Preparation method of sucrose ferric oxide hydroxide

Abstract

The invention discloses a preparation method of sucrose iron oxide hydroxide. Comprising the following steps: dispersing iron oxide hydroxide in a dispersed mixed solvent; sequentially adding cane sugar, potato starch and pregelatinized starch into the dispersed mixed solution obtained in the step S1, dispersing and stirring, and drying under reduced pressure; adding a towing solvent, stirring and dispersing, and carrying out rotary evaporation to dry; and adding a solvent, pulping, filtering and drying to obtain sucrose ferric oxide hydroxide. The sucrose iron oxide hydroxide prepared by the method is uniform in color and luster, and the phosphorus binding force is higher than 0.30 mg P / mg Fe; the residual solvent in the preparation process conforms to the provisions of ICH (Institute of Chemicals) coordination guidance principle Q3C (R8).

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis and provides a method for preparing sucrose ferric hydroxide. Background Art

[0002] Sucrose ferric hydroxide chewable tablets were approved by the FDA on November 27, 2013. They are used to treat hyperphosphatemia in adult chronic kidney disease (CKD) patients receiving hemodialysis (HD) or peritoneal dialysis (PD). They are used for the treatment of hyperphosphatemia in patients aged 12 years and above with CKD stage 4-5 (defined as glomerular filtration rate <30mL / min / 1.73m 2 ) or the treatment of hyperphosphatemia in pediatric patients with CKD receiving dialysis.

[0003] Sucrose ferric hydroxide is a mixture of polynuclear iron (III)-oxyhydroxide (pn-FeOOH) (about 33%), sucrose (about 30%), starch (about 28%) and water (not more than 10%). It binds phosphate by ligand exchange between hydroxyl groups and / or water and phosphate ions, which occurs over the entire physiological pH range of the gastrointestinal tract to reduce dietary phosphate absorption, thereby reducing serum phosphorus levels.

[0004] The existing reported sucrose ferric hydroxide processes include freeze drying, spray drying and solvent crystallization, but freeze drying and spray drying have high requirements on production equipment and high energy consumption, resulting in rising production costs. The solvent crystallization method only requires ordinary equipment, and the factory does not need to invest in freeze drying or spray drying equipment. The existing solvent crystallization method for preparing sucrose ferric hydroxide process is shown in WO2020165781A1, but it is found through research that the sucrose ferric hydroxide prepared by referring to WO2020165781A1, it can be seen that there are a large number of black spots (iron hydroxide clay that is not completely complexed) and white spots (sucrose, starch that is not completely complexed or dissociated by complexation), and there are very hard lumps, which are difficult to crush, and the properties are uneven, which seriously affects the preparation of subsequent preparations. At the same time, the solvent in the existing process is easily mixed in the sucrose ferric hydroxide colloid, resulting in unqualified residual solvents. Summary of the invention

[0005] The purpose of the present invention is to provide a method for preparing sucrose ferric hydroxide in view of the deficiencies of the above-mentioned prior art. The present invention has conducted a lot of exploration work on the process of sucrose ferric hydroxide, studied the selection of dispersion solvent, the type, proportion and dosage of entraining solvent and beating solvent, and finally prepared the raw material sucrose ferric hydroxide with uniform color and phosphorus binding capacity higher than 0.30mg P / mg Fe. The sucrose ferric hydroxide chewable tablet preparation prepared by the raw material has a phosphorus binding capacity higher than 0.41mg P / mg Fe, while the reference preparation Velphoro has a binding capacity of 0.34mg P / mg Fe, which is more effective, and the residual solvent also complies with the provisions of ICH coordination guideline Q3C (R8).

[0006] The objective of the present invention is achieved through the following technical solutions:

[0007] The present invention provides a method for preparing sucrose ferric hydroxide, which comprises the following steps:

[0008] S1, dispersing ferric hydroxide in a dispersed mixed solvent;

[0009] S2, sequentially adding sucrose, potato starch and pregelatinized starch to the dispersed mixed solution obtained in step S1, dispersing and stirring, and drying under reduced pressure;

[0010] S3, adding drag solvent, stirring and dispersing, and rotary evaporating to dryness;

[0011] S4, adding solvent to pulp, filtering and drying to obtain sucrose ferric hydroxide.

[0012] As an embodiment of the present invention, in step S1, ferric hydroxide is prepared by the following method: adding an aqueous solution of ferric chloride hexahydrate dropwise into an aqueous solution of sodium carbonate, stirring after the dropping, adjusting the solution pH to 6.8-7.8, filtering, and obtaining ferric hydroxide.

[0013] Furthermore, in the preparation of ferric hydroxide, the molar ratio of sodium carbonate to ferric chloride hexahydrate is 1.4:1 to 2.3:1;

[0014] Furthermore, in the preparation of ferric hydroxide, the concentration of the sodium carbonate aqueous solution is 15% to 19.5%; the concentration of the ferric chloride hexahydrate aqueous solution is 10% to 13%.

[0015] As an embodiment of the present invention, in step S1, the dispersed mixed solvent is an isopropanol / anhydrous ethanol / acetone mixed solution, or an isopropanol / ethanol mixed solution.

[0016] Furthermore, the volume ratio of isopropanol, anhydrous ethanol and acetone in the isopropanol / anhydrous ethanol / acetone mixed solution is 1:1:1 to 1:2:2.

[0017] Furthermore, the volume ratio of isopropanol to ethanol in the isopropanol / ethanol mixed solution is 1:1 to 1:2.

[0018] As an embodiment of the present invention, in step S1, the volume of the dispersed mixed solvent is 2 to 3 times the mass of ferric chloride hexahydrate.

[0019] As an embodiment of the present invention, in step S2, the mass ratio of iron, sucrose, potato starch and pregelatinized starch is 1:1.5:1.0:0.5 to 1:1.7:1.2:0.7.

[0020] As an embodiment of the present invention, in step S3, the dragging solvent is acetone or a mixed solvent of isopropanol / anhydrous ethanol.

[0021] As an embodiment of the present invention, in step S3, the volume of the entraining solvent is 2 to 3 times the weight of ferric chloride hexahydrate.

[0022] Furthermore, the volume ratio of isopropanol to anhydrous ethanol in the isopropanol / anhydrous ethanol mixed solvent is 1:1 to 1:2.

[0023] As an embodiment of the present invention, in step S4, the pulping solvent is acetone or n-heptane.

[0024] As an embodiment of the present invention, in step S4, the volume of the pulping solvent is 2 to 3 times the weight of ferric chloride hexahydrate.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] 1) The sucrose ferric hydroxide prepared by the present invention has uniform color and a phosphorus binding capacity higher than 0.30 mg P / mg Fe;

[0027] 2) The residual solvent in the preparation process of the present invention complies with the provisions of the ICH Harmonized Guideline Q3C (R8). BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Other features, objects and advantages of the present invention will become more apparent from the detailed description of non-limiting embodiments made with reference to the following drawings:

[0029] Figure 1 This is the DSC graph of the sucrose ferric hydroxide bulk drug prepared in Example 1;

[0030] Figure 2 The figure is a property diagram of the sucrose ferric hydroxide raw material prepared in Example 1 and Comparative Examples 1, 3, and 4;

[0031] Figure 3 for Figure 2An enlarged view of 3 in FIG.

[0032] Figure 4 This is a graph showing the properties of ferric hydroxide clay on filter paper during filtration and washing in Comparative Example 5;

[0033] Figure 5 This is a property diagram of the sucrose ferric hydroxide bulk drug prepared in Comparative Example 5;

[0034] Figure 6 This is the DSC graph of the sucrose ferric hydroxide bulk drug prepared in Comparative Example 5;

[0035] Figure 7 This is the DSC diagram of pure sucrose. DETAILED DESCRIPTION

[0036] The present invention is described in detail below in conjunction with the examples. The following examples will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, several adjustments and improvements can be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention. The test of phosphorus binding capacity in the following examples is to add a fixed amount of excess phosphate to the sample at pH 3.0, fully disperse and bind, centrifuge, discard the clear liquid, dissolve the solid, and determine its phosphorus binding capacity by chromatography.

[0037] Example 1

[0038] Weigh 86.6 g of sodium carbonate and dissolve it in 450 ml of purified water, add 208 g of ferric chloride hexahydrate aqueous solution (iron concentration 10 wt%) dropwise, stir for 1 hour, control the pH to 6.8-7.8 (adjust with 1N hydrochloric acid or 1N sodium hydroxide aqueous solution), filter, wash with purified water until the chloride ion is qualified, filter to obtain ferric hydroxide solid, measure the iron content, transfer the filter cake to 200 ml of mixed solution (isopropanol / anhydrous ethanol / acetone volume ratio 1:1:1), stir and disperse.

[0039] The sucrose and starch contents were calculated based on the iron content (iron: sucrose: potato starch: pregelatinized starch = 1 / 1.5 / 1.0 / 0.5), and sucrose, potato starch, and pregelatinized starch were added to the dispersed mixture in sequence, dispersed and stirred for 1 hour, and dried under reduced pressure (external temperature ≤ 50°C, vacuum degree ≤ -0.095MPa). 200ml of acetone was used as the drag solvent for stirring and dispersion, and rotary evaporation was performed until no liquid droplets were discharged.

[0040] Add 200ml acetone to make pulp, filter and dry, and obtain sucrose ferric hydroxide with a yield of 95% (phosphorus binding capacity: 0.32mgP / mgFe). The product particles are uniform, reddish brown solid, without black spots or white spots; see the properties diagram Figure 24, the differential scanning calorimeter (DSC) detection is shown in Figure 1 DSC also proved that the ferric hydroxide in the sucrose ferric hydroxide produced by this process was completely complexed with sucrose and starch, and there was no uncomplexed sucrose.

[0041] The raw material is further used to prepare the preparation: the preparation process adopts the full powder direct compression process, the raw material sucrose ferric hydroxide and arsenic dioxide are mixed and dispersed, and then raspberry essence, neohesperidin dihydrochalcone and magnesium stearate are added and mixed; the mixed material is directly tableted to obtain sucrose ferric hydroxide chewable tablets. The phosphorus binding capacity of the sucrose ferric hydroxide chewable tablets is higher than 0.41mg P / mg Fe.

[0042] Example 2

[0043] Weigh 86.6 g of sodium carbonate and dissolve it in 450 ml of purified water, add 208 g of ferric chloride hexahydrate aqueous solution (concentration 10%), stir for 1 hour, control the pH to 6.8-7.8 (adjust with 1N hydrochloric acid or 1N sodium hydroxide aqueous solution), filter, wash with purified water until the chloride ion is qualified, filter to obtain ferric hydroxide, measure the iron content, filter the filter cake into 300 ml of isopropanol / anhydrous ethanol (1:1) mixed solution, stir and disperse.

[0044] The sucrose and starch contents were calculated based on the iron content (iron: sucrose: potato starch: pregelatinized starch = 1 / 1.5 / 1.0 / 0.5), and sucrose, potato starch, and pregelatinized starch were added to the dispersed mixture in sequence, dispersed and stirred for 1 hour, and dried under reduced pressure. 300 ml of isopropanol / anhydrous ethanol (1:1) was used as the drag solvent for stirring and dispersion, and rotary evaporation was performed until no liquid droplets were discharged.

[0045] 200 ml of n-heptane was added for pulping, filtered and dried to obtain sucrose ferric hydroxide with a yield of 94% (phosphorus binding capacity: 0.31 mg P / mg Fe), uniform particles of the product, and a reddish brown solid. The raw material was further used to prepare a preparation according to Example 1, and the phosphorus binding capacity was higher than 0.42 mg P / mg Fe.

[0046] Example 3

[0047] Weigh 86.6 g of sodium carbonate and 557 ml of purified water, dissolve, add 172.6 g of ferric chloride hexahydrate aqueous solution (concentration 12%), stir for 1 hour, control the pH to 6.8-7.8 (adjust with 1N hydrochloric acid or 1N sodium hydroxide aqueous solution), filter, wash with purified water until the chloride ion is qualified, filter to obtain ferric hydroxide, measure the iron content, and add 200 ml of isopropanol / anhydrous ethanol / acetone (1:1:1) mixed solution of the filter cake, stir, and disperse.

[0048] According to the iron content, the sucrose and starch contents were calculated (iron: sucrose: potato starch: pregelatinized starch = 1 / 1.6 / 1.0 / 0.5), and sucrose, potato starch, and pregelatinized starch were added to the dispersed mixture in sequence, dispersed and stirred for 1 hour, and dried under reduced pressure. 200 ml of isopropanol / anhydrous ethanol (1:1) was used as the drag solvent for stirring and dispersing, and rotary evaporation was performed until no liquid droplets were discharged.

[0049] 200 ml of n-heptane was added to make pulp, filtered and dried to obtain sucrose ferric hydroxide with a yield of 93% (phosphorus binding capacity: 0.31 mg P / mg Fe), uniform product particles, and reddish brown solid. The raw material was used to further prepare a preparation according to Example 1 with a phosphorus binding capacity higher than 0.41 mg P / mg Fe.

[0050] Comparative Example 1

[0051] Weigh 86.6 g of sodium carbonate and dissolve it in 450 ml of purified water, add 208 g of ferric chloride hexahydrate aqueous solution (concentration 10%) dropwise, stir for 1 hour, control the pH to 6.8-7.8 (adjust with 1N hydrochloric acid or 1N sodium hydroxide aqueous solution), filter, wash with purified water until the chloride ion is qualified, filter to obtain ferric hydroxide, measure the iron content, add the filter cake into 200 ml of purified water, stir, disperse, calculate the sucrose and starch contents according to the iron content (iron: sucrose: potato starch: pregelatinized starch = 1 / 1.5 / 1.0 / 0.5), add sucrose, potato starch, and pregelatinized starch to the dispersed mixed solution in turn, disperse and stir for 1 hour, and dry under reduced pressure. It is difficult to evaporate to dryness and the wall is severely sticky. 200 ml of isopropanol / anhydrous ethanol (1:1) was used as the drag solvent for stirring and dispersion. It was difficult to disperse evenly. Rotary evaporation was performed until no liquid droplets were discharged. 200 ml of n-heptane was added for slurrying. The mixture was filtered and dried to obtain sucrose ferric hydroxide with a yield of 87% (phosphorus binding capacity: 0.26 mg P / mg Fe). The product contained very hard large particles with poor particle size uniformity and a distorted shape. Figure 2 1; failed to meet the uniformity requirements of the preparation, and the screening yield of the preparation was low and the product dissolution was slow.

[0052] Comparative Example 2

[0053] Weigh 43.3g of sodium carbonate and 225ml of purified water, dissolve, add 104g of ferric chloride hexahydrate aqueous solution (concentration 10%), stir for 1h, control pH 6.8-7.8 (adjust with 1N hydrochloric acid or 1N sodium hydroxide aqueous solution), filter, wash with purified water until chloride ion is qualified, filter, measure iron content, filter cake into 100ml of anhydrous ethanol, stir, disperse, calculate sucrose and starch content according to iron content (iron: sucrose: potato starch: pregelatinized starch = 1 / 1.5 / 1.0 / 0.5), add sucrose, potato starch, pregelatinized starch to the dispersed mixed solution in turn, disperse and stir for 1h, dry under reduced pressure, it is difficult to evaporate and there are lumps. Use 100ml of isopropanol as the drag solvent for stirring and dispersion, and evaporate until no liquid drops out. 100 ml of n-heptane was added for slurrying, filtered and dried to obtain sucrose ferric hydroxide with a yield of 86% (phosphorus binding capacity: 0.25 mg P / mg Fe). The product was uneven in shape, with a small amount of hard large particles that were difficult to crush; it failed to meet the uniformity requirements of the preparation, and the screening yield of the preparation was low, and the product dissolution was slow.

[0054] Comparative Example 3

[0055] Weigh 43.3g of sodium carbonate and 225ml of purified water, dissolve, add 104g of ferric chloride hexahydrate aqueous solution (concentration 10%), stir for 1h, control pH 6.8-7.8 (adjust with 1N hydrochloric acid or 1N sodium hydroxide aqueous solution), filter, wash with purified water until chloride ion is qualified, filter, measure iron content, filter cake into 100ml of isopropanol, stir, disperse, calculate sucrose and starch content according to iron content (iron: sucrose: potato starch: pregelatinized starch = 1 / 1.5 / 1.0 / 0.5), add sucrose, potato starch, and pregelatinized starch to the dispersed mixed solution in turn, disperse and stir for 1h, and dry under reduced pressure. Use 100ml of isopropanol as the drag solvent for stirring and dispersion, and rotary evaporate until no liquid drops out. Add 100 ml of n-heptane to slurry, filter and dry to obtain sucrose ferric hydroxide with a yield of 86% (phosphorus binding capacity: 0.24 mg P / mg Fe). The product contains a large amount of hard solids that are difficult to crush. Figure 2 2 of them.

[0056] Comparative Example 4

[0057] Weigh 50g of ferric chloride hexahydrate and add it to 54ml purified water, dissolve it, add sodium carbonate aqueous solution (43.3g of sodium carbonate and 225ml purified water), stir for 1h, control pH 6.8-7.8 (adjust with 1N hydrochloric acid or 1N sodium hydroxide aqueous solution), filter, wash with purified water until the chloride ion is qualified, filter, measure the iron content, add the filter cake to 100ml of isopropanol, stir, disperse, calculate the sucrose and starch content according to the iron content (iron: sucrose: potato starch: pregelatinized starch = 1 / 1.5 / 1.0 / 0.5), add sucrose, potato starch, and pregelatinized starch to the dispersed mixed solution in turn, disperse and stir for 1h, and dry under reduced pressure. Use 100ml of isopropanol as the drag solvent for stirring and dispersion, and evaporate until no liquid drops out. Add 100ml of n-heptane to make pulp, filter, filter cake agglomerates, slowly air-dry to powder, dry, and obtain sucrose ferric hydroxide with a yield of 87% (phosphorus binding capacity: 0.23mg P / mg Fe). There are a lot of black and white spots in the product, and the product is yellow-brown. Figure 2 3 of , and Figure 3 The enlarged image shows a large number of particles, and the black and white dots are very small. DSC detection shows an absorption peak of sucrose.

[0058] Comparative Example 5

[0059] According to the operation of document WO2020165781A1: At 25-30°C, 6.0g of sodium hydroxide and 62.0g of sodium carbonate are dissolved in 1000ml of water, and the obtained solution is added to 100g of ferric chloride hexahydrate in 1000ml of aqueous solution, and the pH is maintained at 6-7.5 by sodium hydroxide solution. The precipitated solid is filtered and washed with purified water to obtain ferric hydroxide solid. This step of filtering and washing ferric hydroxide clay produces black spots on the filter paper, see Figure 4 .

[0060] The ferric hydroxide solid obtained above was added to 300 ml of isopropanol, and 31.0 g of sucrose, 20.0 g of potato starch and 9.0 g of corn starch were added, and stirred for 30 to 45 min, and concentrated under reduced pressure (a large number of black spots and white spots were observed during the concentration of isopropanol), and a mixed solution of isopropanol and cyclohexane was added, and stirred at 25 to 30 ° C for 60 to 90 min to obtain sucrose ferric hydroxide, and then slurried with 300 ml of cyclohexane, filtered, rinsed with 100 ml of cyclohexane, filtered, and dried at 50 ° C to obtain the product. The product is yellow-brown with black solids and white solids in the product. The prepared product has a phosphorus binding capacity of 0.22 to 0.27 mg P / mg Fe, and has very hard lumps that are difficult to crush. The black spots are incompletely complexed ferric hydroxide clay, and the white spots are incompletely complexed or dissociated sucrose and starch ( Figure 5 ), the raw material drug DSC test (see Figure 6: Product) indicates that there is sucrose that is not completely complexed or dissociated from the complex. DSC of pure sucrose is shown in Figure 7 , the absorption peak at 191.25℃ represents sucrose.

[0061] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art may make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A method for preparing sucrose ferric hydroxide, characterized in that: The method comprises the following steps: S1, dispersing ferric hydroxide in a dispersed mixed solvent; S2, sequentially adding sucrose, potato starch and pregelatinized starch to the dispersed mixed solution obtained in step S1, dispersing and stirring, and drying under reduced pressure; S3, adding drag solvent, stirring and dispersing, and rotary evaporating to dryness; S4, adding solvent to pulp, filtering and drying to obtain sucrose ferric hydroxide.

2. The method for preparing sucrose ferric hydroxide according to claim 1, characterized in that: In step S1, ferric hydroxide is prepared by the following method: adding an aqueous solution of ferric chloride hexahydrate dropwise into an aqueous solution of sodium carbonate, stirring after the dropping, adjusting the solution pH to 6.8-7.8, filtering, and obtaining ferric hydroxide.

3. The method for preparing sucrose ferric hydroxide according to claim 1, characterized in that: In step S1, the dispersed mixed solvent is an isopropanol / anhydrous ethanol / acetone mixed solution, or an isopropanol / ethanol mixed solution.

4. The method for preparing sucrose ferric hydroxide according to claim 3, characterized in that: The volume ratio of isopropanol, anhydrous ethanol and acetone in the isopropanol / anhydrous ethanol / acetone mixed solution is 1:1:1 to 1:2:2; the volume ratio of isopropanol and ethanol in the isopropanol / ethanol mixed solution is 1:1 to 1:

2.

5. The method for preparing sucrose ferric hydroxide according to claim 1, characterized in that: In step S1, the volume of the dispersed mixed solvent is 2 to 3 times the mass of ferric chloride hexahydrate.

6. The method for preparing sucrose ferric hydroxide according to claim 1, characterized in that: In step S2, the mass ratio of iron, sucrose, potato starch and pregelatinized starch is 1:1.5:1.0:0.5 to 1:1.7:1.2:0.

7.

7. The method for preparing sucrose ferric hydroxide according to claim 1, characterized in that: In step S3, the dragging solvent is acetone or a mixed solvent of isopropanol / anhydrous ethanol.

8. The method for preparing sucrose ferric hydroxide according to claim 1, characterized in that: In step S4, the pulping solvent is acetone or n-heptane.

9. The method for preparing sucrose ferric hydroxide according to claim 1, characterized in that: In step S3, the volume of the entraining solvent is 2 to 3 times the weight of ferric chloride hexahydrate.

10. The method for preparing sucrose ferric hydroxide according to claim 1, characterized in that: In step S4, the volume of the pulping solvent is 2 to 3 times the weight of ferric chloride hexahydrate.

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