Crystal form of tegoprazan compound, and preparation method therefor and use thereof

Abstract

The present invention relates to a crystal form DCVI of a tegoprazan compound and a preparation method therefor, a pharmaceutical composition comprising the crystal form, and the use of the crystal form in the preparation of a medicament for treating diseases associated with the need to control the pH value of gastric fluid, for example, for treating gastroesophageal reflux disease and erosive esophagitis. The new crystal form DCVI of the tegoprazan compound provided by the present invention is of great value for the future development of the medicament.

Description

Crystal forms, preparation methods and uses of tegoraden compounds Technical Field This invention relates to the field of medicinal chemistry. Specifically, it relates to the crystal forms of ticoraxone compounds, their preparation methods, and their uses. Background Technology Excessive stomach acid and acid reflux are common digestive system disorders, such as gastroesophageal reflux disease (GERD) and gastric ulcers. Traditional medications for treating excessive stomach acid mainly include histamine H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs), but these drugs have some drawbacks, such as slow onset of action, the need for multiple doses, and genotypic influence. To overcome these shortcomings, scientists have begun developing novel acid-suppressing drugs. Potassium-competitive acid blockers (P-CABs) have emerged, which inhibit gastric acid secretion by competitively blocking the K+ binding site on H+ / K+-ATPases on gastric parietal cells. Compared to traditional PPIs, P-CABs have advantages such as rapid onset of action, long-lasting and potent acid suppression, and are unaffected by food intake or genotype. Gastric acid is secreted by parietal cells, and H+ / K+-ATPase is a key enzyme in gastric acid secretion. Traditional PPIs require an acidic environment to be converted into their active form to exert their effects, and they irreversibly bind to H+ / K+-ATPase, resulting in slow onset and limited duration of action. However, tegoprazan (trade name: Tegorazan) does not require activation in an acidic environment to function. It competitively and reversibly binds to the K+ binding site on H+ / K+-ATPase, thereby inhibiting gastric acid secretion. This mechanism of action gives tegoprazan the advantages of rapid onset and long-lasting acid suppression. Furthermore, tegoprazan's inhibition of H+ / K+-ATPase is not affected by the de novo synthesis of proton pumps within gastric parietal cells, thus achieving maximum inhibitory effect more quickly and with a longer duration of action. Tegoprazan, also known as tegoprazan or CJ-12420, was approved for marketing by the Korean Ministry of Food and Drug Safety (MFDS) in July 2018 for the treatment of gastroesophageal reflux disease and erosive esophagitis. The chemical name of tegoprazan is (S)-4-((5,7-difluorochroman-4-yl)oxy)-N,N,2-trimethyl-1H-benzo[d]imidazol-6-carboxamide. Its chemical structure contains a benzimidazole structure and a chiral 5,7-difluorochroman-4-oxy structure. The specific chemical structure is as follows: Crystal form refers to the solid state of a compound's solid molecules, which are arranged in a long-range ordered lattice within a three-dimensional microscopic structure. Drug polymorphism refers to the phenomenon where solid drug molecules exist in two or more different crystal forms. Because different crystal forms have different physicochemical properties, different crystal forms of solid drug molecules may exhibit different dissolution and absorption rates in vivo, thus affecting the clinical efficacy and safety of the drug to some extent. This is especially true for poorly soluble solid drugs, where crystal form has a greater impact on bioavailability. Therefore, drug crystal form is a crucial aspect of solid-state drug research and development, and also an important component of drug quality control. Technical issues Existing patent CN107207478B discloses a crystal form A of tigoracic acid. Although crystal form A has good stability, tigoracic acid has very poor water solubility and belongs to the BCSII class of drugs. The low solubility of crystal form A will lead to poor drug absorption and efficacy. In summary, there is an urgent need in this field for a new crystal form of tegopralate that simultaneously possesses good solubility, good stability, good purification effect, and is suitable for industrial production, so as to meet the requirements of drug bioavailability, suitability for industrial development, and comprehensive performance in all aspects that meet the requirements of pharmaceutical development. Technical solutions The inventors of this application have discovered different crystal forms of the compound tigorase provided by this invention, which have advantages in terms of physicochemical properties, formulation processing performance and bioavailability. For example, they have advantages in at least one aspect of melting point, solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, flowability, in vivo and in vitro dissolution, and bioavailability. This provides a better option for the development of drugs containing the compound tigorase and is of great significance. The main objective of this invention is to provide a new crystal form of the compound ticoraxane, its preparation method, and its uses. According to the purpose of this invention, the present invention provides a crystal form of the compound ticoraxen. Furthermore, the present invention provides that the crystal form of the compound ticoraxane can be crystal form DCVI (hereinafter referred to as crystal form DCVI). On the one hand, using Cu-Ka radiation, the X-ray powder diffraction of the crystalline DCVI has characteristic peaks at one, two, or three of the diffraction angles 2θ values ​​of 17.2º±0.2º, 15.2º±0.2º, and 12.3º±0.2º. Furthermore, using Cu-Ka radiation, the X-ray powder diffraction of the crystalline DCVI exhibits characteristic peaks at one, two, or three of the diffraction angles 2θ values ​​of 11.9º±0.2º, 13.5º±0.2º, and 16.3º±0.2º; preferably, the X-ray powder diffraction of the crystalline DCVI exhibits characteristic peaks at three of the diffraction angles 2θ values ​​of 11.9º±0.2º, 13.5º±0.2º, and 16.3º±0.2º. Furthermore, using Cu-Ka radiation, the X-ray powder diffraction of the DCVI crystal form exhibits characteristic peaks at one, two, or three of the following diffraction angles with 2θ values: 24.9º±0.2º, 23.6º±0.2º, and 22.2º±0.2º; preferably, the X-ray powder diffraction of the DCVI crystal form exhibits characteristic peaks at three of the following diffraction angles with 2θ values: 24.9º±0.2º, 23.6º±0.2º, and 22.2º±0.2º. On the other hand, using Cu-Ka radiation, the X-ray powder diffraction of the crystalline DCVI exhibits characteristic peaks at diffraction angles of 11.9º±0.2º, 12.3º±0.2º, 13.5º±0.2º, 15.2º±0.2º, 16.3º±0.2º, 17.2º±0.2º, 21.0º±0.2º, 22.2º±0.2º, 23.6º±0.2º, 24.9º±0.2º, 26.5º±0.2º, and 27.8º±0.2º, at one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve locations. The non-restrictive X-ray powder diffraction pattern of the crystalline DCVI is shown in Figure 1. Without limitation, the crystalline DCVI begins to show an endothermic peak around 152 degrees, and the differential scanning calorimetry (DSC) curve is basically as shown in Figure 2. According to the purpose of this invention, this invention also provides a method for preparing the crystalline form DCVI, the method comprising: weighing a certain amount of the compound ticoralina into a glass bottle, adding a certain amount of ether solvent or a mixed solvent of ether and alkane, shaking thoroughly, recrystallizing at a certain temperature, and centrifuging to separate the solid to obtain the crystalline form DCVI. Furthermore, the selected temperature is preferably between -20 degrees and 30 degrees, and more preferably 0 degrees. According to the purpose of this invention, the present invention also provides a pharmaceutical composition comprising an effective therapeutic amount of crystalline DCVI and a pharmaceutically acceptable carrier or excipient. Furthermore, the present invention provides the use of crystalline DCVI in the preparation of medicaments for treating diseases related to the control of gastric pH. Beneficial effects The crystalline DCVI of the present invention has the following beneficial effects: (1) Compared with the prior art, the crystalline form DCVI of the present invention has higher solubility. Compared with crystalline form A reported in prior art CN107207478B, the crystalline form DCVI of the present invention has higher solubility in SGF (simulated gastric juice), FaSSIF (simulated intestinal juice under fasting state), and pure water. At 1 hour, 4 hours, and 24 hours, the solubility of the crystalline form DCVI of the present invention is higher than that of crystalline form A reported in prior art CN107207478B. Higher solubility is beneficial to improving the absorption of drugs in the human body, improving the bioavailability of drugs, and achieving better therapeutic effects with less drug loading; in addition, while ensuring the efficacy of the drug, reducing the drug loading can reduce the toxic side effects of the drug and improve the safety of drug use, which has important clinical significance. (2) Compared with the prior art, the crystalline form DCVI of the present invention has lower hygroscopicity. Compared with crystalline form A in CN107207478B, the crystalline form DCVI of the present invention has lower hygroscopic weight gain under conditions of 33%RH, 75%RH and 93%RH. This indicates that the crystalline form DCVI is less prone to deliquescence during drug production and storage, which is beneficial for sample preservation. At the same time, the lower hygroscopicity is beneficial for the production and preparation of pharmaceutical products during formulation production and preparation. Furthermore, the hygroscopicity of the crystalline form DCVI of this invention was investigated according to the methods in the pharmacopoeia (General Chapter 9103 of the Chinese Pharmacopoeia 2020, experimental conditions: 25 ± 1 ℃, 80% relative humidity). The results showed that the hygroscopic weight gain of the crystalline form DCVI was 0.04%. In addition, regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (General Chapter 9103 of the Chinese Pharmacopoeia 2020, experimental conditions: 25 ± 1 ℃, 80% relative humidity), the weight gain range of the crystalline form DCVI is defined as: hygroscopic weight gain less than 0.2%, which is considered to be non-hygroscopic or almost non-hygroscopic. The above results indicate that crystalline DCVI has lower hygroscopicity. Lower hygroscopicity ensures that the sample maintains low moisture gain and does not deliquescence during subsequent production, processing, storage, and transportation, thereby ensuring stable drug quality. (3) Compared with the prior art, the DCVI crystal form of the present invention has lower electrostatic induction and improved flowability. Compared with crystal form A of CN107207478B, the DCVI crystal form of the present invention shows higher packing density (BD) and tap density (TD), and the CI value of the DCVI crystal form of the present invention is lower than that of crystal form A of CN107207478B, thereby indicating that the DCVI crystal form of the present invention has lower electrostatic induction and better flowability than crystal form A of CN107207478B. The DCVI crystal form of this invention has lower electrostatic induction and improved flowability, which increases the convenience of this sample in the formulation process and drug production, improves the uniformity of the formulation product, and is of great significance to the production and quality of drugs. (4) The crystalline DCVI provided by this invention has good stability. The crystalline DCVI of this invention remained unchanged after being sealed for 6 months, 6 months, and 1 month under the conditions of 25 ℃ / 60%RH (relative humidity), 40 ℃ / 75%RH, and 60 ℃ / 75%RH, respectively. This indicates that the crystalline DCVI has good physical stability. In particular, under accelerated conditions of 40 ℃ / 75%RH and high temperature and humidity conditions of 60 ℃ / 75%RH, it remained stable for one month without crystal transformation. This further demonstrates that the crystalline DCVI still has good physical stability even under high temperature and humidity conditions. This ensures that the drug is not prone to crystal transformation during subsequent processes, production, and transportation. Good physical stability ensures that the drug maintains stable quality during subsequent formulation development and process production, as well as during drug production and transportation, which is of great significance for ensuring drug quality and efficacy. Furthermore, crystalline DCVI exhibits good mechanical stability. No crystal transformation occurred in crystalline DCVI before and after grinding, and no significant decrease in crystallinity was observed in the samples, indicating that crystalline DCVI possesses excellent mechanical stability. This good mechanical stability ensures that the samples will not easily undergo crystal transformation due to external forces such as mechanical grinding or pulverization during later formulation processes, reducing the risk of crystal transformation during formulation and improving the developability of the formulation process. Furthermore, DCVI crystals exhibit excellent humidity stability. After being placed under varying humidity levels (22.5%RH~93%RH) for one week, the crystal form of DCVI remained unchanged. This excellent humidity stability prevents mold or deliquescence during storage, thereby improving the quality stability of the drug and ensuring its consistent efficacy. Crystal form stability is crucial for drug development. Crystal transformation directly impacts drug solubility and, consequently, bioavailability, thus altering therapeutic efficacy. Good mechanical stability also enhances a drug's resistance to mechanical damage during formulation, reducing the risk of crystal transformation. Good humidity stability prevents mold growth or deliquescence during storage, improving drug stability and safety. Therefore, DCVI's excellent stability, mechanical stability, and humidity stability provide a guarantee for subsequent drug production and development, demonstrating high industrialization value. Furthermore, the crystalline DCVI of the present invention also has the following beneficial effects: The DCVI crystal form of this invention has a good purification effect and is very suitable for industrial production. After recrystallization to prepare the crystalline form DCVI of this invention, the chemical purity of the sample increased from 99.71% to 100%, indicating that the crystalline form DCVI has a good purification and impurity removal effect, which not only improves the quality and safety of the drug, but is also very suitable for large-scale industrial production. Attached Figure Description Figure 1 is an XRPD diagram of the crystal form DCVI obtained according to Example 1a; Figure 2 is a DSC diagram of the crystal form DCVI obtained according to Example 1a; Figure 3 shows a comparison of XRPD before and after grinding of the DCVI crystal form (the upper curve is the image before grinding, and the lower curve is the image after grinding). Figure 4 shows the XRPD comparison of the DCVI crystal form before and after one week of storage under different ambient humidity levels (from top to bottom: sample before storage; sample stored at RT / 22.5%RH for one week; sample stored at RT / 45%RH for one week; sample stored at RT / 75%RH for one week; sample stored at RT / 92%RH for one week). Figure 5 shows the XRPD comparison of the stability of the DCVI crystal form before and after placement (from top to bottom: sample before placement; sample placed at 25C / 60%RH for 6 months; sample placed at 40C / 75%RH for 6 months; sample placed at 60C / 75%RH for 1 month). The best embodiment of the present invention Example 1: Preparation method of crystalline DCVI A certain amount of the compound ticoralina was weighed and added to a glass bottle. A certain volume of an ether or a mixture of ether and alkane solvent was added at room temperature and the bottle was shaken thoroughly. The bottle was then placed on a magnetic stirrer and recrystallized at a specific temperature. After centrifugation, the solid was removed and XRPD was tested to obtain the crystal form DCVI. The selected solvents and recrystallization temperatures in specific embodiments are shown in Table 1 below. Table 1 Example Starting Material Solvent Solvent System Recrystallization Temperature 1a 500 mg isopropyl ether 10 ml 0°C 1b 20 mg isopropyl ether 0.3 ml -20°C 1c 20 mg 1,4-dioxane / n-heptane (1 / 2, volume ratio) 0.3 ml 0°C The XRPD diagram of the DCVI crystal form obtained in Example 1a is shown in Figure 1, and the XRPD data is shown in Table 2. The DSC diagram of the DCVI crystal form obtained in Example 1a is shown in Figure 2. Diffraction angle 2 thetad value Relative intensity % 5.86 15.07 4.26 11.85 7.47 68.96 12.32 7.18 79.03 13.52 6.55 11.44 15.19 5.83 19.58 16.34 5.43 37.39 17.19 5.16 100.00 17.95 4.94 8.76 19.00 4.67 7.01 19.42 4.57 8.16 20.17 4.40 14.09 20.77 4.28 20.18 21.04 4.22 42.06 22.19 4.01 46.25 22.94 3.88 29.08 23. 623.7760.7324.313.6626.0024.853.5838.7126.123.4117.3926.473.3718.5327.203.2819.7727.793.2121.0729.333.047.4030.232.967.6830.692.9123.9332.012.806.4032.602.7510.0334.242.623.7635.022.563.7036.892.442.8337.792.384.7138.662.331.57 Example 2: Dynamic solubility of crystalline DCVI When conducting drug solubility tests to predict drug performance in vivo, it is important to simulate in vivo conditions as closely as possible. For oral medications, SGF (simulated gastric juice), FaSSIF (fasting state simulated intestinal juice), or pure water can simulate in vivo conditions and predict the effects of fasting. Solubility tested in such media is closer to solubility in the human body environment. Approximately 20 mg each of the crystal form DCVI of this invention and the crystal form A of the prior art CN107207478B were suspended in 1.5 mL of SGF, 1.5 mL of FeSSIF and 1.5 mL of water to prepare suspensions. After equilibration for 1 hour, 4 hours and 24 hours, the content of the sample in the solution (mg / ml) was tested by high performance liquid chromatography. The experimental results are shown in Tables 3 and 4 below: Table 3 Table 4 Dynamic solubility experiments showed that, compared with crystal form A reported in CN107207478B, the crystal form DCVI of this invention has higher solubility in SGF (simulated gastric juice), FaSSIF (simulated intestinal juice under fasting conditions), and pure water. Example 3: Packaging stability of crystalline DCVI Approximately 5 mg of the crystalline DCVI prepared according to this invention was weighed and sealed in an aluminum foil bag. The bag was then placed under conditions of 25 ℃ / 60%RH, 40 ℃ / 75%RH, and 60 ℃ / 75%RH, and the crystal form was determined using XRPD. The experimental results are shown in Table 5 below, and the XRPD overlay is shown in Figure 5. Table 5 Storage conditions and storage time: Crystal form start-up – Crystal form DCVI 25 ℃ / 60%RH 6 months; Crystal form DCVI 40 ℃ / 75%RH 6 months; Crystal form DCVI 60 ℃ / 75%RH 1 month; Crystal form DCVI The results show that the DCVI crystal form of the present invention can remain stable for at least 6 months under conditions of 25 ℃ / 60%RH and 40 ℃ / 75%RH, and can remain stable for at least 1 month under conditions of 60 ℃ / 75%RH. Example 4: Mechanical stability of crystalline DCVI The DCVI crystal was placed in a mortar and manually ground for 5 minutes. XRPD tests were performed before and after grinding. The XRPD comparison before and after grinding is shown in Figure 3. The results show that the crystal form of DCVI remains unchanged after grinding, and no significant decrease in crystallinity is observed, which indicates that the crystal form DCVI has good mechanical stability. Example 5: Humidity stability of crystalline DCVI Weigh about 5 mg of the crystalline form DCVI prepared in this invention and expose it in the open at RT / 22.5%RH, RT / 43%RH, RT / 75%RH and RT / 92%RH for one week, respectively. Then, determine the crystalline form using XRPD. Figure 4 shows the XRPD comparison of the DCVI crystal form of the present invention before and after exposure to different environmental humidity conditions for one week. The results show that the DCVI crystal form of the present invention is stable and unchanged before and after exposure to different environmental humidity conditions for one week. This indicates that the DCVI crystal form has good humidity stability and can be stably stored at different humidity levels at room temperature. Example 6: Hygroscopicity of crystalline DCVI CN107207478B

[0054] The previous section reported on the hygroscopicity experiments of crystal form A. Compounds with low hygroscopicity are advantageous in formulation preparation and storage. To compare the hygroscopicity differences between crystal form A and the present invention's crystal form DCVI, hygroscopicity evaluation experiments were also conducted on the present invention's DCVI, and the results are shown in Table 6 below: Table 6 The results show that, compared with the crystal form A reported in CN107207478B, the crystal form DCVI of the present invention has lower hygroscopicity, which indicates that the crystal form DCVI is less prone to deliquescence during drug production and storage, which is beneficial for sample preservation. At the same time, the lower hygroscopicity is beneficial for the production and preparation of formulation products during the formulation production and preparation process. In addition, the hygroscopicity of the crystalline form DCVI was investigated according to the "Guidelines for Hygroscopicity Tests of Drugs in General Chapter 9103 of the 2020 Edition of the Chinese Pharmacopoeia". Specifically, approximately 20 mg of the crystalline form DCVI of this invention was weighed and placed at 25 ± 1 ℃ and 80% relative humidity for 24 hours, and the mass of the samples before and after the test was recorded. The specific results are shown in the table below. Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Chinese Pharmacopoeia 2020 Edition, General Chapter 9103, Guidelines for Hygroscopicity Tests of Drugs, Experimental Conditions: 25 ± 1 ℃, 80% relative humidity): Deliquescence: Absorbs sufficient water to form a liquid; Extremely hygroscopic: Hygroscopic weight gain not less than 15.0%; Hygroscopic: Hygroscopic weight gain less than 15.0% but not less than 2.0%; Slightly hygroscopic: Hygroscopic weight gain less than 2.0% but not less than 0.2%; No or almost no hygroscopicity: Hygroscopic weight gain less than 0.2%. Table 7 Initial mass (mg) Storage conditions Storage time Mass after storage (mg) Weight gain (mg) Weight gain percentage 52.94 25 ± 1 ℃, 80%RH 24 hours 52.96 0.02 0.04% The results show that the crystalline DCVI of the present invention has little or no hygroscopicity, indicating that the crystalline DCVI is not prone to deliquescence during the production and storage of pharmaceuticals. Example 7: Purification effect of crystalline DCVI Weigh 500 mg of a sample with a purity of 99.71%, add 10 mL of isopropyl ether, recrystallize at 0 degrees Celsius and stir for 3 days, then centrifuge to separate the solid. The solid was tested to be crystalline DCVI. HPLC results showed that the purity was 100%, indicating that crystalline DCVI has a good purification and impurity removal effect and is of great benefit in industrial production and scale-up processes. Example 8: Electrostatic induction experiment of crystalline DCVI CN107207478B

[0059] This paper reports on the electrostatic induction experiments of crystal form A. The purpose is to address the fact that, under pharmaceutical technology conditions, particularly the pharmacological conditions of conventional industrial pharmaceuticals, materials with high electrostatic induction are often difficult to process and not easily realized as drugs with uniform content. Researchers tested the electrostatic induction of the crystal form DCVI of the present invention and compared it with the electrostatic induction of crystal form A of CN107207478B. The results are shown in Table 8 below: Table 8 *Carl Index (CI): ≤30 - Good liquidity CI = 100 × (1 - BD / TD) As shown in Table 8, compared with crystal form A of CN107207478B, crystal form DCVI of the present invention shows higher packing density (BD) and tap density (TD), and the CI value of crystal form DCVI of the present invention is lower than that of crystal form A of CN107207478B. This indicates that crystal form DCVI of the present invention has lower electrostatic induction and better flowability compared with crystal form A of CN107207478B. As can be seen from the above, the DCVI crystal form of the present invention has lower electrostatic induction and improved flowability, which increases the convenience of the sample in the formulation process and drug production, improves the uniformity of the formulation product, and is of great significance to the production and quality of drugs. The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be used to limit the scope of protection of the present invention. Equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention. Embodiments of the present invention In this invention, the "stirring" is performed using conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm. Magnetic stirring is preferably performed at 300-900 rpm, and mechanical stirring is preferably performed at 100-300 rpm. The "separation" is accomplished using conventional methods in the art, such as centrifugation or filtration. The "centrifugation" operation is as follows: the sample to be separated is placed in a centrifuge tube and centrifuged at a rate of 10,000 rpm until all the solid settles to the bottom of the centrifuge tube. The "drying" can be carried out at room temperature or higher. The drying temperature is from room temperature to about 50°C, or up to 40°C. The drying time can be 2 to 48 hours, or overnight. Drying is carried out in a fume hood, forced-air oven, or vacuum oven. In this invention, "crystal" or "polymorphic" refers to a solid confirmed by X-ray powder diffraction (XPD) characterization. Those skilled in the art will understand that the physicochemical properties discussed herein can be characterized, and the experimental errors depend on instrument conditions, sample preparation, and sample purity. In particular, it is known to those skilled in the art that X-ray powder diffraction patterns typically vary with different instrument conditions. It should be particularly noted that the relative intensities of diffraction peaks in X-ray powder diffraction patterns may also vary with experimental conditions; therefore, the order of diffraction peak intensities cannot be considered the sole or decisive factor. In fact, the relative intensities of diffraction peaks in X-ray powder diffraction patterns are related to the preferred orientation of the crystal. The diffraction peak intensities shown in this invention are illustrative rather than intended for absolute comparison. Furthermore, experimental errors in diffraction peak positions are typically 5% or less, and these positional errors should also be taken into account, generally allowing for ±0.2%. Additionally, due to the influence of experimental factors such as sample thickness, an overall shift in diffraction peak angles may occur, and a certain degree of shift is generally permissible. Therefore, those skilled in the art will understand that the X-ray powder diffraction pattern of the protected crystal form of the present invention need not be completely identical to the X-ray powder diffraction pattern in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern with the same or similar characteristic peaks as those in these patterns is within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in this invention with an X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms. In some embodiments, the DCVI crystal form of the present invention is pure and substantially free of any other crystal form. In this invention, "substantially free" when referring to a new crystal form means that the crystal form contains less than 20% (by weight) of other crystal forms, particularly less than 10% (by weight) of other crystal forms, more specifically less than 5% (by weight) of other crystal forms, and even more specifically less than 1% (by weight) of other crystal forms. In this invention, the term "about" when used to refer to a measurable value, such as mass, time, temperature, etc., means that it can fluctuate within a certain range around a specific value, which can be ±10%, ±5%, ±1%, ±0.5% or ±0.1%. The present invention will be described in detail below with reference to the embodiments, which describe in detail the methods for preparing and using the crystal forms of the present invention. It will be apparent to those skilled in the art that many modifications to both the materials and methods can be made without departing from the scope of the present invention. The abbreviations used in this invention are explained as follows: XRPD: X-ray powder diffraction, DSC: differential scanning calorimetry. Instruments and methods used for data acquisition: The X-ray powder diffraction pattern described in this invention was acquired using a Bruker D2 PHASER X-ray powder diffractometer. The parameters of the X-ray powder diffraction method described in this invention are as follows: X-ray source: Cu Ka; Ka1 (A): 1.54060; Ka2 (A) 1.54439; Ka2 / Ka1 intensity ratio: 0.50; voltage: 30 kV; current: 10 mA; scanning range: from 3.0 to 40.0 degrees. The differential scanning calorimetry (DSC) images described in this invention are acquired on a Mettler DSC3. The method parameters for differential scanning calorimetry (DSC) are as follows: scan rate: 10 °C / min; protective gas: nitrogen. Unless otherwise specified, all the following examples are performed at room temperature. "Room temperature" is not a specific temperature value, but refers to a temperature range of 10-30 ℃. According to the present invention, the compound I and / or its salt as raw materials include, but are not limited to, solid forms (crystalline or amorphous), oily forms, liquid forms, and solutions. Preferably, the compound I and / or its salt as raw materials are in solid form. Industrial applicability (1) The crystalline form DCVI of this invention has higher solubility. Compared with crystalline form A reported in prior art CN107207478B, the crystalline form DCVI of this invention has higher solubility in SGF (simulated gastric juice), FaSSIF (simulated intestinal juice under fasting conditions), and pure water. At 1 hour, 4 hours, and 24 hours, the solubility of the crystalline form DCVI of this invention is higher than that of crystalline form A reported in prior art CN107207478B. Higher solubility is beneficial to improving drug absorption in the human body, improving drug bioavailability, and achieving better therapeutic effects with less drug loading; in addition, while ensuring the efficacy of the drug, reducing the drug loading can reduce the toxic side effects of the drug and improve the safety of drug use, which has important clinical significance. (2) The crystalline form DCVI of this invention has lower hygroscopicity. Compared with crystalline form A in CN107207478B, the crystalline form DCVI of this invention exhibits lower hygroscopic weight gain under conditions of 33%RH, 75%RH, and 93%RH. This indicates that crystalline form DCVI is less prone to deliquescence during drug production and storage, which is beneficial for sample preservation. Furthermore, the lower hygroscopicity is advantageous for the production and preparation of pharmaceutical products during formulation manufacturing and preparation. Furthermore, the hygroscopicity of the crystalline form DCVI of this invention was investigated according to the methods in the pharmacopoeia (General Chapter 9103 of the Chinese Pharmacopoeia 2020, experimental conditions: 25 ± 1 ℃, 80% relative humidity). The results showed that the hygroscopic weight gain of the crystalline form DCVI was 0.04%. In addition, regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (General Chapter 9103 of the Chinese Pharmacopoeia 2020, experimental conditions: 25 ± 1 ℃, 80% relative humidity), the weight gain range of the crystalline form DCVI is defined as: hygroscopic weight gain less than 0.2%, which is considered to be non-hygroscopic or almost non-hygroscopic. The above results indicate that crystalline DCVI has lower hygroscopicity. Lower hygroscopicity ensures that the sample maintains low moisture gain and does not deliquescence during subsequent production, processing, storage, and transportation, thereby ensuring stable drug quality. (3) The DCVI crystal form of the present invention has lower electrostatic induction and improved flowability. Compared with crystal form A of CN107207478B, the DCVI crystal form of the present invention shows higher packing density (BD) and tap density (TD), and the CI value of the DCVI crystal form of the present invention is lower than that of crystal form A of CN107207478B, thereby indicating that the DCVI crystal form of the present invention has lower electrostatic induction and better flowability compared with crystal form A of CN107207478B. The DCVI crystal form of this invention has lower electrostatic induction and improved flowability, which increases the convenience of this sample in the formulation process and drug production, improves the uniformity of the formulation product, and is of great significance to the production and quality of drugs. (4) The crystalline DCVI provided by this invention has good stability. The crystalline DCVI of this invention remained unchanged after being sealed for 6 months, 6 months, and 1 month under the conditions of 25 ℃ / 60%RH (relative humidity), 40 ℃ / 75%RH, and 60 ℃ / 75%RH, respectively. This indicates that the crystalline DCVI has good physical stability. In particular, under accelerated conditions of 40 ℃ / 75%RH and high temperature and humidity conditions of 60 ℃ / 75%RH, it remained stable for one month without crystal transformation. This further demonstrates that the crystalline DCVI still has good physical stability even under high temperature and humidity conditions. This ensures that the drug is not prone to crystal transformation during subsequent processes, production, and transportation. Good physical stability ensures that the drug maintains stable quality during subsequent formulation development and process production, as well as during drug production and transportation, which is of great significance for ensuring drug quality and efficacy. Furthermore, crystalline DCVI exhibits good mechanical stability. No crystal transformation occurred in crystalline DCVI before and after grinding, and no significant decrease in crystallinity was observed in the samples, indicating that crystalline DCVI possesses excellent mechanical stability. This good mechanical stability ensures that the samples will not easily undergo crystal transformation due to external forces such as mechanical grinding or pulverization during later formulation processes, reducing the risk of crystal transformation during formulation and improving the developability of the formulation process. Furthermore, DCVI crystals exhibit excellent humidity stability. After being placed under varying humidity levels (22.5%RH~93%RH) for one week, the crystal form of DCVI remained unchanged. This excellent humidity stability prevents mold or deliquescence during storage, thereby improving the quality stability of the drug and ensuring its consistent efficacy. Crystal form stability is crucial for drug development. Crystal transformation directly impacts drug solubility and, consequently, bioavailability, thus altering therapeutic efficacy. Good mechanical stability also enhances a drug's resistance to mechanical damage during formulation, reducing the risk of crystal transformation. Good humidity stability prevents mold growth or deliquescence during storage, improving drug stability and safety. Therefore, DCVI's excellent stability, mechanical stability, and humidity stability provide a guarantee for subsequent drug production and development, demonstrating high industrialization value. (5) The crystalline DCVI of the present invention has a good purification effect and is very suitable for industrial production. After recrystallization to prepare the crystalline DCVI of the present invention, the chemical purity of the sample increased from 99.71% to 100%, indicating that the crystalline DCVI has a good purification and impurity removal effect, which not only improves the quality and safety of the drug, but is also very suitable for large-scale industrial production. Sequence List Free Content none.

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