Maltol iron crystal form DCVIII as well as preparation method and application thereof

Abstract

The invention discloses a maltol iron crystal form DCVIII, a preparation method and application thereof, a pharmaceutical composition containing the crystal form, and application of the crystal form in preparation of drugs for treating diseases related to iron deficiency of adults. The iron maltol crystal form DCVIII disclosed by the invention has good physical and chemical stability, good humidity stability and relatively low hygroscopicity, provides guarantee for subsequent production and development of medicines, and has relatively high industrial development value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical crystal form technology, specifically to maltol iron crystal form DCVIII, its preparation method, and its uses. Background Technology

[0002] Ferrous maltol is a novel oral trivalent iron compound developed by Shield Therapeutics in the UK. It was approved by the European Medicines Agency in 2016 for the treatment of iron deficiency in adults. On July 25, 2019, it received formal approval from the US Food and Drug Administration for the same therapeutic effect.

[0003] Ferrous maltol is an iron ion complex, unlike iron salt compounds. When it is taken up by the gastrointestinal tract, it dissociates, and the iron ions and maltol are absorbed separately. The iron ions are taken up by intestinal wall cells and transferred to transferrin and ferritin, thereby increasing the concentration of iron ions in the serum, including the saturation of ferritin and transferrin, thus achieving the effect of iron supplementation.

[0004] In clinical applications, maltol iron is a drug with a low incidence of adverse reactions, high bioavailability, low risk of iron overload, and good tolerability for treating iron deficiency in adults. It is a reliable alternative to intravenous iron therapy and an ideal alternative for patients who do not respond well to existing oral iron supplements.

[0005] Ferric maltol is a polymorphic compound. Drug polymorphism refers to the phenomenon where a solid drug molecule exists in two or more different crystalline forms. Because different crystalline forms have different physicochemical properties, different crystalline 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 the impact of crystalline form on bioavailability is even greater. Therefore, drug crystalline form is a crucial aspect of solid-state drug research and development, and also an important component of drug quality control.

[0006] CN107001310 discloses four polymorphs of maltol iron: amorphous form I, II, IV, and solvate form III. Form II is a stable polymorph, but it has low solubility, resulting in poor efficacy and low bioavailability. Solvate form III contains organic solvents and has significant toxic side effects, making it unsuitable as a pharmaceutical polymorph.

[0007] This application aims to study maltol iron crystals with good solubility and stability in order to solve the problems existing in the prior art. Summary of the Invention

[0008] The main objective of this invention is to provide a new crystal form of the compound maltol iron, its preparation method, and its uses.

[0009] According to the purpose of this invention, the present invention provides a crystal form of the compound maltol iron.

[0010] Furthermore, the present invention provides that the crystalline form of the compound maltol iron can be crystalline form DCVIII (hereinafter referred to as: crystalline form DCVIII).

[0011] On the one hand, using Cu-Ka radiation, the X-ray powder diffraction of the crystal form DCVIII has characteristic peaks at one, two, or three of the diffraction angles 2theta values ​​of 5.9º±0.2º, 14.8º±0.2º, and 15.7º±0.2.

[0012] Furthermore, using Cu-Ka radiation, the X-ray powder diffraction of the DCVIII crystal form exhibits characteristic peaks at one, two, or three of the following diffraction angles with 2θ values: 12.0º±0.2º, 17.4º±0.2º, and 23.8º±0.2º; preferably, the X-ray powder diffraction of the DCVIII crystal form exhibits characteristic peaks at three of the following diffraction angles with 2θ values: 12.0º±0.2º, 17.4º±0.2º, and 23.8º±0.2º.

[0013] Furthermore, using Cu-Ka radiation, the X-ray powder diffraction of the DCVIII crystal form exhibits characteristic peaks at one, two, or three of the following diffraction angles with 2θ values: 20.2º±0.2º, 21.4º±0.2º, and 22.6º±0.2º; preferably, the X-ray powder diffraction of the DCVIII crystal form exhibits characteristic peaks at three of the following diffraction angles with 2θ values: 20.2º±0.2º, 21.4º±0.2º, and 22.6º±0.2º.

[0014] Non-limiting, the X-ray powder diffraction pattern of crystalline DCVIII is basically as follows Figure 1 As shown.

[0015] Non-limiting, the DCVIII crystal form begins to show an endothermic peak around 294 degrees Celsius, and the differential scanning calorimetry (DSC) chromatogram is basically as follows. Figure 2 As shown.

[0016] Non-limiting, the thermogravimetric analysis (TGA) spectrum of the said crystal form DCVIII shows a weight loss of 1.4% at 25-105 °C, as shown in the thermogravimetric analysis diagram. Figure 3 As shown.

[0017] In a second aspect, the present invention provides a method for preparing the above-mentioned maltol iron crystal form DCVIII, wherein maltol iron is placed in a mixed solvent of tetrahydrofuran and water, and the resulting suspension is separated and dried to obtain the crystal form DCVIII.

[0018] In a preferred embodiment, the crystallization temperature is 0-5°C.

[0019] A third aspect of the present invention provides a pharmaceutical composition comprising the above-described maltol iron crystal form DCVIII and its pharmaceutically acceptable carrier or excipient.

[0020] In a fourth aspect, the present invention provides the use of the above-described maltol iron crystal form DCVIII in the preparation of a pharmaceutical.

[0021] Compared with the prior art, the present invention has the following beneficial effects: (1) Compared with the most stable crystal form II in the original crystal form patent CN107001310, the maltol iron crystal form DCVIII of the present invention has excellent solubility in SGF (simulated gastric juice), FaSSIF (simulated intestinal juice under fasting state), FeSSIF (simulated intestinal juice under eating state) and water, which is conducive 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, under the premise of 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.

[0022] (2) The maltol iron crystal form DCVIII of the present invention remains stable under the conditions of 25°C and 22.5%RH~60%RH, without crystal transformation, and has excellent humidity stability, which brings convenience to subsequent production, storage and formulation processes, reduces the risk of crystal transformation and improves product stability.

[0023] (3) The maltol iron crystal form DCVIII of the present invention has low hygroscopicity, thereby ensuring that it can maintain low hygroscopic weight gain and not deliquescence during subsequent production, processing and storage and transportation, thereby ensuring the stability of drug quality.

[0024] (4) The maltol iron crystal form DCVIII of the present invention remains stable under accelerated conditions, does not undergo crystal transformation, and its chemical purity does not change significantly, thus exhibiting excellent physicochemical stability.

[0025] (5) The maltol iron crystal DCVIII prepared by the present invention has excellent stability, which avoids the risk of crystal transformation, and has improved solubility, which facilitates drug absorption and improves bioavailability. It also has good production scalability and is suitable for industrial development.

[0026] The following will further explain the concept, specific structure, and technical effects of the present invention in conjunction with the accompanying drawings, so as to fully understand the purpose, features, and effects of the present invention. Attached Figure Description

[0027] Figure 1This is the XRPD spectrum of maltol iron crystal form DCVIII prepared in Example 1 of this invention; Figure 2 This is the DSC spectrum of maltol iron crystal form DCVIII prepared in Example 1 of this invention; Figure 3 This is the TGA spectrum of maltol iron crystal form DCVIII prepared in Example 1 of this invention; Figure 4 This is the XRPD spectrum of maltol iron crystal form DCVIII prepared in Example 2 of this invention; Figure 5 These are XRPD spectra of maltol iron crystal DCVIII prepared in Example 5 of this invention before and after being placed under different humidity conditions for 30 days. Figure 6 These are XRPD spectra of maltol iron crystal DCVIII prepared in Example 6 of this invention before and after being placed under different temperature and humidity conditions for 2 weeks. Figure 7 The XRPD spectra of the maltol iron crystal form DCVIII prepared in the embodiments of the present invention before and after being placed at 25℃ / 80%RH for 24 hours are shown. Detailed Implementation

[0029] To make the technical means, inventive features, objectives, and effects of the invention readily understandable, the invention is further illustrated below with reference to specific figures. However, the invention is not limited to the embodiments described below.

[0030] It should be noted that the structures, proportions, sizes, etc., illustrated in the accompanying drawings of this specification are only used to complement the content disclosed in the specification for those skilled in the art to understand and read, and are not intended to limit the conditions under which the present invention can be implemented. Therefore, they have no substantial technical significance. Any modifications to the structure, changes in the proportions, or adjustments to the size, without affecting the effects and objectives that the present invention can produce, should still fall within the scope of the technical content disclosed in the present invention.

[0031] Maltol iron is a complex containing one ferric ion and three maltol anions, with the molecular formula (C6H5O3)3Fe and the structural formula as follows:

[0032] Ferrous maltol is a drug for treating iron deficiency in adults with a low incidence of adverse reactions, high bioavailability, low risk of iron overload, and good tolerability. However, low solubility is a common problem among the various crystal forms of ferrous maltol reported in existing literature, leading to poor efficacy and low bioavailability.

[0033] This application addresses the issue of altering the preparation method of ferric maltol to obtain a new crystalline form, DCVIII. The DCVIII crystalline form combines stability and high solubility, which avoids the risk of crystal transformation and facilitates drug absorption, thereby improving bioavailability.

[0034] XRPD, or X-ray powder diffraction, was used to acquire the X-ray powder diffraction pattern in this application using a Bruker D2 PHASER X-ray powder diffractometer. The X-ray powder diffraction method parameters 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: 3.0-40.0°.

[0035] DSC, or Differential Scanning Calorimetry, was used to acquire the differential scanning calorimetry (DSC) images in this application on a TA DSC X3. The method parameters for differential scanning calorimetry (DSC) are as follows: scan rate: 10 ℃ / min; protective gas: nitrogen.

[0036] TGA, or thermogravimetric analysis, was used to acquire the TGA images in this application on a TA TGA55 thermogravimetric analyzer. The TGA method parameters were as follows: scan rate: 10 °C / min; protective gas: nitrogen.

[0037] 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 ℃.

[0038] The "stirring" described in the following embodiments 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.

[0039] The "separation" described in the following examples was accomplished using conventional methods in the art, such as centrifugation or filtration. The "centrifugation" operation was as follows: the sample to be separated was placed in a centrifuge tube and centrifuged at a rate of 10,000 rpm until all the solids settled to the bottom of the centrifuge tube.

[0040] The "drying" described in the following examples can be carried out at room temperature or higher. The drying temperature is from room temperature to approximately 50°C, or up to 40°C. The drying time can be 2 to 48 hours, or overnight. The drying is carried out in a fume hood, a forced-air oven, or a vacuum oven.

[0041] In the following embodiments, "crystal" 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, but 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 and not 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.

[0042] 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.

[0043] The DCVIII crystal form of the present invention is pure and substantially free from 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, more particularly less than 10% (by weight) of other crystal forms, even more particularly less than 5% (by weight) of other crystal forms, and even more particularly less than 1% (by weight) of other crystal forms.

[0044] 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%.

[0045] Ferric maltol as a raw material includes, but is not limited to, solid forms (crystalline or amorphous), oily forms, liquid forms, and solutions. Preferably, it is in solid form.

[0046] The preparation method of maltol iron crystal form DCVIII in this application is as follows: maltol iron is placed in a solvent and recrystallized at a temperature of 0-10℃. After centrifugation and drying, crystal form DCVIII is obtained.

[0047] The solvent is a mixture of ethers or ketones and water. Preferably, the solvent is any one of tetrahydrofuran and acetone, or a mixture of both.

[0048] The recrystallization temperature is -20℃ to 30℃. Preferably, the recrystallization temperature is 0℃ to 5℃.

[0049] The drying temperature is 20-40℃. Preferably, the drying temperature is 30℃.

[0050] The crystallization time also affects the degree of crystallization or the yield of crystals, and can be flexibly selected according to actual needs.

[0051] Example 1

[0052] Weigh 50 mg of ferric maltol and add it to a liquid chromatography vial; add 0.8 mL of tetrahydrofuran / water (4 / 1 volume ratio), stir at 5 ± 5 °C, centrifuge, and filter to obtain crystals, i.e., crystal form DCVIII. Its XRPD pattern is shown below. Figure 1 As shown in Table 1, the XRPD data is illustrated in the DSC plot. Figure 2 As shown, the TGA diagram is as follows: Figure 3 As shown.

[0053] Table 1 Diffraction angle 2theta d value Relative strength % 5.92 14.92 36.89 6.97 12.68 8.43 10.79 8.20 13.90 11.97 7.39 95.98 12.23 7.24 100.00 12.45 7.11 43.24 14.84 5.97 50.95 15.73 5.63 38.72 16.40 5.41 12.47 16.74 5.30 15.84 17.43 5.09 29.52 18.10 4.90 16.87 18.42 4.82 23.25 19.58 4.53 16.06 20.16 4.41 30.60 20.98 4.24 32.49 21.35 4.16 44.00 21.76 4.08 19.50 22.60 3.93 26.15 22.93 3.88 16.62 23.83 3.73 27.88 24.65 3.61 29.39 25.05 3.56 16.28 25.41 3.51 15.32 26.39 3.38 12.73 27.64 3.23 4.71 28.17 3.17 6.60 33.43 2.68 2.25 38.24 2.35 5.47 39.28 2.29 3.08

[0054] from Figure 2 As can be seen from the data, the maltol iron crystal form DCVIII prepared in Example 1 begins to show an endothermic peak around 294°C. From... Figure 3 It can be seen that maltol iron crystal form DCVIII loses 1.4 wt% of weight at 25-105℃.

[0055] Example 2

[0056] Weigh 50 mg of ferric maltol and add it to a liquid chromatography vial; add 0.8 mL of acetone / water (4 / 1, v / v), stir at 5 ± 5 °C, centrifuge and filter to obtain crystals, i.e., crystal form DCVIII. Its XRPD pattern is shown below. Figure 4 As shown.

[0057] Table 2 Diffraction angle 2theta d value Relative strength % 5.96 14.82 34.29 7.01 12.61 7.94 10.42 8.49 5.35 10.75 8.23 13.06 12.04 7.35 90.94 12.26 7.22 100.00 13.58 6.52 8.19 14.80 5.99 48.34 15.77 5.62 36.25 16.42 5.40 12.09 16.78 5.28 17.01 17.42 5.09 30.36 18.16 4.89 13.79 18.53 4.79 17.95 19.67 4.51 13.94 20.12 4.41 21.81 21.12 4.21 36.23 21.34 4.16 35.09 21.73 4.09 15.54 22.68 3.92 24.70 22.96 3.87 14.49 23.73 3.75 22.61 24.76 3.60 17.45 25.01 3.56 14.74 26.50 3.36 9.40 28.21 3.16 4.05 29.88 2.99 3.65 33.54 2.67 4.10 36.29 2.48 1.55 38.11 2.36 2.52

[0058] Example 3: Biological solubility of the present application's crystal form DCVIII

[0059] 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 (simulated intestinal juice under fasting conditions), and FeSSIF (simulated intestinal juice under eating conditions) can simulate in vivo conditions and predict the effects of eating. Solubility tested in these media is closer to solubility in the human body environment.

[0060] To compare the solubility of crystal form II in the original patent CN107001310 and crystal form DCVIII in this application in biological media, experiments were conducted with reference to the USP method for determining the solubility of biological media. Experimental method: Approximately 25 mg of crystal form DCVIII prepared in Example 1 was weighed and added to 1 mL of pre-prepared SGF (simulated gastric juice), FaSSIF (simulated intestinal juice under fasting conditions), and FeSSIF (simulated intestinal juice under feeding conditions). The mixture was stirred at a constant temperature of 37 ℃ ± 1℃, and samples were taken at 1 hour and 2 hours. The supernatant was then used to determine its content by HPLC. Crystal form II in patent CN107001310B was sampled using the same procedure. The experimental conditions and results are shown in Table 3.

[0061] Table 3

[0062] Solubility experiments in biological solvents showed that, compared to crystal form II in patent CN107001310B, the crystal form DCVIII of this invention exhibits higher solubility in SGF (simulated gastric juice), FeSSIF (simulated intestinal juice under fasting conditions), and FeSSIF (simulated intestinal juice under feeding conditions). Within 2 hours, the solubility of the crystal form DCVIII of this invention is 2 to 2.5 times that of crystal form II reported in prior art CN107001310B. Higher solubility is beneficial for improving drug absorption in the human body, increasing drug bioavailability, and achieving better therapeutic effects with a smaller drug load. Furthermore, reducing the drug load while ensuring drug efficacy can reduce drug toxicity and side effects, improve drug safety, and has significant clinical implications.

[0063] Example 4: Solubility of the present application's crystal form DCVIII in water

[0064] CN107001310B patent, paragraph

[0219] , discloses the solubility of thermally stable crystal form II in water. Following the same method, the solubility of the present invention's crystal form DCVIII in water was tested, and the results are shown in Table 4 below:

[0065] Table 4 Polymorphs Solubility (mg / mL) Crystal form II 5.9 (Data source: CN107001310B, paragraph

[0220] ) The present invention has a crystal form DCVIII 10.15

[0066] The results of the water solubility test show that, compared with the thermally stable crystal form II in patent CN107001310, the crystal forms DCVIII and II of the present invention have higher solubility in water.

[0067] Example 5: Humidity stability of the DCVIII crystal form of this application

[0068] Approximately 5 mg of the crystalline form DCVIII prepared in Example 1 was weighed and placed in open containers at 25°C at 22.5% RH, 45% RH, and 60% RH, respectively. The crystal form was determined using XRPD. The experimental conditions and results are shown in Table 5, and the XRPD overlay images are shown below. Figure 5 As shown.

[0069] Table 5 Placement conditions Placement time Crystal form Start —— Crystal form DCVIII 22.5%RH 30 days Crystal form DCVIII 45%RH 30 days Crystal form DCVIII 60%RH 30 days Crystal form DCVIII

[0070] The results showed that the crystal form of DCVIII of the present invention remained unchanged after being placed for 30 days under three conditions of 22.5%RH, 45%RH, and 60%RH at 25 °C, indicating that the crystal form of DCVIII has good physical stability. 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 quality stability during subsequent formulation development, process production, and drug production and transportation, which is of great significance for ensuring drug quality and efficacy.

[0071] Example 6: Stability of the DCVIII crystal form of this application

[0072] Approximately 5 mg of the crystalline form DCVIII prepared in Example 1 was weighed and placed under both ambient temperature (25 °C / 60%RH) and accelerated conditions (40 °C / 75%RH), respectively. The crystal form was determined using XRPD. The experimental conditions and results are shown in Table 6, and the XRPD overlay images are shown below. Figure 6 As shown.

[0073] Table 6 Placement conditions Placement time Crystal form Purity (peak area %) Start —— Crystal form DCVIII 99.95 25 ℃ / 60%RH 2 weeks Crystal form DCVIII 99.94 40 ℃ / 75%RH 2 weeks Crystal form DCVIII 99.94

[0074] The results showed that the crystalline form of DCVIII remained unchanged after two weeks of storage under both 25 ℃ / 60%RH and 40 ℃ / 75%RH conditions, indicating that the crystalline form of DCVIII possesses good physical stability. In particular, under accelerated conditions of 40 ℃ / 75%RH, the crystalline form remained stable after two weeks without crystal transformation, further demonstrating that the crystalline form of DCVIII maintains good physical stability even under high temperature and humidity conditions. This ensures that the drug is less prone to crystal transformation during subsequent processes, production, and transportation. Furthermore, the chemical purity of the crystalline form of DCVIII remained unchanged before and after storage under 25 ℃ / 60%RH (relative humidity), consistently above 99%, indicating good chemical stability. Moreover, even under accelerated conditions of 40 ℃ / 75%RH, the chemical purity did not show a significant decrease, further demonstrating the good chemical stability of the crystalline form of DCVIII. Good physicochemical stability ensures that the quality of the drug remains stable during subsequent formulation development, manufacturing processes, and transportation, thus guaranteeing drug quality and efficacy, which is of great significance.

[0075] Example 7: Hygroscopicity of the present application's crystal form DCVIII

[0076] The hygroscopicity of drugs was determined according to the guidelines for hygroscopicity testing of drugs in General Chapter 9103 of the 2020 edition of the Chinese Pharmacopoeia. The test conditions were 25 ± 1 ℃ and 80% relative humidity.

[0077] Definition of hygroscopic weight gain: Extremely hygroscopic: hygroscopic weight gain of not less than 15.0%; Hygroscopic: hygroscopic weight gain of less than 15.0% but not less than 2.0%; Slightly hygroscopic: hygroscopic weight gain of less than 2.0% but not less than 0.2%; No or almost no hygroscopicity: hygroscopic weight gain of less than 0.2%.

[0078] Approximately 20 mg of the crystalline form DCVIII prepared in Example 1 of this application was weighed and placed at 25 ± 1 °C and 80% relative humidity for 24 hours. The mass of the sample before and after the event was recorded, and the crystalline form was determined using XRPD. The specific results are shown in Table 7 below, and the XRPD overlay images are shown below. Figure 7 As shown.

[0079] Table 7 Starting mass (mg) Placement conditions Placement time Mass after storage (mg) Weight gain (mg) Percentage of weight gain 17.50 25 ± 1 ℃, 80%RH 24 hours 17.70 0.20 1.14%

[0080] As can be seen from Table 7, the crystalline DCVIII of the present invention is slightly hygroscopic, which indicates that the crystalline DCVIII is not prone to deliquescence during the production and storage of pharmaceuticals.

[0081] Crystal form stability is crucial for drug development. Crystal transformation directly impacts drug solubility and, consequently, bioavailability, thus altering efficacy. Good chemical stability ensures minimal formation or increase in impurity levels during storage, guaranteeing drug safety. Good humidity stability prevents crystal transformation during storage, transportation, and formulation, reducing the risk of transformation and enhancing product development potential. Low hygroscopicity ensures minimal weight gain and prevents deliquescence during production, processing, storage, and transportation, ensuring stable drug quality.

[0082] Therefore, the good physical stability, good humidity stability, and low hygroscopicity of the crystal form DCVIII provide a guarantee for the subsequent production and development of drugs, and have high industrialization development value.

[0083] The preferred embodiments of the present invention have been described in detail above. It should be understood that those skilled in the art can make numerous modifications and variations based on the concept of the present invention without creative effort. Therefore, all technical solutions that can be obtained by those skilled in the art based on the concept of the present invention through logical analysis, reasoning, or limited experimentation on the basis of existing technology should be within the scope of protection defined by the claims.

Claims

1. A maltol iron crystal form DCVIII, characterized in that, The X-ray powder diffraction pattern of the DCVIII crystal form under Cu-Ka radiation has characteristic peaks at diffraction angles of 2theta of 5.9±0.2°, 14.8±0.2°, and 15.7±0.2°.

2. The maltol iron crystal form DCVIII according to claim 1, characterized in that, Using Cu-Ka radiation, its X-ray powder diffraction pattern has one, two, or three characteristic peaks at 2theta values ​​of 12.0º±0.2º, 17.4º±0.2º, and 23.8º±0.2º.

3. A maltol iron crystal form DCVIII according to claim 1 or 2, characterized in that, Using Cu-Ka radiation, its X-ray powder diffraction pattern has one, two, or three characteristic peaks at 2theta values ​​of 20.2º±0.2º, 21.4º±0.2º, and 22.6º±0.2º.

4. A method for preparing maltol iron crystal form DCVIII according to claim 1, 2, or 3, characterized in that: Ferric maltol was placed in a solvent and recrystallized at -20℃ to 30℃. After centrifugation and drying, the crystal form DCVIII was obtained.

5. The method for preparing maltol iron crystal form DCVIII according to claim 4, characterized in that, The preferred temperature range is 0 to 5 degrees Celsius.

6. A pharmaceutical composition comprising the maltol iron crystal form DCVIII as described in claim 1, 2 or 3 and its pharmaceutically acceptable carrier or excipient.

7. The use of a method for preparing a maltol iron crystalline form DCVIII as described in claim 1, 2, or 3, or a method for preparing a maltol iron crystalline form DCVIII as described in claim 4 or 5, or a pharmaceutical composition as described in claim 6, in the preparation of a medicament for the prevention or treatment of iron deficiency in a subject, with or without anemia.

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