Crystal form dciii of ferric maltol, and preparation method therefor and use thereof

Abstract

The present invention relates to crystal form DCIII of compound I and a preparation method therefor, and the use of the crystal form in the preparation of a drug for treating iron deficiency-related conditions with or without iron deficiency anemia. The new crystal form of compound I provided by the present invention has the advantages of high solubility, good chemical stability, solid-state stability, mechanical stability and humidity stability, a simple preparation method, easy crystal form control, and a low production scale-up cost, etc., and is of significant value for the future development of the drug.

Description

Ferric maltitol crystal form DCIII, preparation method and use thereof TECHNICAL FIELD The present application relates to the technical field of drug crystal forms, in particular to a ferric maltitol crystal form DCIII, a preparation method and use thereof. BACKGROUND Ferric maltitol is a new oral trivalent iron compound developed by Shield Therapeutics Company in the United Kingdom. It was approved by the European Medicines Agency in 2016 for the treatment of iron deficiency symptoms in adults. On July 25, 2019, the drug was officially approved by the U.S. Food and Drug Administration to have the same effect. Ferric maltitol is an iron ion-containing complex, which is different from iron salt compounds. When it is taken up by the gastrointestinal tract, it dissociates, and the iron ion and maltitol are absorbed separately. The iron ion is taken up by the intestinal wall cells and transferred to transferrin and ferritin, thereby increasing the concentration of iron ions in the serum, including ferritin and transferrin saturation, to achieve the effect of iron supplementation. Ferric maltitol is a drug for treating iron deficiency in adults with low incidence of adverse reactions, high bioavailability and low risk of iron overload, good tolerance, and is a reliable drug for replacing intravenous iron therapy. It is also an ideal alternative drug for patients who are not tolerant to existing oral iron preparations and have poor treatment effects. Ferric maltitol is a complex containing one trivalent iron positive ion and three maltitol negative ions, with a molecular formula of (C6H5O3)3Fe and a structure as follows: Ferric maltitol is a drug for treating iron deficiency in adults with low incidence of adverse reactions, high bioavailability and low risk of iron overload, good tolerance. However, in the existing literature reported by ferric maltitol crystal forms, there is a common problem of low solubility, which leads to poor efficacy and low bioavailability. Ferric maltitol is a polymorphic compound. Drug polymorphism refers to the phenomenon that two or more different crystal forms of solid drug molecules exist. Because different crystal forms have different physicochemical properties, different crystal forms of solid drug molecules may have different dissolution and absorption in the body, thereby affecting the clinical efficacy and safety of the drug to some extent, especially for poorly soluble solid drugs. The influence of crystal form on bioavailability will be greater. Therefore, drug crystal form is an important part of solid drug research and development, and is also an important part of drug quality control. CN107001310B discloses four polymorphs of ferric maltol, which are anhydrous crystal form I, II, IV, and a solvent complex crystal form III. Among them, crystal form I is not stable and is easy to be converted into crystal form II; crystal form IV is difficult to prepare; and the solvent complex crystal form III has a large toxic side effect due to containing an organic solvent and cannot be used as a medicinal crystal form. Meanwhile, in paragraphs

[0139] and

[0221]

[0225] In paragraphs, the research data of crystal form I, crystal form II, crystal form III and crystal form IV are disclosed, and it is concluded that crystal form II is the main form, so it can be known that crystal form II is the most dominant crystal form which is the most stable in thermodynamics. As the most dominant crystal form, although crystal form II is a stable crystal form, it has the disadvantages of low solubility, poor drug efficacy and low bioavailability. Meanwhile, in paragraphs

[0197] and

[0198] In paragraphs, even if crystal seeds of crystal form II are added, crystal form I is still obtained at 2 hours and 20 hours. Therefore, it is shown that the preparation method of crystal form II in the prior art is prone to crystal form I, which easily leads to the result that the final product is a mixed crystal, which brings great challenges to the crystal form control of the product. In summary, there is an urgent need in the art for a new crystal form of ferric maltol which has good solubility and stability, and the preparation method of the new crystal form is simple and easy to control the crystal form, and no mixed crystal is generated. On the one hand, the risk of crystal transformation can be avoided, and on the other hand, the drug can be easily absorbed, the bioavailability is improved, and the new crystal form also has good production scalability to meet the bioavailability of the drug, suitable for industrial development and comprehensive performance meeting the development of the new crystal form for medicine. The inventors of the present application have unexpectedly found that the different crystal forms of compound I provided by the present application have advantages in physicochemical properties, preparation processing performance and bioavailability, for example, at least one of the aspects of melting point, solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, flowability, in-vivo and in-vitro dissolution, biological effectiveness and the like. The present application provides a better choice for the development of a drug containing compound I, which has very important significance. SUMMARY In view of the above-mentioned defects of the prior art, the present application provides a crystal form DCIII of ferric maltol, which has improved solubility and good stability, and the preparation method is simple and easy to control the crystal form. Therefore, the present application also provides a preparation method of the above-mentioned crystal form DCIII of ferric maltol. In addition, the present application also provides the use of the above-mentioned crystal form DCIII of ferric maltol.​ According to the purposes of the present application, the present application provides a crystalline form of Compound I. Further, the present application provides a crystalline form of Compound I, which can be crystalline form DCIII (hereinafter referred to as crystalline form DCIII). In one aspect, the X-ray powder diffraction of the crystalline form DCIII has characteristic peaks at one, or two, or three of the diffraction angles 2theta values of 13.8°±0.2°, 9.4°±0.2°, 14.4°±0.2° using Cu-Ka radiation. Further, the X-ray powder diffraction of the crystalline form DCIII has characteristic peaks at one, or two, or three of the diffraction angles 2theta values of 6.8°±0.2°, 10.6°±0.2°, 15.1°±0.2° using Cu-Ka radiation; preferably, the X-ray powder diffraction of the crystalline form DCIII has characteristic peaks at three of the diffraction angles 2theta values of 6.8°±0.2°, 10.6°±0.2°, 15.1°±0.2°. Further, the X-ray powder diffraction of the crystalline form DCIII has characteristic peaks at one, or two, or three of the diffraction angles 2theta values of 15.8°±0.2°, 22.9°±0.2°, 24.0°±0.2° using Cu-Ka radiation; preferably, the X-ray powder diffraction of the crystalline form DCIII has characteristic peaks at three of the diffraction angles 2theta values of 15.8°±0.2°, 22.9°±0.2°, 24.0°±0.2°. In another aspect, the X-ray powder diffraction of the crystalline form DCIII has characteristic peaks at one, or two, or three, or four, or five, or six, or seven, or eight, or nine, or ten, or eleven of the diffraction angles 2theta values of 6.8°±0.2°, 9.4°±0.2°, 10.6°±0.2°, 12.1°±0.2°, 13.0°±0.2°, 13.8°±0.2°, 14.4°±0.2°, 15.1°±0.2°, 15.8°±0.2°, 22.9°±0.2°, 24.0°±0.2° using Cu-Ka radiation. Non-limitingly, the X-ray powder diffraction pattern of the crystalline form DCIII is substantially as shown in Figure 1. Non-limitingly, the crystalline form DCIII has an endothermic peak starting at about 292 degrees, and the differential scanning calorimetry pattern is substantially as shown in Figure 2. Non-limitingly, the crystalline form DCIII is an anhydrous crystalline form. According to the purposes of the present application, the present application also provides a preparation method of the crystalline form DCIII, which comprises: A certain amount of compound I is taken into a glass bottle, a certain amount of organic solvent or mixed solvent of organic solvents is added, and the mixture is shaken thoroughly, then recrystallized at a certain temperature, and dried at a certain temperature after centrifugal separation of the solid, to obtain the crystal form DCIII. Specifically, a preparation method of the crystal form DCIII of ferric maltol, wherein ferric maltol is placed in an organic solvent, and recrystallized at a temperature of-20℃ to 30℃, and then centrifuged and dried to obtain the crystal form DCIII. Further, the selected organic solvent is preferably chloroform. Further, the selected recrystallization temperature is preferably-20 degrees to 30 degrees, more preferably 0 degrees to 5 degrees. Further, the selected drying temperature is preferably 100 degrees to 180 degrees, more preferably 150 degrees. According to the purposes of the present application, the present application also provides a pharmaceutical composition comprising an effective therapeutic amount of the crystal form DCIII and a pharmaceutically acceptable carrier or excipient. Further, the present application provides the use of the crystal form DCIII in the preparation of a medicament for preventing or treating iron deficiency with or without anemia in a subject. The crystal form DCIII provided by the present application has the following beneficial effects: 1) Compared with the prior art, the crystal form DCIII of the present application has higher solubility. Compared with the prior art, the crystal form DCIII of the present application has higher solubility in SGF (simulated gastric fluid), FaSSIF (fasted state simulated intestinal fluid), FeSSIF (fed state simulated intestinal fluid) and water. The solubility of the crystal form DCIII of the present application is about 2 times that of Form II reported in the prior art CN107001310B at 1 hour and 2 hours. Higher solubility is beneficial to improve the absorption of the drug in the human body, improve the bioavailability of the drug, and achieve better therapeutic effect with less drug loading; in addition, under the premise of ensuring the efficacy of the drug, reducing the drug loading can reduce the toxic and side effects of the drug, improve the safety of the drug use, and has important clinical significance. 2) Compared with the prior art, the process for preparing the crystal form DCIII of the present application is simpler, and the crystal form is easier to control. According to the analysis of the foregoing prior art, the crystal form II is the main and most advantageous crystal form. However, the patent CN107001310B

[0197] filed without adding crystal seeds of the crystal form II, and obtained the crystal form I. Moreover, in the patent CN107001310B

[0198] The field, and also discloses that even if the crystal seed of Form II is added, Form I is still obtained at 2 hours and 20 hours. It is thus shown that the preparation method of the prior art Form II, Form I is easily generated, which easily leads to the result that the final product is a mixed crystal, which brings great challenges to the crystal form control of the product. The preparation process of the Form DCIII of the present application is simple, and the crystal form control is easier. Without adding a crystal seed, the obtained solid is still pure Form DCIII, and mixed crystals do not occur, which provides convenience for subsequent industrial development. 3) The Form DCIII provided by the present application has good stability. The Form DCIII of the present application is placed at 25℃ / 60%RH (relative humidity), 40℃ / 75%RH, and 60℃ / 75%RH, respectively, for 2 weeks, and the crystal form remains unchanged, indicating that the Form DCIII has good physical stability. In particular, under the accelerated condition of 40℃ / 75%RH and the high temperature and high humidity condition of 60℃ / 75%RH, the crystal form remains stable after being placed for 2 weeks, and no crystal transformation occurs, which further indicates that the Form DCIII still has good physical stability even under high temperature and high humidity conditions, which ensures that the drug is not prone to crystal transformation during subsequent process, production and transportation processes. In addition, the chemical purity of the Form DCIII before and after being placed at 25℃ / 60%RH (relative humidity) does not change, and the purity remains above 99%, indicating that the Form DCIII has good chemical stability. In addition, even under the accelerated condition of 40℃ / 75%RH and the high temperature and high humidity condition of 60℃ / 75%RH, the chemical purity does not decrease significantly, which further indicates that the Form DCIII has good chemical stability. Good physical and chemical stability ensures that the drug can maintain stable quality during subsequent formulation development and process production, and during drug production and transportation, ensuring drug quality and efficacy, which is of great significance. In addition, the Form DCIII has good mechanical stability. The Form DCIII does not undergo crystal transformation before and after grinding, and the crystallinity of the sample does not decrease significantly, which indicates that the Form DCIII has good mechanical stability. Good mechanical stability can ensure that the sample does not easily undergo crystal transformation during the subsequent formulation process due to mechanical grinding, crushing and other external forces, reducing the risk of crystal transformation during the formulation process and improving the developability of the formulation process. Further, the crystal form DCIII has good humidity stability. After a solid sample of the crystal form DCIII is respectively placed in an open state under conditions of about 30% RH / 22.5% RH, about 30% RH / 45% RH and about 30% RH / 80% RH for 2 weeks, the crystal form is still DCIII and no change occurs, thereby indicating that the crystal form DCIII has good stability under low humidity and high humidity conditions. During the preparation, storage and preparation process of the bulk drug, the environmental humidity may change with seasons, locations, weather and other factors, and therefore the stability of the sample under different humidity conditions is an important investigation parameter. The crystal form DCIII of the present application has good stability under low humidity and high humidity conditions, which brings convenience to the sample production, storage and preparation process, reduces the risk of crystal transformation and improves the product stability. The crystal form stability is of great significance to drug development. If crystal transformation occurs, it will directly affect the solubility of the drug and then affect the bioavailability of the drug, thereby changing the efficacy of the drug. Good chemical stability can ensure that almost no new impurities are produced or the content of impurities almost does not increase during the storage process of the drug, thereby ensuring the safety of the drug. Good mechanical stability can also improve the resistance of the drug to mechanical damage during the preparation process, thereby reducing the risk of crystal transformation. Good humidity stability can ensure that the sample will not easily undergo crystal transformation due to the change of environmental humidity during the later storage, transportation and preparation process of the preparation process, thereby reducing the risk of crystal transformation during the sample storage, transportation and preparation process and improving the developability of the product. Therefore, the good physical and chemical stability, good mechanical stability and good humidity stability of the crystal form DCIII provide a guarantee for the subsequent production and development of the drug and have high industrial development value. Further, the crystal form DCIII of the present application has the following beneficial effects: 1) The crystal form DCIII of the present application has low hygroscopicity. According to the pharmacopoeia (Guiding principles for drug hygroscopicity experiment in Chinese Pharmacopoeia 2020 edition 9103, experimental conditions: 25±1℃, 80% relative humidity), the hygroscopicity of the crystal form DCIII of the present application is investigated, and the results show that the crystal form DCIII has a hygroscopic weight gain of 1.03%. In addition, according to the principle of hygroscopicity characteristics description and hygroscopic weight gain definition (Guiding principles for drug hygroscopicity experiment in Chinese Pharmacopoeia 2020 edition 9103, experimental conditions: 25±1℃, 80% relative humidity), the weight gain category of the crystal form DCIII is: the hygroscopic weight gain is less than 2.0% but not less than 0.2%, which belongs to slight hygroscopicity. The results show that the crystal form DCIII has low hygroscopicity. The low hygroscopicity can ensure that the sample can maintain low hygroscopic weight gain without deliquescence during the later production, processing and storage and transportation processes, thereby ensuring the stability of the drug quality. The concept, specific structure and generated technical effects of the present application will be further described below in combination with the drawings, so as to fully understand the purpose, features and effects of the present application. BRIEF DESCRIPTION OF DRAWINGS Fig. 1 is an XRPD spectrum of maltol iron crystal form DCIII prepared in Example 1 of the present application; Fig. 2 is a DSC spectrum of maltol iron crystal form DCIII prepared in Example 1 of the present application; Fig. 3 is an XRPD spectrum of maltol iron crystal form DCIII prepared in Example 2 of the present application; Fig. 4 is an XRPD spectrum of maltol iron crystal form DCIII prepared in Example 1 of the present application before and after stability placement; Fig. 5 is an XRPD spectrum of maltol iron crystal form DCIII prepared in Example 1 of the present application before and after grinding; Fig. 6 is an XRPD spectrum of maltol iron crystal form DCIII prepared in Example 1 of the present application after placement under different humidity; DETAILED DESCRIPTION In order to make the technical means, creative features, purposes and effects achieved by the application easy to understand, the application will be further described below in combination with specific drawings. However, the application is not limited to the following cases. It should be understood that the structures, proportions, sizes, etc. shown in the drawings attached to the present specification are only used to cooperate with the content disclosed in the specification, so as to be understood and read by those skilled in the art, and do not have technical substantive significance, and any modification of the structure, change of the proportion relationship or adjustment of the size, without affecting the effects and purposes that can be achieved by the present application, should still fall within the scope of the technical content disclosed by the present application. XRPD, i.e. X-ray powder diffraction, the X-ray powder diffraction pattern of the present application is collected on a Bruker D2 PHASER X-ray powder diffractometer. The method parameters of X-ray powder diffraction are as follows: X-ray source: Cu Ka; Kal(A): 1.54060; Ka2(A) 1.54439; Ka2 / Ka1 intensity ratio: 0.50; voltage: 30 kilovolts (kV); current: 10 milliampere (mA); scanning range: 3.0-40.0°. DSC, i.e. differential scanning calorimetry, the differential scanning calorimetry (DSC) pattern of the present application is collected on a TA company DSC X3, and the method parameters of differential scanning calorimetry (DSC) are as follows: scanning rate: 10℃ / min; protective gas: nitrogen. TGA, i.e. thermal gravimetric analysis, the thermal gravimetric analysis (TGA) pattern of the present application is collected on a TA company TGA55, and the method parameters of thermal gravimetric analysis (TGA) are as follows: scanning rate: 10℃ / min; protective gas: nitrogen. Unless otherwise indicated, the following examples were conducted at room temperature, which is not a specific temperature value, but refers to a temperature range of 10-30 °C. The term "stirring" as used in the following examples was accomplished using conventional techniques known in the art, such as magnetic or mechanical stirring, at a rate of 50-1800 rpm, preferably 300-900 rpm for magnetic stirring and 100-300 rpm for mechanical stirring. The term "separation" as used in the following examples was accomplished using conventional techniques known in the art, such as centrifugation or filtration, and "centrifugation" was accomplished by placing the sample to be separated in a centrifuge tube and centrifuging at 10,000 rpm until the solids settled to the bottom of the tube. The term "drying" as used in the following examples can be conducted at room temperature or at an elevated temperature. The drying temperature can range from room temperature to about 50 °C, or to 40 °C. The drying time can range from 2 to 48 hours, or overnight. The drying can be conducted in a fume hood, in a forced air oven, or in a vacuum oven. The term "crystal" as used in the following examples refers to a solid characterized by an X-ray powder diffraction pattern. Those skilled in the art will appreciate that the physical and chemical properties discussed herein can be characterized with experimental error that depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known in the art that X-ray powder diffraction patterns can vary with the conditions of the instrument, and in particular, it is noted that the relative intensities of the diffraction peaks in an X-ray powder diffraction pattern can vary with experimental conditions, and therefore the order of the diffraction peaks cannot be used as the sole or determining factor. In fact, the relative intensities of the diffraction peaks in an X-ray powder diffraction pattern are related to the preferred orientation of the crystal, and the intensities shown in the figures are illustrative and not intended for absolute comparison. In addition, the experimental error in the position of the diffraction peaks is typically 5% or less, and this error in the position should be taken into account, typically allowing for a ±0.2 error. In addition, there can be an overall shift in the diffraction peak angles due to experimental factors such as sample thickness, and some shift is typically allowed. Thus, those skilled in the art will appreciate that the X-ray powder diffraction patterns of the crystal forms claimed in the present application need not be identical to the X-ray powder diffraction patterns shown in the examples herein, and any crystal form having an X-ray powder diffraction pattern that is the same or similar to the characteristic peaks of these patterns is within the scope of the present application. Those skilled in the art can compare the X-ray powder diffraction patterns shown in the present application to the X-ray powder diffraction pattern of an unknown crystal form to determine whether the two sets of patterns reflect the same or different crystal forms. The crystal form DCIII of the present application is pure, substantially free of any other crystal form. The term "substantially free of" as used herein in connection with a new crystal form means that the crystal form contains less than 20% by weight of another crystal form, more particularly less than 10% by weight of another crystal form, more particularly less than 5% by weight of another crystal form, more particularly less than 1% by weight of another crystal form. The term "about" as used herein in connection with a measurable numerical value such as a dosage, time, temperature, and the like, denotes an amount that is reasonably close to the value being described, such as within 10% of the value, preferably within 5% of the value, more preferably within 1% of the value, more preferably still within 0.5% of the value, and most preferably within 0.1% of the value. The iron maltol used as a starting material includes, but is not limited to, solid forms (crystalline or amorphous), oily, liquid forms, and solutions. Preferably, it is in solid form. The method for preparing the crystal form DCIII of the present application: the iron maltol is placed in an organic solvent, the resulting mixture is stirred, separated, and dried to obtain the crystal form DCIII. Specifically, the iron maltol is added to a chlorinated hydrocarbon to form a suspension, the chlorinated hydrocarbon is a compound containing chlorine, and the chlorinated hydrocarbon herein can be selected from any one or a mixture of the two of dichloromethane and trichloromethane. Then, the suspension is placed in low temperature (preferably 0-5 degrees) and stirred, and the solid is separated by centrifugation and dried at high temperature for a period of time to obtain the crystal form DCIII. The recrystallization process described above needs to be carried out at a specific temperature, and the temperature used in the present application is -20-30°C, preferably 0-5°C. The drying temperature described above needs to be carried out at a specific temperature, and the temperature used in the present application is 100-180°C, preferably 150°C. The crystal form DCIII of the iron maltol obtained in the present application can be administered in the form of tablets or capsules, and for patients who have difficulty swallowing solid forms, liquid preparations can also be used. For the preparation of tablets or capsules, conventional excipients can be added and prepared in a conventional manner. For example, when preparing tablets, the crystal form DCIII of the iron maltol obtained in the present application is mixed with excipients, rolled into thin sheets and crushed into granules, mixed with additional excipients, and pressed into shape using a suitable mold. When preparing capsules, the crystal form DCIII of the iron maltol obtained in the present application is mixed with excipients, rolled into thin sheets and crushed into granules, mixed with additional excipients, and filled into capsules of suitable size. The crystal form DCIII of the iron maltol prepared in the present application can be used in a medicament for preventing or treating iron deficiency with or without anemia in a subject, for treating a subject with iron deficiency. Symptoms and signs of iron deficiency, before the appearance of iron deficiency anemia, are fatigue, hair loss, convulsions, irritability, dizziness, brittle nails or appetite disorders, etc., impaired immune function, delayed growth in children, etc. Conditions associated with iron deficiency anemia are chronic kidney disease, systemic lupus, rheumatoid arthritis, gastrointestinal diseases, etc. Example 1 Take 5 grams of iron maltol, add 25 milliliters of chloroform, then place the sample in 0°C and stir overnight; after centrifugal separation of the solid, place the sample in a drying oven at 150 degrees for ~1h to obtain crystals, i.e. crystal form DCIII. Its XRPD pattern is shown in Figure 1, and the XRPD data is shown in Table 1, and its DSC pattern is shown in Figure 2. Table 1 As can be seen from Figure 2, the iron maltol crystal form DCIII prepared in this Example 1 begins to appear endothermic peak near 292°C. Example 2 Take 300mg of iron maltol in a 5ml glass vial, add 1.5ml of chloroform solution, stir overnight at 5°C, centrifugal separation of the solid, then heat to 150°C in an oven to obtain the sample, i.e. crystal form DCIII. Its XRPD pattern is shown in Figure 3, and the XRPD data is shown in Table 2. As can be seen from Figure 3, the iron maltol prepared in this Example 2 is crystal form DCIII. Table 2 Example 3: Biological medium solubility of the crystal form DCIII of the present application When performing drug solubility tests to predict the performance of the drug in the body, it is very important to simulate the in vivo conditions as much as possible. For oral drugs, SGF (simulated gastric fluid), FaSSIF (fasted state simulated intestinal fluid), and FeSSIF (fed state simulated intestinal fluid) can simulate in vivo conditions and predict the effects of eating. The solubility tested in such media is closer to the solubility in the human body environment. In order to compare the solubility of Form II in the original research patent CN107001310B and the crystal form DCIII of the present application in biological media, the experiment was carried out by referring to the method for determining the biological medium solubility of USP. Experimental method: take about 25 milligrams of crystal form DCIII prepared in Example 1, respectively, add 1 milliliter of SGF (simulated gastric fluid), FaSSIF (fasted state simulated intestinal fluid), and FeSSIF (fed state simulated intestinal fluid) buffer solution, and stir at 37°C ± 1°C constant temperature, respectively, take samples at 1h, 2h, take the supernatant and determine its content by HPLC method. Form II in CN107001310B patent is also subjected to the above-mentioned operation for sampling. The experimental conditions and results are shown in Table 3. Table 3 The solubility experiment results in biological solvents show that, compared with the crystal form Form II in the CN107001310B patent, the crystal form DCIII of the present application has higher solubility in SGF (simulated gastric fluid), FaSSIF (fasted state simulated intestinal fluid), and FeSSIF (fed state simulated intestinal fluid). Example 4: Solubility of the crystal form DCIII of the present application in water The CN107001310B patent

[0219] The CN107001310B patent Table 4 The solubility experiment results in biological solvents show that, compared with the crystal form Form II in the CN107001310B patent, the crystal form DCIII of the present application has higher solubility in SGF (simulated gastric fluid), FaSSIF (fasted state simulated intestinal fluid), and FeSSIF (fed state simulated intestinal fluid). Example 5: Stability of the crystal form DCIII of the present application About 5 mg of the crystal form DCIII prepared in Example 1 was placed in normal temperature (25℃ / 60%RH) and accelerated conditions (40℃ / 75%RH, 60℃ / 75%RH) respectively, and XRPD was used to determine the crystal form and HPLC was used to determine the chemical purity. The experimental conditions and results are shown in Table 5, and the XRPD superimposition is shown in Figure 4 (in which Figure 4 from top to bottom is the condition of DCIII starting sample, 25 degrees / 60%RH for 2W; 40 degrees / 75%RH for 2W; 60 degrees / 75%RH for 2W). Table 5 The results show that the crystal form DCIII of the present application can maintain physical and chemical stability for at least 2 weeks under the conditions of 25℃ / 60%RH, 40℃ / 75%RH, and 60℃ / 75%RH. Example 6: Mechanical stability of the crystal form DCIII of the present application 10 mg of the crystal form DCIII prepared in Example 1 was placed in a mortar and manually ground for 15 minutes, and XRPD was used to test before and after grinding. The XRPD comparison before and after grinding is shown in Figure 5 (in which Figure 5 from top to bottom is the condition of DCIII starting sample, sample after manual grinding). According to Figure 5, the crystal form DCIII of the present application does not change after grinding, and no obvious decrease in crystallinity is observed, which indicates that the crystal form DCIII has good mechanical stability. Example 7: Humidity stability of the crystalline form DCIII of the present application In order to understand the stability of the crystalline form DCIII of the present application under different humidity, to further understand the risk of crystalline transformation of the crystalline form during the preparation of bulk drug, the preparation process of the preparation, and the storage process of the drug, the stability experiment of the crystalline form DCIII under different humidity was specially carried out. 10 mg of the sample of the crystalline form DCIII was weighed into a vial, and was placed under different humidity conditions. After 2 weeks, the crystalline form of the solid was tested again. The results are shown in Table 6 below, and the XRPD superimposition before and after placement is shown in Figure 6 (in Figure 6, from top to bottom, the conditions are DCIII starting sample, 30℃ / 22.5%RH placed for 2W; 30℃ / 45%RH placed for 2W; 30℃ / 80%RH placed for 2W). As can be seen from Figure 6, after the crystalline form DCIII of the present application was placed under different humidity for 2 weeks, the crystalline form remained unchanged, and was still the crystalline form DCIII. The crystalline form DCIII of the present application has excellent stability under low humidity and high humidity. During the preparation, storage and preparation production process of the bulk drug, the environmental humidity will change with the season, location, weather and other factors. Therefore, the stability of the sample under different humidity is an important investigation parameter. The crystalline form DCIII of the present application has good stability under low humidity and high humidity conditions, which will bring convenience to the sample production, storage and preparation process, reduce the risk of crystalline transformation, and improve the stability of the product. Table 6 Example 8: Hygroscopicity of the crystalline form DCIII of the present application The determination of hygroscopicity was carried out according to the guidance principle of drug hygroscopicity experiment in Chinese Pharmacopoeia 2020 edition 9103. The determination conditions were 25±1℃, 80% relative humidity. Definition of hygroscopic weight gain: Highly hygroscopic: hygroscopic weight gain is not less than 15.0%; Hygroscopic: hygroscopic weight gain is less than 15.0% but not less than 2.0%; Slightly hygroscopic: hygroscopic weight gain is less than 2.0% but not less than 0.2%; No or almost no hygroscopicity: hygroscopic weight gain is less than 0.2%. About 20 mg of the crystalline form DCIII prepared in Example 1 of the present application was placed under the condition of 25±1℃, 80% relative humidity for 24 hours, and the mass of the sample before and after was recorded. The specific results are shown in Table 7 below. Table 7 As can be seen from Table 7, the crystalline form DCIII of the present application is slightly hygroscopic, which indicates that the crystalline form DCIII is not prone to deliquescence during the production and storage of the drug. The preferred embodiments of the present application have been described above in detail. It should be understood that modifications and variations to the preferred embodiments could be made by those skilled in the art without departing from the spirit and scope of the application. Accordingly, it is intended that there be included within the scope of the application, all such modifications and variations as would be apparent to those skilled in the art upon reading this disclosure. It is intended to obtain for the inventors such patent rights as are available for any patent granted on the present application.

Claims

1. A crystalline form DCIII of Compound I, wherein Compound I has the structural formula:

2. The crystalline form DCIII of Compound I according to claim 1, characterized in that, The X-ray powder diffraction pattern has characteristic peaks at one or two or three of 2-theta values of 13.8°±0.2°, 9.4°±0.2°, 14.4°±0.2° using Cu-Ka radiation.

3. The crystalline form DCIII of Compound I according to claim 2, characterized in that, The X-ray powder diffraction pattern has characteristic peaks at one or two or three of 2-theta values of 6.8°±0.2°, 10.6°±0.2°, 15.1°±0.2° using Cu-Ka radiation.

4. The crystalline form DCIII of Compound I according to claim 2, characterized in that, The X-ray powder diffraction pattern has characteristic peaks at one or two or three of 2-theta values of 15.8°±0.2°, 22.9°±0.2°, 24.0°±0.2° using Cu-Ka radiation.

5. Process for the preparation of crystalline Form DCIII of Compound I, characterized in that: Compound I is weighed into a glass bottle, an organic solvent or a mixture of organic solvents is added, and the mixture is shaken thoroughly, recrystallized, and dried after centrifugation to obtain the crystalline form DCIII.

6. The production method according to claim 5, wherein The selected organic solvent is chloroform; the selected recrystallization temperature is -20 to 30°C, and the selected drying temperature is 100 to 180°C.

7. The production method according to claim 6, characterized by, The selected recrystallization temperature is 0 to 5°C, and the selected drying temperature is 150°C.

8. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form DCIII of Compound I and a pharmaceutically acceptable carrier or excipient.

9. Use of the crystalline form DCIII of Compound I in the preparation of a medicament for preventing or treating iron deficiency with or without anemia in a subject.

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