METHOD FOR PREPARING LANTHANUM CARBONATE TETRAHYDRATE AND PRODUCT THEREOF
20230227322 · 2023-07-20
Assignee
Inventors
Cpc classification
C01F17/10
CHEMISTRY; METALLURGY
C01P2002/72
CHEMISTRY; METALLURGY
International classification
Abstract
A method for preparing lanthanum carbonate tetrahydrate and a product thereof. The lanthanum carbonate tetrahydrate is prepared by reacting lanthanum oxide and acetic acid with potassium carbonate or potassium bicarbonate or ammonium bicarbonate to prepare lanthanum carbonate octahydrate, and drying the lanthanum carbonate octahydrate. Compared with the lanthanum carbonate tetrahydrate in the prior art, the prepared lanthanum carbonate tetrahydrate has a characteristic spectral peak on a terahertz spectrum, and has excellent dissociation and dissolution characteristics of lanthanum ions.
Claims
1. A preparation method of lanthanum carbonate tetrahydrate, comprising the following steps: (1) reacting lanthanum oxide with acetic acid to obtain lanthanum acetate;
La.sub.2O.sub.3+CH.sub.3COOH.fwdarw.La(CH.sub.3COO).sub.3 (2) reacting the lanthanum acetate obtained in step (1) with potassium carbonate or potassium bicarbonate or ammonium bicarbonate to obtain lanthanum carbonate octahydrate;
La(CH.sub.3COO).sub.3.fwdarw.La.sub.2(CO.sub.3).sub.3.Math.8H.sub.2O (3) drying the lanthanum carbonate octahydrate obtained in step (2) to obtain lanthanum carbonate tetrahydrate;
La.sub.2(CO.sub.3).sub.3.Math.8H.sub.2O.fwdarw.La.sub.2(CO.sub.3).sub.3.Math.4H.sub.2O.
2. The preparation method according to claim 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 according to claim 1, 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 according to claim 1, 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 according to claim 1, 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 according to claim 1, wherein the temperature for the drying in step (3) is 60° C. to 90° C., preferably 70° C. to 80° C.
7. Lanthanum carbonate tetrahydrate obtained by the preparation method according to claim 1.
8. The lanthanum carbonate tetrahydrate according to claim 7, the X-ray powder diffraction (XRPD) pattern thereof is substantially as shown in
9. The lanthanum carbonate tetrahydrate according to claim 7, the thermogravimetric analysis graph thereof is substantially as shown in
10. The lanthanum carbonate tetrahydrate according to claim 7, wherein the lanthanum carbonate tetrahydrate has a sodium content of less than 0.005 wt %.
11. The lanthanum carbonate tetrahydrate according to claim 7, the terahertz spectrum thereof has no characteristic spectral peak between 1.0 THz and 3.0 THz and has characteristic spectral peaks between 3.0 THz and 3.9 THz.
Description
BRIEF DESCRIPTION OF DRAWINGS
[0023] The accompanying drawings are used to provide an understanding of the technical schemes of the present application, and constitute a part of the specification. The drawings are used to explain the technical schemes of the present application together with the embodiments of the present application, and do not constitute a limitation to the technical schemes of the present application.
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DETAILED DESCRIPTION
[0032] To further elaborate the purpose, technical solutions and advantages of the present application, examples of the present application will be described in detail below. It should be noted that the following examples of the present application and the features of the examples may be arbitrarily combined with each other provided that there is no conflict.
[0033] In the embodiments of the present application, the terahertz testing instrument is: Brooke V80V Fourier infrared spectrometer, 25 μm beam splitter, spectral testing range (0.5 THz to 4 THz), and testing accuracy of 2 cm.sup.−1.
[0034] Test environment: vacuum
[0035] Test method: Solid tableting: mixing pure sample with polyethylene powder in a certain ratio, grinding evenly, pressing into thin tablet and testing (the weight ratio of the sample to polyethylene is 1:3, with 12 mg in total, the diameter of the thin tablet is 13 mm and the thickness is about 1 mm).
[0036] The water used in the examples is double redistilled water, and the residual sodium ions are all less than 10 ppm.
[0037] XRPD is measured using a rotating target X-ray diffractometer, manufacturer: Japan Rigaku Corporation, model: D/max 2500/PC. Test conditions: tube pressure: 40 kV, tube current: 100 mA, Cu target, graphite curved monochromator, continuous scanning, step length of scanning: 0.02°, scanning range: 3° to 40° (2 θ), slit system: DS=SS=1°, RS=0.3 mm.
[0038] TGA is measured using PYRIS 1 TGA manufactured by PE Perkin Elmer.
[0039] The content of sodium ions is measured by ICP-MS in the fourth part of Chinese Pharmacopoeia, 2015 version:
[0040] Instrument: Agilent 7900 ICP-MS (with nickel sampler cone, MicroMist quartz atomizer)
[0041] ELGA PureLab Ultrapure Water Instrument
[0042] AB135-S Type Hundred-thousandth Electronic Balance
[0043] Reagent: CNW® Nitric acid for trace analysis, 67% to 70%;
[0044] Ultrapure water, self-made;
[0045] Plasma gas, the carrier gas is argon, and collision gas is helium, all of which are gases of high purity (>99.999%).
[0046] Acetic acid in the present application generally refers to pure acetic acid with a mass concentration of more than 99.5%.
Example 1
[0047] Preparation of Lanthanum Acetate Solution:
[0048] Lanthanum oxide (150 g) was suspended in double distilled deionized water (2826 ml), heated to 70° C., and an aqueous solution of acetic acid (prepared from 174 g of acetic acid and 174 ml of double distilled deionized water) was added dropwise under stirring. After completion of the dropwise addition, the reaction was stirred for 0.5 h, cooled down, and filtrated under vacuum, and the filtrate was collected to obtain lanthanum acetate solution.
[0049] Preparation of Lanthanum Carbonate Octahydrate:
[0050] The prepared lanthanum acetate solution was heated to 50° C. and a potassium carbonate solution (prepared from 216 g of potassium carbonate and 300 ml of double distilled deionized water) was added dropwise under stirring. After completion of the dropwise addition, the reaction was kept warm and stirred for 3 h. The temperature was lowered, the reaction mixture was filtrated under vacuum, and the filter cake was rinsed with deionized water (900 ml). The resulting solid was added to double distilled deionized water (3000 ml), the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the mixture was filtrated under vacuum, double distilled deionized water (3000 ml) was added into the filter cake, and the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the mixture was filtrated under vacuum, double distilled deionized water (3000 ml) was added into the filter cake, the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and filtrated under vacuum, the filter cake was rinsed with double distilled deionized water (900 ml), and dried in a blast oven at 40° C. to obtain the target compound lanthanum carbonate octahydrate 255.78 g with a yield of 92.29%.
[0051] Preparation of Lanthanum Carbonate Tetrahydrate:
[0052] The prepared lanthanum carbonate octahydrate (240 g) was dried in a blast oven at 80° C., and was weighed every 2 hours to monitor the weight reduced. The target compound of 207.24 g with a yield of 98.09% was obtained.
[0053] The prepared lanthanum carbonate tetrahydrate API was treated until the D90 of the particle size is less than or equal to 30 μm, and the chewable tablets were prepared according to the following formulation:
TABLE-US-00001 Name of raw materials and Amount of the auxiliary materials formulation (g) Lanthanum carbonate tetrahydrate 954 (500 g in lanthanum) Starch hydrolyzed oligosaccharide 1068 Silica 42 Magnesium stearate 20
[0054] Preparation Process:
[0055] Lanthanum carbonate tetrahydrate, starch hydrolyzed oligosaccharide, and silica were uniformly mixed, pressed and molded by extrusion equipment, crushed, and magnesium stearate was added, mixed for about 5 minutes, and compressed into tablets with target weight.
Example 2
[0056] Preparation of Lanthanum Acetate Solution:
[0057] Lanthanum oxide (150 g) was suspended in double distilled deionized water (2826 ml), heated to 70° C., and an aqueous solution of acetic acid (prepared from 174 g of acetic acid and 174 ml of double distilled deionized water) was added dropwise under stirring. After completion of the dropwise addition, the reaction was stirred for 0.5 h, cooled down, and filtrated under vacuum, and the filtrate was collected to obtain lanthanum acetate solution.
[0058] Preparation of Lanthanum Carbonate Octahydrate:
[0059] The prepared lanthanum acetate solution was heated to 50° C. and an ammonium bicarbonate solution (prepared from 247.5 g of ammonium bicarbonate and 1000 ml of double distilled deionized water) was added dropwise under stirring. After completion of the dropwise addition, the reaction was kept warm and stirred for 3 h. The temperature was lowered, the mixture was filtrated under vacuum, and the filter cake was rinsed with double distilled deionized water (900 ml). The resulting solid was added to double distilled deionized water (3000 ml), the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the reaction mixture was filtrated under vacuum, double distilled deionized water (3000 ml) was added into the filter cake, and the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the mixture was filtrated under vacuum, double distilled deionized water (3000 ml) was added into the filter cake, the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the mixture was filtrated under vacuum, the filter cake was rinsed with double distilled deionized water (900 ml), and dried in a blast oven at 40° C. to obtain the target compound lanthanum carbonate octahydrate 254.22 g with a yield of 91.73%.
[0060] Preparation of Lanthanum Carbonate Tetrahydrate:
[0061] The prepared lanthanum carbonate octahydrate (240 g) was dried in a blast oven at 80° C., and was weighed every 2 hours to monitor the weight reduced. The target compound of 205.69 g with a yield of 97.36% was obtained.
[0062] Chewable tablets were prepared according to the formulation and preparation method of the chewable tablets of Example 1.
Example 3
[0063] Preparation of Lanthanum Acetate Solution:
[0064] Lanthanum oxide (150 g) was suspended in double distilled deionized water (3000 ml), heated to 70° C., and an aqueous solution of acetic acid (prepared from 174 g of acetic acid and 180 ml of double distilled deionized water) was added dropwise under stirring. After completion of the dropwise addition, the reaction was stirred for 0.5 h, cooled down, and filtrated under vacuum, and the filtrate was collected to obtain lanthanum acetate solution.
[0065] Preparation of Lanthanum Carbonate Octahydrate:
[0066] The lanthanum acetate solution was heated to 50° C. and a potassium bicarbonate solution (prepared from 313.8 g of potassium bicarbonate and 1000 ml of double distilled deionized water) was added dropwise under stirring. After completion of the dropwise addition, the reaction was kept warm and stirred for 3 h. The temperature was lowered, the mixture was filtrated, and the filter cake was rinsed with double distilled deionized water (900 ml). The resulting solid was added to double distilled deionized water (3000 ml), the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the reaction mixture was filtrated under vacuum, double distilled deionized water (3000 ml) was added into the filter cake, the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the mixture was filtrated under vacuum, double distilled deionized water (3000 ml) was added into the filter cake, the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the mixture was filtrated under vacuum, the filter cake was rinsed with double distilled deionized water (900 ml), and dried in a blast oven at 40° C. to obtain the target compound lanthanum carbonate octahydrate 253.20 g with a yield of 91.36%.
[0067] Preparation of Lanthanum Carbonate Tetrahydrate:
[0068] The prepared lanthanum carbonate octahydrate (240 g) was dried in a blast oven at 80° C., and was weighed every 2 hours to monitor the weight reduced. The target compound of 204.11 g with a yield of 96.61% was obtained.
[0069] The terahertz test spectra of the lanthanum carbonate tetrahydrate prepared in Examples 1 to 3 are substantially as shown in
Comparative Example 1
[0070] Preparation of Lanthanum Acetate Solution:
[0071] Lanthanum oxide (150 g) was suspended in double distilled deionized water (2826 ml), heated to 70° C., and an aqueous solution of acetic acid (prepared from 174 g of acetic acid and 174 ml of double distilled deionized water) was added dropwise under stirring. After completion of the dropwise addition, the reaction was stirred for 0.5 h, cooled down, and filtrated under vacuum, and the filtrate was collected to obtain lanthanum acetate solution.
[0072] Preparation of Lanthanum Carbonate Octahydrate:
[0073] The prepared lanthanum acetate solution was heated to 50° C. and a sodium carbonate solution (prepared from 166 g of sodium carbonate and 900 ml of double distilled deionized water) was added dropwise under stirring. After completion of the dropwise addition, the reaction was kept warm and stirred for 3 h. The temperature was lowered, the mixture was filtrated under vacuum, and the filter cake was rinsed with double distilled deionized water (900 ml). The resulting solid was added to double distilled deionized water (3000 ml), the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the reaction mixture was filtrated under vacuum, double distilled deionized water (3000 ml) was added into the filter cake, the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the mixture was filtrated under vacuum, double distilled deionized water (3000 ml) was added into the filter cake, the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the mixture was filtrated under vacuum, the filter cake was rinsed with double distilled deionized water (900 ml), and dried in a blast oven at 40° C. to obtain the target compound lanthanum carbonate octahydrate 248.25 g with a yield of 89.58%.
[0074] Preparation of Lanthanum Carbonate Tetrahydrate:
[0075] The lanthanum carbonate octahydrate (230 g) was dried in a blast oven at 80° C., and was weighed every 2 hours to monitor the weight reduced. The target compound of 198.54 g with a yield of 98.06% was obtained.
[0076] Chewable tablets were prepared according to the formulation and preparation method of the chewable tablets of Example 1.
Comparative Example 2
[0077] Preparation of Lanthanum Nitrate Solution:
[0078] Lanthanum oxide (150 g) was suspended in double distilled deionized water (2400 ml), heated to 70±5° C., and nitric acid (65% to 68% by mass, 195 ml) was added dropwise under stirring. After completion of the dropwise addition, the solution was clear. The solution was cooled down and filtrated under vacuum, and the filtrate was collected to obtain lanthanum nitrate solution.
[0079] Preparation of Lanthanum Carbonate Octahydrate:
[0080] The prepared lanthanum nitrate solution was heated to 40° C. and a sodium carbonate solution (prepared from 165.91 g of sodium carbonate and 900 ml of double distilled deionized water) was added dropwise under stirring. After completion of the dropwise addition, the reaction was kept warm and stirred for 1 h. The temperature was lowered, the mixture was filtrated under vacuum to obtain a filter cake. Double distilled deionized water (3750 ml) was added to the resulting solid. The temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the mixture was filtrated under vacuum. This procedure was repeated six times. Then the solid was dried in a blast oven at 40° C., obtaining the target compound lanthanum carbonate octahydrate 266.8 g with a yield of 96.27%. XRPD shows abnormal crystal form of the product.
[0081] Preparation of Lanthanum Carbonate Tetrahydrate:
[0082] The prepared lanthanum carbonate octahydrate (250 g) was dried in a vacuum drying oven at 70° C., and was weighed every 2 hours to monitor the weight reduced. The target compound of 209.52 g with a yield of 95.21% was obtained. XRPD shows abnormal crystal form of the product.
[0083] Chewable tablets were prepared according to the formulation and preparation method of the chewable tablets of Example 1.
Comparative Example 3
[0084] Preparation of Lanthanum Chloride Solution:
[0085] Lanthanum oxide (150 g) was suspended in double distilled deionized water (2400 ml), heated to 70±5° C., and hydrochloric acid (36% to 38% by mass, 241.7 ml) was added dropwise under stirring. After completion of the dropwise addition, the solution was clear. The solution was cooled down and filtrated under vacuum, and the filtrate was collected to obtain lanthanum chloride solution.
[0086] Preparation of Lanthanum Carbonate Octahydrate:
[0087] The prepared lanthanum chloride solution was heated to 50° C. and an ammonium bicarbonate solution (prepared from 247.5 g of ammonium bicarbonate and 1000 ml of double distilled deionized water) was added dropwise under stirring. After completion of the dropwise addition, the reaction was kept warm and stirred for 3 h. The temperature was lowered, the mixture was filtrated under vacuum, and the filter cake was rinsed with double distilled deionized water (900 ml). The resulting solid was added to double distilled deionized water (3000 ml), the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the reaction mixture was filtrated under vacuum, double distilled deionized water (3000 ml) was added into the filter cake, the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the mixture was filtrated under vacuum, double distilled deionized water (3000 ml) was added into the filter cake, the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the mixture was filtrated under vacuum, the filter cake was rinsed with double distilled deionized water (900 ml), and dried in a blast oven at 40° C. to obtain the target compound lanthanum carbonate octahydrate 265.3 g with a yield of 95.73%. XRPD shows abnormal crystal form of the product.
[0088] Preparation of Lanthanum Carbonate Tetrahydrate:
[0089] The prepared lanthanum carbonate octahydrate (250 g) was dried in a vacuum drying oven at 70° C., and was weighed every 2 hours to monitor the weight reduced. The target compound of 215.89 g with a yield of 98.10% was obtained.
[0090] Chewable tablets were prepared according to the formulation and preparation method of the chewable tablets of Example 1.
[0091] The terahertz test spectra of the lanthanum carbonate tetrahydrate prepared in Comparative Examples 1 to 3 are substantially as shown in
Comparative Example 4
[0092] Preparation of Lanthanum Acetate Solution:
[0093] Lanthanum oxide (150 g) was suspended in double distilled deionized water (2826 ml), heated to 70° C., and an aqueous solution of acetic acid (prepared from 174 g of acetic acid and 174 ml of double distilled deionized water) was added dropwise under stirring. After completion of the dropwise addition, the reaction was stirred for 0.5 h, cooled down, and filtrated under vacuum, and the filtrate was collected to obtain lanthanum acetate solution.
[0094] Preparation of Lanthanum Carbonate Octahydrate:
[0095] The prepared lanthanum acetate solution was heated to 50° C. and a sodium bicarbonate solution (prepared from 263 g of sodium bicarbonate and 2500 ml of double distilled deionized water) was added dropwise under stirring. After completion of the dropwise addition, the reaction was kept warm and stirred for 3 h. The temperature was lowered, the mixture was filtrated under vacuum, and the filter cake was rinsed with double distilled deionized water (900 ml). The resulting solid was added to double distilled deionized water (3000 ml), the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the reaction mixture was filtrated under vacuum, double distilled deionized water (3000 ml) was added into the filter cake, the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the mixture was filtrated under vacuum, double distilled deionized water (3000 ml) was added into the filter cake, the temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the mixture was filtrated under vacuum, the filter cake was rinsed with double distilled deionized water (900 ml), and dried in a blast oven at 40° C. to obtain the target compound lanthanum carbonate octahydrate 244.33 g with a yield of 88.16%.
[0096] Preparation of Lanthanum Carbonate Tetrahydrate:
[0097] The prepared lanthanum carbonate octahydrate (230 g) was dried in a blast oven at 80° C., and was weighed every 2 hours to monitor the weight reduced. The target compound of 200.12 g with a yield of 98.84% was obtained.
Comparative Example 5
[0098] Preparation of Lanthanum Chloride Solution:
[0099] Lanthanum oxide (150 g) was suspended in double distilled deionized water (2400 ml), heated to 70±5° C., and hydrochloric acid (36% to 38% by mass, 241.7 ml) was added dropwise under stirring. After completion of the dropwise addition, the solution was clear. The solution was cooled down and filtrated under vacuum, and the filtrate was collected to obtain lanthanum chloride solution.
[0100] Preparation of Lanthanum Carbonate Octahydrate:
[0101] The prepared lanthanum chloride solution was heated to 40° C. and a sodium carbonate solution (prepared from 165.91 g of sodium carbonate and 900 ml of double distilled deionized water) was added dropwise under stirring. After completion of the dropwise addition, the reaction was kept warm and stirred for 1 h. The temperature was lowered, the mixture was filtrated under vacuum to obtain a filter cake. Double distilled deionized water (3750 ml) was added to the resulting solid. The temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the mixture was filtrated under vacuum. This procedure was repeated six times. Then the solid was dried in a blast oven at 40° C., obtaining the target compound lanthanum carbonate octahydrate 265.5 g with a yield of 95.80%. XRPD shows abnormal crystal form of the product.
[0102] Preparation of Lanthanum Carbonate Tetrahydrate:
[0103] The prepared lanthanum carbonate octahydrate (250 g) was dried in a vacuum drying oven at 70° C., and was weighed every 2 hours to monitor the weight reduced. The target compound of 212.45 g with a yield of 96.54% was obtained. XRPD shows abnormal crystal form of the product.
Comparative Example 6
[0104] Preparation of Lanthanum Nitrate Solution:
[0105] Lanthanum oxide (150 g) was suspended in double distilled deionized water (2400 ml), heated to 70±5° C., and nitric acid (65% to 68% by mass, 195 ml) was added dropwise under stirring. After completion of the dropwise addition, the solution was clear. The solution was cooled down and filtrated under vacuum, and the filtrate was collected to obtain lanthanum nitrate solution.
[0106] Preparation of Lanthanum Carbonate Octahydrate:
[0107] The prepared lanthanum nitrate solution was heated to 40° C. and a potassium carbonate solution (prepared from 216 g of potassium carbonate and 300 ml of double distilled deionized water) was added dropwise under stirring. After completion of the dropwise addition, the reaction was kept warm and stirred for 1 h. The temperature was lowered, the mixture was filtrated under vacuum to obtain a filter cake. Double distilled deionized water (3750 ml) was added to the resulting solid. The temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the mixture was filtrated under vacuum. This procedure was repeated 3 times. Then the solid was dried in a blast oven at 40° C., obtaining the target compound lanthanum carbonate octahydrate 269.4 g with a yield of 97.21%. XRPD shows abnormal crystal form of the product.
[0108] Preparation of Lanthanum Carbonate Tetrahydrate:
[0109] The prepared lanthanum carbonate octahydrate (250 g) was dried in a vacuum drying oven at 70° C., and was weighed every 2 hours to monitor the weight reduced. The target compound of 215.95 g with a yield of 98.13% was obtained. XRPD shows abnormal crystal form of the product.
Comparative Example 7
[0110] Preparation of Lanthanum Chloride Solution:
[0111] Lanthanum oxide (150 g) was suspended in double distilled deionized water (2400 ml), heated to 70±5° C., and hydrochloric acid (36% to 38% by mass, 241.7 ml) was added dropwise under stirring. After completion of the dropwise addition, the solution was clear. The solution was cooled down and filtrated under vacuum, and the filtrate was collected to obtain lanthanum chloride solution.
[0112] Preparation of Lanthanum Carbonate Octahydrate:
[0113] The prepared lanthanum chloride solution was heated to 40° C. and a potassium carbonate solution (216 g of potassium carbonate, 300 ml of double distilled deionized water) was added dropwise under stirring. After completion of the dropwise addition, the reaction was kept warm and stirred for 1 h. The temperature was lowered, the mixture was filtrated under vacuum to obtain a filter cake. Double distilled deionized water (3750 ml) was added to the resulting solid. The temperature was controlled to 30° C., stirred for 1 h, the temperature was lowered, and the mixture was filtrated under vacuum. This procedure was repeated 3 times. Then the solid was dried in a blast oven at 40° C., obtaining the target compound lanthanum carbonate octahydrate 271.19 g with a yield of 97.85%. XRPD shows abnormal crystal form of the product.
[0114] Preparation of Lanthanum Carbonate Tetrahydrate:
[0115] The prepared lanthanum carbonate octahydrate (250 g) was dried in a vacuum drying oven at 70° C., and was weighed every 2 hours to monitor the weight reduced. The target compound of 217.71 g with a yield of 98.93% was obtained. XRPD shows abnormal crystal form of the product.
Comparative Example 8
[0116] Preparation of Lanthanum Chloride Solution:
[0117] Lanthanum oxide (150 g) was suspended in double distilled deionized water (2400 ml), heated to 60° C., and hydrochloric acid (36% to 38% by mass, 241.7 ml) was added dropwise under stirring. The pH was controlled at 3 to 5. After completion of the dropwise addition, the solution was clear. The solution was cooled down and filtrated under vacuum, and the filtrate was collected to obtain lanthanum chloride solution.
[0118] Preparation of Lanthanum Carbonate Octahydrate:
[0119] The prepared lanthanum chloride solution was heated to below 40° C., for example, 30-40° C., and a sodium bicarbonate solution (prepared from 263 g of sodium bicarbonate and 2500 ml of double distilled deionized water) was added dropwise under stirring. The pH was controlled at 6 to 7. After completion of the dropwise addition, the temperature was kept at 40-50° C. and stirred for 0.5 h. The mixture was filtrated under vacuum to obtain a filter cake. Double distilled deionized water (3750 ml) was added to the resulting solid. The temperature was controlled to 30° C., stirred for 1 h, cooled down, and filtrated under vacuum. This procedure was repeated 3 times. Then the solid was dried in a blast oven at 40° C., obtaining the target compound lanthanum carbonate octahydrate 254.22 g with a yield of 91.73%. XRPD shows abnormal crystal form of the product.
[0120] Preparation of Lanthanum Carbonate Tetrahydrate:
[0121] The prepared lanthanum carbonate octahydrate (250 g) was dried in a vacuum drying oven at 70° C., and was weighed every 2 hours to monitor the weight reduced. The target compound of 209.52 g with a yield of 95.21% was obtained. XRPD shows abnormal crystal form of the product.
Comparative Example 9
[0122] Preparation of Lanthanum Nitrate Solution:
[0123] Lanthanum oxide (150 g) was suspended in double distilled deionized water (2400 ml), heated to 70±5° C., and nitric acid (65% to 68% by mass, 195 ml) was added dropwise under stirring. After completion of the dropwise addition, the solution was clear, and then cooled down and filtrated under vacuum, and the filtrate was collected to obtain lanthanum nitrate solution.
[0124] Preparation of Lanthanum Carbonate Octahydrate:
[0125] The prepared lanthanum nitrate solution was heated to below 40° C., for example, 30-40° C. and a sodium bicarbonate solution (prepared from 263 g of sodium bicarbonate and 2500 ml of double distilled deionized water) was added dropwise under stirring. The pH was controlled at 6 to 7. After completion of the dropwise addition, the temperature was kept at 40 to 50° C. and stirred for 0.5 h. The mixture was filtrated under vacuum to obtain a filter cake. Double distilled deionized water (3750 ml) was added to the resulting solid. The temperature was controlled to 30° C., stirred for 1 h, cooled down, and filtrated under vacuum. This procedure was repeated 3 times. Then the solid was dried in a blast oven at 40° C., obtaining the target compound lanthanum carbonate octahydrate 267.6 g with a yield of 96.56%. XRPD shows abnormal crystal form of the product.
[0126] Preparation of Lanthanum Carbonate Tetrahydrate:
[0127] The prepared lanthanum carbonate octahydrate (250 g) was dried in a vacuum drying oven at 70° C., and was weighed every 2 hours to monitor the weight reduced. The target compound of 214.33 g with a yield of 97.39% was obtained. XRPD shows abnormal crystal form of the product.
[0128] The X-ray powder diffraction (XRPD) patterns of lanthanum carbonate octahydrate with abnormal crystal form prepared in Comparative Examples 5 to 10 are substantially as shown in
Sodium Ion Content
[0129] Sodium ion detection results of lanthanum carbonate tetrahydrate API prepared in Examples 1, 2 and Comparative Examples 1, 2 and 5:
TABLE-US-00002 Examples and product Preparation Sodium ion batch numbers conditions content in API EXAMPLE 1 20190426-1 Acetic acid, potassium 0.6359 ppm carbonate EXAMPLE 2 20190412-1 Acetic acid, ammonium 0.5490 ppm bicarbonate Comparative Example 1 Acetic acid, sodium 578.5462 ppm 20191217-2 carbonate Comparative Example 2 Nitric acid, sodium 274.6957 ppm 20190412-2 carbonate Comparative Example 5 Hydrochloric acid, 432.3226 ppm 20190430-1 sodium carbonate
Dissolution Comparison
[0130] Dissolution comparison 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).
[0131] Dissolution determination method: general rules 0931 the second method (paddle method) of Chinese Pharmacopoeia, 2015 version, volume IV
[0132] Rotating speed: 50 rpm
[0133] Dissolution media: hydrochloric acid medium pH 1.0, acetate buffer pH 3.0 (acetic acid-sodium acetate buffer), acetate buffer pH 4.5 (acetic acid-sodium acetate buffer), borate buffer pH 6.8 (boric acid-sodium hydroxide buffer)
[0134] Volume of dissolution medium: 900 ml
[0135] Time points of sampling: 20 min, 40 min, 60 min, 120 min, 180 min, 240 min, 360 min, 720 min, 1440 min
[0136] Volume of sampling: 7 ml (filtration with filter membrane, discarding initial filtrate, and take subsequent filtrate as the test solution)
[0137] Determination method: EDTA titration
[0138] Results of Dissolution Determination:
[0139] Comparison of the results of dissolution determination in hydrochloric acid medium pH 1.0
TABLE-US-00003 Sample name Time Cumulative dissolution (%) point Comparative Comparative Comparative (min) Example 1 Example 2 Example 1 Example 2 Example 3 20 37.21 32.41 30.68 29.81 18.18 40 49.95 43.55 40.51 32.26 26.07 60 60.70 55.07 52.97 40.82 32.56 120 78.37 70.66 65.80 57.54 51.77 180 88.37 83.37 79.93 70.89 69.53 240 96.88 93.38 92.59 87.77 84.79 360 100.12 100.78 99.43 94.71 92.58
[0140] Comparison of the results of dissolution determination in acetate buffer medium pH 3.0
TABLE-US-00004 Sample name Time Cumulative dissolution (%) point Comparative Comparative Comparative (min) Example 1 Example 2 Example 1 Example 2 Example 3 20 9.66 7.87 6.65 7.05 2.54 40 26.09 18.96 15.23 13.77 9.13 60 41.60 35.21 32.58 23.58 12.75 120 67.20 62.19 51.17 35.62 26.01 180 78.64 73.03 65.49 49.85 43.40 240 90.24 86.12 77.51 64.06 51.91 360 96.60 93.33 82.19 76.98 67.68
[0141] Comparison of the results of dissolution determination in acetate buffer medium pH 4.5
TABLE-US-00005 Sample name Time Cumulative dissolution (%) point Comparative Comparative Comparative (min) Example 1 Example 2 Example 1 Example 2 Example 3 20 3.41 3.02 2.68 3.10 2.56 40 6.13 5.26 4.98 5.02 4.13 60 8.35 6.23 5.07 6.31 4.71 120 11.30 10.18 8.97 7.26 6.84 180 16.32 15.12 12.98 11.44 10.53 240 22.90 20.69 17.39 15.65 14.72 360 30.04 29.37 24.58 24.03 19.58 1440 60.32 59.32 52.79 55.17 34.53
[0142] Comparison of the results of dissolution determination in borate buffer medium pH 6.8
TABLE-US-00006 Sample name Time Cumulative dissolution (%) point Comparative Comparative Comparative (min) Example 1 Example 2 Example 1 Example 2 Example 3 20 0.00 0.00 0.00 0.00 0.00 40 0.15 0.11 0.10 0.12 0.00 60 0.32 0.22 0.19 0.20 0.12 120 0.73 0.58 0.51 0.61 0.38 180 0.98 0.83 0.79 0.86 0.53 240 1.22 1.13 1.09 1.17 0.72 360 1.78 1.57 1.38 1.62 0.99 720 2.15 1.96 1.85 2.04 1.51 1440 2.48 2.37 2.22 2.19 1.76
[0143] According to the dissolution study, the lanthanum carbonate tetrahydrate API prepared in the Examples of the present application has excellent dissolution characteristics. Especially under the conditions of hydrochloric acid medium pH 1.0 and acetate buffer medium pH 3.0, compared with the lanthanum carbonate tetrahydrate API prepared by the existing process, it has remarkably excellent dissolution characteristics, which can ensure the rapid dissociation of lanthanum ions after entering the gastrointestinal tract, providing sufficient ligand, lanthanum ions, for binding phosphate ions in the intestinal tract.
[0144] The disclosure is examples of the principles of the embodiments of the present application, and does not limit the present application formally or substantially in any manner, or limit the present application to specific embodiments. It is obvious to those skilled in the art that the elements, methods and systems of the technical solutions of the embodiments of the present application can be altered, changed, modified and evolved without departing from the principles, spirits and scopes of the embodiments and technical solutions of the present application as defined in the claims. These altered, changed, modified and evolved embodiments are all included in equivalent embodiments of the present application, and these equivalent embodiments are all included in the scope of the present application defined by the claims. Although embodiments of that present application may be embodied in many different manners, some embodiments of the present application are described in detail herein. In addition, the embodiments of the present application include any possible combination of some or all of the various embodiments described herein, which are also included in the scope of the present application as defined by the claims. All patents, patent applications and other cited information mentioned anywhere in the present application or any of the cited patents, cited patent applications or other cited information are hereby incorporated by reference in their entirety.
[0145] The above disclosure is intended to be illustrative rather than exhaustive. For those skilled in the art, this description will suggest many variations and alternatives. All such alternatives and variations are intended to be included within the scope of the claims, wherein the term “including” means “including, but not limited to”.
[0146] The description of alternative embodiments of the present application is completed herein. Those skilled in the art will recognize other equivalent transformations of the embodiments described herein, which are also included by the claims appended hereto.