New crystal form of embelin as well as preparation method and application thereof

Abstract

The invention provides an embelin crystal form A and an embelin crystal form B as well as a preparation method and application thereof. The crystal form is characterized by means of XRD, DSC and the like. The embelin crystal forms A and B have good thermal stability and good wet stability, and are ideal medicinal crystal forms.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical solid chemistry, and in particular relates to a new crystal form of Embelin, a preparation method thereof and a use thereof. Background Art

[0002] The chemical name of anthracene is: 3-undecyl-2,5-dihydroxycyclohexadiene-1,4-dione, molecular formula: C17H26O4, molecular weight 294.4, and its chemical structure is as follows:

[0003]

[0004] Anthraquinone is a natural active small molecule compound widely found in the genus Acanthocephala. It has a wide range of physiological activities and is used in research on anthelmintics, hypoglycemic, anti-tumor, anti-inflammatory, anti-toxin and antioxidant. Anthraquinone is expected to be developed into a drug for use.

[0005] Embelin is generally an amorphous white powder that is not easy to crystallize. The prior art X-Ray Crystal Structure of Embelin and its DFT Scavenging of Superoxide Radical (Journal of Computational Chemistry, 2017, 1-6) reported the X-ray single crystal diffraction structure and crystallization conditions of Embelin.

[0006] Polymorphism refers to the phenomenon that a substance forms two or more solid forms due to different conformations or arrangements of molecules in the crystal lattice. The definition of polymorphism can be divided into two ways: narrow and broad. In a narrow sense, polymorphism refers to a substance with the same chemical composition, but different arrangements of the molecules in the crystal. In a broad sense, polymorphism also includes amorphous and solvates (pseudopolymorphs). For small molecule compounds, polymorphism is very common. Polymorphism also exists in active pharmaceutical ingredients (APIs) and is equally common. Different crystal forms of polymorphic drugs often have different physical and chemical properties, such as color, morphology, melting point, density, solubility, dissolution, compressibility, etc. These differences in physical and chemical properties will directly affect the bioavailability, stability, preparation and processing performance, and even quality, safety and effectiveness of the drug. If the attention to the drug crystal form problem is ignored, it is likely to eventually lead to serious consequences and affect the drug development process.

[0007] Research on the medical uses of anthracene is being effectively advanced, however, research on its polymorphic forms is lagging behind. Providing more crystalline forms and preparation methods of anthracene will help in the development of medical uses. Summary of the invention

[0008] The inventors of the present application have continuously explored and discovered two new crystal forms of anthraquinone based on the comprehensive adoption of new crystal nucleation methods and crystal conditions, named as crystal form A and crystal form B. It should be noted that the stable crystal forms A and B of anthraquinone provided by the present invention, specifically, the present invention provides the following contents:

[0009] The present invention provides a crystalline form A of anthracene, characterized in that its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 11.75°±0.20°, 14.69°±0.20°, 17.67°±0.20°, 29.65°±0.20°, 32.69°±0.20°, and 35.75°±0.20°.

[0010] In a preferred embodiment, the crystalline form A of anthracene is characterized in that its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 5.87°±0.20°, 11.75°±0.20°, 14.69°±0.20°, 17.67°±0.20°, 20.65°±0.20°, 23.61°±0.20°, 29.65°±0.20°, 32.69°±0.20°, 35.75°±0.20°, 38.86°±0.20°, 45.15°±0.20°, and 54.89°±0.20°.

[0011] In a preferred embodiment, the crystalline form A of anthracene is characterized in that its differential scanning calorimetry curve shows that it has two endothermic peaks, the endothermic peak starting temperatures are 86.0℃±3.00℃ and 146.5℃±3.00℃, respectively, and the endothermic peak peak values ​​are 91.0℃±3.00℃ and 149.4℃±3.00℃, respectively.

[0012] The present invention provides a method for preparing the above-mentioned anthraquinone crystal form A, characterized in that the preparation method is the following method: mixing anthraquinone with a certain volume of solvent, heating and stirring to dissolve, obtaining anthraquinone solution of a certain concentration, cooling, precipitating crystals, filtering and collecting the crystals, and drying to obtain anthraquinone crystal form A.

[0013] Further preferably, the solvent used is ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, methyl tert-butyl ether, isopropyl ether, acetonitrile, acetone, preferably ethanol.

[0014] Further preferably, the concentration of the anthraquinone solution is between 0.01-0.50 g / mL, and the preferred solution concentration is between 0.05-0.20 g / mL;

[0015] More preferably, when cooling to precipitate crystals, stirring or standing is performed, preferably stirring.

[0016] The present invention provides a crystalline form B of anthracene, characterized in that its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 11.60°±0.20°, 14.56°±0.20°, 17.42°±0.20°, 20.16°±0.20°, 20.82°±0.20°, 22.58°±0.20°, 24.10°±0.20°, 24.70°±0.20°, 26.70°±0.20°, and 27.08°±0.20°.

[0017] In a preferred embodiment, the crystal form B of anthracene is characterized in that its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 5.74°±0.20°, 11.60°±0.20°, 14.56°±0.20°, 16.62°±0.20°, 17.42°±0.20°, 18.58°±0.20°, 20.16°±0.20°, 20.82°±0. 20°, 22.02°±0.20°, 22.58°±0.20°, 24.10°±0.20°, 24.70°±0.20°, 25.46°±0.20°, 26.70°±0.20°, 27.08°±0.20°, 28.56°±0.20°, 30.28°±0.20°, 32.20°±0.20°, 35.64°±0.20°.

[0018] In a preferred embodiment, the crystalline form B of anthracene is characterized in that its differential scanning calorimetry curve shows that it has two endothermic peaks, the endothermic peak starting temperatures are 84.6°C±3.00°C and 145.7°C±3.00°C, and the endothermic peak peak values ​​are 87.8°C±3.00°C and 148.7°C±3.00°C, respectively.

[0019] The present invention also provides a method for preparing anthraquinone crystal form B, and the preparation process comprises: adding a certain volume of anthraquinone solid solution to an organic solvent to obtain anthraquinone solution with a certain concentration, evaporating the solvent, and drying to obtain anthraquinone crystal form B.

[0020] Further preferably, the solvent used is tetrahydrofuran or 2-methyl-tetrahydrofuran, preferably tetrahydrofuran.

[0021] More preferably, the concentration of the obtained anthraquinone solution is between 0.10-1.00 g / mL, and the preferred solution concentration is between 0.20-0.50 g / mL.

[0022] The present invention provides a pharmaceutical composition, which comprises a therapeutically effective amount of the crystal form A and / or crystal form B of anthrabenin according to the claim, and further comprises a pharmaceutically acceptable carrier. Generally, the crystal form A and / or crystal form B of anthrabenin of therapeutically effective amount is mixed or contacted with one or more pharmaceutical excipients to prepare a pharmaceutical composition or preparation, and the pharmaceutical composition or preparation is prepared in a manner well known in the pharmaceutical field.

[0023] The above-mentioned pharmaceutical composition can be prepared into a certain dosage form and administered by a suitable route. For example, oral, parenteral (including subcutaneous, intramuscular, intravenous or intradermal), rectal, transdermal, nasal, vaginal and other routes. Dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, solutions, syrups or suspensions, which can be suitable for rapid release, delayed release or regulated release of active pharmaceutical ingredients as required; dosage forms suitable for parenteral administration include aqueous or non-aqueous sterile injection solutions, emulsions or suspensions; dosage forms suitable for rectal administration include suppositories or enemas; dosage forms suitable for transdermal administration include ointments, creams, and patches; dosage forms suitable for nasal administration include aerosols, sprays, and nasal drops; dosage forms suitable for vaginal administration include suppositories, plugs, gels, pastes or sprays. Preferably, since the crystal form of the present invention has unexpectedly low hygroscopicity and stability in water or ethanol aqueous solution, it is particularly suitable for preparation into tablets, suspensions, capsules, disintegrating tablets, immediate release, sustained release and controlled release tablets; more preferably tablets, suspensions and capsules.

[0024] The pharmaceutically acceptable excipients in the above-mentioned pharmaceutical composition, in the case of solid oral dosage forms, include but are not limited to: diluents, such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium hydrogen phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, etc.; binders, such as gum arabic, guar gum, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, etc.; disintegrants, such as starch, sodium starch glycolate, pregelatinized starch, cross-linked polyvidone, cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, etc.; lubricants, such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, etc.; glidants, such as colloidal silicon dioxide, etc.; complex formers, such as various grades of cyclodextrin and resins; release rate control agents, such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, methyl methacrylate, wax, etc. Other pharmaceutically acceptable excipients that can be used include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, and the like. Optionally, a coating layer is applied to the tablet, such as a shellac isolation coating, a sugar coating, or a polymer coating, wherein the polymer in the coating layer is, for example, hydroxypropyl methylcellulose, polyvinyl alcohol, ethyl cellulose, methacrylic polymer, hydroxypropyl cellulose, or starch, and may also include anti-adhesive agents such as silicon dioxide, talc, opacifiers such as titanium dioxide, and colorants such as iron oxide colorants. In the case of liquid oral dosage forms, suitable excipients include water, oils, alcohols, glycols, flavoring agents, preservatives, stabilizers, colorants, and the like; aqueous or non-aqueous sterile suspensions may contain suspending agents and thickeners; excipients suitable for aqueous suspensions include synthetic or natural gums such as gum arabic, gum xanthium, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl pyrrolidone, or gelatin. In the case of parenteral dosage forms, the excipients of aqueous or non-aqueous sterile injection solutions are usually sterile water, physiological saline or glucose aqueous solution, and may contain buffers, antioxidants, antibacterial agents and solutes that can make the pharmaceutical composition isotonic with blood. Each excipient must be acceptable, compatible with other ingredients in the formula and harmless to the patient. When used in the preparation of emergency drugs for stroke, powder injections are preferably considered.

[0025] The pharmaceutical composition can be prepared by methods known to those skilled in the art in the art. When preparing the pharmaceutical composition, the crystal form A of the present invention is mixed with one or more pharmaceutically acceptable excipients, and optionally mixed with one or more other active pharmaceutical ingredients. For example, tablets, capsules, and granules can be prepared by mixing, granulating, tableting, or filling capsules; powders are prepared by mixing active pharmaceutical ingredients and excipients ground to a suitable size; solutions and syrups can be prepared by dissolving active pharmaceutical ingredients in appropriately flavored water or aqueous solutions; suspensions can be prepared by dispersing active pharmaceutical ingredients in pharmaceutically acceptable carriers. Particularly mentioned is the wet granulation process of solid preparations. Taking the wet granulation of tablets as an example, the preparation process is: mixing dry solids such as active ingredients, fillers, and binders, wetting with a wetting agent such as water or alcohol, making the wet solids into agglomerates or granules, continuing wet granulation until the desired uniform particle size is obtained, and then drying the granular product. The obtained dry granules are then mixed with a disintegrant, a lubricant, an anti-adhesive agent, etc., and compressed in a tablet machine; optionally, coated with an appropriate coating powder.

[0026] The present invention also provides medical uses of the crystal form A and the crystal form B of anthraquinone, which are used for preparing medicines for preventing or treating various diseases, including botulism, bacterial infection, inflammation, hyperglycemia, tumors, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is an X-ray powder diffraction (XRPD) pattern of the anthracene crystalline form A of the compound of the present invention;

[0028] Figure 2 The X-ray powder diffraction (XRPD) pattern of the anthracene crystalline form B of the compound of the present invention;

[0029] Figure 3 is an X-ray powder diffraction (XRPD) pattern of the amorphous form of the compound anthracene in the present invention;

[0030] Figure 4 This is an X-ray powder diffraction (XRPD) pattern of the anthracene crystalline form A sample of the compound of the present invention after being placed under high temperature conditions (60° C.) for 10 days;

[0031] Figure 5 This is an X-ray powder diffraction (XRPD) pattern of the anthracene crystalline form A sample of the compound of the present invention after being placed under high humidity conditions (92.5% RH) for 10 days;

[0032] Figure 6 This is an X-ray powder diffraction (XRPD) pattern of the anthracene crystalline form A sample of the compound of the present invention after being placed under strong light irradiation conditions (5K Lux) for 10 days;

[0033] Figure 7 This is an X-ray powder diffraction (XRPD) pattern of the anthracene crystalline form B sample of the compound of the present invention after being placed under high temperature conditions (60° C.) for 10 days;

[0034] Figure 8 This is an X-ray powder diffraction (XRPD) pattern of the anthracene crystalline form B sample of the compound of the present invention after being placed under high humidity conditions (92.5% RH) for 10 days;

[0035] Fig. 9 This is an X-ray powder diffraction (XRPD) pattern of the anthracene crystalline form B sample of the compound of the present invention after being placed under strong light irradiation conditions (5K Lux) for 10 days;

[0036] Fig.10 This is an X-ray powder diffraction (XRPD) pattern of an amorphous sample of the compound anthracene in the present invention after being placed under high temperature conditions (60° C.) for 10 days;

[0037] Fig.11 This is an X-ray powder diffraction (XRPD) pattern of an amorphous sample of the compound anthracene in the present invention after being placed under high humidity conditions (92.5% RH) for 10 days;

[0038] Fig.12 This is an X-ray powder diffraction (XRPD) pattern of an amorphous sample of the compound anthracene in the present invention after being placed under strong light irradiation conditions (5K Lux) for 10 days;

[0039] Fig.13 is a differential scanning calorimetry (DSC) diagram of the anthracene crystalline form A of the compound of the present invention;

[0040] Fig.14 The differential scanning calorimetry (DSC) diagram of the anthracene compound crystalline form B in the present invention. DETAILED DESCRIPTION

[0041] The present invention is described in detail below by examples, but it is not intended to limit the present invention in any way. The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination of the specific embodiments with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art, and preferred embodiments include but are not limited to the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and improvements are made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0042] As used herein, the term "therapeutically effective amount" or "therapeutically effective amount" refers to the amount of active compound or agent that elicits the biological or medicinal response sought by a researcher, veterinarian, medical doctor or other clinician in a tissue, system, animal, individual or human.

[0043] As used herein, the terms "treat," "treat," "treat," "treat," and "treat" refer to one or more of the following: (1) preventing a disease, condition, or disorder, e.g., preventing the disease, condition, or disorder in an individual who may be predisposed to developing the disease, condition, or disorder but who does not yet suffer from or display the pathology or symptoms of the disease; (2) inhibiting the disease, e.g., inhibiting the disease, condition, or disorder in an individual who suffers from or displays the pathology or symptoms of the disease, condition, or disorder; and (3) ameliorating the disease, e.g., ameliorating the disease, condition, or disorder (i.e., reversing the pathology and / or symptoms), e.g., reducing the severity of the disease, in an individual who suffers from or displays the pathology or symptoms of the disease, condition, or disorder.

[0044] The term "polymorph" as used herein refers to different crystal forms of the same compound and includes, but is not limited to, other solid molecular forms including hydrates and solvates of the same compound. The phenomenon that the same drug molecule forms multiple crystal forms is called drug polymorphism, which is a common phenomenon in solid drugs. It is known that drug compounds with such polymorphs have different physicochemical properties and affect pharmacological activity, solubility, bioavailability, stability, etc. Therefore, in the case of compounds useful as drugs with polymorphs, it is desirable to manufacture highly useful crystalline compounds from these polymorphs.

[0045] As used herein, the term "X-ray powder diffraction pattern" refers to an experimentally observed diffraction pattern or parameters derived therefrom. An X-ray powder diffraction pattern is characterized by peak positions and peak intensities.

[0046] The term "crystal" or "crystalline form" as used in the present invention refers to the one confirmed by the X-ray diffraction pattern shown. It will be understood by those skilled in the art that the physicochemical properties discussed in the present invention can be characterized, and the experimental errors depend on the conditions of the instrument, the preparation of the sample and the purity of the sample. In particular, it is well known to those skilled in the art that the X-ray diffraction pattern will usually change with the conditions of the instrument. It is particularly important to point out that the relative intensity of the X-ray diffraction pattern may also change with the change of experimental conditions, so the order of peak intensity cannot be used as the only or decisive factor. In addition, the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ±0.2° is usually allowed. In addition, due to the influence of experimental factors such as sample height, the overall deviation of the peak angle will be caused, and a certain deviation is usually allowed. Therefore, it will be understood by those skilled in the art that the X-ray diffraction pattern of a crystal form in the present invention does not have to be completely consistent with the X-ray diffraction pattern in the examples referred to here. Any crystal form having a pattern that is the same or similar to the characteristic peaks in these spectra belongs to the scope of the present invention. A person skilled in the art can compare the spectra listed in the present invention with the spectra of an unknown crystal form to confirm whether the two sets of spectra reflect the same or different crystal forms.

[0047] In order to describe the present invention in more detail, the following preparation examples are given. However, the scope of the present invention is not limited thereto. Unless otherwise specified, the methods and equipment used in the present invention are conventional methods and equipment in the art.

[0048] The experimental conditions involved in the experiments of the present invention are as follows:

[0049] The invention relates to a new crystal form A of anthraquinone, which is characterized by solid-state methods such as X-ray powder diffraction (XRPD), thermogravimetric analysis (TG), differential scanning calorimetry (DSC), infrared spectroscopy (IR), single crystal X-ray diffraction (SCXRD) and the like.

[0050] XRPD analysis: It was carried out at room temperature using a Bruker D8 advance diffractometer from Bruker Instruments, Germany, using Cu Kα radiation. The 2θ angle was scanned from 3 to 40 degrees at a scanning speed of 0.1° / s.

[0051] In the X-ray powder diffraction pattern 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 of the targeted crystal. When judging whether it is the same as a 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 it is not a diffraction line that represents a physical phase, but a specific set of "dI / I 1 "The data represent a certain phase. It should also be pointed out that in the identification of mixtures, some diffraction lines may be missing due to factors such as decreased content. At this time, it is not necessary to rely on all the bands observed in high-purity samples. Even one band may be characteristic for a given crystal.

[0052] DSC analysis: It was tested using a DSC 8500 differential scanning calorimeter from PerkinElmer, USA, with a nitrogen atmosphere and a heating rate of 10°C / min.

[0053] TG analysis: It was detected using a Netzsch TG 209F3 thermogravimetric analyzer from Germany's Netzsch Company, with a temperature range of 30-400°C, a scan rate of 10°C / min, and a purge gas of 25 mL / min.

[0054] IR analysis: The samples were analyzed using a Nicolet-Magna FT-IR 750 infrared spectrometer from Nicolet Corporation of the United States at room temperature with a detection range of 4000-350cm -1 wave number.

[0055] SCXRD analysis: All single crystal X-ray diffraction (SCXRD) experimental data in this experiment were measured by Bruker D8 Venture X-ray single crystal diffractometer from Bruker Instruments. Measurement conditions: graphite monochromator, Cu-Kα ray Temperature: room temperature (296K); Voltage: 50kV; Current: 30mA.

[0056] DVS analysis: All dynamic moisture sorption analyses (SCXRD) in this experiment were performed by a DVS advantage type sorption instrument from SMS, UK, with a relative humidity range of 0-95% and a temperature of 25°C.

[0057] The following describes the specific examples of the preparation method and performance testing of Form A of the present invention.

[0058] Example 1: Preparation of anthracene crystalline form A

[0059] In a 25mL eggplant-shaped reaction bottle equipped with a magnetic stirrer, add 1.00g of anthraquinone, add 10.0mL of anhydrous ethanol, stir magnetically, heat to about 80°C in an oil bath, and after complete dissolution, cool to room temperature under stirring, stop stirring, let stand for 3-4 hours, then filter, wash the filter cake with cold ethanol, and vacuum dry for 12 hours to obtain anthraquinone crystal form A, 0.73g of orange-yellow solid, with a yield of 73%. The X-ray powder diffraction results are shown in the attached Figure 1 The differential scanning calorimetry analysis results are shown in the attached Fig.13 Different solvents such as acetone, ethyl acetate, isopropanol, methanol, and ethanol / water were tried, and the XRPD results showed the same crystal form.

[0060] Example 2: Preparation of anthracene crystalline form B

[0061] Add 1.00 g of anthracene in a 25 mL eggplant-shaped reaction bottle, add 5.0 mL of tetrahydrofuran, heat and shake until completely dissolved, then remove the solvent under reduced pressure on a rotary evaporator, and vacuum dry for 12 hours to obtain anthracene crystal form B, an orange-yellow solid. The X-ray powder diffraction results are shown in the attached Figure 2 The differential scanning calorimetry analysis results are shown in the attached Fig.14 shown.

[0062] Example 3: Preparation of anthracene amorphous form

[0063] Weigh 1.00 g of anthracene, add 5.0 mL of tetrahydrofuran, and after complete dissolution, spray dry it with a spray dryer, collect the solid, and vacuum dry it for 12 hours to obtain anthracene amorphous, orange-yellow solid. The X-ray powder diffraction results are shown in the attached Figure 3 shown.

[0064] Example 4: According to the 2020 edition of the Chinese Pharmacopoeia method, the solubility of anthraquinone crystal form A, anthraquinone crystal form B and anthraquinone amorphous form was studied, and the results are shown in the following table:

[0065]

[0066] From the above results, it is found that it has a certain ester solubility. Since the phenolic hydroxyl group in the structure is acidic, it has a certain solubility under alkaline conditions. Its solubility can be adjusted by controlling the pH. There is no obvious difference in the solubility of anthracene crystalline form A, anthracene crystalline form B and anthracene amorphous form. However, the following tests show that its stability has been greatly improved.

[0067] Example 5: According to the 2020 edition of the Chinese Pharmacopoeia method, the stability data of anthracene crystalline form A, anthracene crystalline form B and anthracene amorphous form were determined under high temperature (60°C), high humidity (92.5% RH) and light (5K Lux) for 10 days through the influencing factor experiment, and the hygroscopicity of the samples was confirmed by the change in sample mass under high humidity conditions, and the sample stability of anthracene crystalline form A and anthracene crystalline form B was investigated. At the same time, anthracene crystalline form A, anthracene crystalline form B and anthracene amorphous form were subjected to X-ray powder diffraction tests after 10 days under high temperature (60°C), high humidity (92.5% RH) and light (5K Lux), respectively, and compared with the crystal form before the experiment to investigate the stability of the crystal form.

[0068] A Waters e2695 high performance liquid chromatograph was used, the detector was PDA2998, the chromatographic column was Sunfire C18 250×4.6mm, 5.0μm (Waters) column, the mobile phase A was 0.1% phosphoric acid methanol, the mobile phase B was pure water, the flow rate was 1.0mL / min, the injection volume was 10μL, the column temperature was 30℃, the detection wavelength was 280nm, the gradient elution was performed, and the elution conditions were shown in the following table:

[0069]

[0070] The experimental results are shown in the following table

[0071]

[0072] The experimental results show that both anthracene crystalline form A and anthracene crystalline form B have good stability, are not hygroscopic under high humidity conditions, and their content does not change significantly. The stability of anthracene amorphous form is significantly lower than that of anthracene crystalline form A and anthracene crystalline form B.

[0073] After 10 days of high temperature (60°C), high humidity (92.5%RH) and light (5K Lux) conditions, the anthracene crystalline form A, anthracene crystalline form B and anthracene amorphous form were tested by X-ray powder diffraction. The results showed that after 10 days of high temperature (60°C), the anthracene crystalline form A showed that ( Figure 4 ), the 2θ values ​​are 5.90°, 11.73°, 14.69°, 17.67°, 20.63°, 23.63°, 29.58°, 32.67°, 35.69°, 38.79°, 45.05°, and 54.71° with characteristic peaks, and the crystal form has not changed.

[0074] After 10 days of exposure to high humidity (92.5% RH), the X-ray powder diffraction results showed that ( Figure 5 ), 2θ values ​​are 5.76°, 11.64°, 14.50°, 17.47°, 20.44°, 23.44°, 29.48°, 32.52°, 35.62°, 38.72°, 45.02°, and 54.78° with characteristic peaks, and the crystal form has not changed.

[0075] After 10 days of exposure to light (5K Lux), the X-ray powder diffraction results showed that ( Figure 4 ), 2θ values ​​are 5.78°, 11.66°, 14.58°, 17.47°, 20.48°, 23.52°, 29.54°, 32.52°, 35.66°, 38.78°, 45.10°, and 54.88° with characteristic peaks, and the crystal form has not changed.

[0076] After 10 days at high temperature (60°C), the X-ray powder diffraction results showed that ( Figure 7 ), 5.78°, 11.66°, 14.62°, 16.58°, 17.44°, 18.56°, 20.20°, 20.88°, 22.08°, 22.58°, 24.14°, 24.66°, 25.86°, 27.06°, 28.54°, 30.24°, 31.52°, 32.20°, 34.22°, 35.70°, 38.24°, 39.50°, and 43.16° have characteristic peaks, and the crystal form has not changed. .

[0077] After 10 days of exposure to high humidity (92.5% RH), the X-ray powder diffraction results showed that ( Figure 8 ), 2θ values ​​are 5.82°, 11.66°, 14.62°, 16.58°, 17.44°, 18.62°, 20.16°, 20.88°, 22.04°, 22.58°, 24.14°, 24.76°, 25.52°, 25.84°, 27.06°, 28.54°, 30.24°, 31.52°, 32.20°, 34.22°, 35.70°, 38.24°, 39.50°, and 43.16° also have characteristic peaks, and the crystal form has not changed.

[0078] After 10 days of exposure to light (5K Lux), the X-ray powder diffraction results showed that ( Fig. 9 ), 2θ values ​​are 5.76°, 11.62°, 14.56°, 16.62°, 17.42°, 18.56°, 20.16°, 20.84°, 22.00°, 22.58°, 23.15°, 24.12°, 24.78°, 25.56°, 26.96°, 28.54°, 29.50°, 30.24°, 32.24°, 34.34°, 35.70°, 38.18°, 39.58°, and 43.20° with characteristic peaks, and the crystal form has not changed.

[0079] After 10 days at high temperature (60°C), the X-ray powder diffraction results showed that ( Fig.10 ), 2θ values ​​show crystalline characteristic peaks at 5.76°, 11.66°, 14.64°, 17.58°, 20.14°, 22.58°, 24.07°, 27.08°, 28.46°, and 35.74°.

[0080] After 10 days of exposure to high humidity (92.5% RH), the X-ray powder diffraction results showed that ( Fig.11 ), 2θ values ​​show crystalline characteristic peaks at 11.52°, 14.44°, 17.42°, 20.10°, 20.44°, 22.44°, 24.10°, 27.00°, 28.50°, 30.26°, and 32.19°.

[0081] After 10 days of exposure to light (5K Lux), the X-ray powder diffraction results showed that ( Fig.12 ), 2θ values ​​show crystalline characteristic peaks at 11.48°, 14.34°, 17.30°, 20.14°, 22.26°, 24.06°, and 26.92°.

[0082] The experimental results show that both anthraquinone crystal form A and anthraquinone crystal form B have good stability and are not hygroscopic under high humidity conditions, and are suitable for developing pharmaceutical compositions or preparations with therapeutic uses such as antitoxin, antibacterial, anti-inflammatory, and hypoglycemic. The crystal form A of the present invention exhibits advantages in multiple physical and chemical properties and is an ideal pharmaceutical crystal form.

Claims

1. A crystalline form A of anthracene, characterized in that: The X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 11.75°±0.20°, 14.69°±0.20°, 17.67°±0.20°, 29.65°±0.20°, 32.69°±0.20°, and 35.75°±0.20°.

2. The crystalline form A according to claim 1, characterized in that The X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 5.87°±0.20°, 11.75°±0.20°, 14.69°±0.20°, 17.67°±0.20°, 20.65°±0.20°, 23.61°±0.20°, 29.65°±0.20°, 32.69°±0.20°, 35.75°±0.20°, 38.86°±0.20°, 45.15°±0.20°, and 54.89°±0.20°.

3. The method for preparing the crystal form A according to claim 1, characterized in that: The preparation method is as follows: mixing anthraquinone with a certain volume of solvent, heating and stirring to dissolve, obtaining anthraquinone solution with a certain concentration, cooling, precipitating crystals, filtering and collecting the crystals, and drying to obtain anthraquinone crystal form A.

4. The method according to claim 3, wherein the solvent used is ethyl acetate, isopropyl acetate, methanol, ethanol, isopropanol, methyl tert-butyl ether, isopropyl ether, acetonitrile, or acetone, and preferably the solvent used is ethanol. The concentration of the anthracene solution is between 0.01 and 0.50 g / mL, and preferably the solution concentration is between 0.05 and 0.20 g / mL. When cooling to separate out crystals, stir or let stand.

5. A crystalline form B of anthracene, characterized in that: Its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 11.60°±0.20°, 14.56°±0.20°, 17.42°±0.20°, 20.16°±0.20°, 20.82°±0.20°, 22.58°±0.20°, 24.10°±0.20°, 24.70°±0.20°, 26.70°±0.20°, and 27.08°±0.20°.

6. The crystal form B according to claim 5, characterized in that Its X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 5.74°±0.20°, 11.60°±0.20°, 14.56°±0.20°, 16.62°±0.20°, 17.42°±0.20°, 18.58°±0.20°, 20.16°±0.20°, 20.82°±0.20°, 22.02°±0. 20°, 22.58°±0.20°, 24.10°±0.20°, 24.70°±0.20°, 25.46°±0.20°, 26.70°±0.20°, 27.08°±0.20°, 28.56°±0.20°, 30.28°±0.20°, 32.20°±0.20°, 35.64°±0.20°.

7. The method for preparing the crystal form B according to claim 5, the preparation process comprising: A certain volume of anthraquinone solid solution is added to an organic solvent to obtain anthraquinone solution of a certain concentration, the solvent is evaporated and dried to obtain anthraquinone crystal form B; more preferably, the solvent used is tetrahydrofuran or 2-methyl-tetrahydrofuran, More preferably, the solvent is tetrahydrofuran, and the concentration of the obtained anthraquinone solution is between 0.10-1.00 g / mL, and preferably the solution concentration is between 0.20-0.50 g / mL.

8. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form A of anthraquinone according to claim 1 and / or the crystalline form B of anthraquinone according to claim 5, and further comprising a pharmaceutically acceptable carrier.

9. Use of the crystalline form A of anthrabenin according to claim 1 in the preparation of a medicament for preventing and treating a disease, wherein the disease is botulism, bacterial infection, inflammation, hyperglycemia, or tumor.

10. Use of the crystal form B of anthraquinone according to claim 5 in the preparation of a medicament for preventing and treating a disease, wherein the disease is botulism, bacterial infection, inflammation, hyperglycemia, or tumor.

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