CN102432055B - Lanthanum carbonate nano-particles for treating hyperphosphatemia, preparation method and use thereof - Google Patents

Abstract

The invention relates to a preparation method of lanthanum carbonate nano-particles for treating hyperphosphatemia, which comprises the steps of: 1) adding the sodium bicarbonate solution into the lanthanum chloride solution to prepare lanthanum carbonate octahydrate; 2) dehydrating to prepare stable lanthanum carbonate with 1-4 H2Os at constant pressure and at 40-120 DEG C; 3) and ball-milling the prepared sample from micron particles to nano-particles by a method of ball-milling. The invention further relates to the lanthanum carbonate octahydrate La2(CO3)3.8H2O and the lanthanum carbonate with 1-4 H2Os La2(CO3)3.xH2O (x arranges from 1 to 4) and the lanthanum carbonate nano-particles obtained by the preparation method as well as the use of the lanthanum carbonate nano-particles in preparing medicines for treating hyperphosphatemia.

Description

Lanthanum carbonate nanoparticles for treating hyperphosphatemia, its preparation method and use

technical field

The present invention relates to a preparation method of lanthanum carbonate nanoparticles for treating hyperphosphatemia, and lanthanum carbonate octahydrate La ₂ (CO ₃ ) ₃ 8H ₂ O obtained by the preparation method, containing 1 to 4 water Lanthanum carbonate La ₂ (CO ₃ ) ₃ ·xH ₂ O (wherein x is between 1-4) and lanthanum carbonate nanoparticle, and the application of the lanthanum carbonate nanoparticle in preparation for treating hyperphosphatemia.

Background technique

Chronic kidney disease is a common public health problem all over the world. One of its main complications is hyperphosphatemia caused by the inability of the kidneys to excrete phosphate in the body, resulting in elevated phosphate levels in the blood.

The symptoms of hyperphosphatemia are mainly blood phosphate levels that exceed normal levels, and may be related to secondary hyperparathyroidism, metabolic bone disease, soft tissue calcification, and cardiovascular calcification.

At present, the treatment of hyperphosphatemia mainly includes dietary control of phosphorus intake, phosphorus removal by dialysis, application of phosphorus binders, and removal of parathyroid glands when necessary. However, 90% to 95% of patients with end-stage renal disease treat hyperphosphatemia by taking phosphorus binders to reduce intestinal absorption of phosphorus.

Phosphorus binders are mainly divided into two types: traditional aluminum or calcium-containing phosphorus binders and non-aluminum, non-calcium phosphorus binders. Aluminum-containing phosphorus binders such as aluminum hydroxide, aluminum carbonate, etc., if taken for a long time, will cause aluminum poisoning, causing microcytic anemia, osteomalacia, Alzheimer's disease, etc. And calcium-containing phosphorus binders such as calcium carbonate, calcium acetate, etc., if used for a long time, will increase the absorption of calcium in the intestine and cause hypercalcemia, causing heart and blood vessel calcification. Therefore, the ideal binder for the treatment of hyperphosphatemia should be non-aluminum and non-calcium. Lanthanum carbonate is one of them.

Lanthanum is a rare earth element with a strong affinity for oxygen donor atoms. Lanthanum salts can combine with phosphate in food to form a lanthanum phosphate complex, which can reduce the level of phosphate in the blood by hindering the absorption of phosphate. Lanthanum carbonate (LC) is currently one of the relatively mature non-aluminum and non-calcium phosphate binders. It has little absorption in the gastrointestinal tract and little accumulation in tissues in the body. It will not cause vascular calcification and other side effects. The tolerance is also good, and it will surely become a new drug for the treatment of hyperphosphatemia. The US FDA approved lanthanum carbonate for clinical use in October 2004. So far, there have been many reports on the treatment of hyperphosphatemia with lanthanum carbonate.

However, lanthanum ion is a hard Lewis acid, which has a strong ability to combine with hydroxide. If you do not pay attention to the conditions when preparing lanthanum carbonate, it is easy to generate basic lanthanum carbonate. So far, basic carbonate has not been approved by the US FDA to treat hyperphosphatemia, and its safety in humans has not been confirmed. For the health and safety of patients with hyperphosphatemia, it is necessary to develop a reliable method for avoiding the generation of lanthanum carbonate in the process of preparing lanthanum carbonate.

The preparation method about lanthanum carbonate in the prior art generally all uses sodium carbonate as raw material to prepare. For example, someone reported in a patent the method of preparing lanthanum carbonate by reacting Na ₂ CO ₃ with LaCl ₃ , but repeating this method found that a certain amount of La(OH)CO ₃ was mixed in the generated lanthanum carbonate precipitate. In addition, the lanthanum carbonate sample produced by the existing method has relatively large particles, most of which are 3-4 μm. Large particles will result in a relatively small surface area, and the effect of absorbing and adsorbing phosphate is not good.

Contents of the invention

One of the purposes of the present invention is to find a method for preparing lanthanum carbonate that can avoid the formation of basic lanthanum carbonate, and the lanthanum carbonate can be better used for treating hyperphosphatemia after further treatment.

We noticed that the Na ₂ CO ₃ aqueous solution is alkaline, and the pH value of the solution is easy to rise if not controlled during the reaction process, resulting in inclusion of La(OH)CO ₃ in the formed precipitate. The inventor has found through research that if _NaHCO3 and _LaCl3 are used as raw materials to prepare lanthanum carbonate, in the preparation process, the following two parallel reactions will take place:

(1) NaHCO ₃ reacts with LaCl ₃ to release H ⁺ ,

(2) H ⁺ will react with HCO ₃ ^- to generate water and CO ₂ .

These two reactions are in dynamic equilibrium during the preparation of lanthanum carbonate, and the reaction can be carried out at a lower pH, thereby avoiding the generation of basic lanthanum carbonate while preparing lanthanum carbonate.

The inventor's research has also found that for the larger lanthanum carbonate sample prepared by the direct method, if the sample is ground by ball milling, the sample particle can be made smaller, even reaching the nanometer level, and its surface area is significantly increased. Capable of better absorption and adsorption of phosphate, thus exhibiting good therapeutic effect in drugs for the treatment of hyperphosphatemia.

Therefore, the present invention provides a kind of preparation method that is used for the treatment of the lanthanum carbonate nanoparticle of hyperphosphatemia, comprises the following steps:

Step 1), adding sodium bicarbonate solution into lanthanum chloride solution to prepare lanthanum carbonate octahydrate, La ₂ (CO ₃ ) ₃ 8H ₂ O, the characteristic peaks of its infrared spectrum are mainly at 850.3cm ^-1 and 746.6cm ^-1 and 678.6cm ^-1 , and there are also characteristic peaks at 1477.9cm ^-1 and 1377.7cm ^-1 ; the La ³⁺ concentration of the lanthanum chloride solution is 0.5-5mol/L;

Step 2), then dehydration at normal pressure, 40-120°C, preferably 50-100°C, more preferably 60-80°C, to prepare stable lanthanum carbonate containing 1-4 water, La ₂ (CO ₃ ) ₃ ·xH ₂ O, where x is between 1-4, the characteristic peaks of its infrared spectrum are mainly at 849.6cm ^-1 , 747.4cm ^-1 and 681.0cm ^-1 ; in addition at 1483.4cm ^-1 and 1394.9cm ^-1 There are also characteristic peaks.

Step 3), finally by ball milling, the lanthanum carbonate containing 1-4 water is ball-milled from micron particles into nanoparticles, the particle size of which is 100-400nm.

The present invention is described in detail below.

In step 1), the equation that generates lanthanum carbonate octahydrate is as follows:

H ⁺ +HCO ^- ＝H ₂ O+CO ₂ ↑

2La ³⁺ +3HCO ₃ ^- ＝La ₂ (CO ₃ ) ₃ ↓+3H ⁺

2La ³⁺ +6HCO ₃ ^- ＝La ₂ (CO ₃ ) ₃ ↓+3H ₂ O+3CO ₂ ↑

It can be seen from the equation that there are two reactions in the solution, one is the reaction of La ³⁺ and HCO ₃ ^- to form La ₂ (CO ₃ ) ₃ precipitation, and the other is the acid-base neutralization of HCO ₃ ^- and H ⁺ in the solution reaction. The above two parallel reactions, the acid-base neutralization reaction, have a very fast reaction rate; the other precipitation formation reaction, under the condition that there is no lanthanum carbonate crystal nucleus in the reaction system, the reaction hardly proceeds. When the speed of adding sodium bicarbonate is slow, because there is no lanthanum carbonate crystal nucleus to generate, the precipitation reaction does not proceed, so the added sodium bicarbonate only participates in the acid-base neutralization reaction, so that the pH of the solution can rise in the initial stage of the reaction. To about 5.5 without the formation of lanthanum carbonate precipitate (see Figure 1). In this case, due to the higher pH value of the system, the risk of inclusion of basic lanthanum carbonate in the prepared lanthanum carbonate product is greater. Therefore, in order to avoid the above risks, we take the following measures:

According to the present invention, in step 1), first add lanthanum chloride aqueous solution in the reactor, its La concentration is ^0.5-5mol /L, preferably 1-3mol/L, more preferably 2mol/L, pH is 0-3 .

Wherein, in step 1), the addition of aqueous sodium bicarbonate solution is divided into two stages:

In the initial stage, first quickly add a small amount of sodium bicarbonate aqueous solution to the aqueous lanthanum chloride solution at a time, the concentration of which is 0.2-4mol/L, preferably 0.3-3mol/L, more preferably 1mol/L, and the aqueous sodium bicarbonate solution accounts for The volume of the aqueous solution is 0.05-0.4, preferably 0.1-0.3, more preferably 0.15-0.25, most preferably 0.2.

In this case, when a small amount of sodium bicarbonate solution was quickly added at one time, the pH value of the solution rose to about 3, and flocculent La ₂ (CO ₃ ) ₃ precipitates appeared at the same time. This is because a part of NaHCO ₃ neutralizes the H ⁺ in the system, which increases the pH value of the solution. On the other hand, the addition of pulsed NaHCO ₃ will cause a higher local concentration of NaHCO ₃ in the reaction system, which will promote HCO ₃ ^- and La ^{3 +} reaction to generate lanthanum carbonate nuclei.

Then, with 0.01mL/s-10mL/s, preferably 0.05mL/s-5mL/s, more preferably 0.08mL/s-2mL/s, most preferably 0.1mL/s-1mL/s speed to lanthanum chloride Sodium bicarbonate solution was added in the solution until the reaction stopped when the inflection point appeared in the pH value.

During this process, the pH value of the reaction system decreased after further adding HCO ₃ ^- , which was mainly due to the reaction of HCO ₃ ^- and La ³⁺ to generate La ₂ (CO ₃ ) ₃ and release a large amount of H ⁺ . With the further addition of sodium bicarbonate, the amount of La ₂ (CO ₃ ) ₃ produced in the solution reaction system increases continuously, but the pH value of the system remains basically unchanged, which is due to the acid-base neutralization reaction and precipitation reaction reaching a Due to dynamic equilibrium, the entire La ₂ (CO ₃ ) ₃ generation reaction is carried out at a lower pH (such as around 4). When the La ³⁺ in the system is completely converted into La ₂ (CO ₃ ) ₃ precipitation, with the further addition of NaHCO ₃ , the pH of the system rises abruptly, so we can judge the reaction by the last jump. end.

According to the present invention, in step 1), after the reaction stops, the filtrate is sucked and washed three times with distilled water, and the octahydrate lanthanum carbonate filter cake is placed in a ventilated place to dry naturally. According to infrared spectrum identification, the infrared spectrum characteristic peaks of the octahydrate lanthanum carbonate are mainly at 850.3cm ^-1 , 746.6cm ^-1 and 678.6cm ^-1 , and there are also characteristic peaks at 1477.9cm ^-1 and 1377.7cm ^-1 .

In step 2), in order to dehydrate the eight-hydrated lanthanum carbonate formed in step 1), according to the present invention, octahydrated lanthanum carbonate is placed in an oven under normal pressure at a temperature of 40 to 120° C., preferably 50 to 100 °C, more preferably at 60-80 °C for 18-24 hours, you can get a more stable lanthanum carbonate with 1-4 water, La ₂ (CO ₃ ) ₃ ·xH ₂ O, where x is between 1-4, Preferably x is 1.5-3.5, more preferably x is 2.5-3.4, most preferably x is 3.3.

According to the infrared spectrum identification, the characteristic peaks of the infrared spectrum of the lanthanum carbonate of the 1 to 4 waters are mainly at 849.6cm ^-1 , 747.4cm ^-1 and 681.0cm ^-1 ; there are also characteristic peaks at 1483.4cm ^-1 and 1394.9cm ^-1 peak.

In step 3), in order to prepare nano-scale lanthanum carbonate, according to the present invention, the lanthanum carbonate obtained in step 2) containing 1 to 4 water is placed in a ball mill for 1-5 hours, preferably 1.5-3 hours, most preferably After 2 hours, lanthanum carbonate particles with a particle size of 100-400 nm, preferably 200-300 nm, are obtained.

According to the above preparation method of the present invention, lanthanum carbonate nanoparticles are prepared in step 3), and the particle diameter thereof is 100-400 nm, preferably 200-300 nm.

The lanthanum carbonate nanoparticles prepared according to the present invention can be used to prepare medicines for treating hyperphosphatemia.

The innovation of the present invention is mainly reflected in the following aspects:

1. To avoid the formation of lanthanum subcarbonate, we use NaHCO ₃ instead of Na ₂ CO ₃ . And at the beginning of the reaction, add a certain amount of NaHCO ₃ aqueous solution quickly in the low pH LaCl ₃ solution at one time, so that the local pH of the solution is too high to generate crystal nuclei of lanthanum carbonate precipitation, and then add drop by drop to the LaCl ₃ solution NaHCO ₃ aqueous solution, so that the newly formed lanthanum carbonate precipitates epitaxial growth on the initial nucleus. Only in this way, the two parallel reactions in the system are carried out synchronously, so that the pH value of the reaction system can achieve a dynamic balance, thereby preparing lanthanum carbonate in a lower pH environment.

2. We monitor the pH value of the solution throughout the process, and draw the pH-reaction time curve of the entire reaction process. When the lanthanum ions in the system are completely converted into lanthanum carbonate, the pH of the system will suddenly jump. This jump can be used as a criterion to stop the reaction. Utilizing the pH-reaction time curve of the reaction process, the production automation of lanthanum carbonate can be realized.

3. The lanthanum carbonate sample prepared by the direct method has relatively large particles, most of which are 3-4 μm. In order to make the sample particles smaller and increase the surface area, better absorb and adsorb phosphate, the sample is ground by ball milling, thus obtaining Particles with a particle diameter of 100 to 400 nm, preferably 200 to 300 nm.

Description of drawings

Figure 1: Add volume-pH change curve in the process of slowly adding NaHCO ₃ ;

Figure 2: The time-pH curve for the preparation of lanthanum carbonate octahydrate by the direct method;

Fig. 3: Direct method synthesis octahydrate lanthanum carbonate compares with standard card (25-1400);

Figure 4: Infrared spectrum of lanthanum carbonate octahydrate;

Figure 5: Infrared spectrum of lanthanum carbonate containing 1 to 4 water; the lanthanum carbonate in this figure contains 3.3 water, and its characteristic wavenumber is in the low band;

Figure 6: SEM image of hydrous lanthanum carbonate;

Figure 7: SEM image of nanoparticle lanthanum carbonate obtained after ball milling;

Figure 8: Thermogravimetric curve of lanthanum carbonate octahydrate;

Fig. 9: the thermogravimetric curve of the lanthanum carbonate containing 1～4 water;

Figure 10: Standard curve for phosphate;

Figure 11: Phosphate adsorption curve at pH 3.0;

Figure 12: Phosphate adsorption curve at pH 3.0;

Figure 13: Phosphate adsorption curve at pH 5.4;

Figure 14: XRD pattern of nanoparticles.

Detailed ways

The present invention is further described by the following examples, but the present invention is not limited to these embodiments.

1. Characterization experiment of lanthanum carbonate

1. XRD

单色辐射源，加速电压40KV，电流150mV，用于测定样品的晶型及其变化、结晶度、结晶完善程度。扫描范围：5～60°，采用连续扫描方式。并与La₂(CO₃)₃·8H₂O标准卡片25-1400进行比较。X-ray polycrystal diffractometer (XRD, Rigaku Dmax-2000): CuK

Monochromatic radiation source, accelerating voltage 40KV, current 150mV, used to determine the crystal form and its change, crystallinity and crystallization perfection of the sample. Scanning range: 5~60°, using continuous scanning mode. And compared with La ₂ (CO ₃ ) ₃ ·8H ₂ O standard card 25-1400.

2. Titration and elemental analysis

2.1 The experiment uses EDTA to titrate the sample to obtain the content of lanthanum element

Prepare 250mL 0.02mol/L zinc standard solution:

The standard zinc oxide was dried in a muffle furnace at 1000°C for 5 hours, cooled to 120°C, placed in a desiccator, and cooled to room temperature. Weigh 0.8118g of zinc oxide, add hydrochloric acid to dissolve it, dilute to 250mL, and prepare a zinc solution with a concentration of 1.995×10 ^-2 M

Prepare EDTA solution:

Weigh 7.4464g of EDTA and dissolve it in 1000mL of water.

EDTA calibration:

Use a pipette to draw 20.00mL Zn ²⁺ standard solution into the conical flask, add 2 drops of xylenol orange indicator, add 200g/L hexamethylenetetramine dropwise until the solution becomes stable purple, then add 5mL Methylenetetramine. Titrate with EDTA, when the solution changes from purple to yellow, it is the end point. Measured three times in parallel.

Determination of La ³⁺ content:

Weigh a certain amount of sample, add hydrochloric acid to dissolve it completely, set the volume to 100.00mL, draw 15.00mL with a pipette, and titrate with EDTA. Measured three times in parallel.

2.2 Elemental analysis

Using the vario EL elemental analyzer (Elementar Analysensysteme GmbH) to analyze the elements of samples C and H to obtain the carbon content and hydrogen content of the sample, and at the same time, the amount of water in the sample can be calculated through the H content.

3. Infrared spectroscopy

NICOLET iN10 MX micro-infrared spectrometer from Thermo Scientific Company was used; detector: MCT/A; beam splitter: KBr/Ge; number of scans: 64; resolution: 4cm ^-1 .

4. SEM (scanning electron microscope) to observe the particle size

JSM-6700F Field Emission Scanning Electron Microscope produced by JEOL Company was used, and the accelerating voltage was 5kV.

5. Thermogravimetric Characterization

The Q600SDT TGA-DTA-DSC synchronous analyzer from Thermal Analysis Company of the United States was used, the scanning range was 10°C--1000°C, and the heating rate was 10°C/min.

Two, preparation embodiment

Example 1:

First add 50 mL of lanthanum chloride aqueous solution into the flask, its La ³⁺ concentration is 2 mol/L, and its pH is 0-2. At the beginning, first quickly add 10 mL of sodium bicarbonate aqueous solution to the lanthanum chloride aqueous solution at one time, and its concentration is 1mol/L. At this time, the pH value of the solution has a sudden rise to about 3, and flocculent La ₂ ( CO ₃ ) ₃ precipitates. Then add sodium bicarbonate solution to the lanthanum chloride solution at a speed of 0.08mL/s until the pH value shows an inflection point, and the reaction stops when the pH value rises abruptly, and a total of 320mL of sodium bicarbonate solution is added. Figure 2 shows the time-pH curve for the preparation of lanthanum carbonate octahydrate by the direct method.

The filtrate was suction filtered, washed three times with distilled water, and the filter cake was placed in a ventilated place to dry naturally.

Figure 3 shows the obtained lanthanum carbonate octahydrate (labeled 03-25) compared with the standard card (25-1400). It can be seen that the peak positions are basically the same, and the matching degree with the standard card is about 920 (the value is 1000 for 100% matching).

Put the obtained lanthanum carbonate octahydrate in an oven, keep it at a certain temperature under normal pressure for 18 hours, and obtain lanthanum carbonate containing 1 to 4 water, specifically, when the temperature is 55°C, you can get lanthanum carbonate containing 3.3 The lanthanum carbonate of water, when this temperature is 75 ℃, obtains the lanthanum carbonate that contains 2.5 waters, and when this temperature is 120 ℃, obtains the lanthanum carbonate that contains 1 water.

The prepared lanthanum carbonate containing 1 to 4 water is placed in a ball mill and ball milled for 2 hours to obtain lanthanum carbonate particles with a size of 200 to 300 nm.

Table 1 shows the results of EDTA titration of La content in La ₂ (CO ₃ ) ₃ ·8H ₂ O.

Table 1

Table 3 shows the elemental analysis results of lanthanum carbonate octahydrate before and after drying and dehydration.

table 3

Table 4 shows the changes in C and La content of the samples before and after drying.

Table 4

It can be seen that there is basically no lanthanum carbonate subsistence.

Fig. 4 is the infrared spectrum of octahydrate lanthanum carbonate,

Fig. 5 is the infrared spectrum of lanthanum carbonate containing 1 to 4 waters.

It can be seen that, at lower wavenumbers, the characteristic peaks of lanthanum carbonate octahydrate are respectively at 850, 746, and 678cm ^-1 , while the characteristic peaks of lanthanum carbonate basic are at 858,724, and 696cm ^-1 ; The product obtained was lanthanum carbonate rather than lanthanum hydroxycarbonate.

Fig. 6 is the SEM figure of hydrous lanthanum carbonate;

Figure 7 is the SEM of the nanoparticle lanthanum carbonate obtained after ball milling.

It can be seen from Figure 6 that the sample is a sheet-like structure with a particle size of 3-4 μm;

It can be seen from Fig. 7 that nanoscale particles are obtained after ball milling, and the sample particles become 200-300nm.

Fig. 8 is the thermogravimetric curve of octahydrate lanthanum carbonate;

Fig. 9 is the thermogravimetric curve of lanthanum carbonate containing 1 to 4 waters.

Example 2:

First add 50 mL of lanthanum chloride aqueous solution to the flask, the La ³⁺ concentration is 2.5 mol/L, and the pH is 1.5. At the beginning, add 15mL sodium bicarbonate aqueous solution to the lanthanum chloride aqueous solution at one time quickly, and its concentration is 0.81mol/L _. (CO ₃ ) ₃ precipitates. Then add sodium bicarbonate solution to the lanthanum chloride solution at a rate of 2 mL/s until the pH value shows an inflection point, and the reaction stops when the pH value rises abruptly, and a total of 380 mL of sodium bicarbonate solution is added. The filtrate was suction filtered, washed three times with distilled water, and the filter cake was placed in a ventilated place to dry naturally.

Figure 3 shows the obtained lanthanum carbonate octahydrate (labeled 02-23) compared with the standard card (25-1400). It can be seen that the peak positions are basically the same, and the matching degree with the standard card is about 920.

Put the obtained lanthanum carbonate octahydrate in an oven, keep it at a certain temperature under normal pressure for 24 hours, and obtain lanthanum carbonate with 1 to 4 hydrates. Specifically, when the temperature is 60°C, you can get The lanthanum carbonate of water, when this temperature is 75 ℃, obtains the lanthanum carbonate that contains 2.4 waters, and when this temperature is 110 ℃, obtains the lanthanum carbonate that contains 1.5 waters.

The prepared lanthanum carbonate of 1-4 water is placed in a ball mill and ball-milled for 3 hours to obtain lanthanum carbonate particles of 200-300 nm.

Table 2 EDTA titration results of La content in La ₂ (CO ₃ ) ₃ ·8H ₂ O

Table 2

Example 3:

First add 50 mL of lanthanum chloride aqueous solution to the flask, its La ³⁺ concentration is 1.5 mol/L, and its pH is 1.0. At the beginning, add 8 mL of sodium bicarbonate solution to the aqueous solution of lanthanum chloride quickly at one time, and its concentration is 1.51 mol/L _. (CO ₃ ) ₃ precipitates. Then add sodium bicarbonate solution to the lanthanum chloride solution at a rate of 1.5 mL/s until the pH value shows an inflection point, and the reaction stops when the pH value rises abruptly, and 260 mL of sodium bicarbonate solution is added in total. The filtrate was suction filtered, washed three times with distilled water, and the filter cake was placed in a ventilated place to dry naturally.

Put the obtained lanthanum carbonate octahydrate in an oven, keep it at a certain temperature under normal pressure for 20 hours, and obtain lanthanum carbonate with 3 to 4 water, specifically, when the temperature is 50°C, you can get The lanthanum carbonate of water, when this temperature is 80 ℃, obtain the lanthanum carbonate that contains 2.0 water, when this temperature is 120 ℃, obtain the lanthanum carbonate that contains 1 water.

The prepared lanthanum carbonate with 1 to 4 water is placed in a ball mill and ball milled for 1.5 hours to obtain lanthanum carbonate particles with a size of 200 to 300 nm.

3. Application Examples

Phosphate Binding Assay: Molybdenum Antimony Antimolybdenum Blue Photometric Determination of Phosphate Content

Drawing of phosphate standard curve

Take 7 50mL colorimetric tubes, add 1mL ascorbic acid solution to the phosphoric acid standard operating solution 0mL, 0.50mL, 1.00mL, 3.00mL, 5.00mL, 10.00mL, 15.00mL respectively, and mix well. After 30s, add 2mL molybdate solution and mix well. Stand for 15 minutes, measure the absorbance at a wavelength of 700nm with the reagent blank solution as a reference, and draw a standard curve.

Figure 10 is a phosphate standard curve.

Phosphate binding curve at pH 2.0

Glycine-hydrochloric acid was prepared as 2.0 buffer solution, and the phosphate content in the solution was determined by molybdenum-antimony anti-molybdenum blue ultraviolet spectrophotometry to determine the binding rate of lanthanum carbonate.

Figure 11 is a pH 2.0 phosphate binding curve.

It can be seen from Fig. 11 that the reaction appeared an inflection point at 10 min, 80% of PO ₄ ^3- was converted into LaPO ₄ , and then no more phosphate was incorporated.

Phosphate binding curve at pH 3.0

Prepare acetic acid-lithium hydroxide as 3.0 buffer solution, use molybdenum antimony antimolybdenum blue ultraviolet photometry to measure the phosphate content in the solution, and determine the binding rate of lanthanum carbonate.

Figure 12 is a pH 3.0 phosphate binding curve.

It can be seen from Figure 12 that an inflection point appeared in the reaction at 10 minutes, 55% of PO ₄ ^3- was converted into LaPO ₄ , and then the reaction speed slowed down, and almost 100% of PO ₄ ^3- in the solution was converted into LaPO ₄ after 4 hours.

Phosphate binding curve at pH 5.4

Prepare hexamethylenetetramine-HCl as pH5.4 buffer solution, use molybdenum antimony antimolybdenum blue ultraviolet photometry to measure the phosphate content in the solution, and determine the binding rate of lanthanum carbonate.

Figure 13 is a pH 5.4 phosphate binding curve.

It can be seen from Fig. 13 that under the condition of pH 5.4, the binding curve did not show an obvious inflection point, and after 4 hours, the phosphate in the solution was basically completely bound.

Claims (15)

1. a preparation method for treating hyperphosphatemia lanthanum carbonate nanoparticles, comprising the following steps: Step 1), adding sodium bicarbonate solution into lanthanum chloride solution to prepare lanthanum carbonate octahydrate, La ₂ (CO ₃ ) ₃ 8H ₂ O, the La ³⁺ concentration of the lanthanum chloride solution is 0.5-5mol/ L, pH 0-3, The addition of aqueous sodium bicarbonate solution is divided into two stages: In the initial stage, first quickly add a small amount of sodium bicarbonate aqueous solution to the lanthanum chloride aqueous solution at one time, and its concentration is 0.2-4mol/L, and the sodium bicarbonate aqueous solution accounts for 0.1-0.3 of the volume of the lanthanum chloride aqueous solution; Then, add sodium bicarbonate solution to the lanthanum chloride solution at a speed of 0.05mL/s-5mL/s until the reaction stops when an inflection point occurs in the pH value; Step 2), then dehydration under normal pressure and temperature of 50-100°C to prepare stable lanthanum carbonate containing 1-4 water, La ₂ (CO ₃ ) ₃ ·xH ₂ O, wherein x is in the range of 1-4 between; Step 3), finally by ball milling, the lanthanum carbonate containing 1-4 water is ball-milled from micron particles into nanoparticles, the particle size of which is 100-400nm. 2. according to the preparation method of claim 1, it is characterized in that, In step 1), add lanthanum chloride aqueous solution to the reactor earlier, its La concentration is ^1-3mol /L, and pH is 0-3; The addition of aqueous sodium bicarbonate solution is divided into two stages: In the initial stage, first quickly add a small amount of sodium bicarbonate aqueous solution to the lanthanum chloride aqueous solution at one time, and its concentration is 0.3-3mol/L, and the sodium bicarbonate aqueous solution accounts for 0.15-0.25 of the volume of the lanthanum chloride aqueous solution; Then, add sodium bicarbonate solution into the lanthanum chloride solution at a rate of 0.08mL/s-2mL/s until the reaction stops when the pH value appears at an inflection point. 3. according to the preparation method of claim 2, it is characterized in that, In step 1), add aqueous lanthanum chloride solution to the reactor earlier, its La ^{Concentration} is 2mol/L, pH is 0-3; The addition of aqueous sodium bicarbonate solution is divided into two stages: In the initial stage, first quickly add a small amount of sodium bicarbonate aqueous solution to the lanthanum chloride aqueous solution at one time, and its concentration is 1mol/L, and the sodium bicarbonate aqueous solution accounts for 0.2 of the volume of the lanthanum chloride aqueous solution; Then, add sodium bicarbonate solution to the lanthanum chloride solution at a rate of 0.1mL/s-1mL/s until the pH value reaches an inflection point and the reaction stops. 4. according to the preparation method of claim 1, it is characterized in that, In step 2), dehydration is then carried out at normal pressure and at a temperature of 60-80°C. 5. according to the preparation method of claim 1, it is characterized in that, In step 1), after the reaction stops, the filtrate is filtered with suction, washed three times with distilled water, and the filter cake of lanthanum carbonate octahydrate is placed in a ventilated place to dry naturally. 6. according to the preparation method of claim 1, it is characterized in that, In step 2), lanthanum carbonate octahydrate is placed in an oven, and kept at a temperature of 50-100° C. for 18-24 hours under normal pressure to obtain more stable lanthanum carbonate with 1-4 hydrates, La ₂ (CO ₃ ) ₃ ·xH ₂ O, where x is between 1-4. 7. according to the preparation method of claim 6, it is characterized in that, In step 2), put lanthanum carbonate octahydrate in an oven and keep it at 60-80°C for 18-24 hours under normal pressure to obtain more stable lanthanum carbonate with 1-4 hydrates, La ₂ (CO ₃ ) ₃ ·xH ₂ O, where x is between 1-4. 8. The preparation method according to claim 6, wherein x is 1.5-3.5. 9. The preparation method according to claim 8, wherein x is 2.5-3.4. 10. The preparation method according to claim 9, wherein x is 3.3. 11. The preparation method according to one of claims 1 to 10, characterized in that In step 3), the lanthanum carbonate containing 1-4 water is placed in a ball mill and ball-milled for 1-5 hours to obtain lanthanum carbonate particles with a particle size of 200-300 nm. 12. according to the preparation method of claim 11, it is characterized in that, In step 3), the lanthanum carbonate containing 1-4 water is placed in a ball mill and ball-milled for 1.5-3 hours. 13. The lanthanum carbonate nanoparticles prepared according to the method according to any one of claims 1 to 12, the particle diameter of which is 100-400 nm. 14. The lanthanum carbonate nanoparticles according to claim 13, having a particle diameter of 200-300 nm. 15. Use of lanthanum carbonate nanoparticles produced according to a process according to one of claims 1 to 12 or according to claim 13 or 14 for the preparation of a medicament for the treatment of hyperphosphatemia.

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