A maltol iron-oxalic acid eutectic and its preparation method

Abstract

This invention discloses a maltol-ferric oxalate cocrystal, which is formed using maltol-ferric as the active pharmaceutical ingredient and oxalate as the cocrystal ligand via a suspension stirring method. In the X-ray powder diffraction pattern obtained using Cu-Kα radiation, the maltol-ferric oxalate cocrystal exhibits characteristic diffraction peaks at diffraction angles 2θ of approximately 14.7±0.2°, 17.0±0.2°, 17.6±0.2°, 24.8±0.2°, 26.6±0.2°, and 26.9±0.2°. The maltol-ferric oxalate cocrystal of this invention exhibits good stability, showing no crystal transformation for at least 60 days under accelerated conditions. Compared to maltol-ferric, the maltol-ferric oxalate cocrystal has relatively lower solubility in water. Low-solubility cocrystals typically dissolve more slowly, avoiding rapid drug concentration peaks, reducing the toxic side effects of maltol-ferric, and improving medication adherence.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to drug cocrystals, specifically to a maltol iron-oxalic acid cocrystal and its preparation method. Background Technology

[0002] Drug cocrystals refer to novel crystal structures formed by the assembly of active pharmaceutical ingredients and suitable cocrystal ligands in a certain proportion under the influence of hydrogen bonds, π-π stacking, van der Waals forces, or other non-covalent bonds. They do not change the original chemical structure of the drug, but improve the physicochemical properties and efficacy of the drug through physical means, such as improving solubility, enhancing stability, and improving bioavailability.

[0003] Ferric maltol is a novel, chemically stable, non-salt complex formed from iron and maltol. It exhibits phenol-like properties and is a reddish-brown crystalline solid. Its chemical structural formula is as follows:

[0004]

[0005] Ferrous maltol provides iron, supplementing the body's nutritional needs and preventing or treating iron-deficiency anemia. Ferrous maltol has a unique absorption mechanism, offering significant advantages compared to similar iron supplements. Developed by Shield Therapeutics in the UK, ferrous maltol capsules were approved by the European Medicines Agency (EMA) in 2016 and the US Food and Drug Administration (FDA) in 2019 for the treatment of iron deficiency in adults (with or without anemia symptoms). For patients who are intolerant to or do not respond well to existing oral iron supplements, ferrous maltol capsules are an ideal alternative. Currently, several polymorphs of ferrous maltol have been reported. Patent application WO2016066555A1 discloses four polymorphic forms of ferrous maltol (i.e., polymorphs I, II, III, and IV), and patent US20210139518A1 discloses a new polymorph of ferrous maltol (i.e., polymorph V). However, current methods cannot quickly and efficiently obtain stable crystal forms of ferric maltol, and there is a risk of mixing crystal form I and crystal form II, which poses a certain challenge to large-scale production. It has also been reported that the main adverse reactions of ferric maltol include: gastrointestinal inflammation, flatulence, constipation, diarrhea, etc. (Khoury A, Pagan KA, Farland MZ. Ferric maltol: A new oral iron formulation for the treatment of iron deficiency in adults. Ann Pharmacother. 2021, 55(2):222-229).

[0006] There are currently no reports on maltol iron eutectic, therefore developing a novel solid form of maltol iron is of great significance for improving its drug-like properties and clinical application. Summary of the Invention

[0007] The purpose of this invention is to provide a maltol iron-oxalic acid eutectic formed by combining maltol iron and the pharmaceutical small molecule excipient oxalic acid, and its preparation method.

[0008] The objective of this invention is achieved through the following technical solution:

[0009] A maltol iron-oxalic acid cocrystal is formed by using maltol iron as the active pharmaceutical ingredient and oxalic acid as the cocrystal ligand, and by a suspension stirring method.

[0010] In the X-ray powder diffraction pattern obtained using Cu-Kα radiation measurement, the maltol iron-oxalic acid eutectic exhibits characteristic diffraction peaks at diffraction angles of approximately 14.7±0.2°, 17.0±0.2°, 17.6±0.2°, 24.8±0.2°, 26.6±0.2°, and 26.9±0.2°. The 2θ angle of the characteristic peak with a relative intensity of 100% is 26.6±0.2°.

[0011] Preferably, in the X-ray powder diffraction pattern obtained using Cu-Kα radiation measurement, the maltol iron-oxalic acid eutectic exhibits characteristic diffraction peaks at diffraction angles 2θ of approximately 14.7±0.2°, 15.9±0.2°, 17.0±0.2°, 17.6±0.2°, 22.0±0.2°, 24.8±0.2°, 25.7±0.2°, 26.6±0.2°, and 26.9±0.2°.

[0012] More preferably, the maltol iron-oxalic acid eutectic has the following properties: Figure 1 or Figure 5 The X-ray powder diffraction pattern shown is shown.

[0013] The infrared spectrum obtained by compressing the maltol iron-oxalic acid eutectic with potassium bromide into tablets is at 1074.41 cm⁻¹. -1 1205.56cm -1 1277.91cm -1 1353.16cm -1 1384.55cm -1 1399.84cm -1 1495.65cm -1 1560.58cm -1 1606.82cm -1 1664.18cm -1 3256.93cm -1An absorption peak is observed at 310.93 °C; in the differential scanning calorimetry (DSC) spectrum, the maltol iron-oxalic acid eutectic exhibits a single endothermic melting peak at 310.93 °C.

[0014] The maltol iron-oxalic acid eutectic is a eutectic formed by the interaction of maltol iron and oxalic acid through hydrogen bonding.

[0015] The molar ratio of maltol iron to oxalic acid in the maltol iron-oxalic acid eutectic is 1:1 to 1:2, preferably 1:1.

[0016] Another object of the present invention is to provide a method for preparing the maltol iron-oxalic acid eutectic, wherein the preparation method adopts a suspension stirring method and includes the following steps: adding maltol iron and oxalic acid to an organic solvent to form a suspension, stirring and reacting, filtering, and vacuum drying to obtain maltol iron-oxalic acid eutectic.

[0017] The molar ratio of maltol iron to oxalic acid is 1:1 to 1:2, preferably 1:1.

[0018] The organic solvent is ethanol, methanol, acetonitrile, ethyl acetate, or a mixture of at least two of the above organic solvents, preferably ethanol.

[0019] The ratio of maltol iron to organic solvent is 2:1 to 500:1 mg / mL, preferably 50:1 to 200:1 mg / mL.

[0020] The reaction temperature is 25-45°C, preferably 15-30°C, and most preferably room temperature (25°C).

[0021] The reaction time is 3 to 7 days, preferably 5 to 6 days.

[0022] The stirring speed is 50-1000 rpm, preferably 200-400 rpm.

[0023] Another object of the present invention is to provide a pharmaceutical composition comprising the aforementioned maltol iron-oxalate cocrystal, and a pharmaceutically acceptable carrier.

[0024] The beneficial effects of this invention are:

[0025] (1) The PXRD, DSC and IR spectra of the maltol iron-oxalic acid eutectic crystal of the present invention are different from those of maltol iron crystal, oxalic acid crystal and physical mixture of maltol iron-oxalic acid, which is a new solid-state material that is completely different from the existing maltol iron and oxalic acid.

[0026] (2) The maltol iron-oxalic acid cocrystal of the present invention will not undergo crystal transformation for at least 60 days under accelerated conditions (40°C, 75%RH), exhibiting good stability. This can extend the shelf life of the cocrystal preparation, reduce the decline in efficacy and quality problems caused by crystal transformation, and simultaneously reduce the risks of production and quality control.

[0027] (3) Compared with maltol iron, maltol iron-oxalic acid eutectic has a higher melting point, indicating that the eutectic system has higher thermal stability. Under high temperature conditions, such as spray drying and hot melt extrusion in the pharmaceutical industry, it is less likely to decompose or undergo phase change, thus giving it better processability and adaptability. At the same time, it can improve the stability of the eutectic system and the consistency of the product.

[0028] (4) By introducing the co-crystallized ligand oxalic acid, the co-crystallized maltol iron has a relatively lower solubility in water compared with maltol iron. Co-crystallized maltol iron usually dissolves slowly, which provides a new solution for the design of sustained-release and long-acting drug delivery systems. This can avoid drug concentration peaks in a short period of time, reduce the toxic side effects of maltol iron, and improve medication compliance.

[0029] (5) The method for preparing maltol iron oxalic acid eutectic of the present invention is simple, low in cost, easy to control, and conducive to industrial production.

[0030] (6) Compared with amorphous solid dispersion technology, which usually requires a polymer carrier several times larger than the drug to fully disperse the drug, the maltol iron-oxalate cocrystal of the present invention has a high drug loading capacity, has a significant drug loading advantage, and has better stability; compared with nanotechnology, the maltol iron-oxalate cocrystal of the present invention is easier to industrialize and the quality is easier to control. Attached Figure Description

[0031] Figure 1 The image shows the PXRD pattern of the maltol iron-oxalic acid eutectic obtained in Example 1.

[0032] Figure 2 The image shows a comparison of the PXRD patterns of the maltol iron-oxalic acid eutectic obtained in Example 1 with those of maltol iron and oxalic acid.

[0033] Figure 3 The image shows a DSC comparison of the maltol iron-oxalic acid eutectic, maltol iron, and oxalic acid prepared in Example 1.

[0034] Figure 4 Comparison of infrared spectra of ferric maltol, oxalic acid, a physical mixture of ferric maltol and oxalic acid, and a eutectic mixture of ferric maltol and oxalic acid.

[0035] Figure 5 The image shows the PXRD pattern of the maltol iron-oxalic acid eutectic obtained in Example 2.

[0036] Figure 6 The image shows a comparison of the PXRD values ​​of maltol iron-oxalic acid eutectic after 60 days and 0 days of storage under accelerated conditions (40°C, 75% RH) in Example 1.

[0037] Figure 7 The image shows the PXRD pattern of the product prepared by slurrying maltol iron and L-cysteine ​​in acetone, ethanol, acetonitrile or ethyl acetate, as shown in Comparative Example 1.

[0038] Figure 8 The image shows the PXRD pattern of the product prepared by slurrying maltol iron and nicotinamide in acetone, ethanol, acetonitrile, or ethyl acetate, as shown in Comparative Example 2. Detailed Implementation

[0039] The maltol iron used in the preparation of the maltol iron-oxalic acid eutectic is maltol iron crystal form II; the maltol iron (crystal) used for comparison with the maltol iron-oxalic acid eutectic is maltol iron crystal form II.

[0040] Example 1

[0041] Preparation of maltol iron-oxalic acid eutectic:

[0042] Weigh 30 mg of ferric maltol and 6.26 mg of oxalic acid according to a molar ratio of 1:1. Add 0.5 mL of anhydrous ethanol and stir magnetically (400 rpm) at room temperature (25°C) for 6 days. Filter and vacuum dry the filter cake at 40°C for 24 hours. The resulting solid product is ferric maltol-oxalic acid eutectic.

[0043] The product was characterized using X-ray powder diffraction (PXRD) with Cu-Kα radiation. The PXRD pattern is shown below. Figure 1 As shown.

[0044] The PXRD pattern of the maltol iron-oxalic acid cocrystal was compared with that of maltol iron and oxalic acid, as follows: Figure 2 As shown, the PXRD pattern of the eutectic is significantly different from that of maltol iron and oxalic acid. Further comparison of the characteristic peaks of the three is shown in Table 1. The eutectic exhibits characteristic diffraction peaks at diffraction angles of approximately 14.71°, 17.03°, 17.57°, 24.82°, 26.58°, and 26.94°, which are significantly different from those of maltol iron and oxalic acid.

[0045] Table 1. Comparison of PXRD characteristic diffraction peak positions of maltol iron-oxalic acid eutectic and oxalic acid, maltol iron.

[0046]

[0047]

[0048] The thermal properties of the maltol iron-oxalic acid eutectic, maltol iron, and oxalic acid prepared in this example were analyzed using differential scanning calorimetry (DSC). The method was as follows: approximately 3 mg of sample was taken, nitrogen was used as a protective gas at a flow rate of 100 mL / min, the heating rate was 10 °C / min, and the temperature range was 40-400 °C. Figure 3 It is evident that the thermal behaviors of ferric maltol, oxalic acid, and the ferric maltol-oxalic acid eutectic differ significantly. Ferric maltol has a melting point of 288.87℃, oxalic acid 198.02℃, and the ferric maltol-oxalic acid eutectic 310.93℃. The higher melting point indicates that the ferric maltol-oxalic acid eutectic exhibits better thermal stability, making it less prone to decomposition or phase transition under high-temperature conditions such as spray drying and hot melt extrusion. This often results in better processability and adaptability, while simultaneously improving product stability and consistency.

[0049] Comparison of infrared spectra of maltol iron-oxalic acid eutectic: The maltol iron-oxalic acid eutectic, maltol iron and oxalic acid, and maltol iron-oxalic acid physical mixture (the molar ratio of maltol iron to oxalic acid was 1:1) prepared in this example were pressed into thin sheets with KBr and analyzed using an infrared spectrometer in the range of 4000–400 cm⁻¹. -1 The scan was performed within the range, and the infrared absorption spectra were compared. The results are as follows: Figure 4 As shown.

[0050] from Figure 4 It can be seen that the maltol iron-oxalic acid eutectic is at 1074.41 cm⁻¹ -1 1205.56cm -1 1277.91cm -1 1353.16cm -1 1384.55cm -1 1399.84cm -1 1495.65cm -1 1560.58cm -1 1606.82cm -1 1664.18cm -1 3256.93cm -1 It exhibits characteristic peaks in the vicinity, which are significantly different from those of maltol iron and oxalic acid. Specifically, the peak at 3256.93 cm⁻¹ is... -1 Located in the stretching vibration region of OH in oxalic acid, 1664.18 cm⁻¹ -1 Located in the stretching vibration region of C=O in oxalic acid, 1606.82 cm -1 Located in the C=O stretching vibration region of maltol iron, 1495.65 cm -1 1560.58cm -1It lies within the C=C stretching vibration region of ferromaltol. The spectral differences between the ferromaltol-oxalic acid eutectic and ferromaltol / oxalic acid in these regions indicate that the OH and C=O functional groups in the eutectic have changed relative to the two components, suggesting that the ferromaltol-oxalic acid eutectic was formed through hydrogen bonding.

[0051] Example 2

[0052] Preparation of maltol iron-oxalic acid eutectic:

[0053] Weigh 30 mg of ferric maltol and 6.26 mg of oxalic acid at a molar ratio of 1:1, add 0.5 mL of ethanol, and stir magnetically (200 rpm) for 6 days at room temperature (25°C). Filter, and vacuum dry the filter cake at 40°C for 24 hours. The resulting solid product is the ferric maltol-oxalic acid eutectic. Characterize the product using X-ray powder diffraction (PXRD) with Cu-Kα radiation. The PXRD pattern is shown below. Figure 5 As shown.

[0054] Example 3

[0055] Stability study of maltol iron-oxalic acid eutectic

[0056] The maltol iron-oxalic acid eutectic obtained in Example 1 was placed in a constant temperature and humidity chamber under accelerated conditions (40°C, 75% RH). Samples were taken on day 60 and characterized using X-ray powder diffraction (PXRD). The results are as follows: Figure 6 As shown. From Figure 6 It is known that maltol iron-oxalic acid eutectic does not undergo crystal transformation for at least 60 days under accelerated conditions.

[0057] Table 2. Comparison of characteristic PXRD peak positions of maltol iron-oxalic acid eutectic crystals at 40℃ and 75%RH for 0 and 60 days.

[0058]

[0059]

[0060] Example 4

[0061] Solubility determination

[0062] Test solution: Measure 5 mL of water into a vial, add excess maltol iron or maltol iron-oxalic acid eutectic (Example 1), seal the vial, place it at 25 °C and stir magnetically until equilibrium is reached (24 h), then filter through a 0.22 μm microporous membrane to obtain the test solution.

[0063] Reference solution: Weigh 5.0 mg of maltol iron reference standard accurately, place it in a 100 mL volumetric flask, dissolve and dilute with water to the mark, shake well, and filter through a 0.22 μm microporous membrane to obtain the solution.

[0064] The content of maltol iron was determined by ultraviolet spectrophotometry at a wavelength of 411 nm.

[0065] The results showed that at 25℃, the solubility of maltol iron-oxalate cocrystal in water was 5.40 mg / mL, lower than that of maltol iron crystals (9.03 mg / mL). From a formulation perspective, the low solubility of maltol iron-oxalate cocrystal offers several unique advantages for readily soluble maltol iron, particularly in the design and development of sustained-release and controlled-release drug formulations. The slower dissolution rate of the cocrystal can be used to design long-acting drug release systems, ensuring a more stable and sustained drug release rate in vivo and avoiding short-term peak drug concentrations.

[0066] Comparative Example 1

[0067] Screening and preparation of maltol iron and L-cysteine ​​cocrystals

[0068] Weigh out maltol iron and L-cysteine ​​according to Table 3, add 0.5 mL of organic solvent, and magnetically stir and slurry at room temperature (25℃) for 6 days. Filter, and vacuum dry the filter cake at 40℃ for 24 hours. Characterize the product using X-ray powder diffraction (PXRD) with Cu-Kα radiation. The PXRD pattern is shown below. Figure 7 As shown. From Figure 7 It can be seen that the characteristic diffraction peaks of the obtained product are basically consistent with those of maltol iron and L-cysteine, that is, maltol iron and L-cysteine ​​cannot form a eutectic.

[0069] Table 3. Conditions for preparing cocrystals of maltol iron and L-cysteine

[0070] Serial Number Ferric maltol / mg L-cysteine / mg Moor ratio organic solvents Stirring time 1 20 5.62 1:1 acetone 6 days 2 20 5.62 1:1 ethanol 6 days 3 20 5.62 1:1 Acetonitrile 6 days 4 20 5.62 1:1 Ethyl acetate 6 days

[0071] Comparative Example 2

[0072] Screening and preparation of maltol iron and nicotinamide cocrystals

[0073] Weigh the specified amounts of maltol iron and nicotinamide according to Table 4, add 0.5 mL of organic solvent, and magnetically stir and slurry at room temperature (25℃) for 6 days. Filter, and vacuum dry the filter cake at 40℃ for 24 hours. Characterize the product using X-ray powder diffraction (PXRD) with Cu-Kα radiation. The PXRD pattern is shown below. Figure 8 As shown. From Figure 8It can be seen that the characteristic diffraction peaks of the obtained product are basically consistent with those of maltol iron and nicotinamide, that is, maltol iron and nicotinamide cannot form a eutectic.

[0074] Table 4. Conditions for preparing eutectic from maltol iron and nicotinamide

[0075] Serial Number Ferric maltol / mg Nicotinamide / mg Moor ratio organic solvents Stirring time 1 20mg 5.67mg 1:1 acetone 6 days 2 20mg 5.67mg 1:1 ethanol 6 days 3 20mg 5.67mg 1:1 Acetonitrile 6 days 4 20mg 5.67mg 1:1 Ethyl acetate 6 days

Claims

1. A maltol iron-oxalic acid eutectic, characterized in that: It is a cocrystal formed by maltol iron as the active pharmaceutical ingredient and oxalic acid as the cocrystal ligand using a suspension stirring method. In the X-ray powder diffraction pattern obtained by Cu-Kα radiation measurement, the maltol iron-oxalic acid cocrystal has characteristic diffraction peaks at diffraction angles 2θ of 14.7±0.2°, 15.9±0.2°, 17.0±0.2°, 17.6±0.2°, 22.0±0.2°, 24.8±0.2°, 25.7±0.2°, 26.6±0.2°, and 26.9±0.2°.

2. The maltol iron-oxalic acid eutectic according to claim 1, characterized in that: The maltol iron-oxalic acid eutectic has an X-ray powder diffraction pattern as shown in Figure 1 or Figure 5.

3. The maltol iron-oxalic acid eutectic according to claim 1, characterized in that: The infrared absorption spectrum of the maltol iron-oxalic acid eutectic is at 1074.41 cm⁻¹. -1 1205.56cm -1 1277.91cm -1 1353.16 cm -1 1384.55cm -1 1399.84cm -1 1495.65cm -1 1560.58cm -1 1606.82cm -1 1664.18cm -1 3256.93cm -1 Characteristic peaks are present in the vicinity; in the differential scanning calorimetry spectrum, the maltol iron-oxalic acid eutectic has a single endothermic melting peak at 310.93℃.

4. A method for preparing maltol iron-oxalic acid eutectic according to claim 1, characterized in that: include: The process involves adding maltol iron and oxalic acid to an organic solvent, stirring the mixture, filtering, and vacuum drying to obtain a maltol iron-oxalic acid eutectic. The organic solvent is ethanol, methanol, acetonitrile, ethyl acetate, or a mixture of at least two of the above organic solvents.

5. The method for preparing maltol iron-oxalic acid eutectic according to claim 4, characterized in that: The organic solvent is ethanol.

6. The method for preparing maltol iron-oxalic acid eutectic according to claim 4, characterized in that: The molar ratio of maltol iron to oxalic acid is 1:1 to 1:

2.

7. The method for preparing maltol iron-oxalic acid eutectic according to claim 6, characterized in that: The molar ratio of maltol iron to oxalic acid is 1:

1.

8. The method for preparing maltol iron-oxalic acid eutectic according to claim 4, characterized in that: The ratio of maltol iron to organic solvent is 2:1 to 500:1 mg / mL.

9. The method for preparing maltol iron-oxalic acid eutectic according to claim 8, characterized in that: The ratio of maltol iron to organic solvent is 50:1 to 200:1 mg / mL.

10. The method for preparing maltol iron-oxalic acid eutectic according to claim 4, characterized in that: The reaction temperature is 25–45°C; the reaction time is 3–7 days.

11. The method for preparing maltol iron-oxalic acid eutectic according to claim 10, characterized in that: The reaction temperature is 15℃~30℃; the reaction time is 5~6 days.

12. A pharmaceutical composition, characterized in that: It comprises the maltol iron-oxalate eutectic as described in claim 1, and a pharmaceutically acceptable carrier.

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