A crystal form, preparation method and application thereof

Abstract

The present application relates to a kind of compound 2-[(full-E)3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetracosaalkyl]-5,6-dimethoxy-3-methyl-p-benzoquinone crystal form and its preparation method and application, belong to chemical engineering crystallization field.The technical problem to be solved is to provide a crystal form with significantly improved stability, significantly improve the light stability of the compound, and further more conducive to storage and transportation, better ensure the consistency of therapeutic effect, reduce the effect fluctuation or adverse reaction caused by dissolution difference.Characteristic diffraction peak of X-ray powder diffraction pattern expressed by 2θ value ± 0.2° using Cu-Kα radiation includes 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 27.39.

Description

Technical Field

[0001] This invention relates to the field of chemical engineering crystallization technology, and more specifically, to a crystal form, its preparation method, and its application. Background Technology

[0002] Compound 2-[(all-E)3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetradecenyl]-5,6-dimethoxy-3-methyl-p-benzoquinone (Coenzyme Q10) is a vitamin-like compound, a fat-soluble organic quinone compound widely distributed in organisms, and has important physiological and pharmacological effects. It is primarily a coenzyme bound to the mitochondrial membrane, forming a link in the respiratory chain, and participates in hydrogen transfer during energy metabolism in the body. It is a metabolic activator that activates cellular respiration, generates cellular energy, and accelerates the production of adenosine triphosphate (ATP). It is also a natural antioxidant produced by the cell itself, inhibiting mitochondrial peroxidation and protecting the integrity of biological membrane structures. Simultaneously, it is a non-vitamin nutrient that, after consumption, activates cellular respiration, accelerates the production of high-energy ATP, strengthens myocardial metabolism, improves heart rate, regulates cellular and tissue hypoxia, and has good protective and improving effects on the liver, brain, heart, and nervous system. It also has a very specific immune-enhancing effect, increasing the phagocytic rate of phagocytes and increasing antibody production. Due to these excellent properties, Coenzyme Q10 has become an important pharmaceutical and health supplement with broad application prospects.

[0003] Coenzyme Q10 comes in two forms: oxidized and reduced. Currently, most coenzyme Q10 products on the market are oxidized. Oxidized coenzyme Q10, also known as decenquinone or ubiquinone, is chemically named 2-[(all-E)3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetradecenyl]-5,6-dimethoxy-3-methyl-p-benzoquinone. It is a lipid-soluble quinone compound with a structure similar to vitamin K, vitamin E, and plastoquinone. It is a yellow or light yellow crystalline powder, readily soluble in chloroform, benzene, and carbon tetrachloride; soluble in acetone and ether; slightly soluble in ethanol; and insoluble in water and methanol. Oxidized coenzyme Q10 (structure shown below) suffers from poor photostability and easily decomposes into a red substance upon exposure to light. The photostability of oxidized coenzyme Q10 greatly limits its applications. Current solutions to this problem include either protecting it from light during production and storage, or preparing it into coated tablets, capsules, or other formulations to improve its stability.

[0004]

[0005] For example, Chinese patent application CN119385957A discloses a tablet with high bioavailability and its preparation method; Chinese patent application CN101744288A discloses a clarified oral formulation containing coenzyme Q10 and its preparation method; Chinese patent application CN101053556A discloses a scheme for encapsulating coenzyme Q10 with hydroxypropyl-β-cyclodextrin as cyclodextrin, followed by drying to prepare a coenzyme Q10 inclusion complex; Chinese patent application CN109953967A discloses a process study of coenzyme Q10 tablets, the technical solution of which uses a film coating as an enteric film coating premix for coenzyme Q10, which can obtain coenzyme Q10 tablets with high release. The above technical solutions involve formulating coenzyme Q10 into a formulation form, but none of these technical solutions have investigated the photostability of the formulation.

[0006] The phenomenon that a compound can exist in at least one crystalline structure or solid form is called polymorphism. Many compounds can exist in multiple crystalline forms, as well as in amorphous solid forms. Before discovering polymorphism in a compound, it is difficult to predict: (1) whether a particular compound exhibits polymorphism; (2) how to prepare these unknown polymorphs; and (3) what the properties of these polymorphs will be, such as stability. Since the properties of any solid depend on its structure and the properties of the compound itself, different solid forms of a compound can and often exhibit different physical and chemical properties. Differences in chemical properties can be measured, analyzed, and compared using various analytical techniques. These differences can ultimately be used to distinguish between different solid forms. Many existing patents disclose methods for preparing coenzyme Q10 crystal forms. However, the methods for preparing oxidized coenzyme Q10 disclosed in the prior art all yield existing crystal forms. For example, the main characteristic peaks of oxidized coenzyme Q10, expressed as 2θ values ​​± 0.2°, appear at 11.3, 18.5, 20.2, 22.7, and 23.3, as described in "Design of Coenzyme Q10 solid dispersion for improved solubilization and stability" (Jin-Seok, et al. International journal of pharmaceutics 572(2019):118832-118832.).

[0007] However, this crystal form A does not solve the problem of poor photostability of coenzyme Q10. Therefore, investigating whether there are new crystal structures for coenzyme Q10 is of great significance to overcome its insufficient photostability. Summary of the Invention

[0008] The purpose of this invention is to provide: A crystal form of compound 2-[(all-E)3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetradecenyl]-5,6-dimethoxy-3-methyl-p-benzoquinone, its preparation method and application, and related technologies, to solve technical problems such as providing a new crystal form with significantly improved stability, especially overcoming the defect of poor photostability, or a combination thereof.

[0009] Terminology Explanation: Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent inventions, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0010] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0011] The definition of standard chemical terms can be found in the reference "Basic Course in Materials Science", edited by Wang Yanan et al., Higher Education Press, 2019 edition.

[0012] The definition of standard chemical terms can be found in the reference "Basic Organic Chemistry (Volumes 1 & 2)" by Xing Qiyi, Higher Education Press, 3rd Edition, 2005-06.

[0013] Unless otherwise stated, conventional methods within the scope of the art, such as mixing, filtering, stirring, dropping, centrifugation, crystallization, crystal growth, rinsing, and drying, shall be used.

[0014] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0015] The terms “optional / arbitrary” or “optionally / arbitrarily” mean that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0016] The term "mixing" as used in this article refers to the process of reducing the heterogeneity of two or more substances (such as solid powders, liquids, or solid-liquid mixtures) and achieving a uniform combination through the action of external forces (such as stirring, convection, or shearing).

[0017] The term "filtration" as used in this article refers to the core operation in organic chemistry for separating solid-liquid mixtures. It involves using a porous medium to trap solid particles, allowing the liquid to pass through, thus achieving separation. Specifically, it is the physical process of using a filter medium (such as filter paper) to trap solid particles in a suspension, allowing the liquid to pass through; relying on gravity, pressure, or centrifugal force to drive the liquid through the pores of the medium, while the solids are trapped to form a filter cake.

[0018] The term "stirring" as used in this article refers to the process of thoroughly mixing reactants by mechanical or magnetic means, which is especially crucial in heterogeneous reactions (such as solid-liquid and liquid-liquid reactions). It accelerates the contact of reactants, promotes uniform heat distribution, and avoids localized overheating that could lead to side reactions.

[0019] The term "drop addition" as used in this article refers to the gradual addition of reactants dropwise using a device such as a constant-pressure funnel, primarily for controlling reaction rate and temperature. For example, in strongly exothermic reactions, drop addition can prevent violent reactions; in reactions involving reactive substances, drop addition can maintain stable reactant concentrations.

[0020] As used in this article, "centrifugation" refers to the technique of separating components of different densities in a mixture using the centrifugal force generated by a centrifuge. In organic chemistry, it is often used to separate precipitates from solutions or to remove small particles from reaction systems.

[0021] The term "crystallization" as used in this article refers to the process by which a solute in a solution precipitates out of a supersaturated state to form crystals. By controlling conditions such as temperature and stirring speed, crystal products with high purity can be obtained.

[0022] The term "crystal growth" as used in this article refers to maintaining specific conditions (such as temperature and stirring) for a period of time after crystallization to allow the crystals to grow more completely and with higher purity. This process can reduce impurity inclusions and improve product quality.

[0023] As used in this article, "rinsing" refers to the process of washing a solid surface with a solvent to remove residual impurities. For example, after crystallization, rinsing the crystal with a low-boiling-point solvent can facilitate subsequent drying.

[0024] As used in this article, "drying" refers to the process of removing moisture or other solvents from a compound by heating, vacuuming, or using a desiccant.

[0025] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, such as liquid or solid fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickeners, solvents, or encapsulating materials, relating to the carrying or transport of any pharmaceutical composition from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of compatibility with other components of the pharmaceutical composition and harmlessness to the patient.

[0026] The term “X-ray powder diffraction” as used in this article refers to an analytical technique used to analyze and identify the crystal structure of polycrystalline or powdered materials. Its theoretical basis is that when a beam of monochromatic X-rays is irradiated onto countless randomly oriented tiny crystals, interference diffraction occurs, producing a diffraction pattern with a specific design.

[0027] The term "2θ angle" as used in this paper refers to twice the angle between the incident X-ray direction and the diffracted X-ray direction in the geometry of an X-ray diffraction experiment. It is the abscissa of the XRD pattern and is the angle directly measured in the experiment.

[0028] The term "crystal form" as used in this article refers to a solid form with a microstructure that has a long-range ordered arrangement, generally referring to a solid form with a microstructure that has a long-range ordered arrangement in three-dimensional space.

[0029] The term "diffraction peak" as used in this article refers to a peak in powder X-ray diffraction (XRD) analysis that has a significantly higher intensity than the background signal on a diffraction pattern (a curve showing the intensity as a function of the diffraction angle 2θ). Each diffraction peak corresponds to the coherent diffraction of incident X-rays by a specific set of crystal planes (hkl) in the crystalline sample. The position of the diffraction peak (peak position, usually expressed as a 2θ angle) and the interplanar spacing (d-value) follow Bragg's law, reflecting the lattice structure parameters of the crystal. The intensity of the diffraction peak (peak height or integrated intensity) is related to factors such as the type, number, and arrangement of atoms on the diffracting crystal plane, as well as the content of that phase in the sample. The width of the diffraction peak (e.g., half-maximum width at half maximum) is related to the crystal's grain size, microstrain, and other structural characteristics.

[0030] As used in this article, the term "characteristic diffraction peak" or "characteristic peak" refers to a set of highly specific and reproducible diffraction peaks exhibited by a specific crystalline phase (such as a specific crystal form of a drug) in its powder X-ray diffraction pattern. The positions (2θ values) of these diffraction peaks and their relative intensities constitute the "fingerprint" pattern of that phase, which can be used to distinguish it from other phases or crystal forms.

[0031] The term "Cu-Kα radiation" used in this article refers to Cu-Kα radiation, also known as Cu Kα rays, which is a characteristic X-ray source commonly used in X-ray diffraction analysis. Its generation principle is as follows: when a high-energy electron beam bombards a copper (Cu) target, it ionizes the inner-shell (K-shell) electrons of the copper atoms, creating vacancies. Subsequently, outer-shell (L-shell) electrons jump to these K-shell vacancies, releasing X-ray photons with specific energies—this is Cu Kα radiation. It mainly consists of two spectral lines with very close wavelengths: Kα1 (wavelength approximately 1.54056 Å) and Kα2 (wavelength approximately 1.54439 Å). In conventional diffraction analysis, their weighted average wavelength is often taken as approximately 1.5418 Å. Due to its fixed wavelength, relatively good monochromaticity, and high intensity, Cu-Kα radiation is widely used in laboratory X-ray diffractometers as a standard incident light source for the structural analysis of crystal materials.

[0032] In a first aspect, the present invention provides: a crystal form of 2-[(all-E)3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetradecenyl]-5,6-dimethoxy-3-methyl-p-benzoquinone, wherein characteristic diffraction peaks in X-ray powder diffraction, expressed as 2θ values ​​± 0.2°, using Cu-Kα radiation, include 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, and 27.39.

[0033] Preferably, the crystal form, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks in X-ray powder diffraction expressed as 2θ value ± 0.2°, including any one or more of 3.14, 18.79, 22.96, 23.50, and 30.45.

[0034] The crystal form, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, and 27.39, and also includes any one or more of 3.14, 18.79, 22.96, 23.50, and 30.45.

[0035] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, and 27.39.

[0036] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, and 27.39.

[0037] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, and 27.39.

[0038] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 23.50, and 27.39.

[0039] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 27.39, and 30.45.

[0040] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, and 27.39.

[0041] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, and 27.39.

[0042] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 23.50, and 27.39.

[0043] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 27.39, and 30.45.

[0044] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, and 27.39.

[0045] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 23.50, and 27.39.

[0046] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 27.39, and 30.45.

[0047] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, 23.50, and 27.39.

[0048] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, 27.39, and 30.45.

[0049] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 23.50, 27.39, and 30.45.

[0050] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, and 27.39.

[0051] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 23.50, and 27.39.

[0052] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 27.39, and 30.45.

[0053] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, 23.50, and 27.39.

[0054] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, 27.39, and 30.45.

[0055] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 23.50, 27.39, and 30.45.

[0056] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, and 27.39.

[0057] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, and 30.45.

[0058] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, 23.50, 27.39, and 30.45.

[0059] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, and 27.39.

[0060] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, and 30.45.

[0061] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, 23.50, 27.39, and 30.45.

[0062] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, 27.39, and 30.45.

[0063] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, 27.39, and 30.45.

[0064] Preferably, the characteristic diffraction peaks of the X-ray powder diffraction pattern of the crystal form, expressed as 2θ value ± 0.2° using Cu-Kα radiation, further include any one or more of 7.80, 9.38, 14.05, 28.67, and 29.73.

[0065] The crystal form, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks in X-ray powder diffraction, expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, and 27.39, and also includes any one or more of 7.80, 9.38, 14.05, 28.67, and 29.73.

[0066] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, and 27.39.

[0067] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 19.18, 20.45, and 27.39.

[0068] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, and 27.39.

[0069] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 27.39, and 28.67.

[0070] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 27.39, and 29.73.

[0071] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 7.80, 9.38, 15.65, 17.22, 19.18, 20.45, and 27.39.

[0072] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 7.80, 14.05, 15.65, 17.22, 19.18, 20.45, and 27.39.

[0073] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, 27.39, and 28.67.

[0074] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, 27.39, and 29.73.

[0075] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 14.05, 15.65, 17.22, 19.18, 20.45, and 27.39.

[0076] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 19.18, 20.45, 27.39, and 28.67.

[0077] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 19.18, 20.45, 27.39, and 29.73.

[0078] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, 27.39, and 28.67.

[0079] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, 27.39, and 29.73.

[0080] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 27.39, 28.67, and 29.73.

[0081] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 7.80, 9.38, 14.05, 15.65, 17.22, 19.18, 20.45, and 27.39.

[0082] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 7.80, 9.38, 15.65, 17.22, 19.18, 20.45, 27.39, and 28.67.

[0083] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 7.80, 9.38, 15.65, 17.22, 19.18, 20.45, 27.39, and 29.73.

[0084] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 14.05, 15.65, 17.22, 19.18, 20.45, 27.39, and 28.67.

[0085] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 14.05, 15.65, 17.22, 19.18, 20.45, 27.39, and 29.73.

[0086] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, 27.39, 28.67, and 29.73.

[0087] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 7.80, 9.38, 14.05, 15.65, 17.22, 19.18, 20.45, 27.39, and 28.67.

[0088] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 7.80, 9.38, 14.05, 15.65, 17.22, 19.18, 20.45, 27.39, and 29.73.

[0089] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 14.05, 15.65, 17.22, 19.18, 20.45, 27.39, 28.67, and 29.73.

[0090] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 7.80, 9.38, 14.05, 15.65, 17.22, 19.18, 20.45, 27.39, 28.67, and 29.73.

[0091] The crystal form, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks in X-ray powder diffraction, expressed as 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, and 27.39, and further including any one or more of 3.14, 7.80, 9.38, 14.05, 18.79, 22.96, 23.50, 28.67, 29.73, and 30.45.

[0092] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, and 27.39.

[0093] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 18.79, 19.18, 20.45, and 27.39.

[0094] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, 22.96, and 27.39.

[0095] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, 23.50, and 27.39.

[0096] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, 27.39, and 30.45.

[0097] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 18.79, 19.18, 20.45, and 27.39.

[0098] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, 22.96, and 27.39.

[0099] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, 23.50, and 27.39.

[0100] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, 27.39, and 30.45.

[0101] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, and 27.39.

[0102] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 18.79, 19.18, 20.45, 23.50, and 27.39.

[0103] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 18.79, 19.18, 20.45, 27.39, and 30.45.

[0104] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, 22.96, 23.50, and 27.39.

[0105] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, 22.96, 27.39, and 30.45.

[0106] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, 23.50, 27.39, and 30.45.

[0107] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, and 27.39.

[0108] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 18.79, 19.18, 20.45, 23.50, and 27.39.

[0109] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 18.79, 19.18, 20.45, 27.39, and 30.45.

[0110] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, 22.96, 23.50, and 27.39.

[0111] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, 22.96, 27.39, and 30.45.

[0112] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, 27.39, 23.50, and 30.45.

[0113] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 18.79, 4.70, 6.25, 7.80, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, and 27.39.

[0114] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 18.79, 4.70, 6.25, 7.80, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, and 30.45.

[0115] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 18.79, 4.70, 6.25, 7.80, 15.65, 17.22, 19.18, 20.45, 22.96, 23.50, 27.39, and 30.45.

[0116] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, and 27.39.

[0117] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, and 30.45.

[0118] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 7.80, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, 27.39, and 30.45.

[0119] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 9.38, 15.65, 17.22, 19.18, 20.45, and 27.39.

[0120] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 18.79, 19.18, 20.45, and 27.39.

[0121] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 19.18, 20.45, 22.96, and 27.39.

[0122] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 19.18, 20.45, 23.50, and 27.39.

[0123] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 19.18, 20.45, 27.39, and 30.45.

[0124] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 9.38, 15.65, 17.22, 18.79, 19.18, 20.45, and 27.39.

[0125] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 9.38, 15.65, 17.22, 19.18, 20.45, 22.96, and 27.39.

[0126] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 9.38, 15.65, 17.22, 19.18, 20.45, 23.50, and 27.39.

[0127] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 9.38, 15.65, 17.22, 19.18, 20.45, 27.39, and 30.45.

[0128] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, and 27.39.

[0129] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 18.79, 19.18, 20.45, 23.50, and 27.39.

[0130] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 18.79, 19.18, 20.45, 27.39, and 30.45.

[0131] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 19.18, 20.45, 22.96, 23.50, and 27.39.

[0132] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 19.18, 20.45, 22.96, 27.39, and 30.45.

[0133] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 19.18, 20.45, 23.50, 27.39, and 30.45.

[0134] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 9.38, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, and 27.39.

[0135] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 9.38, 15.65, 17.22, 18.79, 19.18, 20.45, 23.50, and 27.39.

[0136] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 9.38, 15.65, 17.22, 18.79, 19.18, 20.45, 27.39, and 30.45.

[0137] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, and 27.39.

[0138] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, and 30.45.

[0139] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 18.79, 19.18, 20.45, 23.50, 27.39, and 30.45.

[0140] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 19.18, 20.45, 22.96, 23.50, 27.39, and 30.45.

[0141] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 9.38, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, and 27.39.

[0142] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 9.38, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, and 30.45.

[0143] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 9.38, 15.65, 17.22, 19.18, 20.45, 22.96, 23.50, 27.39, and 30.45.

[0144] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 9.38, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, 27.39, and 30.45.

[0145] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, and 27.39.

[0146] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, and 27.39.

[0147] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, 22.96, and 27.39.

[0148] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, 23.50, and 27.39.

[0149] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, 27.39, and 30.45.

[0150] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, and 27.39.

[0151] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, 22.96, and 27.39.

[0152] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, 23.50, and 27.39.

[0153] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, 27.39, and 30.45.

[0154] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, and 27.39.

[0155] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 23.50, and 27.39.

[0156] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 27.39, and 30.45.

[0157] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, 22.96, 23.50, and 27.39.

[0158] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, 22.96, 27.39, and 30.45.

[0159] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, 23.50, 27.39, and 30.45.

[0160] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, and 27.39.

[0161] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 23.50, and 27.39.

[0162] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 27.39, and 30.45.

[0163] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, 22.96, 23.50, and 27.39.

[0164] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, 22.96, 27.39, and 30.45.

[0165] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 14.05, 15.65, 17.22, 19.18, 20.45, 23.50, 27.39, and 30.45.

[0166] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, and 27.39.

[0167] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, and 30.45.

[0168] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 23.50, 27.39, and 30.45.

[0169] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, and 27.39.

[0170] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, and 30.45.

[0171] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 23.50, 27.39, and 30.45.

[0172] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 27.39, and 28.67.

[0173] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 27.39, and 28.67.

[0174] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, 27.39, and 28.67.

[0175] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 23.50, 27.39, and 28.67.

[0176] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 27.39, 28.67, and 30.45.

[0177] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 27.39, and 28.67.

[0178] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, 27.39, and 28.67.

[0179] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 23.50, 27.39, and 28.67.

[0180] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 27.39, 28.67, and 30.45.

[0181] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, and 28.67.

[0182] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 23.50, 27.39, and 28.67.

[0183] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 27.39, 28.67, and 30.45.

[0184] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, 23.50, 27.39, and 28.67.

[0185] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, 27.39, 28.67, and 30.45.

[0186] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 23.50, 27.39, 28.67, and 30.45.

[0187] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, and 28.67.

[0188] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 23.50, 27.39, and 28.67.

[0189] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 27.39, 28.67, and 30.45.

[0190] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, 27.39, and 28.67.

[0191] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, 28.67, and 30.45.

[0192] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, 27.39, and 28.67.

[0193] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, 28.67, and 30.45.

[0194] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, 23.50, 27.39, 28.67, and 30.45.

[0195] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 27.39, and 29.73.

[0196] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 27.39, and 29.73.

[0197] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, 27.39, and 29.73.

[0198] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 23.50, 27.39, and 29.73.

[0199] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 27.39, 29.73, and 30.45.

[0200] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 27.39, and 29.73.

[0201] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, 27.39, and 29.73.

[0202] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 23.50, 27.39, and 29.73.

[0203] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 27.39, 29.73, and 30.45.

[0204] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, and 29.73.

[0205] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 23.50, 27.39, and 29.73.

[0206] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 27.39, 29.73, and 30.45.

[0207] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, 23.50, 27.39, and 29.73.

[0208] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, 27.39, 29.73, and 30.45.

[0209] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 23.50, 27.39, 29.73, and 30.45.

[0210] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, and 29.73.

[0211] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 23.50, 27.39, and 29.73.

[0212] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 27.39, 29.73, and 30.45.

[0213] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, 27.39, and 29.73.

[0214] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, 29.73, and 30.45.

[0215] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.96, 23.50, 27.39, 29.73, and 30.45.

[0216] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, 29.73, and 30.45.

[0217] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 9.38, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 27.39, 28.67, 29.73, and 30.45.

[0218] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 9.38, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, 27.39, 28.67, 29.73, and 30.45.

[0219] Preferably, the crystal form, using Cu-Kα radiation, further includes any one or more of the characteristic diffraction peaks of X-ray powder diffraction expressed in 2θ values ​​± 0.2°, including 10.88, 12.50, 20.72, 21.10, 22.05, 24.72, and 25.76.

[0220] The crystal form, when subjected to Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed as 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, and 27.39, and further including any one or more of 3.14, 7.80, 9.38, 10.88, 12.50, 14.05, 18.79, 20.72, 21.10, 22.05, 22.96, 23.50, 24.72, 25.76, 28.67, 29.73, and 30.45.

[0221] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 10.88, 15.65, 17.22, 19.18, 20.45, and 27.39.

[0222] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 12.50, 15.65, 17.22, 19.18, 20.45, and 27.39.

[0223] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 20.72, and 27.39.

[0224] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 21.10, and 27.39.

[0225] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.05, and 27.39.

[0226] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 24.72, and 27.39.

[0227] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 25.76, and 27.39.

[0228] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 10.88, 12.50, 15.65, 17.22, 19.18, 20.45, and 27.39.

[0229] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 10.88, 15.65, 17.22, 19.18, 20.45, 22.05, and 27.39.

[0230] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 10.88, 15.65, 17.22, 19.18, 20.45, 24.72, and 27.39.

[0231] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 12.50, 15.65, 17.22, 19.18, 20.45, 22.05, and 27.39.

[0232] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 12.50, 15.65, 17.22, 19.18, 20.45, 24.72, and 27.39.

[0233] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, has characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, 22.05, 24.72, and 27.39.

[0234] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 10.88, 12.50, 15.65, 17.22, 19.18, 20.45, 22.05, and 27.39.

[0235] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 10.88, 12.50, 15.65, 17.22, 19.18, 20.45, 21.10, 24.72, and 27.39.

[0236] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 4.70, 6.25, 10.88, 12.50, 15.65, 17.22, 19.18, 20.45, 21.10, 22.05, 24.72, 25.76, and 27.39.

[0237] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 10.88, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 21.10, 22.96, 23.50, 25.76, 27.39, and 30.45.

[0238] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed as 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 10.88, 12.50, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, 27.39, and 30.45.

[0239] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 10.88, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 20.72, 22.05, 22.96, 23.50, 27.39, and 30.45.

[0240] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 10.88, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 20.72, 22.96, 23.50, 24.72, 27.39, and 30.45.

[0241] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 10.88, 12.50, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 20.72, 22.96, 23.50, 27.39, and 30.45.

[0242] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 12.50, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.05, 22.96, 23.50, 27.39, and 30.45.

[0243] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.05, 22.96, 23.50, 24.72, 27.39, and 30.45.

[0244] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 10.88, 12.50, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.05, 22.96, 23.50, 24.72, 27.39, and 30.45.

[0245] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 9.38, 10.88, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, 27.39, 28.67, 29.73, and 30.45.

[0246] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 9.38, 12.50, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, 27.39, 28.67, 29.73, and 30.45.

[0247] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 9.38, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.05, 22.96, 23.50, 27.39, 28.67, 29.73, and 30.45.

[0248] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 9.38, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, 24.72, 27.39, 28.67, 29.73, and 30.45.

[0249] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 9.38, 10.88, 12.50, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.96, 23.50, 27.39, 28.67, 29.73, and 30.45.

[0250] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 9.38, 12.50, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 22.05, 22.96, 23.50, 27.39, 28.67, 29.73, and 30.45.

[0251] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 9.38, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 21.10, 22.05, 22.96, 23.50, 24.72, 25.76, 27.39, 28.67, 29.73, and 30.45.

[0252] Specifically, and as a specific embodiment of the present invention, the crystal form, using Cu-Kα radiation, exhibits characteristic diffraction peaks in its X-ray powder diffraction pattern expressed in 2θ values ​​± 0.2°, including 3.14, 4.70, 6.25, 7.80, 9.38, 10.88, 12.50, 14.05, 15.65, 17.22, 18.79, 19.18, 20.45, 20.72, 21.10, 22.05, 22.96, 23.50, 24.72, 25.76, 27.39, 28.67, 29.73, and 30.45.

[0253] In one or more of the above embodiments, preferably, one or more of the characteristic diffraction peaks are characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in 2θ value ± 0.15° using Cu-Kα radiation.

[0254] In one or more of the above embodiments, more preferably, one or more of the characteristic diffraction peaks are characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in 2θ value ± 0.10° using Cu-Kα radiation.

[0255] In one or more of the above embodiments, more preferably, one or more of the characteristic diffraction peaks are characteristic diffraction peaks of an X-ray powder diffraction pattern expressed in 2θ value ± 0.05° using Cu-Kα radiation.

[0256] Furthermore, the crystal form is subjected to Cu-Kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction, expressed in terms of 2θ value ± 0.2°, do not include the characteristic diffraction peaks at 11.30–11.70.

[0257] Secondly, the present invention provides a method for preparing the crystal form, wherein the preparation method is an antisolvent addition recrystallization method, an evaporation solvent crystallization method, or a temperature-controlled crystallization method.

[0258] Preferably, the preparation method is an antisolvent addition recrystallization method, which includes the following steps: mixing the compound with a normal solvent and filtering to obtain a filtrate; adding an antisolvent dropwise to the filtrate while stirring to induce crystallization.

[0259] Preferably, the positive solvent is 1,4-dioxane, and the antisolvent is water; or The positive solvent is dichloromethane, and the antisolvent is acetonitrile.

[0260] Preferably, the mixing is selected from one or more of ultrasound, oscillation or heating, and the specific operation is not limited, as long as the dissolution of the compound can be achieved.

[0261] Preferably, the amount of the positive solvent should be as small as possible, and kept at the minimum amount that can dissolve the compound.

[0262] Preferably, the temperature of the antisolvent is 0-5°C.

[0263] The technical effects of this invention can be achieved at any point or sub-range value within the range of 0-5℃, including but not limited to 0℃, 0.5℃, 1℃, 1.5℃, 2℃, 2.5℃, 3℃, 3.5℃, 4℃, 4.5℃, and 5℃.

[0264] Preferably, the crystallization temperature is -20℃ to 5℃.

[0265] The technical effects of this invention can be achieved at any point or sub-range within the range of -20℃ to 5℃, including but not limited to -20℃, -19.5℃, -19℃, -18.5℃, -18℃, -17.5℃, -17℃, -16.5℃, -16℃, -15.5℃, -15℃, -14.5℃, -14℃, -13.5℃, -13℃, -12.5℃, -12℃, -11.5℃, and -1℃. 1℃, -10.5℃, -10℃, -9.5℃, -9℃, -8.5℃, -8℃, -7.5℃, -7℃, -6.5℃, -6℃, -5.5℃, -5℃, -4.5℃, -4℃, -3.5℃, -3℃, -2.5℃, -2℃, -1.5℃, -1℃, -0.5℃, 0℃, 0.5℃, 1℃, 1.5℃, 2℃, 2.5℃, 3℃, 3.5℃, 4℃, 4.5℃, 5℃.

[0266] Preferably, the preparation method is an evaporation solvent crystallization method, which includes the following steps: mixing the compound with a solvent to obtain a saturated clear solution, filtering, evaporating the solvent, and obtaining the crystal form; The solvent is a mixture of solvent A and cyclohexane; Solvent A is selected from one or two of isopropyl acetate, acetone, and petroleum ether.

[0267] Preferably, the mass-to-volume ratio of the compound to the solvent is 2-4 g: 60-90 mL.

[0268] The technical effects of this invention can be achieved by any point value or any sub-range value within the range of 2-4g: 60-90mL, including but not limited to 2g: 60mL, 2g: 60mL, 2g: 80mL, 4g: 60mL, 4g: 60mL, 4g: 80mL, 3g: 60mL, 3g: 60mL, 3g: 80mL, and 3g: 75mL.

[0269] More preferably, the mass-to-volume ratio of the compound to the solvent is 3g:75mL.

[0270] More preferably, the solvent is: ①A mixture of isopropyl acetate and cyclohexane; Alternatively, ② a mixture of acetone, petroleum ether, and cyclohexane.

[0271] Preferably, the volume ratio of isopropyl acetate to cyclohexane in ① is 1:1.8-2.2.

[0272] More preferably, the volume ratio of isopropyl acetate to cyclohexane in ① is 1:2.

[0273] Preferably, the volume ratio of acetone, petroleum ether, and cyclohexane in step ② is 6:1:1.8-2.2.

[0274] More preferably, the volume ratio of acetone, petroleum ether, and cyclohexane in step ② is 6:1:2.

[0275] Preferably, the preparation method is an evaporation solvent crystallization method, which includes the following steps: mixing the compound with a solvent to obtain a saturated clear solution, filtering it through a 0.4-0.6 μm filter membrane, evaporating the solvent from the filtrate, and crystallizing to obtain the final product.

[0276] Preferably, the preparation method is a temperature-controlled crystallization method, comprising the following steps: mixing the compound with a solvent, controlling the temperature to crystallize, and obtaining a crystal form; The solvent is a mixture of solvent C, solvent D and solvent E; The solvent C is isopropanol or ethyl acetate; The solvent D is n-hexane or n-heptane; The solvent E is ethanol or methyl tert-butyl ether.

[0277] More preferably, the solvent is: ③ A mixture of ethyl acetate, n-hexane, and ethanol; Alternatively, ④ a mixture of isopropanol, n-heptane, and methyl tert-butyl ether.

[0278] Preferably, the volume ratio of ethyl acetate, n-hexane, and ethanol in step ③ is 3:1:5.8-6.2; More preferably, the volume ratio of ethyl acetate, n-hexane, and ethanol in step ③ is 3:1:6.

[0279] Preferably, the volume ratio of isopropanol, n-heptane, and methyl tert-butyl ether in step ④ is 5:3:0.8-1.2; More preferably, the volume ratio of isopropanol, n-heptane, and methyl tert-butyl ether in step ④ is 5:3:1.

[0280] Preferably, the temperature control includes the following steps: heating to 45-55°C, filtering, and cooling the filtrate.

[0281] The filtrate is cooled down until it forms a solid, and then stirring is stopped immediately.

[0282] Thirdly, the present invention provides a drug comprising the crystal form described above.

[0283] Preferably, the dosage form of the drug is selected from pills, capsules, granules, powders, tablets, lozenges, or suspensions.

[0284] Preferably, the drug further includes a pharmaceutically acceptable carrier.

[0285] More preferably, the pharmaceutically acceptable carrier is selected from at least one of buffers, emulsifiers, stabilizers, diluents, binders, preservatives, lubricants, pH adjusters, cryoprotectants, flavoring agents, fillers, or antioxidants.

[0286] Preferably, the buffer is selected from at least one of sodium dihydrogen phosphate, sodium bicarbonate, ammonium bicarbonate, sodium acetate, citrate, histidine, and succinate.

[0287] Preferably, the emulsifier is selected from at least one of magnesium stearate, zinc stearate, calcium stearate, glyceryl stearate, sorbitan isostearate, sorbitan oleate, and polyglycerol-3 polyricinoleate.

[0288] Preferably, the stabilizer is selected from at least one of farnesian gum, agar, alginate, cellulose ether, and carboxymethyl chitosan.

[0289] Preferably, the diluent is selected from at least one of erythritol, mannitol, sorbitol, xylitol, lactose, sucrose, corn starch, potato starch, calcium phosphate, calcium citrate, and crystalline cellulose.

[0290] Preferably, the adhesive is selected from at least one of ethanol, starch paste, pregelatinized starch, dextrin, syrup, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyvinyl alcohol, polyethylene glycol, sodium alginate, polyvinylpyrrolidone, gum arabic, gelatin, and alginic acid.

[0291] Preferably, the preservative is selected from at least one of methylparaben, propylparaben, methylparaben, ethylparaben, propylparaben, chlorobutanol, thimerosal, mercuric oxycyanide, phenoxyethanol, chlorhexidine, benzoic acid, sodium benzoate, chlorocresol, benzalkonium bromide, benzalkonium chloride, and ethylparaben.

[0292] Preferably, the lubricant is selected from at least one of magnesium stearate, zinc stearate, glyceryl monostearate, polyethylene glycol, stearic acid, talc, sodium chloride, sodium oleate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearate fumarate, and poloxamer.

[0293] Preferably, the pH adjuster is selected from at least one of citric acid, fumaric acid, succinic acid, tartaric acid, malic acid, and ascorbic acid.

[0294] Preferably, the flavoring agent is selected from at least one of sweet orange flavoring, vanilla flavoring, strawberry flavoring, milk flavoring, banana flavoring, and cherry flavoring.

[0295] Preferably, the filler is selected from at least one of mannitol, xylitol, sorbitol, maltose, microcrystalline cellulose, glucose, lactose, sucrose, dextrin, starch, sodium alginate, and sodium bicarbonate.

[0296] Preferably, the antioxidant may be selected from at least one of L-cysteine ​​hydrochloride, L-cysteine ​​base, 4,4-(2,3-dimethyltetramethylenediamine), tocopherol-rich extracts (natural vitamin E), α-tocopherol (synthetic vitamin E), β-tocopherol, 6-tocopherol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, octyl gallate, dodecyl gallate, tert-butylhydroquinone (TBHQ), fumaric acid, malic acid, ascorbic acid (vitamin C), sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbate palmitate, and ascorbate stearate.

[0297] Preferably, the drug is a drug for treating, adjuvant treating, or improving cardiovascular diseases, liver diseases, metabolic diseases, and tumors.

[0298] More preferably, the cardiovascular disease includes viral myocarditis, chronic heart failure, mild to moderate congestive heart failure during basic treatment, angina pectoris, coronary heart disease, or arrhythmia.

[0299] More preferably, the liver disease includes viral hepatitis, subacute liver necrosis, or chronic active hepatitis.

[0300] More preferably, the metabolic disease includes metabolic syndrome or diabetic neuropathy.

[0301] More preferably, the cancer includes solid tumors.

[0302] Preferably, the solid tumor is selected from carcinoma, melanoma, sarcoma, and lymphoma.

[0303] Preferably, the solid tumor is selected from breast cancer, bladder cancer, colon cancer, rectal cancer, endometrial cancer, kidney (renal cell) cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, thyroid cancer, skin cancer, bone cancer, brain cancer, cervical cancer, liver cancer, stomach cancer, oral and oral cavity cancer, neuroblastoma, testicular cancer, uterine cancer, thyroid cancer, and vulvar cancer.

[0304] Preferably, the cancer includes leukemia.

[0305] More preferably, the leukemia is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AmL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CmL), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, and adult T-cell leukemia.

[0306] Fourthly, the present invention provides a cosmetic product comprising the crystal form.

[0307] Preferably, the cosmetics include toner, serum, lotion, face cream, sunscreen, face mask, hand cream, whitening cream, skin-awakening lotion, eye cream, antifreeze cream, lotion, perfume, liquid foundation, foundation cream, concealer, blush, lipstick, eyeshadow, or blush.

[0308] Fifthly, the present invention provides the use of the above-described crystal form in the preparation of a drug containing the compound 2-[(all-E)3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetradecenyl]-5,6-dimethoxy-3-methyl-p-benzoquinone.

[0309] Furthermore, the drug is a drug for treating, adjuvant treating, or improving cardiovascular diseases, metabolic diseases, and tumors.

[0310] The present invention has at least the following beneficial effects: 1. This invention provides a novel crystalline form of compound 2-[(all-E)3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetradecenyl]-5,6-dimethoxy-3-methyl-p-benzoquinone. Compared with the crystalline forms disclosed in the prior art, this invention has better technical effects in terms of crystalline form stability and formulation stability, with the improved stability manifested in photostability, high-temperature stability, and high-humidity stability.

[0311] 2. The stability of the new crystal form provided by this invention is significantly improved, especially the photostability, which solves the defects caused by poor photostability of coenzyme Q10 during storage, transportation and application, and provides more possibilities for the widespread application of coenzyme Q10 in the fields of medicine, food, cosmetics and other fields. Attached Figure Description

[0312] Figure 1The compound 2-[(all-E)3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetradecenyl]-5,6-dimethoxy-3-methyl-p-benzoquinone prepared in this invention 1 H-NMR spectrum.

[0313] Figure 2 This is an XRPD diagram of the crystal form of the present invention.

[0314] Figure 3 This is the DVS diagram of the crystal form of the present invention.

[0315] Figure 4 The HPLC chromatogram of crystal form A in the prior art is shown at 0h.

[0316] Figure 5 This is the HPLC chromatogram of the crystal form of the present invention at 0h.

[0317] Figure 6 The image shows the HPLC chromatogram of crystal form A under natural light for 72 hours, according to existing technology.

[0318] Figure 7 This is the HPLC chromatogram of the crystal form of the present invention under natural light for 72 hours.

[0319] Figure 8 The HPLC chromatogram of crystal form A in the prior art after 72 hours in a light chamber is shown.

[0320] Figure 9 This is the HPLC chromatogram of the crystal form of the present invention after 72 hours in a light-illuminated chamber. Detailed Implementation

[0321] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0322] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all instruments, devices, equipment, reagents, products, etc., used in the embodiments of the present invention are obtained through conventional commercial means.

[0323] In the following specific embodiments, crystal form A refers to: according to the prior art "Design of Coenzyme Q10 soliddispersion for improved solubilization and stability" (Jin-Seok, et al. International journal of pharmaceutics 572(2019):118832-118832.), using Cu-Kα radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in 2θ value ±0.2° include 11.3±0.2°, 18.7±0.2°, 22.5±0.2°, and also include at least one of 11.7±0.2°, 14.1±0.2°, 20.2±0.2°, 22.8±0.2°, and 23.3±0.2°.

[0324] Instruments and testing methods X-ray powder diffraction (XRPD) was performed using a SmartLab 3W X-ray powder diffractometer. The parameters for the X-ray powder diffraction method are as follows: X-ray source: Cu Ka; Voltage: 40 kilovolts (kV); Current: 40 milliamperes (mA); Scan range: 2θ from 3.0 to 40.0 degrees; Scanning speed: 20.00 deg / min; Thermogravimetric analysis (TGA) plots were acquired on a Mettler TGA2, with the following method parameters: Test temperature: room temperature to 350℃; Heating rate: 10℃ / min; Protective gas: Nitrogen; Differential scanning calorimetry (DSC) plots were acquired on a Mettler DSC3. The method parameters for differential scanning calorimetry (DSC) analysis are as follows: Scan rate: 10 ℃ / min; Test temperature: room temperature to 350 degrees Celsius; Protective gas: Nitrogen; Dynamic moisture adsorption (DVS) maps were acquired on an SMS (surface measurement system) DVS intrinsic, with the following method parameters: Test temperature: 25℃; Sample amount: 20 mg; Gas and flow rate: Nitrogen, 200 mL / min; Minimum stay time: 0 min; Maximum stay: 180 minutes; Humidity range: 0%RH - 90%RH - 0%RH (0%RH - 90%RH; 90%RH - 0%RH, with a 10%RH interval between each step); The specific steps are as follows: Weigh 20 mg of the crystal form sample of the present invention and place it in the DVS instrument; the program is set to: 0%RH-90%RH-0%RH, with an interval of 10%RH between each step. After the test is completed, the sample is recovered and the XRPD after testing its hygroscopicity is tested.

[0325] Methods for analyzing impurity content: The chromatographic conditions are as follows: High-performance liquid chromatography (HPLC) was used to collect sample purity data. The chromatographic conditions were as follows: Instrument: Waters ACQUITY ARCHPL (W2998PDA); Column: Agilent Poroshell 120 EC-C18 4.6×150mm, 4μm; Mobile phase: MeOH / EtOH 1:1; Detector: W2998PDA; Column temperature: 30℃; Flow rate: 1.0 mL / min; Injection volume: 50 μL; Needle washing solvent: 50% MeOH; Diluent: EtOH.

[0326] Basic Example 1: Synthesis of oxidized coenzyme Q10 as a starting material: 28.0 g of decaisoprene alcohol (purchased from Yichang Zhongyitai Trading Co., Ltd.) was dissolved in 400 mL of a petroleum ether:diethyl ether (1:1) mixture with stirring. 7.6 g of 2,3-dimethoxy-5-methyl-hydroquinone (purchased from Keanlong (Tianjin) Industrial Co., Ltd.) was added and stirred until dissolved. Then, 4.4 g of anhydrous zinc chloride and 0.32 mL of glacial acetic acid were added. The mixture was stirred under nitrogen protection for 3 h. Nitrogen gas was then stopped, and 72 g of 30% ferric chloride solution was added. The mixture was stirred at room temperature for 1 h. The organic phase was collected after standing and separating into layers. It was washed with 5 wt% brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain an orange-red oily substance. Ethanol was added to give a yellow solid. The 1H NMR spectrum is attached. Figure 1The compound identified as 2-[(all-E)3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetradecenyl]-5,6-dimethoxy-3-methyl-p-benzoquinone was selected as the starting material for subsequent experiments.

[0327] Example 1 1.1 Preparation (1) Preparation - Batch 1 2.5 g of the compound obtained in Basic Example 1 was added to a beaker containing 50 mL of petroleum ether as a starting material and stirred until dissolved, yielding a 50 mg / mL petroleum ether solution of the compound. This solution was rapidly added to an ethanol solution containing PVP K30 (where the mass fraction of PVP K30 was 0.3%, and the volume ratio of ethanol to petroleum ether solution was 6:1), and mixed and stirred under controlled temperature conditions in a propylene glycol-ethanol (coolant) bath (stirring rate 4000 r / min, stirring time 10 min), continuously precipitating crystals to form a pale yellow suspension. The suspension was filtered through a Buchner funnel and washed with ethanol to remove residual petroleum ether and surfactant. The collected wet powder was frozen at -40°C for 2 h, and then freeze-dried under vacuum (vacuum pressure 10-50 Pa, freezing temperature -45°C to 50°C) to obtain a yellow dry particulate solid.

[0328] The obtained solid was subjected to crystal form XRPD diffraction analysis using the method described in the embodiments of this application. The diffraction angle (2θ) of the obtained solid crystal exhibited diffraction peaks at 11.3±0.2°, 11.7±0.2°, 14.1±0.2°, 18.7±0.2°, 20.2±0.2°, 22.5±0.2°, 22.8±0.2°, and 23.3±0.2°. Comparison with the characteristic peaks of crystal forms disclosed in the prior art confirms that it is a known crystal form, defined as crystal form A.

[0329] (2) Preparation - Batch 2 In a 100mL three-necked flask, add 60mL of anhydrous ethanol and 15mL of isobutanol. While stirring, add 5g of the compound obtained in Basic Example 1 as the starting material. Heat to 55-60℃ to dissolve, filter, pour the filtrate into a 100mL three-necked flask, stir and cool, crystallize, grow crystals, centrifuge, wash with a small amount of anhydrous ethanol, and dry at 35-40℃ to obtain a yellow crystalline solid.

[0330] (3) Preparation - Batch 3 In a 100 mL three-necked flask, 50 mL of cyclohexane and 25 mL of isopropyl acetate were added. 3 g of the compound prepared in Basic Example 1 was added as the starting material while stirring. The mixture was heated to 50 °C to dissolve, filtered, and the filtrate was transferred to a 100 mL three-necked flask. The mixture was concentrated under reduced pressure and dried at 35-40 °C to obtain a yellow crystalline solid.

[0331] 1.2 Product stability test The stability test method for all batches of products prepared above was as follows: approximately 5 mg of sample was weighed and placed in a vial, and stability studies were conducted under high humidity (25ºC / 60% RH) and light (25ºC / 4500 Lux) conditions, respectively. HPLC tests were performed on samples taken at 0 days and 30 days.

[0332] The results are shown in Table 1 below: Table 1

[0333] As shown in Table 1, through stability tests of different batches of products, the inventors found that there were significant differences in the stability of different batches of products under light conditions. The product obtained in batch 3 showed significantly better light stability than other batches, while the products obtained in other batches had poor light stability and the amount of impurities increased far beyond the standard of less than 1% for total impurities stipulated in the pharmacopoeia.

[0334] 1.3 Identification of the crystal form of this invention: Based on the aforementioned differences in performance, further research and characterization were conducted on the product obtained in batch 3. It was found that the crystal form of the product obtained in batch 3 differed from other batches and known crystal forms, as shown in its XRPD diffraction pattern. Figure 2 As shown.

[0335] It has been confirmed that the main characteristic diffraction peaks in the above-mentioned diffraction peaks include 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, and 27.39. The characteristic diffraction peaks of this crystal form are significantly different from those of the known crystal form A, indicating a new crystal form, which is named the crystal form of this invention. Figure 2 The XRPD diffraction pattern of the crystal form of this invention is shown.

[0336] The DSC results of the crystal form of this invention show that an endothermic peak appears at 49.67℃; the TGA results show that its weight loss is only 0.37% before 100℃; the above data indicate that the crystal form of this invention is an amorphous form.

[0337] The DVS evaluation results of the crystal form of this invention are as follows: Figure 3 As shown, the results indicate that the crystal form of the present invention has a moisture absorption weight gain of 0.07% at 25℃ / 80% humidity, which, according to the Chinese Pharmacopoeia, is considered to be non-hygroscopic or almost non-hygroscopic, and the crystal form remains unchanged before and after DVS.

[0338] 1.4 Determination of the bulk density of the crystal form of the present invention: The bulk density was measured according to the first method disclosed in the Chinese Pharmacopoeia (2020 edition). Specifically, one accurately graduated sample vial was weighed using a balance with a weight of 0.01%. The crystal form of the present invention was allowed to fall freely into the vial until the top of the solid was level with the 1 mL mark. The top was then gently scraped flat with a spatula. The total loose weight of each sample was accurately weighed, and the bulk density of the crystal form of the present invention was calculated to be 0.45 g / mL.

[0339] Example 2 Crystal sieve test When the inventors discovered that there were significant differences in the stability of different batches of products, and that the crystal form obtained through crystal form characterization was different from the known crystal form in the prior art, they conducted crystal sieve tests on the crystal form system in order to obtain crystal forms with further differences in properties.

[0340] 2.1 Recrystallization by Antisolvent Addition Method Weigh approximately 20 mg of sample into a 5 mL glass vial. Simultaneously, pre-cool the corresponding antisolvent at 5°C. Dissolve the sample in the corresponding normal solvent at room temperature (using methods such as sonication, shaking, and heating, using the minimum amount of solvent possible to ensure a higher solution concentration), and filter through a 0.45 μm nylon filter. Reserve the filtrate. Then, stir the normal solvent filtrate while slowly adding the antisolvent dropwise to induce crystallization. Once a solid forms, immediately stop stirring and characterize with XRPD. If the sample is clear, place it at 5°C and continue stirring; if it remains clear, transfer it to -20°C and continue stirring until a solid forms for characterization. Each vial was wrapped in aluminum foil during the experiment to prevent photodegradation. The results of the antisolvent addition method are shown in Table 2. Table 2 Group normal solvent antisolvent Crystal form 1 Tetrahydrofuran ethanol Crystal form A 2 ethanol water Crystal form A 3 1,4-Dioxane water Crystal form of the present invention 4 acetone water Crystal form A 5 Methyl isobutyl ketone methanol Crystal form A 6 2MeTHF ethanol amorphous 7 THF water Crystal form A 8 aniline ethanol amorphous 9 dichloromethane Acetonitrile Crystal form of the present invention 10 dichloromethane Isopropanol Crystal form of the present invention 2.2 Evaporation Solvent Crystallization Method Approximately 20 mg of sample was weighed into a 5 mL glass bottle. A certain amount of solvent was added to dissolve the sample, resulting in a saturated, clear solution. This solution was then filtered through a 0.45 μm nylon filter. The filtrate was collected in another glass bottle, which was then sealed with aluminum foil with 3-5 small holes punched in it to ensure slow evaporation of the solvent in the environment. The solid was collected for XRPD characterization. Each vial was wrapped with aluminum foil during the experiment to prevent photodegradation. The results of the solvent evaporation crystallization method are shown in Table 3 below. Table 3 Group solvent Crystal form 11 petroleum ether Crystal form A 12 Cyclohexane Crystal form A 13 Isopropanol / n-heptane (3%, v:v) amorphous 14 Cyclohexane / isopropyl acetate (2:1, v / v) Crystal form of the present invention 15 Cyclohexane / ethyl acetate (1.6:1, v:v) amorphous 17 Ethyl acetate / n-hexane (5%, v:v) amorphous 19 Ethyl acetate / petroleum ether (7%, w / w) Crystal form A 20 Acetone / petroleum ether / cyclohexane (6:1:2) Crystal form of the present invention 21 1,4-Dioxane / n-heptane (1:1, v:v) amorphous 22 Petroleum ether / diethyl ether (3:1, v / v) amorphous 2.3 Temperature-controlled crystallization method Approximately 20 mg of sample was weighed into a vial, and the appropriate solvent was added. The system was stirred at 25°C to form a suspension, and then stirred at a high temperature (50°C) until the solution became clear. After cooling, crystallization occurred. Once a solid was formed, stirring was immediately stopped, and the solution was characterized by XRPD. Each vial was wrapped in aluminum foil during the experiment to prevent photodegradation. The results of the cooling crystallization method are shown in Table 4 below. Table 4 Group solvent Crystal form 23 Anhydrous ethanol Crystal form A 24 methanol Crystal form A 25 95% ethanol Crystal form A 26 Isopropanol Crystal form A 27 n-Propanol Crystal form A 28 tert-Butanol Crystal form A 29 n-Pentanol Crystal form A 30 acetone Crystal form A 31 dipropylene glycol Crystal form A 32 Diethyl ether Crystal form A 33 Ethyl acetate Crystal form A 34 Methyl acetate Crystal form A 35 Butyl acetate amorphous 36 n-Hexane Crystal form A 37 DMF Crystal form A 38 Ethanol / dimethyl ether (4.2:1, v:v) Crystal form A 39 Isopropanol / ethyl acetate (21.7:1, v:v) Crystal form A 40 Anhydrous ethanol / isobutanol (4:1, v:v) Crystal form A 41 Anhydrous ethanol / isopropanol (2:1, v:v) Crystal form A 42 Anhydrous ethanol / n-propanol (2:1, v:v) Crystal form A 43 Methanol / butyl acetate (1:1.5, w:w) Crystal form A 44 Cyclohexane / isopropanol (1:1, w:w) Crystal form A 45 Methanol / ethyl acetate (1:1, v:v) Crystal form A 46 Acetone / ethanol (1:4, v:v) Crystal form A 47 Butanone / ethanol (1:1, v:v) Crystal form A 48 Acetone / ethanol (2:1, v:v) Crystal form A 49 2-Pentyl ketone / methanol (1:6, v:v) Crystal form A 50 Butanone / ethanol (1:12, v:v) Crystal form A 51 Ethanol / tetrahydrofuran (4:1, v:v) amorphous 52 Acetone / petroleum ether (1:1, v:v) amorphous 53 Ethyl acetate / n-hexane / ethanol (3:1:6, v:v:v) Crystal form of the present invention 54 Isopropanol / n-heptane / methyl tert-butyl ether (5:3:1, v:v:v) Crystal form of the present invention 2.4 Antisolvent Coupled Cooling Crystallization Method A certain amount of sample and 8.8756 g of tetrahydrofuran were added to a crystallizer. The temperature in the crystallizer was maintained at 303.15 K, and the mixture was stirred at 200 r / min until completely dissolved, resulting in an initial concentration of 18%. Ethanol (the volume ratio of the positive solvent tetrahydrofuran to the antisolvent ethanol was 1:7) was added dropwise to the solution at 2.0 mL / min, along with 2% seed crystals. The temperature was lowered to 282.15 K at 0.5 K / min, and the mixture was crystallized and matured for 90 min. The mixture was filtered, the filter cake was washed with ethanol, and then air-dried at room temperature. The resulting solid was characterized by XRPD using the method described in this application. The diffraction angles (2θ) of the obtained solid crystal showed diffraction peaks at 11.3±0.2°, 11.7±0.2°, 14.1±0.2°, 18.7±0.2°, 20.2±0.2°, 22.5±0.2°, 22.8±0.2°, and 23.3±0.2°. By comparing the characteristic peaks with those of the crystal forms disclosed in the prior art, its known crystal form is defined as crystal form A.

[0341] Example 3 Impurity changes in crystal form A and the crystal form of this invention were tested under illumination (natural light, light box) conditions. The HPLC detection method is as described in the embodiments of this application. The results are shown in Tables 5 and 5 (continued). Figures 4-9 As shown: Table 5

[0342] Table 5 (continued)

[0343] Note: ND indicates not detected.

[0344] As can be seen from Tables 5 and 5 (continued), under illumination conditions (including natural light and an illuminated chamber), the content of crystal form A decreases significantly with increasing time. The content of some known impurities (such as impurities with RRT=0.81) increases significantly, even exceeding the single impurity limit (0.5%). Some unknown impurities (such as impurities with RRT=0.57) begin to form, and their content even exceeds the single impurity limit (0.5%). In contrast, under illumination conditions, the content of the crystal form of this invention remains basically stable with increasing time, with virtually no change or almost no impurity formation.

[0345] Therefore, crystal form A must be strictly protected from light during production and storage, and special treatment measures or packaging must be taken to prevent the compound from being affected by light, which increases production and storage costs. Moreover, crystal form A will develop photochemical degradation product impurities (including unknown impurities with RRT=0.096, RRT=0.24, RRT=0.25, RRT=0.57, and RRT=0.63) over time during storage.

[0346] Furthermore, according to the Chinese Pharmacopoeia (2020 Edition, Part II), the content of a single impurity must not exceed 0.5%, and the total impurities must not exceed 1.0%. If crystal form A is not subjected to strict light-protection measures during production and storage, the impurity content (including single and total impurities) will increase significantly, exceeding the Chinese Pharmacopoeia standard. This necessitates repeated crystallization, preventing its direct use in the formulation process; recrystallization is required before it can be used in the next stage of formulation production. In contrast, the crystal form of this invention has no special requirements for production and storage conditions, saving production and storage costs and reducing the possibility of photochemical degradation products appearing over time during storage.

[0347] Application Example 1 Crystal form A and the crystal form of the present invention are prepared into formulations according to the formulations in Table 6 below.

[0348] Table 6 Material Name Prescription (mg / tablet) Prescription percentage (wt%) Coenzyme Q10 10.00 10.00 Hydroxypropyl cellulose 1.50 1.50 lactose 56.00 56.00 microcrystalline cellulose 21.00 21.00 Brazilian carnauba wax 0.50 0.50 Carboxymethyl cellulose calcium 10.00 10.00 colloidal silica 0.50 0.50 Calcium stearate 0.50 0.50 total 100.00 100.00 Preparation process: (1) Premixing: Weigh the raw materials (crystal form A or the crystal form of this invention), hydroxypropyl cellulose (commercially available, purchased from Japan Soda Co., Ltd.), lactose (commercially available, purchased from DMV-Fonterra Excipients GmbH & Co. KG), microcrystalline cellulose (commercially available, purchased from Japan Asahi Kasei Corporation), and calcium carboxymethyl cellulose (commercially available, purchased from Bolak Co., Ltd.), and then mix each raw material with purified water for 4 minutes to obtain a mixed powder; (2) Wet granulation: The mixed powder is granulated using a wet granulator. The granulator blade speed is 900 rpm and the stirring speed is 300 rpm. Water is added for granulation, and the process is run for 60 seconds. Then, a second granulation is performed with the granulator blade speed at 1500 rpm and the stirring speed at 300 rpm for 30 seconds. (3) Drying and granulation: The particles obtained by wet granulation are dried by fluidized bed drying, and then colloidal silica (commercially available, purchased from Evonik Operations GmbH) is granulated together with the dry particles; (4) Premixing: Add the granulated material, microcrystalline cellulose (commercially available, purchased from Asahi Kasei Corporation, Japan) and calcium carboxymethyl cellulose (commercially available, purchased from Bolak Co., Ltd.) to the mixer hopper for premixing; (5) Final mixing: Add magnesium stearate (commercially available, purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd.) to the premixed material and perform final mixing; (6) Tableting: The final mixed material is added to a double-outlet high-speed tablet press and tableted to obtain the tablets (Formulation 1 uses the crystal form of the present invention as raw material, and Formulation 2 uses crystal form A as raw material), with a specification of 100mg / tablet and a total of 500 tablets.

[0349] Application Test Case 1 Stability tests of the formulation under high temperature, high humidity, and light exposure: To further investigate the effects of different crystal forms on the impurities and content of the formulation, stability tests were conducted on formulation 1 containing the crystal form of the present invention and formulation 2 containing crystal form A, as follows: Weigh 5 mg of the sample and place it into a vial. Stability studies were conducted under high temperature (40ºC), high humidity (92.5% RH), and light conditions. HPLC tests were performed at 0, 14, or 30 days.

[0350] The stability results of the formulation are shown in Table 7 below: Table 7

[0351] As shown in Table 7, under 30 days of high temperature and high humidity conditions, the total impurities in Formulation 2 containing crystal form A increased significantly, with a slight decrease at high temperature and a relatively constant content under high humidity conditions. Under 14 days of light exposure conditions, the total impurities in Formulation 2 increased, while the content decreased significantly. In contrast, under 30 days of high temperature and high humidity conditions, the total impurities in Formulation 1 containing the crystal form of this invention remained essentially unchanged, while the content remained essentially constant. Under 14 days of light exposure conditions, the total impurities in Formulation 1 changed slightly, while the content remained essentially constant. Therefore, Formulation 1 exhibits better stability than Formulation 2 under the same conditions, making it easier to store and transport, thus saving on storage and transportation costs.

[0352] Application Test Example 2 Dissolution stability test of formulation: The stability test method for formulation 1 containing the crystal form of the present invention and formulation 2 containing crystal form A, prepared in the above application test example 1, was as follows: 5 mg of sample was weighed and placed in a vial, and stability studies were conducted under high temperature (40ºC) and high humidity (92.5% RH) conditions. Samples were taken at 0 days (same as parameter control), 10 days, and 30 days to test the dissolution of the formulations. Dissolution conditions: Agilent, slurry method, 900 mL, 50 rpm, 5% Triton (octylphenol polyoxyethylene ether, density 1.07 g / mL, pH 6.0-8.0). The results are shown in Table 8 below: Table 8

[0353] As shown in Table 8, under high-temperature testing conditions, the dissolution of formulation 2 containing crystal form A showed significant changes before 1 hour, reaching a dissolution plateau after 1 hour. Dissolution accelerated significantly by day 10, and increased slightly by day 30 compared to day 10. Under high-humidity testing conditions, the dissolution of formulation 2 remained essentially unchanged by day 0 after day 10, but there was virtually no dissolution before day 15 by day 30, and dissolution slowed significantly after day 15. In contrast, formulation 1 containing the crystal form of this invention showed essentially unchanged dissolution by day 0 under both high-temperature and high-humidity testing conditions, whether at day 10 or day 30. Therefore, the dissolution stability of formulation 1 containing the crystal form of this invention is significantly higher than that of formulation 2 containing crystal form A, making it easier to store and transport, better ensuring the consistency of (therapeutic) effects, and reducing fluctuations in efficacy or adverse reactions caused by dissolution differences.

[0354] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A crystal form of a compound 2-[(all-E)3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetradecenyl]-5,6-dimethoxy-3-methyl-p-benzoquinone, characterized in that, Characteristic diffraction peaks of X-ray powder diffraction, expressed in 2θ values ​​± 0.2°, using Cu-Kα radiation, include 4.70, 6.25, 15.65, 17.22, 19.18, 20.45, and 27.

39.

2. The crystal form according to claim 1, characterized in that, Characteristic diffraction peaks of X-ray powder diffraction, expressed in 2θ values ​​± 0.2°, using Cu-Kα radiation, also include any one or more of 3.14, 18.79, 22.96, 23.50, and 30.

45.

3. The crystal form according to claim 1 or claim 2, characterized in that, Characteristic diffraction peaks of X-ray powder diffraction, expressed in 2θ values ​​± 0.2°, using Cu-Kα radiation, also include any one or more of 7.80, 9.38, 14.05, 28.67, and 29.

73.

4. The crystal form according to claim 1 or claim 2, characterized in that, Characteristic diffraction peaks of X-ray powder diffraction, expressed in 2θ values ​​± 0.2°, using Cu-Kα radiation, also include any one or more of 10.88, 12.50, 20.72, 21.10, 22.05, 24.72, and 25.

76.

5. The method for preparing the crystal form according to any one of claims 1-4, characterized in that, The preparation method is the antisolvent addition recrystallization method, the solvent evaporation crystallization method, or the temperature-controlled crystallization method.

6. The preparation method according to claim 5, characterized in that, When the preparation method is an antisolvent addition recrystallization method, it includes the following steps: Compound 2-[(all-E)3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetradecenyl]-5,6-dimethoxy-3-methyl-p-benzoquinone was mixed with a normal solvent and filtered to obtain a filtrate; the antisolvent was added dropwise to the filtrate while stirring to induce crystallization. The positive solvent is 1,4-dioxane, and the antisolvent is water; or, the positive solvent is dichloromethane, and the antisolvent is acetonitrile or isopropanol.

7. The preparation method according to claim 5, characterized in that, When the preparation method is the solvent evaporation crystallization method, it includes the following steps: compound 2-[(all-E)3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetradecenyl]-5,6-dimethoxy-3-methyl-p-benzoquinone is mixed with a solvent to obtain a saturated clear solution, filtered, and the solvent is evaporated to obtain the crystal form; The solvent is a mixture of solvent A and cyclohexane; Solvent A is selected from one or two of isopropyl acetate, acetone, and petroleum ether.

8. The preparation method according to claim 7, characterized in that, The solvent is: ①A mixture of isopropyl acetate and cyclohexane; Or ② a mixture of acetone, petroleum ether and cyclohexane.

9. The preparation method according to claim 7, characterized in that, When the preparation method is the solvent evaporation crystallization method, it includes the following steps: the compound is mixed with a solvent to obtain a saturated clear solution, which is then filtered through a 0.4-0.6 μm filter membrane. The filtrate is evaporated to evaporate the solvent, and crystallization occurs to obtain the final product.

10. The preparation method according to claim 5, characterized in that, When the preparation method is a temperature-controlled crystallization method, it includes the following steps: compound 2-[(all-E)3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetradecenyl]-5,6-dimethoxy-3-methyl-p-benzoquinone is mixed with a solvent, and the crystallization is controlled at a controlled temperature to obtain the crystal form; The solvent is a mixture of solvent C, solvent D and solvent E; The solvent C is isopropanol or ethyl acetate; The solvent D is n-hexane or n-heptane; The solvent E is ethanol or methyl tert-butyl ether.

11. The preparation method according to claim 10, characterized in that, The solvent is: ③ A mixture of ethyl acetate, n-hexane, and ethanol; Alternatively, ④ a mixture of isopropanol, n-heptane, and methyl tert-butyl ether.

12. A drug, characterized in that, Includes the crystal form described in any one of claims 1-4.

13. The medicament according to claim 12, characterized in that, The dosage form of the drug is selected from pills, capsules, granules, powders, tablets, lozenges, or suspensions.

14. The medicament according to claim 12, characterized in that, The drug also includes a pharmaceutically acceptable carrier selected from at least one of buffers, emulsifiers, stabilizers, diluents, binders, preservatives, lubricants, pH adjusters, cryoprotectants, flavoring agents, fillers, or antioxidants.

15. A cosmetic product, characterized in that, Includes the crystal form described in any one of claims 1-4.

16. The cosmetic product according to claim 15, characterized in that, The cosmetics include toners, serums, lotions, face creams, sunscreens, face masks, hand creams, whitening creams, skin-awakening lotions, soothing eye creams, antifreeze creams, lotions, perfumes, liquid foundations, foundation creams, concealers, blush, lipsticks, eyeshadows, or blushes.

17. The use of the crystal form according to any one of claims 1-4 in the preparation of a medicament containing the compound 2-[(all-E)3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetradecenyl]-5,6-dimethoxy-3-methyl-p-benzoquinone.

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