Preparation process of iron maltol crystal form alpha

Abstract

The invention discloses a preparation process of an iron maltol crystal form alpha, which comprises the following steps of: dissolving iron maltol in any form in good solvents (hexafluoroethanol and trifluoroisopropanol), and dropwise adding anti-solvents (methyl isopropyl ketone and methyl tert-butyl ether) to separate out the iron maltol crystal form alpha. A conventional organic solvent is used in production, the process operation is simple and convenient, the energy consumption is low, the yield is high, and the cost is low. The technological operation has reproducibility, and industrial production is easy to realize.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical crystal forms, and specifically relates to maltol iron crystal form α and its preparation method. Background Art

[0002] Maltol iron is a novel oral trivalent iron compound developed by the British company Shield Therapeutics. It was approved by the European Medicines Agency in 2016 for the treatment of iron deficiency in adults. On July 25, 2019, the drug was officially approved by the US Food and Drug Administration to exert the same efficacy.

[0003] Maltol iron is an iron ion complex. Different from iron salt compounds, it dissociates when taken up by the gastrointestinal tract, and the iron ion and maltol are absorbed separately. The iron ion is taken up by 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.

[0004] In clinical applications, maltol iron is a drug for the treatment of iron deficiency in adults with a low incidence of adverse reactions, high bioavailability, low risk of iron overload, and good tolerance. It is a reliable alternative to intravenous iron therapy and is also an ideal alternative for patients who are intolerant to existing oral iron preparations and have poor treatment effects.

[0005] Maltol iron is a polymorphic compound. The phenomenon of pharmaceutical polymorphism refers to the phenomenon that 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 have different dissolution and absorption in the body, and thus may affect the clinical efficacy and safety of drugs to a certain extent. Especially for poorly soluble solid drugs, the influence of crystal form on bioavailability will be greater. Therefore, pharmaceutical crystal form is an important part of the research and development process of solid drugs and an important content of drug quality control.

[0006] CN107001310 discloses 4 polymorphic forms of maltol iron, namely anhydrous crystal forms I, II, IV, and solvate crystal form III. Among them, crystal form II is the stable crystal form, but it has the disadvantages of low solubility, poor drug efficacy, and low bioavailability. Solvate crystal form III contains organic solvents and has large toxic and side effects, so it cannot be used as a pharmaceutical crystal form.

[0007] US2021139518 discloses 1 polymorphic form of maltol iron and its preparation method, which is named crystal form α. The preparation method described in the article has harsh conditions, requires dissolution in dichloromethane, and then rotary evaporation at 90 °C to remove the solvent, with high energy consumption, and this process cannot be industrialized.

[0008] It was found in this application that this crystal form can be obtained by a conventional crystallization method, and its scale-up preparation was carried out while studying its preparation process, realizing a stable process at the gram scale. Summary of the Invention

[0009] In view of the above-mentioned defects of the prior art, the present invention provides a ferric maltol crystal form α, and the crystal form α can be used as an intermediate for industrial production. For this purpose, the present invention also provides comprehensive characterization data of the above-mentioned ferric maltol crystal form α and its process preparation method.

[0010] In order to solve the above technical problems, in the first aspect of the present invention, there is provided a ferric maltol crystal form α, and the X-ray powder diffraction pattern of the crystal form α under Cu-Kα radiation has characteristic peaks at diffraction angle 2θ values of 9.6±0.2°, 10.9±0.2°, 12.9±0.2°, 13.2±0.2°, 14.6±0.2°, 17.5±0.2°, 18.6±0.2°, 19.2±0.2°, 20.0±0.2°, 21.2±0.2°, 22.1±0.2°, 23.1±0.2°, 23.7±0.2°, 24.4±0.2°, 24.9±0.2°, 25.8±0.2°, 26.0±0.2°, 28.7±0.2°, 29.0±0.2°, 30.2±0.2°, 31.7±0.2°.

[0011] In the second aspect of the present invention, there is provided a preparation method of the above-mentioned ferric maltol crystal form α. Ferric maltol is dissolved in 2 volumes of hexafluoroisopropanol or trifluoroethanol. The solution is filtered to remove mechanical impurities. By dropping 20 volumes of methyl tert-butyl ether or methyl isopropyl ketone, a solid is precipitated. The obtained suspension is separated and dried to obtain the crystal form α.

[0012] As a preferred embodiment, the crystallization temperature is 5-25°C.

[0013] Compared with the prior art, the present invention has the following beneficial effects: The preparation process of the ferric maltol crystal form α of the present invention is simple, easy to operate, and easy to scale up; the solvents required for the ferric maltol crystal form α of the present invention are conventional organic solvents, with less production consumption and low production cost.

[0014] The following will further illustrate the concept, specific structure and technical effects generated by the present invention with reference to the accompanying drawings, so as to fully understand the purpose, features and effects of the present invention. Brief Description of the Drawings

[0015] Figure 1 is the XRPD pattern of the ferric maltol crystal form α prepared in Example 1 of the present invention; Figure 2 is the XRPD pattern of the ferric maltol crystal form α prepared in Example 2 of the present invention; Figure 3 This is the XRPD pattern of iron maltol crystal form α prepared in Example 3 of the present invention; Detailed implementation manners

[0017] In order to make the technical means, creative features, achieved purposes and effects of the invention easy to understand, the present invention will be further described below in conjunction with specific drawings. However, the present invention is not limited to the following implemented cases.

[0018] It should be noted that the structures, ratios, sizes, etc. shown in the drawings of this specification are only used to cooperate with the content disclosed in the specification for those skilled in this technology to understand and read, and are not used to limit the limiting conditions under which the present invention can be implemented. Therefore, they do not have technical essential significance. Any modification of the structure, change of the proportional relationship or adjustment of the size, without affecting the effects that the present invention can produce and the purposes that can be achieved, should still fall within the scope covered by the technical content disclosed in the present invention.

[0019] Iron maltol is a complex containing one ferric ion and three maltol anions, and its molecular formula is (C6H5O3)3Fe.

[0020] Iron maltol is a drug for treating iron deficiency in adults with low incidence of adverse reactions, high bioavailability, not prone to iron overload and good tolerance. Among the various crystal forms of iron maltol reported in the existing literature, there is generally a problem of low solubility, resulting in poor drug efficacy and low bioavailability.

[0021] From the perspective of changing the preparation method of iron maltol, the present application obtains a new crystal form α of iron maltol, and the preparation of crystal form α is simple and easy.

[0022] XRPD, that is, 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 milliamperes (mA); scanning range: 3.0 - 40.0°.

[0023] Unless otherwise specified, the following examples are all operated at room temperature. The "room temperature" here is not a specific temperature value, but refers to the temperature range of 10 - 30 °C.

[0024] In the following examples, the "stirring" is completed by using conventional methods in the art, such as magnetic stirring or mechanical stirring. The stirring speed is 50 - 1800 revolutions per minute. Among them, the magnetic stirring is preferably 300 - 900 revolutions per minute, and the mechanical stirring is preferably 100 - 300 revolutions per minute.

[0025] In the following examples, the "separation" is completed by using conventional methods in the art, such as centrifugation or filtration. The operation of "centrifugation" is as follows: place the sample to be separated in a centrifuge tube and centrifuge at a rate of 10,000 revolutions per minute until all the solids sink to the bottom of the centrifuge tube.

[0026] In the following examples, the "drying" can be carried out at room temperature or a higher temperature. The drying temperature is from room temperature to 50 °C, or to 40 °C. The drying time can be 2 - 48 hours. The drying is carried out in a fume hood, a forced-air oven or a vacuum oven.

[0027] In the following examples, the "crystal" refers to a solid characterized by an X-ray powder diffraction pattern. Those skilled in the art can understand that the physical and chemical properties discussed here can be characterized, and the experimental errors therein depend on the instrument conditions, sample preparation and sample purity. In particular, as is well known to those skilled in the art, the X-ray powder diffraction pattern usually changes with different instrument conditions. It should be particularly noted that the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern may also change with the experimental conditions. Therefore, the order of the diffraction peak intensities cannot be used as the only or decisive factor. In fact, the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystal. The diffraction peak intensities shown in the present invention are illustrative rather than for absolute comparison. In addition, the experimental error of the diffraction peak positions is usually 5% or less, and the errors at these positions should also be taken into account, usually allowing an error of ±0.2. In addition, due to the influence of experimental factors such as sample thickness, an overall shift of the diffraction peak angles will occur, and a certain shift is usually allowed. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be exactly the same as the X-ray powder diffraction pattern in the examples referred to here. Any crystal form with an X-ray powder diffraction pattern having the same or similar characteristic peaks as those in these spectra belongs to the scope of the present invention.

[0028] Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with the X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two groups of patterns reflect the same or different crystal forms.

[0029] The crystalline form α of the present invention is pure and contains substantially no admixture of any other crystalline forms. When the term "substantially no" is used in the present invention to refer to a new crystalline form, it means that this crystalline form contains less than 20% (by weight) of other crystalline forms, particularly less than 10% (by weight) of other crystalline forms, more particularly less than 5% (by weight) of other crystalline forms, and even more particularly less than 1% (by weight) of other crystalline forms.

[0030] In the present invention, the term "about", when used to refer to a measurable value such as mass, time, temperature, etc., means a range with a certain fluctuation around the specific value, and this range can be ±10%, ±5%, ±1%, ±0.5% or ±0.1%.

[0031] Ferric maltol as a raw material includes, but is not limited to, solid forms (crystalline or amorphous), oily, liquid forms and solutions. Preferably, it is in solid form.

[0032] The preparation method of the crystalline form α of ferric maltol in the present application: Place ferric maltol in 2 volumes of hexafluoroisopropanol or trifluoroethanol for dissolution, filter the solution to remove mechanical impurities, and precipitate a solid by dropwise adding 20 volumes of methyl tert-butyl ether or methyl isopropyl ketone. Separate and dry the obtained suspension to obtain the crystalline form α.

[0033] In the process of preparing the crystalline form α of ferric maltol in the present application, the amounts of ferric maltol and the solvent are strictly limited. The use of hexafluoroisopropanol is to dissolve ferric maltol, and its amount is limited to complete dissolution of ferric maltol; while the use of methyl isobutyl ketone and methyl tert-butyl ether is to precipitate ferric maltol, and different amounts of them will result in differences in crystal yield.

[0034] Moreover, different crystallization times also affect the degree of crystallization or the yield of crystals, which can be flexibly selected according to actual needs.

[0035] Example 1: Weigh 5.0 grams of ferric maltol and add it to a 250 ml three-necked flask; add 10 ml of hexafluoroisopropanol, heat to 35 ±5 °C, and stir until clear; pre-filter the solution to remove mechanical impurities, and transfer the filtrate to a 250 ml reaction kettle; keep the reaction kettle at 15 ±10 °C and stir, and add 100 ml of methyl isobutyl ketone dropwise to the reaction kettle; at this time, a large amount of solid precipitates; keep the reaction kettle at 15 ±10 °C and stir for 2 - 16 hours; filter the reaction kettle under reduced pressure, and wash the filter cake with 10 ml of methyl isobutyl ketone; vacuum-dry the filter cake at 30 ±5 °C for 6 - 16 hours; obtain 4.8 grams of crystals, namely the crystalline form α, with a yield of 96 wt%. Its XRPD is as Figure 1 shown, and the XRPD data is shown in Table 1.

[0036] Table 1 Diffraction angle 2θ d value Relative intensity Diffraction angle 2θ d value Relative intensity Diffraction angle 2θ d value Relative intensity 9.61 9.20 100.00% 19.22 4.61 4.00% 24.92 3.57 2.80% 10.93 8.09 3.80% 19.97 4.44 11.90% 25.83 3.45 5.60% 12.88 6.87 16.30% 21.21 4.19 4.70% 26.05 3.42 6.20% 13.21 6.70 2.10% 22.14 4.01 1.20% 28.71 3.11 2.80% 14.65 6.04 40.20% 23.14 3.84 39.90% 29.04 3.07 3.00% 17.51 5.06 6.90% 23.67 3.76 2.60% 30.18 2.96 3.90% 18.57 4.78 5.60% 24.44 3.64 5.80% 31.72 2.82 4.80%

[0037] Example 2: Weigh 5.0 g of iron maltol and add it to a 250 mL three-necked flask; add 10 mL of hexafluoroisopropanol, heat up to 35 ± 5 °C, and stir until clear; pre-filter the solution to remove mechanical impurities, and transfer the filtrate to a 250 mL reaction kettle; keep the reaction kettle warm and stir at 15 ± 10 °C, and add 100 mL of methyl tert-butyl ether dropwise to the reaction kettle; at this time, a large amount of solid precipitates; keep the reaction kettle warm and stir at 15 ± 10 °C for 2 - 16 hours; carry out vacuum filtration on the reaction kettle, and wash the filter cake with 10 mL of methyl tert-butyl ether; dry the filter cake in vacuum at 30 ± 5 °C for 6 - 16 hours; obtain crystals, namely crystal form α, 4.8 g, and the yield is 96 wt%. Its XRPD is as Figure 2 shown.

[0038] Example 3: Weigh 5.0 g of iron maltol and add it to a 250 mL three-necked flask; add 10 mL of trifluoroethanol, heat up to 35 ± 5 °C, and stir until clear; pre-filter the solution to remove mechanical impurities, and transfer the filtrate to a 250 mL reaction kettle; keep the reaction kettle warm and stir at 15 ± 10 °C, and add 100 mL of methyl tert-butyl ether dropwise to the reaction kettle; at this time, a large amount of solid precipitates; keep the reaction kettle warm and stir at 15 ± 10 °C for 2 - 16 hours; carry out vacuum filtration on the reaction kettle, and wash the filter cake with 10 mL of methyl tert-butyl ether; dry the filter cake in vacuum at 30 ± 5 °C for 6 - 16 hours; obtain crystals, namely crystal form α, 4.7 g, and the yield is 94 wt%. Its XRPD is as Figure 3 shown.

[0039] The preferred specific embodiments of the present invention have been described in detail above. It should be understood that those of ordinary skill in the art can make many modifications and variations according to the concept of the present invention without creative labor. Therefore, all technical solutions that can be obtained by those skilled in the art in the technical field of the present invention based on the concept of the present invention through logical analysis, reasoning or limited experiments on the basis of the prior art should be within the protection scope determined by the claims.

Claims

1. An iron maltol crystal form α, characterized in that, The X-ray powder diffraction pattern of the crystalline form α under Cu-Kα radiation has characteristic peaks at diffraction angles 2θ of 9.6±0.2°, 10.9±0.2°, 12.9±0.2°, 13.2±0.2°, 14.6±0.2°, 17.5±0.2°, 18.6±0.2°, 19.2±0.2°, 20.0±0.2°, 21.2±0.2°, 22.1±0.2°, 23.1±0.2°, 23.7±0.2°, 24.4±0.2°, 24.9±0.2°, 25.8±0.2°, 26.0±0.2°, 28.7±0.2°, 29.0±0.2°, 30.2±0.2°, 31.7±0.2°.

2. The ferric maltol crystal form α according to claim 1, wherein The crystalline form α is a hydrate crystalline form.

3. A method for preparing maltol iron crystal form α, characterized in that, Ferric maltol is dissolved in 2 volumes of trifluoroethanol. The solution is filtered to remove mechanical impurities. By adding 20 volumes of methyl tert-butyl ether dropwise, a solid is precipitated, and it is kept warm and stirred for 2 - 16 hours. The obtained suspension is separated and dried to obtain the crystalline form α.

4. A method for preparing maltol iron crystal form α, characterized in that, Ferric maltol is dissolved in 2 volumes of hexafluoroisopropanol. The solution is filtered to remove mechanical impurities. By adding 20 volumes of methyl tert-butyl ether dropwise, a solid is precipitated, and it is kept warm and stirred for 2 - 16 hours. The obtained suspension is separated and dried to obtain the crystalline form α.

5. A method for preparing maltol iron crystal form α, characterized in that, Ferric maltol is dissolved in 2 volumes of hexafluoroisopropanol. The solution is filtered to remove mechanical impurities. By adding 20 volumes of methyl isopropyl ketone dropwise, a solid is precipitated, and it is kept warm and stirred for 2 - 16 hours. The obtained suspension is separated and dried to obtain the crystalline form α.

6. The preparation method of maltol iron crystal form α as described in claim 3, characterized in that, The crystallization temperature is 5 - 25°C.

7. The preparation method of maltol iron crystal form α as described in claim 4, characterized in that, The crystallization temperature is 5 - 25°C.

8. The preparation method of maltol iron crystal form α according to claim 5, characterized in that, The crystallization temperature is 5 - 25°C.

9. The preparation method of maltol iron crystal form α as described in claim 3, characterized in that, The drying temperature is 25 - 35°C.

10. The preparation method of maltol iron crystal form α as described in claim 4, characterized in that, The drying temperature is 25 - 35°C.

11. The preparation method of maltol iron crystal form α according to claim 5, characterized in that, The drying temperature is 25 - 35°C.

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