral, white blood cell increase, liver protection and choleretic, anti-tumor, blood pressure lowering, blood lipid lowering, free radical scavenging and central nervous system excitation. The hygroscopicity of different crystalline forms of chlorogenic acid will be significantly different. Too much hygroscopicity will cause the product to easily produce problems such as moisture absorption, deliquescence, deformation and mold during process production, transportation and storage. The hygroscopicity of several existing chlorogenic acid crystal forms is not ideal and cannot solve the above problems.

[0034] In order to solve the above technical problems, in a first aspect, the present invention provides a crystalline form IV of chlorogenic acid, and the crystalline form IV powder diffraction pattern obtained by the Cu Kα X-ray powder diffraction method has the following characteristic peaks at 2θ values: 4.53°±0.2°, 9.14°±0.2°, 16.02°±0.2°, 16.48°±0.2°, 17.12°±0.2°, 17.46°±0.2°, 20.16°±0.2°, 20.90°±0.2°, 24.66°±0.2°, 25.51°±0.2° and 28.97°±0.2°.

[0035] Compared with the prior art, the crystalline form IV of chlorogenic acid of the present invention has high crystallinity, low hygroscopicity, and a regular crystal morphology, which solves the technical problem that the existing crystalline form of chlorogenic acid has high hygroscopicity, which causes chlorogenic acid products to easily absorb moisture, deliquescence, deform and mold during process production, transportation and storage.

[0036] It should be understood that the characteristic peak of the above-mentioned Form IV powder diffraction pattern at the 2θ value is only the most characteristic part of the Form IV. In order to more comprehensively characterize the Form IV, the remaining characteristic peaks need to be described. For example, the Form IV powder diffraction pattern has the following characteristic peaks at the 2θ value: 13.78°±0.2°, 14.11°±0.2°, 14.63°±0.2°, 15.23°±0.2°, 18.40°±0.2°, 18.90°±0.2°, 20.49° ±0.2°, 21.55°±0.2°, 22.64°±0.2°, 23.03°±0.2°, 23.90°±0.2°, 28.11°±0.2°, 28.64°±0.2°, 31.32°±0.2°, 32.46°±0.2°, 33.56°±0.2°, 35.80°±0.2°, 36.24°±0.2°, 36.63°±0.2°, 38.20°±0.2° and 39.29°±0.2°.

[0037] It should also be understood that in order to more comprehensively characterize the Form IV, the present invention performs differential scanning calorimetry analysis on the Form IV, and in the obtained thermal analysis spectrum, the Form IV has a characteristic endothermic peak at 200-212°C.

[0038] In a second aspect, the present invention provides a method for preparing the crystalline form IV of chlorogenic acid, which is applied to the crystalline form IV of chlorogenic acid, and comprises the following preparation steps:

[0039] dissolving chlorogenic acid in a good solvent to obtain a chlorogenic acid solution;

[0040] The chlorogenic acid solution is added to a first container, and a poor solvent for chlorogenic acid is added to a second container; the first container is opened and placed in the second container, and the second container is sealed, and then allowed to stand at room temperature until solids precipitate, and filtered to obtain the crystalline form IV of the chlorogenic acid.

[0041] The present invention adopts the above technical solution, and adopts the anti-solvent crystallization method, that is, the poor solvent of the chlorogenic acid is used to inhibit the dissolution of the chlorogenic acid to reduce the solubility of the chlorogenic acid, so that the chlorogenic acid crystals are precipitated, and the crystalline form IV of the chlorogenic acid is obtained. Specifically, the first container containing the chlorogenic acid solution is placed open in the second container containing the chlorogenic acid poor solvent, and the second container is sealed. During the standing process, the solubility of the chlorogenic acid in the first container is reduced, and the chlorogenic acid in the first container is crystallized and precipitated, and the crystalline form IV of the chlorogenic acid can be obtained after filtration.

[0042] It should be understood that in order to ensure that the above preparation method successfully prepares the crystal form IV and further improves the preparation efficiency of the crystal form IV, the present invention also needs to control the types of the good solvent and the poor solvent of the chlorogenic acid. For example, the good solvent can be isopropanol or methyl ethyl ketone, and the poor solvent can be n-heptane.

[0043] In a third aspect, the present invention further provides a method for preparing the crystalline form IV of chlorogenic acid, which is applied to the crystalline form IV of chlorogenic acid, and comprises the following preparation steps:

[0044] The chlorogenic acid is dissolved in an organic solvent to obtain a chlorogenic acid solution, and the chlorogenic acid solution is evaporated and dried at a temperature of 40 to 65° C. to obtain the crystalline form IV of the chlorogenic acid; wherein the mass ratio of the chlorogenic acid to the organic solvent is 1:(30 to 60).

[0045] By adopting the above technical scheme, the present invention can obtain the crystalline form IV of the chlorogenic acid by slowly volatilizing and drying the chlorogenic acid solution at a temperature of 40 to 65°C. In order to control the volatilization rate of the chlorogenic acid solution, the present invention controls the temperature of the chlorogenic acid solution during volatilization to be 40 to 65°C. For example, the temperature of the chlorogenic acid solution during volatilization can be 40°C, 55°C or 65°C. For example, the mass ratio of the chlorogenic acid to the organic solvent can be 1:30, 1:40 or 1:60.

[0046] It should be understood that in the preparation method of the above-mentioned crystalline form IV of chlorogenic acid, in order to ensure that the above-mentioned preparation method successfully prepares the crystalline form IV and further improves the preparation efficiency of the crystalline form IV, it is also necessary to control the type of the organic solvent. For example, the organic solvent includes a single solvent or a mixed solvent. The single solvent includes: methyl ethyl ketone, isopropanol; the mixed solvent includes: methanol / methyl isobutyl ketone, ethanol / isopropyl acetate, isopropanol / ethyl ether, isoamyl alcohol / methyl tert-butyl ether, isoamyl alcohol / toluene, isoamyl alcohol / methyl isobutyl ketone, isoamyl alcohol / n-hexane, acetone / acetonitrile, acetone / methyl tert-butyl ether, acetone / toluene, acetone / methyl isobutyl ketone, acetone / isopropyl acetate, methyl ethyl ketone / acetonitrile, methyl ethyl ketone / nitromethane, methyl ethyl ketone / methyl tert-butyl ether, methyl ethyl ketone / toluene, methyl ethyl ketone / methyl isobutyl ketone.

[0047] In a fourth aspect, the present invention provides a pharmaceutical composition, comprising the above-mentioned crystalline form IV of chlorogenic acid, and a pharmaceutically acceptable carrier.

[0048] Compared with the prior art, the beneficial effects of the pharmaceutical composition of the present invention are the same as those of the above-mentioned crystalline form IV of chlorogenic acid, which will not be described in detail here.

[0049] In a fifth aspect, the present invention provides an application of chlorogenic acid crystal form IV in antibacterial, antiviral, antioxidant, free radical scavenging, anti-aging, anti-musculoskeletal aging, mutation inhibition and anti-tumor, as well as cardiovascular protection.

[0050] In order to better understand the present invention, the content of the present invention is further explained below in conjunction with specific embodiments, but the content of the present invention is not limited to the following embodiments.

[0051] Unless otherwise specified, the raw materials used in the following examples are all commercially available raw materials. The experimental conditions involved in the following examples are as follows:

[0052] The crystalline form IV of chlorogenic acid of the present invention is characterized by solid-state methods such as X-ray powder diffraction (XRPD), thermogravimetric analysis (TG), differential scanning calorimetry (DSC), infrared spectroscopy (IR), hygroscopic properties (DVS), and Raman spectroscopy (Raman).

[0053] XRPD analysis: All XRPD patterns of the present invention were detected by a Bruker D8advance diffractometer from Bruker Instruments Co., Ltd., Germany, at room temperature using Cu Kα radiation. The 2θ angle scan was from 3 to 40 degrees with a scanning speed of 0.1° / step.

[0054] In the X-ray powder diffraction spectrum of the sample powder, the diffraction spectrum obtained from a specific crystal form is often characteristic. Due to differences in crystallization conditions, particle size, relative content of the mixture and other test conditions, the diffraction spectrum may produce a preferential orientation effect, resulting in changes in the relative intensity of certain bands in the spectrum (especially at low angles). Therefore, the relative intensity of the diffraction peak is not characteristic for the targeted crystal. When judging whether it is the same as the known crystal form, more attention should be paid to the position of the peak rather than their relative intensity. In addition, when judging whether the crystal form is the same, it is important to maintain an overall concept, because not one diffraction line represents a physical phase, but a set of specific "dI / I1" data represents a physical phase. It should also be pointed out that in the identification of a mixture, some diffraction lines may be missing due to factors such as decreased content. At this time, there is no need to rely on all the bands observed in the high-purity sample, and even one band may be characteristic for a given crystal.

[0055] DSC analysis: All DSC spectra of the present invention were detected by a DSC Q2000 differential scanning calorimeter of TA Company, USA, with a nitrogen atmosphere and a heating rate of 10°C / min.

[0056] TG analysis: All TGA spectra of the present invention were detected by TGA55 thermogravimetric analyzer of TA Company, USA, with temperature range: 30-400°C, scanning rate: 10°C / min, and purge gas: 40mL / min.

[0057] DVS analysis: All DVS spectra of the present invention were measured by DVS advantage type adsorption instrument of SMS Company, UK, with relative humidity range of 0-95% and temperature of 25°C.

[0058] Raman analysis: All Raman spectra of the present invention were measured by Renishaw inViaQONTOR Raman spectrometer of Renishaw Company of the United Kingdom, with laser wavelength of 785nm and scanning range of 3200 to 100.

[0059] IR analysis: All IR spectra of the present invention were detected by Thermo Scientific Nicolet 6700 infrared spectrometer of Thermo Fisher Scientific, USA, at room temperature, with a detection range of 4000-350 cm -1 wave number.

[0060] Example 1

[0061] This embodiment provides a method for preparing the crystalline form IV of chlorogenic acid, comprising the following steps:

[0062] S100, adding 12 g of chlorogenic acid to 500 ml of isopropanol, and stirring at a stirring rate of 200 rpm until the chlorogenic acid is completely dissolved to obtain a chlorogenic acid solution; wherein the mass ratio of the chlorogenic acid to the isopropanol is 1:33;

[0063] S200, volatilizing and drying the chlorogenic acid solution at a temperature of 40° C. to obtain 11.8 g of crystalline form IV of chlorogenic acid, wherein the crystalline form IV is a white crystalline powder, and the yield of the crystalline form IV is 98.4%.

[0064] Example 2

[0065] This embodiment provides a method for preparing the crystalline form IV of chlorogenic acid, comprising the following steps:

[0066] S100, adding 5 g of chlorogenic acid to 250 ml of isopropanol, and stirring at a stirring rate of 200 rpm until the chlorogenic acid is completely dissolved to obtain a chlorogenic acid solution; wherein the mass ratio of the chlorogenic acid to the isopropanol is 1:39;

[0067] S200, volatilizing and drying the chlorogenic acid solution at a temperature of 65° C. to obtain 4.92 g of crystalline form IV of chlorogenic acid, wherein the crystalline form IV is a white crystalline powder, and the yield of the crystalline form IV is 98.4%.

[0068] Example 3

[0069] This embodiment provides a method for preparing the crystalline form IV of chlorogenic acid, comprising the following steps:

[0070] S100, mixing 200 ml of methanol and 250 ml of methyl isobutyl ketone to obtain a mixed solvent, adding 10 g of chlorogenic acid to the mixed solvent, and stirring at a stirring rate of 200 rpm until the chlorogenic acid is completely dissolved to obtain a chlorogenic acid solution; wherein the mass ratio of the chlorogenic acid to the mixed solvent is 1:36;

[0071] S200, volatilizing and drying the chlorogenic acid solution at a temperature of 50° C. to obtain 9.58 g of crystalline form IV of chlorogenic acid, wherein the crystalline form IV is a white crystalline powder, and the yield of the crystalline form IV is 95.8%.

[0072] Example 4

[0073] This embodiment provides a method for preparing the crystalline form IV of chlorogenic acid, comprising the following steps:

[0074] S100, mixing 200 ml of ethanol and 250 ml of isopropyl acetate to obtain a mixed solvent, adding 10 g of chlorogenic acid to the mixed solvent, and stirring at a stirring rate of 200 rpm until the chlorogenic acid is completely dissolved to obtain a chlorogenic acid solution; wherein the mass ratio of the chlorogenic acid to the mixed solvent is 1:38;

[0075] S200, volatilizing and drying the chlorogenic acid solution at a temperature of 50° C. to obtain 9.6 g of crystalline form IV of chlorogenic acid, wherein the crystalline form IV is a white crystalline powder, and the yield of the crystalline form IV is 96.0%.

[0076] Example 5

[0077] This embodiment provides a method for preparing the crystalline form IV of chlorogenic acid, comprising the following steps:

[0078] S100, mixing 200 ml of acetone and 250 ml of methyl isobutyl ketone to obtain a mixed solvent, adding 10 g of chlorogenic acid to the mixed solvent, and stirring at a stirring rate of 200 rpm until the chlorogenic acid is completely dissolved to obtain a chlorogenic acid solution; wherein the mass ratio of the chlorogenic acid to the mixed solvent is 1:36;

[0079] S200, volatilizing and drying the chlorogenic acid solution at a temperature of 50° C. to obtain 9.67 g of crystalline form IV of chlorogenic acid, wherein the crystalline form IV is a white crystalline powder, and the yield of the crystalline form IV is 96.7%.

[0080] Example 6

[0081] This embodiment provides a method for preparing the crystalline form IV of chlorogenic acid, comprising the following steps:

[0082] S100, adding 100 ml of isopropanol into a first beaker of 250 ml, adding 2 g of chlorogenic acid into the first beaker, and stirring evenly at a stirring rate of 55 rpm to obtain a nearly saturated solution of chlorogenic acid;

[0083] S200, add 200 ml of n-hexane to a 500 ml second beaker, and place the first beaker containing the nearly saturated solution of chlorogenic acid openly in the second beaker. After sealing, let it stand at room temperature until solid precipitates. After filtering, 1.2 g of crystalline form IV of chlorogenic acid is obtained. The crystalline form IV is a white crystalline powder, and the yield of the crystalline form IV is 60.0%.

[0084] Example 7

[0085] This embodiment provides a method for preparing the crystalline form IV of chlorogenic acid, comprising the following steps:

[0086] S100, adding 100 ml of methyl ethyl ketone into a first beaker of 250 ml, adding 3 g of chlorogenic acid into the first beaker, and stirring evenly at a stirring rate of 55 rpm to obtain a nearly saturated solution of chlorogenic acid;

[0087] S200, add 200 ml of n-heptane to a 500 ml second beaker, and place the first beaker containing the nearly saturated solution of chlorogenic acid openly in the second beaker. After sealing, let it stand at room temperature until solid precipitates. After filtering, 1.9 g of crystalline form IV of chlorogenic acid is obtained. The crystalline form IV is a white crystalline powder, and the yield of the crystalline form IV is 63.3%.

[0088] Example 8

[0089] This embodiment provides a method for preparing the crystalline form IV of chlorogenic acid, comprising the following steps:

[0090] S100, adding 100 ml of isopropanol into a first beaker of 250 ml, adding 4 g of chlorogenic acid into the first beaker, and stirring evenly at a stirring rate of 55 rpm to obtain a nearly saturated solution of chlorogenic acid;

[0091] S200, add 200 ml of n-hexane to a 500 ml second beaker, and place the first beaker containing the nearly saturated solution of chlorogenic acid openly in the second beaker. After sealing, let it stand at room temperature until solid precipitates. After filtering, 3.1 g of crystalline form IV of chlorogenic acid is obtained. The crystalline form IV is a white crystalline powder, and the yield of the crystalline form IV is 77.5%.

[0092] The crystalline form IV of the chlorogenic acid prepared in the above Examples 1 to 8 was characterized. The X-ray powder diffraction (XRPD) pattern of the crystalline form IV of the chlorogenic acid is as follows: Figure 1 As shown; the thermogravimetric analysis (TG) diagram of the chlorogenic acid form IV is as shown Figure 2 As shown; the differential scanning calorimetry (DSC) diagram of the chlorogenic acid crystal form IV is as shown Figure 3 As shown; the infrared spectrum (IR) of the chlorogenic acid crystal form IV is as shown Figure 4 As shown; the hygroscopicity (DVS) relationship diagram of the chlorogenic acid crystal form IV is as shown Figure 5 As shown; the Raman spectrum (Raman) of the chlorogenic acid crystal form IV is as shown Figure 6 As shown; the polarized photo of the chlorogenic acid crystal form IV is as shown Figure 7 shown.

[0093] Comparative Example

[0094] The hygroscopicity of the crystalline form IV of chlorogenic acid in Example 1 of the present invention was compared with the amorphous form and known crystalline forms of chlorogenic acid. Under storage conditions of room temperature and a relative humidity of 65%, the hygroscopicity of the crystalline form IV of chlorogenic acid of the present invention was the lowest, and after 6 months of storage, the purity and crystalline form of the crystalline form IV of chlorogenic acid of the present invention did not change.

[0095] It can be seen from the above-mentioned embodiments, comparative examples, and test data that the crystalline form IV of chlorogenic acid can be prepared under the conditions of the embodiments of the present invention, and the hygroscopicity of the crystalline form IV of chlorogenic acid is lower than that of the existing crystalline form of chlorogenic acid, which solves the technical problem that the existing crystalline form of chlorogenic acid has high hygroscopicity, resulting in chlorogenic acid products being prone to moisture absorption, deliquescence, deformation and mold during process production, transportation and storage.

[0096] In the description of the above embodiments, specific features, structures, materials or characteristics may be combined in a suitable manner in any one or more embodiments or examples.

[0097] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A crystalline form IV of chlorogenic acid, characterized in that: The powder diffraction pattern of the form IV obtained by the X-ray powder diffraction method using Cu Kα has the following characteristic peaks at 2θ values: 4.53°±0.2°, 9.14°±0.2°, 16.02°±0.2°, 16.48°±0.2°, 17.12°±0.2°, 17.46°±0.2°, 20.16°±0.2°, 20.90°±0.2°, 24.66°±0.2°, 25.51°±0.2° and 28.97°±0.2°.

2. The crystalline form IV of chlorogenic acid according to claim 1, characterized in that: The powder diffraction pattern of the crystalline form IV has the following characteristic peaks at 2θ values: 13.78°±0.2°, 14.11°±0.2°, 14.63°±0.2°, 15.23°±0.2°, 18.40°±0.2°, 18.90°±0.2°, 20.49°±0.2°, 21.55°±0.2°, 22.64°±0.2°, 23.03° ±0.2°, 23.90°±0.2°, 28.11°±0.2°, 28.64°±0.2°, 31.32°±0.2°, 32.46°±0.2°, 33.56°±0.2°, 35.80°±0.2°, 36.24°±0.2°, 36.63°±0.2°, 38.20°±0.2° and 39.29°±0.2°.

3. The crystalline form IV of chlorogenic acid according to claim 1 or 2, characterized in that: In the thermal analysis spectrum obtained by differential scanning calorimetry analysis of the crystal form IV, the crystal form IV has a characteristic endothermic peak at 200-212°C.

4. A method for preparing the crystalline form IV of chlorogenic acid, applied to the crystalline form IV of chlorogenic acid according to any one of claims 1 to 3, characterized in that: The method comprises the following preparation steps: dissolving chlorogenic acid in a good solvent to obtain a chlorogenic acid solution; The chlorogenic acid solution is added to a first container, and a poor solvent for chlorogenic acid is added to a second container; the first container is opened and placed in the second container, and the second container is sealed, and then allowed to stand at room temperature until solids precipitate, and filtered to obtain the crystalline form IV of the chlorogenic acid.

5. The method for preparing the crystalline form IV of chlorogenic acid according to claim 4, characterized in that: The good solvent is isopropanol and methyl ethyl ketone, and the poor solvent is n-heptane.

6. A method for preparing the crystalline form IV of chlorogenic acid, applied to the crystalline form IV of chlorogenic acid according to any one of claims 1 to 3, characterized in that: The method comprises the following preparation steps: The chlorogenic acid is dissolved in an organic solvent to obtain a chlorogenic acid solution, and the chlorogenic acid solution is evaporated and dried at a temperature of 40 to 65° C. to obtain the crystalline form IV of the chlorogenic acid; wherein the mass ratio of the chlorogenic acid to the organic solvent is 1:(30 to 60).

7. The method for preparing the crystalline form IV of chlorogenic acid according to claim 6, characterized in that: The organic solvent includes a single solvent or a mixed solvent, and the single solvent includes methyl ethyl ketone and isopropanol; The mixed solvent includes: methanol / methyl isobutyl ketone, ethanol / isopropyl acetate, isopropyl alcohol / ethyl ether, isoamyl alcohol / methyl tert-butyl ether, isoamyl alcohol / toluene, isoamyl alcohol / methyl isobutyl ketone, isoamyl alcohol / n-hexane, acetone / acetonitrile, acetone / methyl tert-butyl ether, acetone / toluene, acetone / methyl isobutyl ketone, acetone / isopropyl acetate, methyl ethyl ketone / acetonitrile, methyl ethyl ketone / nitromethane, methyl ethyl ketone / methyl tert-butyl ether, methyl ethyl ketone / toluene, and methyl ethyl ketone / methyl isobutyl ketone.

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the crystalline form IV of chlorogenic acid according to any one of claims 1 to 3, and a pharmaceutically acceptable carrier.

9. Use of a chlorogenic acid crystal form IV in antibacterial, antiviral, antioxidant, free radical scavenging, anti-aging, anti-musculoskeletal aging, mutation inhibition and anti-tumor, as well as cardiovascular protection.

Images