Process for the preparation of sucrose hydroxide ferrite

Abstract

The application discloses a preparation method of sucrose ferric hydroxide, which comprises the following steps: dispersing ferric hydroxide in a dispersion mixed solvent; adding sucrose, potato starch and pregelatinized starch into the dispersion mixed solution obtained in step S1 in sequence, dispersing and stirring, and drying under reduced pressure; adding a drag solvent to stir and disperse, and rotary evaporating to dryness; adding a solvent to beat up, filtering and drying to obtain sucrose ferric hydroxide. The sucrose ferric hydroxide prepared by the method has uniform color, and the phosphorus binding capacity is higher than 0.30 mg P / mg Fe; and the residual solvent in the preparation process meets the requirements of ICH harmonized guideline Q3C(R8).

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis and provides a preparation method of 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 patients with chronic kidney disease (CKD) undergoing 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 a glomerular filtration rate <30 mL / min / 1.73 m 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) (approximately 33%), sucrose (approximately 30%), starch (approximately 28%), and water (not more than 10%). It binds phosphate through ligand exchange between hydroxyl groups and / or water and phosphate ions. This binding occurs throughout the physiological pH range of the gastrointestinal tract, thereby reducing dietary phosphate absorption and lowering serum phosphorus levels.

[0004] The sucrose ferric hydroxide process of existing reports has freeze drying, spray drying and solvent crystallization, but freeze drying and spray drying have high requirements on production equipment, high energy consumption, resulting in rising production costs, and the solvent crystallization rule only requires ordinary equipment, and the factory does not need to invest in freeze drying or spray drying equipment. Existing solvent crystallization method prepares sucrose ferric hydroxide process referring to 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 (for incompletely complexed ferric hydroxide clay) and white spots (sucrose, starch that are not completely or dissociated by complexation) produced, and there are very hard pimples, which are difficult to crush, and the properties are uneven, which seriously affects the preparation of subsequent preparations. Meanwhile, the solvent in the existing process is easily mixed in the sucrose ferric hydroxide colloid, causing the residual solvent to be unqualified. Summary of the Invention

[0005] The object of the present invention is to provide a method for preparing sucrose ferric hydroxide in response to the deficiencies in the above-mentioned prior art. The present invention has conducted a large amount of exploratory work on the process of sucrose ferric hydroxide, and studied the selection of dispersion solvents, the types, proportions and dosages of entraining solvents and beating solvents. The raw material drug sucrose ferric hydroxide finally prepared has a uniform color and a phosphorus binding capacity higher than 0.30 mg P / mg Fe. The sucrose ferric hydroxide chewable tablet preparation prepared by the raw material drug has a phosphorus binding capacity higher than 0.41 mg P / mg Fe, while the reference preparation Velphoro has a binding capacity of 0.34 mg P / mg Fe, which is more effective, and the residual solvent also complies with the provisions of the ICH Harmonized Guideline Q3C (R8).

[0006] The object 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. Add sucrose, potato starch, and pregelatinized starch to the dispersed mixed solution obtained in step S1 in sequence, disperse and stir, and dry under reduced pressure;

[0010] S3, add the drag solvent, stir and disperse, and evaporate to dryness;

[0011] S4. Add solvent to pulp, filter and dry to obtain sucrose ferric hydroxide.

[0012] As one 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 to an aqueous sodium carbonate solution, stirring after the addition, adjusting the solution pH to 6.8-7.8, and filtering to obtain 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 dispersing mixed solvent is an isopropyl alcohol / anhydrous ethanol / acetone mixed solution, or an isopropyl alcohol / ethanol mixed solution.

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

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

[0024] As an embodiment of the present invention, in step S4, the volume of the beating 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 a 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 upon reading the detailed description of non-limiting embodiments 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 shows the properties of the sucrose ferric hydroxide bulk drug obtained in Example 1 and Comparative Examples 1, 3, and 4;

[0031] Figure 3 for Figure 2Enlarged view of the 3 in

[0032] Figure 4 Appearance of the iron oxyhydroxide gummy on the filter paper during the filtration of the wash of the Comparative Example 5;

[0033] Figure 5 Appearance of the sucrose iron oxyhydroxide drug substance prepared for the Comparative Example 5;

[0034] Figure 6 DSC of the sucrose iron oxyhydroxide drug substance prepared for the Comparative Example 5;

[0035] Figure 7 DSC of pure sucrose. DETAILED DESCRIPTION

[0036] The present application will be described in detail below with reference to the examples. The following examples will help those skilled in the art to further understand the present application, but do not limit the present application in any form. It should be noted that those skilled in the art can make several adjustments and improvements without departing from the concept of the present application. These are within the scope of protection of the present application. The test of phosphorus binding capacity in the following examples is as follows: the sample is dispersed with a fixed amount of excess phosphate at pH 3.0, centrifuged, the supernatant is discarded, and the solid is dissolved and its phosphorus binding capacity is determined by chromatography.

[0037] Example 1

[0038] 86.6 g of sodium carbonate was weighed into 450 ml of purified water, dissolved, and 208 g of an aqueous solution of ferric chloride hexahydrate (iron concentration 10 wt%) was added dropwise. After the dropwise addition was completed, stirring was continued for 1 h while the pH was controlled at 6.8-7.8 (adjusted with 1 N aqueous hydrochloric acid or 1 N aqueous sodium hydroxide). Filtration was performed, and the filtrate was washed with purified water until the chloride ion was qualified. Filtration was performed again to obtain an iron oxyhydroxide solid. The iron content was measured, and the filter cake was transferred to 200 ml of a mixed solution (isopropyl alcohol / absolute ethanol / acetone at a volume ratio of 1:1:1) and stirred and dispersed.

[0039] The sucrose, potato starch, and pre-gelatinized starch were added in turn to the dispersed mixed solution in the amounts calculated from the iron content (iron:sucrose:potato starch:pre-gelatinized starch = 1 / 1.5 / 1.0 / 0.5), and stirring and dispersion were continued for 1 h. Drying was performed under reduced pressure (external temperature ≤ 50°C, vacuum degree ≤ -0.095 MPa). Stirring and dispersion were performed using 200 ml of acetone as a trailing solvent, and rotary evaporation was performed until no liquid droplets were dropped.

[0040] Slurry was prepared by adding 200 ml of acetone, and the slurry was filtered and dried to obtain sucrose iron oxyhydroxide at a yield of 95% (phosphorus binding capacity: 0.32 mg P / mg Fe). The product was a uniform red-brown solid without black / white spots. The appearance is shown in Figure 24, the differential scanning calorimetry (DSC) test 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] This API is further prepared using a full-powder direct compression process. Sucrose ferric hydroxide and cadmium dioxide are mixed and dispersed, and then raspberry flavor, neohesperidin dihydrochalcone, and magnesium stearate are added. The mixture is then directly compressed into sucrose ferric hydroxide chewable tablets. Testing shows that the phosphate binding capacity of the sucrose ferric hydroxide chewable tablets exceeds 0.41 mg 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%) 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, filter the filter cake into 300 ml of isopropanol / anhydrous ethanol (1:1) mixed solution, stir and disperse.

[0044] Calculate the sucrose and starch contents based on 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 mixture in that order. Stir and disperse for 1 hour, then dry under reduced pressure. Use 300 ml of isopropanol / anhydrous ethanol (1:1) as the drag solvent, stirring and dispersing, and rotary evaporation until no more liquid drips out.

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

[0046] Example 3

[0047] Weigh 86.6 g of sodium carbonate and dissolve it in 557 ml of purified water, add 172.6 g of ferric chloride hexahydrate aqueous solution (concentration 12%) 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 content is qualified, filter to obtain ferric hydroxide, measure the iron content, and add 200 ml of the filter cake to a mixed solution of isopropanol / anhydrous ethanol / acetone (1:1:1), stir, and disperse.

[0048] Calculate the sucrose and starch contents based on the iron content (iron: sucrose: potato starch: pregelatinized starch = 1 / 1.6 / 1.0 / 0.5). Add sucrose, potato starch, and pregelatinized starch to the dispersed mixture in that order. Stir and disperse for 1 hour, then dry under reduced pressure. Use 200 ml of isopropanol / anhydrous ethanol (1:1) as the drag solvent, stirring and dispersing, and rotary evaporation until no more liquid drips out.

[0049] 200 ml of n-heptane was added for slurrying, and the mixture was filtered and dried to obtain sucrose ferric hydroxide with a yield of 93% (phosphorus binding capacity: 0.31 mg P / mg Fe). The product was uniformly granulated and a reddish-brown solid. This raw material was further used to prepare a formulation according to Example 1, and the phosphate binding capacity was greater 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 content is qualified, filter to obtain ferric hydroxide, measure the iron content, add the filter cake to 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 mixture in turn, disperse and stir for 1 hour, and dry under reduced pressure. It is difficult to evaporate to dryness and the wall sticks seriously. 200 ml of isopropanol / anhydrous ethanol (1:1) was used as the drag solvent for stirring and dispersion, but 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, and 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 dissolve it in 225ml of purified water. Add 104g of 10% ferric chloride hexahydrate aqueous solution dropwise. Stir for 1 hour, control the pH to 6.8-7.8 (adjust with 1N hydrochloric acid or 1N sodium hydroxide solution), filter, and wash with purified water until the chloride ion content meets the requirements. Filter and measure the iron content. Add the filter cake to 100ml of anhydrous ethanol, stir, and disperse. Calculate the sucrose and starch contents based on 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 mixture in that order. Disperse and stir for 1 hour. Dried under reduced pressure. Evaporation is difficult and lumps are present. Use 100ml of isopropyl alcohol as the drag solvent for stirring and dispersion. Rotary evaporation is performed until no liquid drips 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. At the same time, the preparation had a low screening yield and the product dissolution was slow.

[0054] Comparative Example 3

[0055] Weigh 43.3g of sodium carbonate and dissolve it in 225ml of purified water. Add 104g of 10% ferric chloride hexahydrate aqueous solution 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 and wash with purified water until the chloride ion content is acceptable. Filter and measure the iron content. Add the filter cake to 100ml of isopropanol, stir, and disperse. Calculate the sucrose and starch contents based on 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 mixture in that order. Disperse and disperse with stirring for 1 hour. Dry under reduced pressure. Use 100ml of isopropanol as the drag solvent for stirring and dispersing. Rotary evaporate until no more liquid drips 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] Take 50 g of iron trichloride hexahydrate and 54 ml of purified water, dissolve, add sodium carbonate aqueous solution (sodium carbonate 43.3 g and 225 ml of purified water), after dropping, stir for 1 h, 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, filter cake to 100 ml of isopropyl alcohol, stir, disperse, calculate the content of sucrose, starch according to the iron content (iron: sucrose: potato starch: pregelatinized starch = 1 / 1.5 / 1.0 / 0.5), sucrose, potato starch, pregelatinized starch are added to the dispersed mixture in turn, disperse and stir for 1 h, dry under reduced pressure. Stir and disperse with 100 ml of isopropyl alcohol as a drag solvent, rotary evaporation until no liquid drops are dropped. Add 100 ml of n-heptane to pulp, filter, filter cake, slowly air dry into powder, dry, get sucrose iron oxide hydroxide, yield 87% (phosphorus binding capacity: 0.23 mg P / mg Fe), there are a large number of black and white spots in the product, the product is yellow brown. The properties are shown in Figure 2 3, and Figure 3 Enlarged view, a large number of particles, black and white spots are very small. DSC detection, there is a sucrose absorption peak.

[0058] Comparative example 5

[0059] According to the operation of the literature WO2020165781A1: 6.0 g of sodium hydroxide and 62.0 g of sodium carbonate are dissolved in 1000 ml of water at 25-30℃, the obtained solution is added to 100 g of iron trichloride hexahydrate in 1000 ml of water, the pH is maintained at 6-7.5 by sodium hydroxide solution, the precipitated solid is filtered, washed with purified water, and the obtained iron oxide hydroxide solid. This step of filtering and washing the iron oxide hydroxide paste produces black spots on the filter paper, see Figure 4 .

[0060] The obtained iron oxide hydroxide solid is added to 300 ml of isopropyl alcohol, 31.0 g of sucrose, 20.0 g of potato starch and 9.0 g of corn starch are added, stirred for 30-45 min, concentrated under reduced pressure (during the concentration of isopropyl alcohol, a large number of black and white spots can be seen), a mixed solution of isopropyl alcohol and cyclohexane is added, stirred at 25-30℃ for 60-90 min to obtain sucrose iron oxide hydroxide, then 300 ml of cyclohexane is added to pulp, filtered, 100 ml of cyclohexane is used for washing, filtered, dried at 50℃ to obtain the product. The product is yellow brown, with black and white solids in the product, the prepared product has a phosphorus binding capacity of 0.22-0.27 mg P / mg Fe, and has very hard lumps that are difficult to crush. The black spots are incompletely complexed iron hydroxide paste, and the white spots are incompletely complexed or dissociated sucrose and starch Figure 5 , DSC detection of the raw material (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 variations or modifications 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; the ferric hydroxide is prepared by the following method: adding an aqueous solution of ferric chloride hexahydrate dropwise to an aqueous sodium carbonate solution, stirring after the addition, adjusting the solution pH to 6.8-7.8, and filtering to obtain ferric hydroxide; the dispersed mixed solvent is an isopropyl alcohol / anhydrous ethanol / acetone mixed solution, or an isopropyl alcohol / ethanol mixed solution, wherein the volume ratio of isopropyl alcohol, anhydrous ethanol, and acetone in the isopropyl alcohol / anhydrous ethanol / acetone mixed solution is 1:1:1-1:2:2; and the volume ratio of isopropyl alcohol to ethanol in the isopropyl alcohol / ethanol mixed solution is 1:1-1:2; 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, add the drag solvent, stir and disperse, and evaporate to dryness; S4. Add solvent to pulp, filter and dry to obtain sucrose ferric hydroxide.

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

3. The method for preparing sucrose ferric hydroxide according to claim 1, wherein 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.

4. The method for preparing sucrose ferric hydroxide according to claim 1, wherein In step S3, the dragging solvent is acetone or a mixed solvent of isopropyl alcohol / anhydrous ethanol.

5. The method for preparing sucrose ferric hydroxide according to claim 1, wherein In step S4, the pulping solvent is acetone or n-heptane.

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

7. The method for preparing sucrose ferric hydroxide according to claim 1, wherein In step S4, the volume of the beating solvent is 2 to 3 times the weight of the ferric chloride hexahydrate.

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