Method for preparing lanthanum carbonate tetrahydrate and its product

Abstract

This application discloses a method for preparing lanthanum carbonate tetrahydrate and a product thereof, which comprises reacting lanthanum oxide, acetic acid, and potassium carbonate, potassium bicarbonate, or ammonium bicarbonate to obtain lanthanum carbonate octahydrate, and then drying the lanthanum carbonate octahydrate. Compared with lanthanum carbonate tetrahydrate prepared by conventional techniques, the lanthanum carbonate tetrahydrate prepared by this application has a characteristic spectral peak in the terahertz spectrum and significantly better lanthanum ion dissociation and elution properties.

Description

Technical Field

[0001] The present application relates to the field of pharmaceutical technology, but is not limited thereto, and particularly relates to a method for preparing lanthanum carbonate tetrahydrate and its products.

Background Art

[0002] Hyperphosphatemia is one of the complications of chronic renal failure, and 80% of patients undergoing kidney dialysis suffer from this symptom. This symptom causes diseases on the skeletal surface such as fractures, and also causes damage to the cardiovascular system. According to reports, 50% of patients die due to this (Shen Lei, Jin Zhan, Lanthanum carbonate, a new drug for treating hyperphosphatemia, Progress in Pharmaceutical Sciences, 2005, 29(6): 286-287.).

[0003] Currently, the treatment of this disease mainly involves dietary control and the use of phosphate binders. Phosphate binders can chelate phosphorus in food and prevent the absorption of phosphorus in the gastrointestinal tract. Common phosphate binders include aluminum-containing phosphorus binders such as aluminum hydroxide, calcium-containing phosphorus binders such as calcium carbonate and calcium acetate, and magnesium-containing phosphorus binders such as magnesium carbonate. Among them, aluminum hydroxide is the phosphorus-lowering drug with the strongest phosphorus-binding ability. However, in long-term clinical practice, it has been found that the use of aluminum preparations causes aluminum poisoning, and it is now rarely used. When using calcium salts, long-term administration may cause flatulence, belching, and constipation, and may lead to cardiovascular diseases such as cardiovascular calcification. When using magnesium-containing phosphorus binders, there is a risk of causing hypermagnesemia in patients with renal insufficiency.

[0004] In addition, Shire developed and marketed lanthanum carbonate under the trade name Fosrenol. As a non-calcium, non-aluminum phosphate binder, lanthanum carbonate has the effect of reducing the phosphate level in the serum of patients similar to conventional binders.

[0005] Chinese Patent CN1102393C of ANORMED INC discloses that lanthanum carbonate tetrahydrate is used for the treatment of hyperphosphatemia in patients with renal insufficiency by gastrointestinal administration, and also discloses a preparation method of lanthanum carbonate tetrahydrate. The preparation method includes reacting lanthanum oxide with nitric acid or hydrochloric acid to obtain lanthanum nitrate or lanthanum chloride, and then reacting with sodium carbonate to obtain lanthanum carbonate tetrahydrate through calcination. There is a problem that the residual sodium ions in the lanthanum carbonate tetrahydrate prepared by this preparation method exceed 250 ppm. However, the residual and intake of sodium ions increase the renal burden of patients with kidney disease.

Summary of the Invention

[0006] The following is an overview of the themes described in this specification. This overview does not limit the scope of protection of the claims.

[0007] This application provides a preparation method of lanthanum carbonate tetrahydrate. The product obtained by this preparation method has the advantages that the crystal form of the product is stable, it is easy to operate, and the dissolution performance is excellent.

[0008] This application provides a preparation method of lanthanum carbonate tetrahydrate, and the preparation method includes: Step (1) of reacting lanthanum oxide with acetic acid to obtain lanthanum acetate, La2O3 + CH3COOH → La(CH3COO)3 Step (2) of reacting the lanthanum acetate obtained in step (1) with potassium carbonate or potassium bicarbonate or ammonium bicarbonate to obtain lanthanum carbonate octahydrate, La(CH3COO)3 → La2(CO3)3·8H2O And step (3) of drying the lanthanum carbonate octahydrate obtained in step (2) to obtain lanthanum carbonate tetrahydrate, La2(CO3)3·8H2O → La2(CO3)3·4H2O including.

[0009] In the preparation method according to the embodiments of the present application, in step (1), the weight ratio of lanthanum oxide to acetic acid may be 1:1 to 1:1.3, preferably 1:1.1 to 1:1.2.

[0010] In the preparation method according to the embodiments of the present application, in step (1), the reaction temperature may be 40°C to 100°C, preferably 60°C to 80°C, and the reaction time may be 0.1 h to 2 h, preferably 0.5 h to 1 h.

[0011] In the preparation method according to the embodiments of the present application, in step (2), the weight ratio of lanthanum acetate to potassium carbonate or potassium bicarbonate or ammonium bicarbonate may be 1:1.2 to 1:1.8, preferably 1:1.4 to 1:1.5.

[0012] In the preparation method according to the embodiments of the present application, in step (2), the reaction temperature may be 30°C to 60°C, preferably 40°C to 50°C, and the reaction time may be 1 h to 4 h, preferably 2 h to 3 h.

[0013] In the preparation method according to the embodiments of the present application, in step (3), the drying temperature may be 60°C to 90°C, preferably 70°C to 80°C.

[0014] In one aspect, the present application provides lanthanum carbonate tetrahydrate obtained by the above preparation method.

[0015] In the embodiments of the present application, the active pharmaceutical ingredient (API) of the lanthanum carbonate tetrahydrate according to the present application has an X-ray powder diffraction pattern (X-RPD) substantially shown in Figure 3.

[0016] In the embodiments of the present application, the API of the lanthanum carbonate tetrahydrate according to the present application has a thermogravimetric analysis diagram substantially shown in Figure 4.

[0017] In the embodiments of the present application, the lanthanum carbonate tetrahydrate according to the present application has no characteristic spectral peak between 1.0 THz and 3.0 THz in the terahertz spectrum, and has a characteristic spectral peak between 3.0 THz and 3.9 THz.

[0018] In one embodiment of the present application, the lanthanum carbonate tetrahydrate obtained by the preparation method has a sodium content of less than 0.005% by weight.

[0019] Other features and advantages of the present application will be described in the following description, and will be partly clear from the description or understood by the implementation of the present application. Other advantages of the present application are realized and obtained by the technical solutions described in the description.

Brief Description of the Drawings

[0020] The drawings are provided for understanding the technical solutions of the present application, form a part of the description, and are used to interpret the technical solutions of the present application together with the embodiments of the present application, and are not used to limit the technical solutions of the present application.

[0021]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Mode for Carrying Out the Invention

[0022] To clarify the object, technical solution and advantages of the present application in more detail, the examples of the present application will be described in detail below. Unless there is a conflict, the examples in the present application and the features in the examples can be arbitrarily combined with each other.

[0023] In the examples of the present application, the terahertz test equipment: Bruker V80V Fourier infrared spectrometer, 25 μm beam splitter, spectrum test range (0.5 THz to 4 THz), test accuracy 2 cm-1. Test environment: vacuum Test method: The solid is tableted, mixed with polyethylene powder in a certain proportion and polished uniformly, and then tableted into a thin slice for testing (the weight ratio of the sample to polyethylene is 1:3, the total is 12 mg, the diameter of the thin slice is 13 mm, and the thickness is about 1 mm).

[0024] All the water used in this example is secondary distilled water, and the residual sodium ions are all less than 10 ppm.

[0025] A rotating target X-ray diffractometer is used for the measurement of XRPD. The manufacturer is Rigaku Corporation, and the model is D / max 2500 / PC type. Test conditions: Pipe pressure: 40 kV, pipe flow: 100 mA, Cu target, graphite bent monochromator, continuous scanning, scanning step length: 0.02°, scanning range: 3° to 40° (2θ), slit system: DS = SS = 1°, RS = 0.3 mm.

[0026] PYRIS 1 TGA manufactured by PE Perkin Elmer is used for the measurement of TGA.

[0027] Content of sodium ions measured by inductively coupled plasma mass spectrometry (ICP-MS) in the 4th part of the Chinese Pharmacopoeia 2015 Edition Equipment: Agilent 7900 ICP-MS (installed with nickel cone, MicroMist quartz atomizer) ELGA PureLab ultrapure water device AB135-S type one-hundred-thousandth electronic balance Reagents: CNW (registered trademark) nitric acid for trace analysis, 67% - 70%; Ultrapure water, self-made; Plasma gas and carrier gas are argon, and the collision gas is helium, all of which are high-purity gases (>99.999%).

[0028] In this application, acetic acid refers to pure acetic acid with a mass concentration generally above 99.5%.

[0029] Example 1 Preparation of lanthanum acetate solution: Lanthanum oxide (150 g) was suspended in secondary distilled deionized water (2826 ml), heated to 70 °C, and an acetic acid aqueous solution (prepared by mixing 174 g of acetic acid and 174 ml of secondary distilled deionized water) was added dropwise with stirring. After the addition was completed, it was stirred for 0.5 h, the temperature was reduced, suction filtration was carried out, and the filtrate was collected to obtain a lanthanum acetate solution.

[0030] Preparation of lanthanum carbonate octahydrate: The prepared lanthanum acetate solution was heated to 50 °C, and a potassium carbonate solution (prepared by mixing 216 g of potassium carbonate and 300 ml of secondary distilled deionized water) was added dropwise while stirring. After the addition was complete, it was kept warm and stirred for 3 h. The temperature was reduced, and suction filtration was carried out. The filter cake was eluted with deionized water (900 ml). Secondary distilled deionized water (3000 ml) was added to the obtained solid, the temperature was controlled at 30 °C, and it was stirred for 1 h. The temperature was reduced, and suction filtration was carried out. Secondary distilled deionized water (3000 ml) was added to the filter cake, the temperature was controlled at 30 °C, and it was stirred for 1 h. The temperature was reduced, and suction filtration was carried out. Secondary distilled deionized water (3000 ml) was added to the filter cake, the temperature was controlled at 30 °C, and it was stirred for 1 h. The temperature was reduced, and suction filtration was carried out. The filter cake was washed with secondary distilled deionized water (900 ml) and dried in a forced-air drying oven at 40 °C to obtain 255.78 g of lanthanum carbonate octahydrate as the target compound, and the yield was 92.29%.

[0031] Preparation of lanthanum carbonate tetrahydrate: The prepared lanthanum carbonate octahydrate (240 g) was dried in a forced-air drying oven at 80 °C, weighed and monitored every 2 hours, and the weight was reduced to obtain 207.24 g of the target compound, and the yield was 98.09%.

[0032] The API particle size of the prepared lanthanum carbonate tetrahydrate was processed so that D90 was 30 μm or less, and the preparation formula of the chewable tablet was as follows.

[0033]

Table 1

[0034] Preparation process: Lanthanum carbonate tetrahydrate, starch hydrolyzed oligosaccharide, and silicon dioxide were uniformly mixed, extruded and formed by an extrusion device, then crushed, magnesium stearate was added, and mixed for about 5 minutes, and then extruded into tablets of the target weight.

[0035] Example 2 Preparation of lanthanum acetate solution: Lanthanum acetate (150 g) was suspended in secondary distilled deionized water (2826 ml), heated to 70°C, and an acetic acid aqueous solution (prepared by mixing 174 g of acetic acid and 174 ml of secondary distilled deionized water) was added dropwise with stirring. After the addition was complete, stirring was continued for 0.5 h, the temperature was reduced, suction filtration was performed, and the filtrate was collected to obtain a lanthanum acetate solution.

[0036] Preparation of lanthanum carbonate octahydrate: The prepared lanthanum acetate solution was heated to 50°C, and an ammonium bicarbonate solution (prepared by mixing 247.5 g of ammonium bicarbonate and 1000 ml of secondary distilled deionized water) was added dropwise with stirring. After the addition was complete, the mixture was kept warm and stirred for 3 h. The temperature was reduced, suction filtration was performed, and the filter cake was eluted with secondary distilled deionized water (900 ml). Secondary distilled deionized water (3000 ml) was added to the obtained solid, the temperature was controlled at 30°C, stirring was carried out for 1 h, the temperature was reduced, suction filtration was performed, secondary distilled deionized water (3000 ml) was added to the filter cake, the temperature was controlled at 30°C, stirring was carried out for 1 h, the temperature was reduced, suction filtration was performed, secondary distilled deionized water (3000 ml) was added to the filter cake, the temperature was controlled at 30°C, stirring was carried out for 1 h, the temperature was reduced, suction filtration was performed, the filter cake was washed with secondary distilled deionized water (900 ml), and dried in a forced-air drying oven at 40°C to obtain 254.22 g of lanthanum carbonate octahydrate as the target compound, with a yield of 91.73%.

[0037] Preparation of lanthanum carbonate tetrahydrate: The prepared lanthanum carbonate octahydrate (240 g) was dried in a forced-air drying oven at 80°C, weighed and monitored every 2 hours, and the weight was reduced to obtain 205.69 g of the target compound, with a yield of 97.36%.

[0038] Chewable tablets were prepared according to the chewable tablet formulation and preparation method of Example 1.

[0039] Example 3 Preparation of lanthanum acetate solution: Lanthanum oxide (150 g) was suspended in secondary distilled deionized water (3000 ml), heated to 70 °C, and an acetic acid aqueous solution (prepared by mixing 174 g of acetic acid and 180 ml of secondary distilled deionized water) was added dropwise with stirring. After the addition was complete, stirring was continued for 0.5 h, the temperature was reduced, suction filtration was performed, and the filtrate was collected to obtain a lanthanum acetate solution.

[0040] Preparation of lanthanum carbonate octahydrate: The lanthanum acetate solution was heated to 50 °C, and a potassium hydrogen carbonate solution (prepared by mixing 313.8 g of potassium hydrogen carbonate and 1000 ml of secondary distilled deionized water) was added dropwise with stirring. After the addition was complete, the mixture was kept warm and stirred for 3 h. The temperature was reduced, suction filtration was performed, and the filter cake was eluted with secondary distilled deionized water (900 ml). Secondary distilled deionized water (3000 ml) was added to the obtained solid, the temperature was controlled at 30 °C, stirring was carried out for 1 h, the temperature was reduced, suction filtration was performed, secondary distilled deionized water (3000 ml) was added to the filter cake, the temperature was controlled at 30 °C, stirring was carried out for 1 h, the temperature was reduced, suction filtration was performed, secondary distilled deionized water (3000 ml) was added to the filter cake, the temperature was controlled at 30 °C, stirring was carried out for 1 h, the temperature was reduced, suction filtration was performed, the filter cake was washed with secondary distilled deionized water (900 ml), and dried in a forced-air drying oven at 40 °C to obtain 253.20 g of lanthanum carbonate octahydrate as the target compound, with a yield of 91.36%.

[0041] Preparation of lanthanum carbonate tetrahydrate: The prepared lanthanum carbonate octahydrate (240 g) was dried in a forced-air drying oven at 80 °C, weighed and monitored every 2 hours, and the weight was reduced to obtain 204.11 g of the target compound, with a yield of 96.61%.

[0042] The terahertz test spectra of lanthanum carbonate tetrahydrate according to Examples 1 to 3 are substantially shown in Figure 5.

[0043] Comparative Example 1 Preparation of lanthanum acetate solution: Lanthanum oxide (150 g) was suspended in secondary distilled deionized water (2826 ml), heated to 70 °C, and an acetic acid aqueous solution (prepared by mixing 174 g of acetic acid and 174 ml of secondary distilled deionized water) was added dropwise with stirring. After the addition was complete, stirring was carried out for 0.5 h, the temperature was reduced, suction filtration was performed, and the filtrate was collected to obtain a lanthanum acetate solution.

[0044] Preparation of lanthanum carbonate octahydrate: The prepared lanthanum acetate solution was heated to 50 °C, and a sodium carbonate solution (prepared by mixing 166 g of sodium carbonate and 900 ml of secondary distilled deionized water) was added dropwise with stirring. After the addition was complete, it was kept warm and stirred for 3 h. The temperature was reduced, suction filtration was performed, and the filter cake was eluted with secondary distilled deionized water (900 ml). Secondary distilled deionized water (3000 ml) was added to the obtained solid, the temperature was controlled at 30 °C, stirring was carried out for 1 h, the temperature was reduced, suction filtration was performed, secondary distilled deionized water (3000 ml) was added to the filter cake, the temperature was controlled at 30 °C, stirring was carried out for 1 h, the temperature was reduced, suction filtration was performed, secondary distilled deionized water (3000 ml) was added to the filter cake, the temperature was controlled at 30 °C, stirring was carried out for 1 h, the temperature was reduced, suction filtration was performed, the filter cake was washed with secondary distilled deionized water (900 ml), and dried in a forced-air drying oven at 40 °C to obtain 248.25 g of lanthanum carbonate octahydrate as the target compound, with a yield of 89.58%.

[0045] Preparation of lanthanum carbonate tetrahydrate: Lanthanum carbonate octahydrate (230 g) was dried in a forced-air drying oven at 80 °C, weighed and monitored every 2 hours, the weight was reduced, and 198.54 g of the target compound was obtained, with a yield of 98.06%.

[0046] Chewing tablets were prepared according to the chewing tablet formulation and preparation method of Example 1.

[0047] Comparative Example 2 Preparation of lanthanum nitrate solution: Suspend lanthanum oxide (150 g) in secondary distilled deionized water (2400 ml), heat to 70 ± 5 °C, and while stirring, add dropwise nitric acid (65 wt% - 68 wt%, 195 ml). After the addition is complete, clarify the solution, reduce the temperature, perform suction filtration, and collect the lanthanum nitrate solution, which is the filtrate.

[0048] Preparation of lanthanum carbonate octahydrate: Heat the prepared lanthanum nitrate solution to 40 °C, and while stirring, add dropwise a sodium carbonate solution (prepared by mixing 165.91 g of sodium carbonate and 900 ml of secondary distilled deionized water). After the addition is complete, keep warm and stir for 1 h. Reduce the temperature, perform suction filtration, obtain the filter cake, add secondary distilled deionized water (3750 ml) to the obtained solid, control the temperature to 30 °C, stir for 1 h, reduce the temperature, and perform suction filtration. Repeat this operation 6 times, dry the solid in a forced-air drying oven at 40 °C to obtain 266.8 g of lanthanum carbonate octahydrate as the target compound, with a yield of 96.27%. XRPD shows that the crystal form of the product is abnormal.

[0049] Preparation of lanthanum carbonate tetrahydrate: Dry the prepared lanthanum carbonate octahydrate (250 g) in a vacuum drying oven at 70 °C, weigh and monitor every 2 hours, reduce the weight, obtain 209.52 g of the target compound, with a yield of 95.21%. XRPD shows that the crystal form of the product is abnormal.

[0050] Chewing tablets were prepared according to the chewing tablet formulation and preparation method of Example 1.

[0051] Comparative Example 3 Preparation of lanthanum chloride solution: Suspend lanthanum oxide (150 g) in secondary distilled deionized water (2400 ml), heat to 70 ± 5 °C, and while stirring, add dropwise hydrochloric acid (36 wt% - 38 wt%, 241.7 ml). After the addition is complete, clarify the solution, reduce the temperature, perform suction filtration, and collect the lanthanum chloride solution, which is the filtrate.

[0052] Preparation of Lanthanum Carbonate Octahydrate: The prepared lanthanum chloride solution was heated to 50 °C, and an ammonium bicarbonate solution (prepared by mixing 247.5 g of ammonium bicarbonate and 1000 ml of secondary distilled deionized water) was added dropwise while stirring. After the addition was complete, it was kept warm and stirred for 3 h. The temperature was reduced, and suction filtration was carried out. The filter cake was eluted with secondary distilled deionized water (900 ml). Secondary distilled deionized water (3000 ml) was added to the obtained solid, the temperature was controlled at 30 °C, and it was stirred for 1 h. The temperature was reduced, and suction filtration was carried out. Secondary distilled deionized water (3000 ml) was added to the filter cake, the temperature was controlled at 30 °C, and it was stirred for 1 h. The temperature was reduced, and suction filtration was carried out. Secondary distilled deionized water (3000 ml) was added to the filter cake, the temperature was controlled at 30 °C, and it was stirred for 1 h. The temperature was reduced, and suction filtration was carried out. The filter cake was washed with secondary distilled deionized water (900 ml) and dried in a forced-air drying oven at 40 °C to obtain 265.3 g of lanthanum carbonate octahydrate as the target compound, and the yield was 95.73%. XRPD indicated that the crystal form of the product was abnormal.

[0053] Preparation of Lanthanum Carbonate Tetrahydrate: The prepared lanthanum carbonate octahydrate (250 g) was dried in a vacuum drying oven at 70 °C, weighed and monitored every 2 hours, and the weight was reduced to obtain 215.89 g of the target compound, and the yield was 98.10%.

[0054] Chewable tablets were prepared according to the chewable tablet formulation and preparation method of Example 1.

[0055] The terahertz test spectra of lanthanum carbonate tetrahydrate according to Comparative Examples 1 to 3 are approximately shown in Figure 6.

[0056] Comparative Example 4 Preparation of Lanthanum Acetate Solution: Lanthanum oxide (150 g) was suspended in secondary distilled deionized water (2826 ml), heated to 70 °C, and while stirring, an acetic acid aqueous solution (prepared by mixing 174 g of acetic acid and 174 ml of secondary distilled deionized water) was added dropwise. When the addition was complete, it was stirred for 0.5 h, the temperature was reduced, suction filtration was performed, and the filtrate was collected to obtain a lanthanum acetate solution.

[0057] Preparation of lanthanum carbonate octahydrate: The prepared lanthanum acetate solution was heated to 50 °C, and while stirring, a sodium bicarbonate solution (prepared by mixing 263 g of sodium bicarbonate and 2500 ml of secondary distilled deionized water) was added dropwise. When the addition was complete, it was kept warm and stirred for 3 h. The temperature was reduced, suction filtration was performed, and the filter cake was eluted with secondary distilled deionized water (900 ml). Secondary distilled deionized water (3000 ml) was added to the obtained solid, the temperature was controlled at 30 °C, stirred for 1 h, the temperature was reduced, suction filtration was performed, secondary distilled deionized water (3000 ml) was added to the filter cake, the temperature was controlled at 30 °C, stirred for 1 h, the temperature was reduced, suction filtration was performed, secondary distilled deionized water (3000 ml) was added to the filter cake, the temperature was controlled at 30 °C, stirred for 1 h, the temperature was reduced, suction filtration was performed, the filter cake was washed with secondary distilled deionized water (900 ml), and dried in a forced-air drying oven at 40 °C to obtain 244.33 g of lanthanum carbonate octahydrate as the target compound, with a yield of 88.16%.

[0058] Preparation of lanthanum carbonate tetrahydrate: The prepared lanthanum carbonate octahydrate (230 g) was dried in a forced-air drying oven at 80 °C, weighed and monitored every 2 hours, the weight was reduced, and 200.12 g of the target compound was obtained, with a yield of 98.84%.

[0059] Comparative Example 5 Preparation of lanthanum chloride solution: Lanthanum oxide (150 g) was suspended in secondary distilled deionized water (2400 ml), heated to 70 ± 5 °C, and hydrochloric acid (36 wt% - 38 wt%, 241.7 ml) was added dropwise with stirring. After the addition was complete, the solution was clarified, the temperature was reduced, and suction filtration was performed to collect the lanthanum chloride solution, which was the filtrate.

[0060] Preparation of lanthanum carbonate octahydrate: The prepared lanthanum chloride solution was heated to 40 °C, and a sodium carbonate solution (prepared by mixing 165.91 g of sodium carbonate and 900 ml of secondary distilled deionized water) was added dropwise with stirring. After the addition was complete, it was kept warm for 1 h with stirring. The temperature was reduced, and suction filtration was performed to obtain a filter cake. Secondary distilled deionized water (3750 ml) was added to the obtained solid, the temperature was controlled at 30 °C, and it was stirred for 1 h. The temperature was reduced, and suction filtration was performed. This operation was repeated 6 times, and the solid was dried in a forced-air drying oven at 40 °C to obtain 265.5 g of lanthanum carbonate octahydrate as the target compound, with a yield of 95.80%. XRPD indicated that the crystal form of the product was abnormal.

[0061] Preparation of lanthanum carbonate tetrahydrate: The prepared lanthanum carbonate octahydrate (250 g) was dried in a vacuum drying oven at 70 °C, weighed and monitored every 2 hours, and the weight was reduced to obtain 212.45 g of the target compound, with a yield of 96.54%. XRPD indicated that the crystal form of the product was abnormal.

[0062] Comparative Example 6 Preparation of lanthanum nitrate solution: Lanthanum oxide (150 g) was suspended in secondary distilled deionized water (2400 ml), heated to 70 ± 5 °C, and nitric acid (65 wt% - 68 wt%, 195 ml) was added dropwise with stirring. After the addition was complete, the solution was clarified, the temperature was reduced, and suction filtration was performed to collect the lanthanum nitrate solution, which was the filtrate.

[0063] Preparation of lanthanum carbonate octahydrate: The prepared lanthanum nitrate solution was heated to 40 °C, and while stirring, a potassium carbonate solution (prepared by mixing 216 g of potassium carbonate and 300 ml of secondary distilled deionized water) was added dropwise. After the dropping was completed, it was kept warm for 1 h with stirring. The temperature was reduced, suction filtration was carried out to obtain a filter cake, secondary distilled deionized water (3750 ml) was added to the obtained solid, the temperature was controlled at 30 °C, stirred for 1 h, the temperature was reduced, and suction filtration was carried out. This operation was repeated 3 times, and the solid was dried in a forced-air drying oven at 40 °C to obtain 269.4 g of lanthanum carbonate octahydrate as the target compound, and the yield was 97.21%. XRPD indicates that the crystal form of the product is abnormal.

[0064] Preparation of lanthanum carbonate tetrahydrate: The prepared lanthanum carbonate octahydrate (250 g) was dried in a vacuum drying oven at 70 °C, weighed and monitored every 2 hours, the weight was reduced, and 215.95 g of the target compound was obtained, and the yield was 98.13%. XRPD indicates that the crystal form of the product is abnormal.

[0065] Comparative Example 7 Preparation of lanthanum chloride solution: Lanthanum oxide (150 g) was suspended in secondary distilled deionized water (2400 ml), heated to 70 ± 5 °C, and while stirring, hydrochloric acid (36 wt% - 38 wt%, 241.7 ml) was added dropwise. After the dropping was completed, the solution was clarified, the temperature was reduced, suction filtration was carried out, and the filtrate, lanthanum chloride solution, was collected.

[0066] Preparation of lanthanum carbonate octahydrate: The prepared lanthanum chloride solution was heated to 40 °C, and while stirring, a potassium carbonate solution (216 g of potassium carbonate, 300 ml of secondary distilled deionized water) was added dropwise. After the dropwise addition was completed, it was kept warm and stirred for 1 h. The temperature was reduced, suction filtration was carried out to obtain a filter cake, secondary distilled deionized water (3750 ml) was added to the obtained solid, the temperature was controlled at 30 °C, stirred for 1 h, the temperature was reduced, and suction filtration was carried out. This operation was repeated 3 times, and the solid was dried in a forced-air drying oven at 40 °C to obtain 271.19 g of lanthanum carbonate octahydrate as the target compound, with a yield of 97.85%. XRPD indicates that the crystal form of the product is abnormal.

[0067] Preparation of lanthanum carbonate tetrahydrate: The prepared lanthanum carbonate octahydrate (250 g) was dried in a vacuum drying oven at 70 °C, weighed and monitored every 2 hours, the weight was reduced, and 217.71 g of the target compound was obtained, with a yield of 98.93%. XRPD indicates that the crystal form of the product is abnormal.

[0068] Comparative Example 8 Preparation of lanthanum chloride solution: Lanthanum oxide (150 g) was suspended in secondary distilled deionized water (2400 ml), heated to 60 °C, and while stirring, hydrochloric acid (36 wt% - 38 wt%, 241.7 ml) was added dropwise. It was controlled to be pH = 3 - 5. After the dropwise addition was completed, the solution was clarified, the temperature was reduced, and suction filtration was carried out to collect the lanthanum chloride solution as the filtrate.

[0069] Preparation of lanthanum carbonate octahydrate: The prepared lanthanum chloride solution was heated to 40 °C or lower, for example, 30 - 40 °C, and while stirring, a sodium hydrogen carbonate solution (prepared by mixing 263 g of sodium hydrogen carbonate and 2500 ml of secondary distilled deionized water) was added dropwise. It was controlled to have a pH of 6 - 7. After the addition was completed, the temperature was maintained at 40 - 50 °C and stirred for 0.5 h. It was suction filtered to obtain a filter cake. Secondary distilled deionized water (3750 ml) was added to the obtained solid, the temperature was controlled to 30 °C, stirred for 1 h, the temperature was reduced, and suction filtered. This operation was repeated 3 times, and the solid was dried in a forced-air drying oven at 40 °C to obtain 254.22 g of lanthanum carbonate octahydrate as the target compound, with a yield of 91.73%. XRPD indicated that the crystal form of the product was abnormal.

[0070] Preparation of lanthanum carbonate tetrahydrate: The prepared lanthanum carbonate octahydrate (250 g) was dried in a vacuum drying oven at 70 °C, weighed and monitored every 2 hours, the weight was reduced, and 209.52 g of the target compound was obtained, with a yield of 95.21%. XRPD indicated that the crystal form of the product was abnormal.

[0071] Comparative Example 9 Preparation of lanthanum nitrate solution: Lanthanum oxide (150 g) was suspended in secondary distilled deionized water (2400 ml), heated to 70 ± 5 °C, and while stirring, nitric acid (65 wt% - 68 wt%, 195 ml) was added dropwise. After the addition was completed, the solution was clarified, the temperature was reduced, and suction filtered to collect the lanthanum nitrate solution, which was the filtrate.

[0072] Preparation of lanthanum carbonate octahydrate: The prepared lanthanum nitrate solution was heated to 40 °C or lower, for example, 30 - 40 °C, and while stirring, a sodium bicarbonate solution (prepared by mixing 263 g of sodium bicarbonate and 2500 ml of secondary distilled deionized water) was added dropwise. It was controlled to have a pH of 6 - 7. After the addition was completed, the temperature was maintained at 40 - 50 °C and stirred for 0.5 h. It was suction filtered to obtain a filter cake. Secondary distilled deionized water (3750 ml) was added to the obtained solid, the temperature was controlled to 30 °C, stirred for 1 h, the temperature was reduced, and suction filtered. This operation was repeated 3 times, and the solid was dried in a forced-air drying oven at 40 °C to obtain 267.6 g of lanthanum carbonate octahydrate as the target compound, with a yield of 96.56%. XRPD indicated that the crystal form of the product was abnormal.

[0073] Preparation of lanthanum carbonate tetrahydrate: The prepared lanthanum carbonate octahydrate (250 g) was dried in a vacuum drying oven at 70 °C, weighed and monitored every 2 hours. The weight decreased, and 214.33 g of the target compound was obtained, with a yield of 97.39%. XRPD indicated that the crystal form of the product was abnormal.

[0074] Comparative Example 5 - 9 The X-ray powder diffraction pattern (XRPD) of lanthanum carbonate octahydrate with abnormal crystal form according to Comparative Examples 5 - is approximately shown in Figure 7, and the X-ray powder diffraction pattern (XRPD) of lanthanum carbonate tetrahydrate with abnormal crystal form is approximately shown in Figure 8.

[0075] Sodium ion content The sodium ion detection results of the APIs of lanthanum carbonate tetrahydrate according to Examples 1, 2 and Comparative Examples 1, 2, 5 are as follows.

[0076]

Table 2

[0077] Dissolution rate comparison Comparison of the dissolution rates of the tablets of Examples 1, 2 and Comparative Examples 1, 2, 3 (pH 1.0, pH 3.0, pH 4.5, pH 6.8) Dissolution rate measurement method: The second method (paddle method) of General Rule 0931 in the Fourth Edition of the Chinese Pharmacopoeia 2015 Rotation speed: 50 rpm Dissolution medium: pH 1.0 hydrochloric acid medium, pH 3.0 acetate buffer (acetic acid - sodium acetate buffer), pH 4.5 acetate buffer (acetic acid - sodium acetate buffer), pH 6.8 borate buffer (boric acid - sodium hydroxide buffer) Volume of dissolution medium: 900 ml Sampling times: 20, 40, 60, 120, 180, 240, 360, 720, 1440 min Sampling volume: 7 ml (filtered through a filter membrane, excluding the first filtrate, and using the next filtrate as the sample solution) Measurement method: EDTA titration method

[0078]

Table 3

[0079]

Table 4

[0080]

Table 5

[0081]

Table 6

[0082] As can be seen from the examination of the dissolution rate, the API of lanthanum carbonate tetrahydrate according to the examples of the present application has excellent dissolution characteristics. Especially under the conditions of pH 1.0 hydrochloric acid medium and pH 3.0 acetate buffer medium, compared with the API of lanthanum carbonate tetrahydrate by the conventional process, it has significantly excellent dissolution characteristics, can ensure the rapid dissociation of lanthanum ions after entering the gastrointestinal tract, and provides sufficient ligand lanthanum ions for binding with phosphate ions in the intestinal tract.

[0083] This disclosure is a principle illustration of the embodiments of this application, and is not any formal or substantial limitation to this application, nor is it for specifically restricting this application to specific embodiments. It is obvious to those skilled in the art that elements, methods, systems, etc. of the technical solutions of the embodiments of this application can be changed, varied, modified, and improved without departing from the principles, spirit, and scope defined in the above embodiments of this application, technical solutions, for example, the claims. Any embodiments with these changes, variations, modifications, and improvements are all included in the equivalent embodiments of this application, and all these equivalent embodiments are included within the scope defined by the claims of this application. Although the embodiments of this application can be embodied in many different forms, only some embodiments of this application are detailed herein. Also, the embodiments of this application include any possible combinations of some or all of each embodiment described herein and are included within the scope defined by the claims of this application. All patents, patent applications, and other cited materials mentioned anywhere in this application, or any one cited patent, cited patent application, or other cited materials, are hereby incorporated by reference in their entirety based on this.

[0084] The above disclosure is for illustrative purposes and not for exhaustive purposes. To those skilled in the art, this specification suggests many variations or alternative technical solutions. These alternative technical solutions and variations are included within the scope of the claims of this application, and the terms "comprising" and "include" mean "including but not limited to".

[0085] Here, the description of the alternative embodiments of this application is completed. As can be understood by those skilled in the art, other equivalent substitutions of the technical solutions described herein are also included in the claims of this application. The invention described in the original patent claims of the present application is appended as follows. [1] Step (1) of reacting lanthanum oxide with acetic acid to obtain lanthanum acetate, La 2 O 3 + CH 3 COOH → La(CH 3 COO) 3 Step (2) of reacting the lanthanum acetate obtained in step (1) with potassium carbonate or potassium bicarbonate or ammonium bicarbonate to obtain lanthanum carbonate octahydrate, La(CH 3 COO) 3 → La 2 (CO 3) 3 ·8H 2 O And step (3) of drying the lanthanum carbonate octahydrate obtained in step (2) to obtain lanthanum carbonate tetrahydrate, La 2 (CO 3 ) 3 ·8H 2 O → La 2 (CO 3 ) 3 ·4H 2 O A method for preparing lanthanum carbonate tetrahydrate containing [2] The preparation method described in [1], wherein the weight ratio of lanthanum oxide to acetic acid in step (1) is 1:1 to 1:1.3, preferably 1:1.1 to 1:1.2. [3] The preparation method described in [1] or [2], wherein the reaction temperature in step (1) is 40°C to 100°C, preferably 60°C to 80°C, the reaction time is 0.1 h to 2 h, preferably 0.5 h to 1 h. [4] The preparation method described in any one of [1] to [3], wherein the weight ratio of lanthanum acetate to potassium carbonate or potassium bicarbonate or ammonium bicarbonate in step (2) is 1:1.2 to 1:1.8, preferably 1:1.4 to 1:1.5. [5] The preparation method described in any one of [1] to [4], wherein the reaction temperature in step (2) is 30°C to 60°C, preferably 40°C to 50°C, the reaction time is 1 h to 4 h, preferably 2 h to 3 h. [6] The preparation method described in any one of [1] to [5], wherein the drying temperature in step (3) is 60°C to 90°C, preferably 70°C to 80°C. [7] Lanthanum carbonate tetrahydrate obtained by the preparation method described in any one of [1] to [6]. [8] The lanthanum carbonate tetrahydrate described in [7], the X-ray powder diffraction pattern (XRPD) of which is substantially shown in Figure 3. [9] The lanthanum carbonate tetrahydrate described in [7] or [8], the thermogravimetric analysis diagram of which is substantially shown in Figure 4.

[10] The lanthanum carbonate tetrahydrate described in any one of [7] to [9], the sodium content of which is less than 0.005% by weight.

[11] The terahertz spectrum is the hydrated lanthanum carbonate according to any one of [7] to

[10] , in which there is no characteristic spectral peak between 1.0 THz and 3.0 THz, and there is a characteristic spectral peak between 3.0 THz and 3.9 THz.

Claims

1. Reacting lanthanum oxide with acetic acid to obtain lanthanum acetate, wherein the weight ratio of the lanthanum oxide to the acetic acid is 1:1 to 1:1.3 (step (1)); La ２ O ３ + CH ３ COOH → La(CH ３ COO) ３ Reacting the lanthanum acetate obtained in step (1) with potassium carbonate or potassium bicarbonate or ammonium bicarbonate to obtain lanthanum carbonate octahydrate, wherein the weight ratio of the lanthanum acetate to the potassium carbonate or the potassium bicarbonate or the ammonium bicarbonate is 1:1.2 to 1:1.8 (step (2)); La(CH ３ COO) ３ →La ２ (CO ３ ) ３ ·8H ２ O And drying the lanthanum carbonate octahydrate obtained in step (2) to obtain lanthanum carbonate tetrahydrate, wherein the sodium content of the lanthanum carbonate tetrahydrate is less than 0.005% by weight (step (3)); La ２ (CO ３ ) ３ ·8H ２ O → La ２ (CO ３ ) ３ ·4H ２ O A method for preparing lanthanum carbonate tetrahydrate comprising the above steps.

2. The preparation method according to claim 1, wherein in step (1), the reaction temperature is 40°C to 100°C and the reaction time is 0.1 h to 2 h.

3. The preparation method according to claim 1 or 2, wherein in step (2), the reaction temperature is 30°C to 60°C and the reaction time is 1 h to 4 h.

4. The preparation method according to claim 1 or 2, wherein in step (3), the drying temperature is 60°C to 90°C.

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