HK1082242B - Rare earth metal compounds, methods of making, and methods of using the same - Google Patents

Description

Rare earth metal compound, method for producing same, and method for using same

The priority of USSN60/396989 as filed on 24/2002, USSN60/403868 as filed on 14/8/2002, USSN60/430284 as filed on 2/12/2002, USSN60/461175 as filed on 8/4/2003, and USSN10/444774 as filed on 23/5/2003 are hereby incorporated by reference in their entireties.

The present invention relates to a rare earth metal compound, and particularly to a rare earth metal compound having a porous structure. The invention also includes methods of making such porous rare earth metal compounds and methods of using the compounds of the invention. The compounds of the invention are useful for binding or adsorbing metals such as arsenic, selenium, antimony, and the like, and metal ions such as arsenic III⁺And V⁺. The compounds of the invention may then be used in water filters or other devices, or in methods for removing metals and metal ions from fluids, especially water.

The compounds of the invention may also be used to bind or adsorb anions, such as phosphate in the gastrointestinal tract of mammals. Thus, one use of the compounds of the present invention is to treat high serum phosphate levels in patients with end stage renal disease undergoing renal dialysis. In this aspect, the compound can be disposed on a filter in fluid communication with a kidney dialysis machine, thereby allowing blood to reduce phosphate content after passing through the filter.

In another aspect, the compounds can be used to deliver lanthanum or other rare earth compounds that will bind to phosphate present in the intestine (gut), thereby preventing their transfer into the bloodstream. The compounds of the invention may also be used for the delivery of drugs or as filters or adsorbents for the gastrointestinal tract or the bloodstream. For example, these materials may be used to deliver inorganic chemical agents in the gastrointestinal tract or other organs.

It was found that a porous particle structure and a high surface area would be beneficial for a high adsorption rate of anions. Advantageously, these characteristics allow the compounds of the invention to bind phosphate directly in the filtration means in fluid connection with the renal dialysis equipment.

The use of rare earth hydrated oxides, particularly hydrated oxides of La, Ce and Y in combination with phosphates is disclosed in Japanese published patent application 61-004529 (1986). Similarly, U.S. patent 5968976 discloses lanthanum carbonate hydrate which removes phosphate from the gastrointestinal tract and treats hyperphosphatemia in renal failure patients. It also discloses that lanthanum carbonate hydrate with about 3 to 6 crystalline water molecules can provide the highest removal rates. Us patent 6322895 discloses a silicon with micro-or nano-scale pores that can be used to slowly release drugs in the body. U.S. patent 5782792 discloses a method for treating rheumatoid arthritis in which a "protein a immunoadsorbent" is placed on silica or other inert binding agent in a cartridge and then the antibodies in the bloodstream are physically removed.

It has now surprisingly been found that the specific surface area (measured by the BET method) of the compounds according to the invention varies from one preparation method to another and that this specific surface area has a significant influence on the product properties. Therefore, the specific properties of the resulting compound can be adjusted by varying one or more parameters in the compound manufacturing process. In this connection, the compounds according to the invention have a BET specific surface area of at least about 10m²Per g, BET specific surface area of at least about 20m²(ii)/g, optionally a BET specific surface area of at least about 35m²(ii) in terms of/g. In one embodiment, the BET specific surface area of the compound is about 10m²G to about 40m²In the range of/g.

It has also been found that changes to the preparation of rare earth compounds will result in different species, for example different kinds of hydrated or amorphous oxycarbonates instead of carbonates, which differ and are improved in their properties. It has also been found that variations in the manufacturing process can produce different porous physical structures with improved properties.

The compounds of the invention, in particular lanthanum compounds, especially lanthanum oxycarbonate of the invention, show binding or removal of at least 40% of the initial concentration of phosphate within 10 minutes. Ideally, the lanthanum compound will bind to or scavenge at least 60% of the initial phosphate concentration in 10 minutes. In other words, lanthanum compounds, in particular lanthanum oxycarbonate compounds of the invention, especially lanthanum oxycarbonate, have a phosphate binding capacity of at least 45mg phosphate per gram of lanthanum compound. Preferably, the lanthanum compound has at least 50mg PO₄Phosphate binding capacity per g lanthanum compound, preferably at least 75mg PO₄Phosphate binding capacity per g lanthanum compound. Desirably, the lanthanum compound has at least 100mg PO₄Phosphate binding capacity per gram lanthanum compound, more desirably at least 110mg PO₄Phosphate binding capacity per g lanthanum compound.

In accordance with the present invention, rare earth metal compounds, particularly rare earth metal oxy-chlorides and oxy-carbonates, are provided. The oxycarbonate may be hydrated or anhydrous. These compounds can be manufactured according to the invention as particles with a porous structure. The rare earth metal compound particles of the present invention can be conveniently produced in a range in which the surface area is controllable, and variable and controllable ion adsorption rates can be obtained.

The porous particles or structures of the present invention are comprised of nano-or micro-scale crystals having a controlled surface area. Desirably, the rare earth oxychloride is lanthanum oxychloride (LaOCl). Desirably, the rare earth oxycarbonate hydrate is lanthanum oxycarbonate hydrate (La)₂O(CO₃)₂·xH₂O, where x is from 2 (inclusive 2) to 4 (inclusive 4)). This compound is also referred to as La in the present specification₂O(CO₃)₂·xH₂And O. Desirably, the anhydrous rare earth oxycarbonate is lanthanum oxycarbonate La₂O₂CO₃Or La₂CO₅They have several crystalline forms. Low temperature form of La₂O₂CO₃Means that the form obtained after calcination at high temperature or for a long time is La₂CO₅And (4) showing.

However, it will be understood by those of ordinary skill in the art that the lanthanum oxycarbonate can be in the form of a mixture of hydrated and anhydrous forms. In addition, the anhydrous lanthanum oxycarbonate can be La₂O₂CO₃And La₂CO₅Not only in single crystal form.

A method for producing a rare earth metal compound particle comprises: preparing a rare earth metal chloride solution, allowing the solution to evaporate substantially completely using a spray dryer or other suitable equipment, thereby forming an intermediate product, and calcining the resulting intermediate product at a temperature of about 500 to about 1200 degrees celsius. The product of the calcination step may be washed, filtered and dried to obtain a suitable final product. Optionally, the intermediate product may be milled to the desired surface area in a horizontal or vertical pressure media mill and then spray dried or dried by other means to obtain a powder, which may then be washed and filtered.

An alternative method for the preparation of rare earth metal compounds, especially rare earth metal anhydrous oxycarbonate particles, comprises: a solution of the acetate salt of the rare earth metal is prepared, the solution is allowed to evaporate substantially completely using a spray dryer or other suitable equipment to provide an intermediate product, and the intermediate product is calcined at a temperature of about 400 to about 700 degrees celsius. The product of the calcination step may be washed, filtered and dried to obtain the appropriate final product. Optionally, the intermediate product may be milled to a desired surface area in a horizontal or vertical pressure media mill and then spray dried or dried by other means to form a powder, which may be washed, filtered and dried.

Another method of making rare earth metal compounds includes making rare earth metal oxycarbonate hydrate pellets. The rare earth metal oxycarbonate hydrate particles can be produced by sequentially: preparing a rare earth chloride solution, stirring while slowly and stably feeding a sodium carbonate solution to the solution at a temperature ranging from about 30 to about 90 degrees celsius, then filtering and washing the precipitate to form a filter cake, and then drying the filter cake at a temperature ranging from about 100 to 120 degrees celsius to prepare a desired rare earth oxycarbonate hydrate. Optionally, the filter cake may be sequentially dried, slurried, then milled to a desired surface area in a horizontal or vertical pressure media mill, spray dried or dried by other means to form a powder, which may be washed, filtered and dried.

Alternatively, the method of making the rare earth metal oxycarbonate hydrate particles can be modified to make anhydrous particles. The improvement comprises: the dried filter cake is heat treated at a prescribed temperature of about 400 to about 700 degrees celsius for a prescribed time of 1 hour to 48 hours. Optionally, the heat-treated product may be slurried, milled to a desired surface area in a horizontal or vertical pressure media mill, spray dried or dried by other means to produce a powder, which may be washed, filtered and dried.

In accordance with the present invention, the compounds of the present invention are useful for treating patients suffering from hyperphosphatemia. The compounds can be prepared in a form that can be delivered to a mammal and can be used to remove phosphate from the digestive tract or reduce adsorption of phosphate into the bloodstream. For example, the compounds may be formulated for oral administration as a liquid solution or suspension, a tablet, a capsule, a gel plug (gelcap), or other suitable and known oral forms. Thus, the present invention contemplates a method of treating hyperphosphatemia comprising providing an effective amount of a compound of the invention. The compounds produced under different conditions correspond to different oxycarbonate or oxychloride compounds which possess different surface areas, exhibit different rates of reaction with phosphate, and also differ in their solubility properties for lanthanum or other rare earth metals into the digestive tract. The present invention can vary these properties according to the therapeutic requirements.

In another aspect of the invention, the compound made according to the invention as a porous structure with sufficient mechanical strength can be placed in a device in fluid communication with a dialysis machine through which blood flows, to directly remove phosphate by reaction of the rare earth compound with phosphate in the blood stream. The present invention therefore contemplates a device having an inlet and an outlet and having one or more compounds of the invention disposed between the inlet and the outlet. The present invention also contemplates a method of reducing the amount of phosphate in blood comprising contacting the blood with one or more compounds of the present invention for a time sufficient to reduce the amount of phosphate in the blood.

In yet another aspect of the invention, the compounds of the invention can be used as a substrate for a filter having an inlet and an outlet, whereby the compounds of the invention are disposed between the inlet and the outlet. A fluid containing metal, metal ions, phosphate or other ions may enter from an inlet, contact the compounds of the present invention, and then pass through an outlet. Thus, in one aspect of the invention, a method of reducing the metal content of a fluid (e.g., water) comprises passing the fluid through a filter containing one or more compounds of the invention to reduce the amount of metal present in the water.

Brief description of the drawings

Fig. 1 is a general flow diagram of a process for the preparation of LaOCl (lanthanum oxychloride) according to the present invention.

Fig. 2 is a flow chart of a method of making a coated titanium dioxide structure according to the present invention.

Fig. 3 is a flow chart of a method for producing lanthanum oxycarbonate in accordance with the present invention.

FIG. 4 shows and passes through a technical grade lanthanum carbonate La₂(CO₃)₃·4H₂O removing phosphateIn comparison with the ratio, LaO (CO) produced by the method according to the invention under the same conditions₃)₂·xH₂Graph of the percentage of phosphate in the O (where x is 2 (inclusive) to 4 (inclusive) removal solution) versus time.

FIG. 5 is a graph showing the amount of phosphate removed from solution per g of lanthanum compound as a function of time when the lanthanum compound is used as a drug for treating hyperphosphatemia. In one aspect, the drug is La prepared according to the method of the invention₂O(CO₃)₂·xH₂O (where x is 2 (inclusive) to 4 (inclusive), in the case of the comparative example, the drug is lanthanum carbonate La of technical grade₂(CO₃)₃·4H₂O。

FIG. 6 is a graph showing the amount of phosphate removed from solution per g of lanthanum compound as a function of time when the lanthanum compound is used as a drug for treating hyperphosphatemia. In one aspect, the drug is La prepared according to the method of the invention₂O₂CO₃. In the case of the comparative example, the drug is technical grade lanthanum carbonate La₂(CO₃)₃·4H₂O。

FIG. 7 shows and utilizes industrial grade lanthanum carbonate La₂(CO₃)₃·4H₂Percentage of O phosphate removal La prepared according to the process of the invention₂O₂CO₃Graph of percentage phosphate removal as a function of time.

FIG. 8 is a graph showing the relationship between the specific surface area of an oxycarbonate prepared according to the method of the present invention and the amount of phosphate or phosphate binding removed from the solution after 10 minutes from the addition of the oxycarbonate.

FIG. 9 is a graph showing the linear relationship between the specific surface area of the oxycarbonate of the present invention and the first order rate constant calculated from the initial reaction rate of the phosphate.

FIG. 10 is lanthanum oxycarbonate hydrate La according to the present invention₂(CO₃)₂·xH₂O, a flow chart of the manufacturing method.

FIG. 11 is an anhydrous lanthanum oxycarbonate La according to the present invention₂O₂CO₃Or La₂CO₅A flow chart of the manufacturing method of (1).

Fig. 12 is a scanning electron micrograph of lanthanum oxychloride made according to the method of the invention.

Fig. 13 is an X-ray diffraction scan of lanthanum oxychloride LaOCl made in accordance with the method of the present invention and its comparison with a standard map library card of lanthanum oxychloride.

FIG. 14 shows a commercial grade lanthanum carbonate La₂(CO₃)₃·H₂O and La₂(CO₃)₃·4H₂Graph of the percentage of phosphate removed from solution by LaOCl prepared by the process according to the invention under equivalent conditions as a function of time compared to the amount of phosphate removed by O.

FIG. 15 shows La₂O(CO₃)₂·xH₂Scanning electron micrographs of O, where x ranges from 2 (inclusive 2) to 4 (inclusive 4).

FIG. 16 is La made in accordance with the present invention₂O(CO₃)₂·xH₂X-ray diffraction scan of O, and La₂O(CO₃)₂·xH₂Comparison of the O gallery standards, where x ranges from 2 (inclusive) to 4 (inclusive).

FIG. 17 shows and utilizes commercially available La₂(CO₃)₃·H₂O and La₂(CO₃)₃·4H₂Phosphorus removal rate obtained from O compared to La under the same conditions₂O(CO₃)₂·xH₂Graph of the rate of removal of phosphorus from solution.

FIG. 18 is anhydrous lanthanum oxycarbonate La₂O₂CO₃Scanning electron micrographs of (a).

FIG. 19 is an anhydrous La cell made in accordance with the present invention₂O₂CO₃The X-ray diffraction scan of (1), further comprising a second X-ray diffraction scan of La₂O₂CO₃Comparison of "gallery criteria".

FIG. 20 shows La prepared according to the method of the present invention₂O₂CO₃A graph of phosphorus removal rates of (a), which includes the use of commercially available La₂(CO₃)₃·H₂O and La₂(CO₃)₃·4H₂Comparison of the obtained rates.

FIG. 21 is La according to the method of the present invention₂CO₅Scanning electron micrographs of (a).

FIG. 22 is an anhydrous La made in accordance with the present invention₂CO₅And comprises an X-ray diffraction scan of₂CO₅Comparison of "gallery criteria".

FIG. 23 shows La prepared by a method according to the present invention₂CO₅Obtained phosphorus removal rate graph, which is compared with the use of commercially available La₂(CO₃)₃·H₂O and La₂(CO₃)₃·4H₂The rates obtained were compared.

FIG. 24 is a TiO produced according to the method of the present invention₂Scanning electron micrographs of the support material.

FIG. 25 shows LaOCl coated and 800 ℃ baked TiO according to the method of the present invention₂An electronic scanned photograph of the structure.

FIG. 26 shows LaOCl coated and 600 degree Celsius baked TiO made according to the method of the present invention₂An electronic scanned photograph of the structure.

FIG. 27 shows LaOCl coated and 900 deg.C calcined TiO made according to the method of the present invention₂An electronic scanned photograph of the structure.

FIG. 28 shows LaOCl coated TiO calcined at different temperatures made according to the method of the present invention₂X-ray scans of the structure were compared to X-ray scans of pure LaOCl.

FIG. 29 shows the plasma lanthanum concentration over time for dogs treated with lanthanum oxycarbonate prepared according to the method of the present invention.

FIG. 30 shows the change over time of phosphorus concentration in the urine of rats treated with lanthanum oxycarbonate prepared according to the method of the present invention, compared to the measured phosphorus concentration of untreated rats.

FIG. 31 shows a device having an inlet, an outlet, and one or more compounds of the invention disposed between the inlet and the outlet.

Disclosure of Invention

The method of the present invention will now be described with reference to the accompanying drawings. Although lanthanum compounds are generally referred to in this specification, lanthanum is used only to facilitate the description and thus the invention and claims are not limited to lanthanum compounds alone. Indeed, it is understood that the methods and compounds described in this specification are equally applicable to rare earth metals other than lanthanum, such as Ce and Y.

Referring now to fig. 1, a method of making a rare earth oxychloride compound, particularly a lanthanum oxychloride compound, in accordance with one embodiment of the invention is illustrated. First, a lanthanum chloride solution is provided. The source of lanthanum chloride may be any suitable source and the invention is not limited to any particular source. One source of lanthanum chloride solution is to dissolve industrial lanthanum chloride crystals into water or HCl solution. Another source is the dissolution of lanthanum oxide into the hydrochloric acid solution.

The lanthanum chloride solution was allowed to evaporate to form an intermediate product. The evaporation 20 is carried out under conditions to achieve substantially total evaporation. Ideally, the evaporation can be carried out at a temperature above the boiling point of the feed liquid (lanthanum chloride), but below the temperature at which substantial crystal growth occurs. The resulting intermediate product may be an amorphous solid formed into a thin film, or may be spherical or partially spherical.

The term "substantially complete evaporation" or "substantially complete evaporation" as used in the specification and claims refers to evaporation such that the resulting solid intermediate product contains less than 15% free water, desirably less than 10% free water, and more desirably less than 1% free water. The term "free water" is understood to mean and refers to water that has not been chemically bound and that can be removed by heating at a temperature below 150 degrees celsius. After substantially complete evaporation or substantially complete evaporation, the intermediate product will have no visible moisture present.

The evaporation step is carried out in a spray dryer. In this case, the intermediate product will consist of a spherical or partially spherical structure. Spray dryers typically operate at a discharge temperature of about 120 degrees celsius to about 500 degrees celsius.

The intermediate product may then be fired in any suitable firing apparatus 30 at a temperature of up to about 500 to 1200 degrees celsius for about 2 to 24 hours, followed by cooling to room temperature. The cooled product may be washed 40 by immersion in water or dilute acid to remove any water soluble phase that may remain after the calcination step 30.

The temperature and length of time of the calcination process can be varied in order to adjust the particle size and reactivity of the product. The size of the particles obtained by calcination is generally between 1 and 1000. mu.m. The fired particles consist of individual crystals that are bonded together to form a structure with good physical strength and a porous structure. The size of the individual crystals constituting the particles is generally between 20nm and 10 μm.

As shown in fig. 2, in accordance with another embodiment of the present invention, the titanium chloride or titanium oxychloride feed solution is provided from any suitable source. One source is to dissolve anhydrous titanium chloride in water or hydrochloric acid solution. Chemical control agents or additives 104 may be introduced into the feed solution to affect the crystal form and particle size of the final product. A chemical additive is sodium phosphate Na₃PO₄. In a suitable mixing step 110 willA feed solution of titanium chloride or titanium oxychloride is mixed with an optional chemical control agent 104. The mixing may be carried out using any suitable known mixer.

Allowing the feed liquid to evaporate into an intermediate product, in this case titanium dioxide (TiO)₂). Vaporization 120 may be carried out at a temperature above the boiling point of the feed liquid but below the temperature at which substantial crystal growth occurs, achieving substantially total vaporization. Desirably, the resulting intermediate product may be an amorphous solid formed into a thin film, which may be spherical or partially spherical in shape.

The intermediate product is then fired in any suitable firing apparatus 130 at a temperature of about 400 to 1200 degrees celsius for a firing time of about 2 to 24 hours, and then cooled to room temperature (25 degrees celsius). The cooled product is then washed 140 by immersing in water or dilute acid to wash away any water soluble phase that may still be present after the calcination step.

The method of making the intermediate product according to the present invention may be adjusted and selected to produce a structure having the desired particle size and porosity. For example, the evaporation step 120 and the calcination step 130 may be adjusted for this purpose. The particle size and porosity can be adjusted to make the intermediate product structure suitable for use as an inert filter in the bloodstream.

Then the washed TiO is put into an inorganic compound solution₂The product is suspended or slurried. The inorganic compound is desirably a rare earth or lanthanum compound, especially lanthanum chloride. Allowing TiO in the inorganic compound solution to react again under the same conditions as the ranges defined in step 120₂The suspension undergoes total evaporation 160 to achieve substantially total evaporation. In this regard, both evaporation steps 120 and 160 may be performed in a spray dryer. The inorganic compound will precipitate as a salt, oxide or oxysalt. If the inorganic compound is lanthanum chloride, the precipitated product will be lanthanum oxychloride. If the starting compound is lanthanum acetate, the precipitated product will be lanthanum oxide.

The product of step 160 is further calcined 170 at a temperature of about 500 to 1100 degrees celsius for 2 hours. The temperature and time of the calcination process affect the properties and particle size of the product. The product 180 may be washed after the second firing step 170.

The resulting product can be described as formed on TiO₂Lanthanum oxychloride or lanthanum oxide crystals on a substrate. The resulting product may be in the form of hollow thin film spheres or partial spheres. The spheres have a size of about 1 to 1000 μm and are composed of a structure of individually bound particles. The size of the individual particles is between 20nm and 10 μm.

When the final product is on TiO₂When lanthanum oxychloride crystals on the substrate are formed, these crystals can be hydrated. It was found that this product efficiently reacts with phosphate and combines into insoluble compounds. It is believed that if the final product is released into the human stomach and gastrointestinal tract, the product will bind phosphate present therein and reduce the transfer of phosphate from the stomach and gastrointestinal tract to the bloodstream. Thus, the products of the present invention can be used to limit the phosphorus content in the blood stream of a patient undergoing renal dialysis.

In accordance with another embodiment of the present invention, FIG. 3 illustrates a method of making anhydrous lanthanum oxycarbonate. In this method, the lanthanum acetate solution may be formed by any method. A lanthanum acetate solution is formed by dissolving industrial lanthanum acetate crystals in water or HCl solution.

The lanthanum acetate solution was evaporated to form an intermediate product. Evaporation 220 may be carried out at a temperature above the boiling point of the lanthanum acetate solution, but below the temperature at which large scale crystal growth occurs, under conditions to achieve substantially complete evaporation. Ideally, the resulting intermediate products are amorphous solids formed into thin films, which are spherical or partially spherical in shape.

The intermediate product may then be fired in any suitable firing apparatus 230 by raising the temperature to a temperature of about 400 to 800 degrees celsius for a firing time of about 2 to 24 hours, and then cooling to room temperature. The cooled product is then washed 240 by immersing in water or dilute acid to wash out any water soluble phase that may still be present after the calcination step. The temperature and time of the calcination process can be varied to adjust the particle size and reactivity of the product.

The size of the particles obtained after calcination is generally between 1 and 1000. mu.m. The fired particles consist of individual crystals that are bonded together to form a structure with good physical strength and a porous structure. The size of the individual crystals is generally between 20nm and 10 μm.

The product obtained according to the method shown in fig. 1, 2 and 3 comprises ceramic particles having a porous structure. The size of the individual particles is in the micrometer range. These particles are composed of crystals in the nanometer size range, which fuse together to form a structure with good strength and porosity.

The particles produced according to the process of the present invention have the following common characteristics:

a. they have a very low solubility in aqueous solutions, especially in serum and gastric digestive juices, compared to non-ceramic compounds.

b. Their hollow shape makes them less dense in bulk than solid particles. While low density particles are less likely to cause retention in the gastro-intestinal tract.

c. They have good phosphate binding kinetics. The kinetics observed are generally better than the industrial carbonate hydrate La₂(CO₃)₃·H₂O and La₂(CO₃)₃·4H₂And O. In the case of lanthanum oxychloride, the relationship between phosphate binding or adsorption capacity and time is more linear than in the case of commercial lanthanum carbonate hydrate. The initial reaction rate is low, but the reaction rate does not decrease significantly with time over a long period of time. This property is defined as linear or substantially linear binding kinetics. This may mean better phosphate binding selectivity in the presence of other anions.

d. The above properties a, b and c are expected to be less likely to produce gastro-digestive complications than existing products.

e. Due to their specific structure and low solubility, the products of the invention have the potential for use on filtration devices placed directly within the bloodstream.

Different lanthanum oxycarbonates are prepared by different methods. It has been found that lanthanum oxycarbonate compounds having greatly different reaction rates can be obtained depending on the production method.

The lanthanum oxycarbonate is desirably La₂O(CO₃)₂·xH₂O, wherein x is more than or equal to 2 and less than or equal to 4. The lanthanum oxycarbonate is preferred because of its higher rate of phosphate removal. To determine the reactivity of the lanthanum oxycarbonate compounds with respect to phosphate, the following method can be employed. To prepare anhydrous Na containing 13.75g/l₂HPO₄And a stock solution of HCl 8.5 g/l. The stock solution was adjusted to pH3 by addition of concentrated HCl. 100ml of the stock solution was placed in a beaker equipped with a stir bar. A sample of lanthanum oxycarbonate powder was added to the solution. The amount of lanthanum oxycarbonate powder was such that the amount of lanthanum in suspension was 3 times the stoichiometric amount required for complete reaction with phosphate. Periodically, the suspended sample is removed through a filter that separates all solids from the liquid. The liquid sample was analyzed for phosphorus. FIG. 4 shows La after 10 minutes₂O(CO₃)₂·xH₂O removed 86% of the phosphate from the solution, while the lanthanum carbonate La was industrially hydrated under the same experimental conditions for the same period of time₂(CO₃)，·4H₂O removes only 38% of the phosphate.

FIG. 5 shows La shown in FIG. 4₂O(CO₃)₂·xH₂O has a PO removal of 110mg PO per g La compound after 10 min under the above conditions₄Phosphate removal capacity of (1), and industrial lanthanum carbonate as reference was 45mg PO₄/g。

Another preferred lanthanum carbonate is anhydrous lanthanum oxycarbonate La₂O₂CO₃. This compound is preferred because it has a particularly high binding capacity for phosphate, which allows removal of mgPO₄The compound is expressed in terms of/g. FIG. 6 shows La after 10 minutes₂O₂CO₃Binding 120mg PO₄(La)/g La Compound, La used as reference₂(CO₃)₃·4H₂O bound to 45mg PO only₄(ii)/g La compound.

FIG. 7 shows lanthanum oxycarbonate La₂O₂CO₃The rate of reaction with phosphate. After 10 minutes of reaction, it was able to remove 73% of the phosphate, compared to 38% for the commercial lanthanum carbonate used as reference.

Samples of different oxycarbonates made by different methods are shown in table 1 below.

TABLE 1

Sample (I)	Compound (I)	Example No. corresponding to manufacturing method	BET surface area m/g	PO remaining after 10 minScore of	Initial first order rate constant K(min)
						12345678910	LaO(CO)·xHOLaO(CO)·xHOLaO(CO)·xHOLaCO(4h polishing) LaOC0LaCO(2h polishing) LaOCOLaCO(No polishing) La(CO)·4HOLa(CO)·1HO	11111175775 Industrial sample industry	41.335.938.825.61818.816.511.94.32.9	0.1300.1530.1710.2750.2780.3080.3270.4830.6230.790	0.9490.9290.8370.5450.4830.3910.360.4340.1960.094

For each example, the surface area measured by the BET method and the phosphate fraction remaining after 10 minutes of reaction are tabulated. The table also shows the rate constant K corresponding to the initial reaction rate of phosphate₁It is assumed that this reaction is the first order reaction of phosphate concentration. Rate constant k₁Expressed by the following equation:

d[PO₄]/dt＝-k₁[PO₄]

wherein [ PO ]₄]Is the phosphate concentration in solution (mol/liter), t is the time (min), and k₁Is the first order rate constant (min)^-1). The table gives the rate constant for the initial reaction rate, i.e. the rate constant calculated from the experimental point of the first minute reaction.

FIG. 8 shows that there is a good correlation between the specific surface area and the amount of phosphate reacted after 10 minutes. This indicates that in this series of experiments, the most important factor affecting the reaction rate is the surface area, which is independent of the composition and manufacturing process of the oxycarbonate. High surface area can be achieved by adjusting the manufacturing process or by grinding the resulting product.

FIG. 9 shows that a good correlation is obtained by plotting the first order rate constants and BET specific surface areas given in FIG. 1 for these compounds. These correlations can be represented by straight lines passing through the origin. In other words, within experimental error, the initial reaction rate is proportional to the phosphate concentration and also to the surface area available.

Without being bound by any theory, it is suggested that the observed correlation of surface area to phosphoric acid concentration allows nucleophilic attack of the La atoms in the oxycarbonate with phosphate ions to form lanthanum phosphate LaPO₄For explanation. For example, if the oxycarbonate is La₂O₂CO₃The reaction will be:

1/2La₂O₂CO₃+PO₄ ^3-+2H₂O→LaPO₄+1/2H₂CO₃+3OH^-

if the rate is PO₄ ^3-The observed relationship shown in fig. 9 can be explained by the diffusion of ions to the surface of the oxycarbonate and the limitation of the available area of the oxycarbonate. The mechanism does not require the presence of La as a dissolved species. This reasoning also explains the decrease in reaction rate after the first minute: lanthanum phosphate formed on the surface of the oxycarbonate reduces the area available for reaction.

In general, the data obtained with increasing pH show a decrease in the reaction rate. This can be done by hydronium ion (H)₃O⁺) The reduced concentration of (a) explains that hydronium ions may catalyze the reaction by promoting the formation of carbonate molecules from the oxycarbonate.

Referring now to fig. 10, another method of making lanthanum oxycarbonate, particularly tetrahydrate is shown. First, an aqueous lanthanum chloride solution is prepared by any method. One method of preparing the solution is to dissolve industrial lanthanum chloride crystals into water or HCl solution. Another method of preparing lanthanum chloride solution is to dissolve lanthanum oxide in hydrochloric acid solution.

Adding LaCl₃The solution was placed in a well stirred tank reactor. Then adding LaCl₃The solution was heated to 80 degrees celsius. The analytically pure sodium carbonate prepared in advance was added stably over a period of 2 hours, and stirred vigorously. The required mass of sodium carbonate is calculated per 2 mol of LaCl₃6 moles of sodium carbonate are required. After adding the required massSodium carbonate solution, the resulting slurry or suspension is allowed to age (cure) at 80 degrees celsius for 2 hours. The suspension was then filtered off and washed with deionized water to give a clear filtrate. The filter cake was placed in a conventional oven at 105 degrees celsius for 2 hours, or until a weight stabilization was seen. LaCl₃The initial pH of the solution was 2, while the final pH of the suspension after maturation was 5.5. A white powder was obtained. The resulting powder was lanthanum oxycarbonate (La) tetrahydrate₂O(CO₃)₂·xH₂O). The number of water molecules in the compound is approximate and varies between 2 and 4 (including 2 and 4).

Referring to fig. 11, another method of making anhydrous lanthanum oxycarbonate is shown. First, an aqueous lanthanum chloride solution is prepared by any method. One method of preparing the solution is to dissolve industrial lanthanum chloride crystals into water or HCl solution. Another method of preparing lanthanum chloride solution is to dissolve lanthanum oxide in hydrochloric acid solution.

Adding LaCl₃The solution was placed in a well stirred tank reactor. Then adding LaCl₃The solution was heated to 80 degrees celsius. The analytically pure sodium carbonate prepared in advance was added stably over a period of 2 hours, and stirred vigorously. The mass of sodium carbonate required is expressed as per 2 moles of LaCl₃6 moles of sodium carbonate are required. Upon addition of the desired mass of sodium carbonate solution, the resulting slurry or suspension was allowed to age at 80 ℃ for 2 hours. The suspension was then washed and filtered to remove NaCl (a reaction by-product) to give a clear filtrate. The filter cake was placed in a conventional oven at 105 degrees celsius for 2 hours, or until a weight stabilization was seen. LaCl₃The initial pH of the solution was 2.2 and the final pH of the suspension after maturation was 5.5. White lanthanum oxycarbonate hydrate powder was obtained. The lanthanum oxycarbonate hydrate was then placed in an alumina tray, which was placed in a high temperature muffle furnace. The white powder was heated to 500 degrees celsius and held at that temperature for 3 hours. Form anhydrous La₂O₂CO₃。

Alternatively, the anhydrous lanthanum oxycarbonate formed as in the previous stage may be heated at 500 degrees Celsius for 15 to 24 hours without heatingIs 3 hours or 600 degrees rather than 500 degrees celsius. The resulting products have the same chemical formula, but they differ in their pattern in the X-ray diffraction scan, and have higher physical strength and lower surface area. The product corresponding to a higher temperature or longer firing time is defined herein as La₂CO₅。

Referring to fig. 31, there is disclosed an apparatus 500 having an inlet 502 and an outlet 504. The device 500 may be in the form of a filter or other suitable container. Disposed between inlet 502 and outlet 504 is a plurality of substrates 506 in the form of one or more compounds of the present invention. The device is in fluid communication with a dialysis machine through which blood flows so that phosphate can be removed directly by reaction of rare earth compounds with phosphate in the blood stream. In contrast, the present invention also contemplates a method of reducing the level of phosphate in blood comprising contacting the blood with one or more compounds of the present invention for a time sufficient to reduce the amount of phosphate in the blood.

In another aspect of the invention, the apparatus 500 may be disposed in a fluid stream such that a fluid containing metal, metal ions, phosphate or other ions may flow from an inlet 502 through a substrate 506, contact a compound of the invention, and then exit an outlet 504. Thus, in one aspect of the invention, a method of reducing the amount of metal in a fluid (e.g., water) comprises flowing the fluid through an apparatus 500 containing one or more compounds of the invention to reduce the amount of metal present in the water.

The following examples are intended to illustrate, but not to limit, the present invention.

Example 1

An aqueous lanthanum chloride solution containing 100g/l of La was injected into a spray dryer with an outlet temperature of 250 ℃. The intermediate product corresponding to the spray drying step was recovered on a bag filter. The intermediate product was calcined at 900 ℃ for 4 hours. FIG. 12 shows a scanning electron micrograph of the product, which is magnified 25000 times. The micrographs show the porous structure of the acicular particles. The X-ray diffraction pattern of the product (fig. 13) shows that it consists of lanthanum oxychloride LaOCl.

To determine the reactivity of the lanthanum compound with phosphate, the following experiment was performed. To prepare anhydrous Na containing 13.75g/l₂HPO₄And a stock solution of 8.5g/l HCl. The stock solution was adjusted to pH3 by addition of concentrated HCl. 100ml of the stock solution was placed in a beaker equipped with a stir bar. The above lanthanum oxychloride was added to the solution to form a suspension. The amount of lanthanum oxychloride is such that the amount of La in the suspension is 3 times the stoichiometric amount required for complete reaction with the phosphate. The suspended sample is removed from time to time through a filter that separates all solids from the liquid. The liquid sample was analyzed for phosphorus. FIG. 14 shows the rate of removal of phosphate from a solution.

Example 2 (comparative example)

To determine the reactivity of technical lanthanum with phosphate, except for the technical lanthanum carbonate La₂(CO₃)₃·H₂O and La₂(CO₃)，·4H₂The relevant part of example 1 was repeated under the same conditions, except that O was substituted for lanthanum oxychloride of the present invention. FIG. 14 shows another curve corresponding to the industrial lanthanum carbonate La₂(CO₃)₃·H₂O and La₂(CO₃)₃·4H₂Phosphate removal curve rate for O. Figure 14 shows that the phosphate removal rate of commercial lanthanum carbonate starts fast and slows down after about 3 minutes.

Example 3

The solution was stirred at a volume of 334.75ml and a concentration of 29.2 wt.% as La₂O₃Measured LaCl₃Aqueous HCl (lanthanum chloride) solution was added to a four liter beaker and heated to 80 degrees celsius with stirring. LaCl₃The initial pH of the solution was 2.2. 63.59g of sodium carbonate (Na) were added over 2 hours using a small pump₂CO₃) 265 ml of aqueous solution was metered into a hot beaker at a steady flow rate. The filtrate was separated from the white powder product using a buchner filter unit fitted with filter paper. The filter cake was mixed four times with 2 liters of distilled water, filtered and washed free of NaCl formed during the reaction. The washed filter cake was placed in a conventional oven at 105 deg.CFor 2 hours, or until a weight stabilization is observed. FIG. 15 shows a scanning electron micrograph of the product, which is magnified 120000 times. The micrograph shows that the compound has a needle-like structure. The X-ray diffraction pattern of the product (FIG. 16) shows that it is formed by hydrated lanthanum oxycarbonate hydrate (La)₂O(CO₃)₂·xH₂O), x is more than or equal to 2 and less than or equal to 4.

To determine the reactivity of the lanthanum compound with phosphate, the following experiment was performed. Preparation of anhydrous Na containing 13.75g/l₂HPO₄And 8.5g/l HCl stock. The stock solution was adjusted to pH3 by the addition of concentrated HCl. 100ml of the stock solution was added to a beaker equipped with a stir bar. To this solution was added the lanthanum oxycarbonate hydrate powder prepared in the above manner. The amount of lanthanum oxycarbonate hydrate powder was such that the amount of La in the suspension was 3 times the stoichiometric amount required for complete reaction with the phosphate. Suspended samples were taken from time to time using a filter that separated all solids from the liquid. The liquid sample was analyzed for phosphorus. Figure 17 shows the rate of phosphate removal from solution.

Example 4 (comparative example)

To determine the reactivity of technical lanthanum with phosphate, except for the technical lanthanum carbonate La₂(CO₃)₃·H₂O and La₂(CO₃)₃·4H₂The second part of example 3 was repeated under the same conditions except that O replaced the lanthanum oxychloride of the invention. FIG. 17 shows the utilization of industrial lanthanum carbonate La₂(CO₃)，·H₂O and La₂(CO₃)₃·4H₂Rate of phosphate removal by O. FIG. 17 shows that phosphate removal rate using lanthanum oxycarbonate is higher than that of industrial lanthanum carbonate (La)₂(CO₃)₃·H₂O and La₂(CO₃)₃·4H₂O) fast phosphate removal rate.

Example 5

A volume of 334.75ml, containing La₂O₃LaCl at a concentration of 29.2 wt%₃(lanthanum chloride) in aqueous HCl was added to a 4 liter beaker,heated to 80 degrees celsius with stirring. LaCl₃The initial pH of the solution was 2.2. 63.59g of sodium carbonate (Na) were added over 2 hours using a small pump₂CO₃) 265 ml of aqueous solution was metered into a hot beaker at a steady flow rate. The filtrate was separated from the white powder product using a buchner filter unit fitted with filter paper. The filter cake was mixed four times with 2 l of distilled water, filtered and the NaCl formed during the reaction was washed off. The washed cake was placed in a conventional oven at 105 degrees celsius for 2 hours or until a weight stabilization was observed. Finally, lanthanum oxycarbonate was placed in an aluminum pan in a muffle furnace. The muffle furnace temperature was raised to 500 degrees centigrade and held at that temperature for 3 hours. The obtained product is determined to be anhydrous oxygen-containing lanthanum carbonate La₂O₂CO₃。

The above process was repeated 3 times. In one case, the surface area of the white powder was determined to be 26.95m²And/gm. In the other two cases, the surface area and reaction rate are shown in table 1. FIG. 18 is a scanning electron micrograph of the structure of the product, which is magnified 60000 times. The micrograph shows that the structure of the compound consists of equi-or approximately circular particles with a size of approximately 100 nm. FIG. 19 is an X-ray diffraction pattern which shows that the product produced herein is anhydrous lanthanum oxycarbonate written La₂O₂CO₃。

To determine the reactivity of the lanthanum compound with phosphate, the following experiment was performed. Preparation of anhydrous Na containing 13.75g/l₂HPO₄And a stock solution of 8.5g/l HCl. The stock solution was adjusted to pH3 by addition of concentrated HCl. 100ml of the stock solution was added to a beaker equipped with a stir bar. The anhydrous lanthanum oxycarbonate prepared as described above is added to the solution. The amount of lanthanum oxycarbonate was such that the amount of La in the suspension was 3 times the stoichiometric amount required for complete reaction with the phosphate. Suspended samples were taken from time to time using a filter that separated all solids from the liquid. The liquid sample was analyzed for phosphorus. FIG. 20 shows the phosphate removal rate.

Example 6 (comparative example)

For determining industrial lanthanum and phosphateReactivity except with industrial lanthanum carbonate La₂(CO₃)₃·H₂O and La₂(CO₃)₃·4H₂O instead of La of the present invention₂O₂CO₃The second part of example 5 was repeated under the same conditions. FIG. 20 shows the utilization of industrial lanthanum carbonate La₂(CO₃)₃·H₂O and La₂(CO₃)₃·4H₂Rate of phosphate removal by O. FIG. 20 shows the phosphate removal rate of anhydrous lanthanum oxycarbonate prepared according to the method of the present invention compared to La hydrate prepared using industrial lanthanum carbonate hydrate₂(CO₃)₃·H₂O and La₂(CO₃)₃·4H₂The phosphate removal rate observed for O is fast.

Example 7

A lanthanum acetate solution containing 100g/lLa was fed into a spray dryer with an outlet temperature of 250 ℃. The intermediate product corresponding to the spray drying step was recovered using a bag filter. The intermediate product was calcined at 600 degrees celsius for 4 hours. FIG. 21 shows a scanning electron micrograph of the product, which is magnified 80000 times. FIG. 22 shows an X-ray diffraction pattern of the product, which shows that the product is composed of anhydrous lanthanum oxycarbonate. The X-ray diffraction pattern differs from the diffraction pattern corresponding to example 5, although the chemical composition of the compound is the same. The formula of the compound is written as (La)₂CO₅). Comparison of fig. 21 and 18 shows that the compound of this example has a leaf-like and needle-like structure, unlike the round particles formed in example 5. These particles can be used to remove phosphate directly from aqueous or non-aqueous media (e.g., the digestive tract or bloodstream).

To determine the reactivity of the lanthanum compound with phosphate, the following experiment was performed. Preparation of a solution containing 13.75g/l of anhydrous Na₂HPO₄And a stock solution of 8.5g/l HCl. The stock solution was adjusted to pH3 by addition of concentrated HCl. 100ml of the stock solution was added to a beaker equipped with a stir bar. La prepared by the method₂CO₅Is added to the solution. The amount of lanthanum oxycarbonate is such that the amount of La in the suspension is 3 times greater than the amount of La in the suspension with phosphorusThe stoichiometric amount required for complete reaction of the acid salt. Suspended samples were taken from time to time using a filter that separated all solids from the liquid. The liquid sample was analyzed for phosphorus. Figure 23 shows the rate of phosphate removal from solution.

Example 8 (comparative example)

To determine the reactivity of technical lanthanum with phosphate, technical lanthanum carbonate La was used₂(CO₃)₃·H₂O and La₂(CO₃)₃·4H₂O replaces the lanthanum oxycarbonate of the invention described above. FIG. 23 shows the utilization of industrial lanthanum carbonate La₂(CO₃)₃·H₂O and La₂(CO₃)₃·4H₂Phosphate removal rate of O. FIG. 23 also shows that phosphate removal rate using lanthanum oxycarbonate is greater than that using industrial lanthanum carbonate hydrate La₂(CO₃)₃·H₂O and La₂(CO₃)₃·4H₂The rate of phosphate removal by O is fast.

Example 9

Equivalent to 2.2g/l sodium phosphate Na₃PO₄To a solution of titanium chloride or oxychloride containing 120g/l Ti and 450g/l Cl. The solution was injected into a spray dryer with an outlet temperature of 250 degrees celsius. The spray dryer product was calcined at 1050 degrees celsius for 4 hours. The product was then washed twice in 2 molar HCl and twice in water. FIG. 24 shows the resulting TiO₂Scanning electron micrographs of the materials. It shows a porous structure of connected individual particles of about 250 nm. The structure has excellent mechanical strength. Such materials may be used as inert filter materials in fluid streams such as blood.

Example 10

The product of example 9 was reslurried to a lanthanum chloride solution containing 100g/l La. The slurry contained about 30% by weight TiO₂. The slurry was dried using a spray dryer with an outlet temperature of 250 degrees celsius. The spray dryer product was then calcined at 800 ℃ for 5 hours. At this point the productFrom porous TiO with a nanoscale lanthanum oxychloride coating₂The structure is formed. Fig. 25 is a scanning electron micrograph of the coated product. The electron micrograph shows TiO₂The size of the particles is a few microns. LaOCl appears as a crystalline precipitate of elongated crystals, typically about 10 microns long and 0.1 micron wide, that are firmly attached to TiO₂On the surface of the catalyst carrier, a thin film having a thickness of the order of nanometers is formed. Growth of LaOCl is affected by TiO₂And controlling the structure of the catalyst carrier. The orientation of the rutile crystal serves as a template for LaOCl crystal growth. By varying the temperature of the second calcination step, the particle size of the precipitate can be varied from nano-scale to micro-scale.

Fig. 26 is a scanning electron micrograph corresponding to firing at 600 degrees celsius instead of 800 degrees celsius. It shows less and less strong adhesion to the TiO₂LaOCl particles on a substrate. Fig. 27 is a scanning electron micrograph corresponding to firing at 900 degrees celsius instead of 800 degrees celsius. The product was similar to that formed at 800 degrees celsius, but the LaOCl precipitated crystals were larger and more densely coated with TiO₂A layer of carrier crystals. FIG. 28 shows X-ray diffraction patterns corresponding to firing at 600, 800, and 900 degrees Celsius. The figure also shows a graph corresponding to pure LaOCl. Peaks not present in the pure LaOCl pattern correspond to rutile TiO₂. The peaks tended to become more and more narrow with increasing temperature, indicating that LaOCl and TiO₂The crystal size of (a) becomes larger as the temperature increases.

Example 11

A volume of 334.75ml, containing La₂O₃LaCl at a concentration of 29.2 wt%₃Aqueous HCl (lanthanum chloride) was added to a 4 liter beaker and heated to 80 degrees celsius with stirring. LaCl₃The initial pH of the solution was 2.2. 63.59g of sodium carbonate (Na) were added over 2 hours using a small pump₂CO₃) 265 ml of aqueous solution was metered into a hot beaker at a steady flow rate. The filtrate was separated from the white powder product using a buchner filter unit fitted with filter paper. The filter cake was mixed with 2 liters of distilled water each timeAnd combining four times, filtering, and washing off NaCl formed in the reaction process. The washed cake was placed in a conventional oven at 105 degrees celsius for 2 hours, or until a weight stabilization was seen. The X-ray diffraction pattern of the product shows that it is made of hydrated lanthanum oxycarbonate La₂O(CO₃)₂·xH₂O (x is more than or equal to 2 and less than or equal to 4). The surface area of the product was measured by the BET method. The experiment was repeated 3 times to obtain slightly different surface areas and different reaction rates, which are listed in table 1.

Example 12

Six adult beagle dogs were given oral cross-over design lanthanum oxycarbonate La twice a day (6 hours apart)₂O(CO₃)₂·xH₂O (Compound A) or La₂O₂CO₃(Compound B) capsules, the dose of elemental lanthanum was 2250 mg. The animals were allowed to take the medication 30 minutes after feeding them. At least 14 days of washout may be allowed between each crossing group (arm). Plasma was obtained before dosing, 1.5, 3, 6, 7.5, 9, 12, 24, 36, 48, 60 and 72 hours after dosing and analyzed for lanthanum by ICP-MS. Urine samples were collected by catheterization before dosing and 24 hours after dosing, and creatinine and phosphorus concentrations were measured.

This experiment shows a reduction in urinary phosphate excretion (phosphorus binding marker). The urinary phosphate excretion values are shown in table 2 below. TABLE 2

Lanthanum oxycarbonate compounds	Intermediate phosphorus/creatinine ratio (% reduction compared to before dosing)	10 th and 90 th percentiles
			A	48.4％	22.6-84.4％
B	37.0％	-4.1-63.1％

Lanthanum in plasma revealed: table 3 summarizes all plasma lanthanum indications for dogs. The plasma concentration profile is shown in figure 29.

TABLE 3

La Compound of Oxycarbonate to be tested	Curve lineAverage (sd) area (ng.h/ml) of (standard deviation)	Maximum concentration C(ng/ml); (Standard deviation)
			A	54.6(28.0)	2.77(2.1)
B	42.7(34.8)	2.45(2.2)

Example 13 first Living Studies in mice

5/6 nephrectomies were performed for six adult Sprague-Dawley mice per group at two stages over a 2-week period and allowed to recover for an additional 2 weeks prior to randomization. The groups were administered vehicle (0.5% w/v carboxymethylcellulose) or lanthanum oxycarbonate A or B suspended in vehicle once a day (10 ml/kg/day) for 14 days by oral gavage. The dose released 314mg lanthanum per kg per day. The drug was taken daily prior to the night (feeding) cycle. Urine samples were collected twice weekly (24 hours) before surgery, before treatment initiation, and during treatment, respectively. Urine-like volume and phosphorus concentration were measured.

Feeding-animals were provided with Teklad phosphate-rich diet (0.5% Ca, 0.3% P, Teklad No. td85343) ad libitum during acclimation and surgery. Animals were fed in pairs at the beginning of treatment based on the average food consumption of the vehicle-treated animals of the previous week.

5/6 nephrectomy-one week after acclimation of all animals, 5/6 nephrectomy surgery was performed. The operation is performed in two stages. First, the two lower branches of the left renal artery were ligated. One week later, a right nephrectomy was performed. Before each surgery, animals were anesthetized by intraperitoneal injection of a mixture of ketamine/xylazine (100 mg/ml in ketaject) and 20mg/ml in xylazine (Xylaject) at a dose of 10ml per kg. After each surgery, the animals were relieved of post-operative pain at a dose of 0.25mg/kg buprenorphine. Animals were allowed to stabilize for 2 weeks after surgery to begin treatment.

The results are given in figure 30 for the amount of urinary phosphorus excretion. The results show that phosphorus excretion was reduced in rats dosed with lanthanum oxycarbonate (times >0) compared to untreated rats (a sign of uptake of bound phosphorus).

Example 14: secondary in vivo study in mice

Adult male Sprague-Dawley mice, six young adults, were randomized into each group. The experimental item is lanthanum oxycarbonate La₂O₂CO₃And La₂CO₅(Compound B and Compound C) in an amount of 0.3 and 0.6% of the food intake for each experiment. There was another negative control group receiving Sigmacell cellulose instead of the experimental item.

The experimental items were thoroughly mixed into the Teklad 7012CM diet. All groups received equal amounts of dietary nutrition.

Table 4 describes the dietary composition of each group: TABLE 4

Group ID	Treatment of	Experimental items	Sigmacell cellulose	Teklad diet
					I	Negative control	0.0％	1.2％	98.8％
II	Compound B-intermediate level	0.3％	0.9％	98.8％
					III	Compound B-high levels	0.6％	0.6％	98.8％
IV	Compound C-intermediate level	0.3％	0.9％	98.8％
					V	Compound C-high level	0.6％	0.6％	98.8％

Before use, rats were allowed to remain in the animal facility for at least 5 days and were individually housed in stainless steel suspension cages. The first day of experiment initiation, they were placed in metabolic cages separately along with their experimental meals. Urine and fecal excretion was measured every 24 hours and their overall health was assessed visually. The study lasted 4 days. Daily food consumption during the study was recorded. The initial and final weight of the animal was recorded.

Plasma samples were collected by retroorbital bleeds (retro-orbital bleeds) comparing (I) to high-dose oxycarbonate groups III and V. Using CO according to IACUC protocol₂Rats were euthanized.

The urine samples were analyzed for phosphorus, calcium and creatinine concentrations using the Roche reagent in a Hitachi 912 analyzer. Daily urine phosphorus excretion was calculated for each mouse using daily urine volume and phosphorus concentration. No significant change was seen in animal body weight, urine volume or creatinine excretion from group to group. Food consumption was good for all groups.

Although the lanthanum dose in the diet was low compared to the amount of phosphate, as shown in table 5 below, the phosphate excretion was reduced for the case where 0.3% or 0.6% La was added to the diet. Table 5 shows the average urinary phosphate levels on days 2, 3 and 4 of the experiment. Urine phosphorus excretion is a marker of diet-bound phosphorus.

TABLE 5

	Urinary phosphate excretion (mg/day)
		Comparison of	4.3
Compound B ═ La0CO	2.3
		Compound C ═ LaCO	1.9

Example 15:

experiments were performed to determine the binding efficiency of eight different compounds to twenty-four different elements. Table 6 gives the experimental compounds. TABLE 6

Experiment ID	Compound (I)	Preparation technology
			1	LaO	Industrial (Prochem) La was treated at 850 deg.C(CO)·HO roasting for 16 hours
2	LaCO	Prepared by spray drying a lanthanum acetate solution and calcining at 600 degrees celsius for 7 hours (corresponding to the method of figure 3)
			3	LaOCl	Prepared by spray-drying a lanthanum chloride solution and calcining at 700 deg.C for 10 hours (corresponding to the method of FIG. 1)
4	La(CO)·4HO	Purchased from Prochem (comparative example)
			5	Carbonic acid Ti	Prepared by the process of FIG. 11, wherein LaClTiOCl for solutionThe solution was replaced.
6	TiO	Preparation by addition of sodium chloride using the method corresponding to FIG. 2
			7	LaO(CO)·xHO	Sodium carbonate was added to a lanthanum chloride solution at 80 degrees centigrade and precipitated (corresponding to the method of FIG. 10)
8	LaOCO	The sodium carbonate solution was added to the lanthanum chloride solution at 80 degrees centigrade, precipitated, and then calcined at 500 degrees centigrade for 3 hours (method of fig. 11)

Since these compounds are intended for the removal of arsenic and selenium from drinking water, the main objective of these experiments was to examine the efficiency of these compounds in binding arsenic and selenium. Twenty-one different anions were included to explore further feasibility. The experiment was carried out in the following manner:

the compounds given in Table 6 were added to water and spike and shaken vigorously at room temperature. The sample is filtered and the filtrate is analyzed for a series of elements including: sb, As, Be, Cd, Ca, Cr, Co, Cu, Fe, Pb, Mg, Mn, Mo, Ni, Se, Tl, Ti, V, Zn, Al, Ba, B, Ag and P.

Spike solutions were prepared as follows:

1. adding 400ml of deionized water into a measuring cylinder with the volume of 500 ml;

2. a standard solution of the above elements was added to prepare a solution containing about 1mg/l of each element.

3. Diluted to 500ml with deionised water.

The experiment was carried out in the following manner:

1. each compound weighed 0.50g and was added to their respective 50ml centrifuge tubes.

2. 30.0ml of spike solution was added for each.

3. The cap was secured and shaken vigorously for 18 hours.

4. The solution was filtered from each centrifuge tube using a 0.2 micron syringe filter. 6ml of filtrate was obtained.

5. With 2% HNO₃The filtrate was diluted at 5: 10. Final matrix 1% HNO₃。

6. And (6) carrying out analysis.

The results of the experiment are shown in table 7.

TABLE 7

The compounds that appear to be most effective in removing arsenic and selenium are titanium-based compounds 5 and 6. Lanthanum oxycarbonate produced according to the process of the present invention is at least 90% arsenic removed. Its efficiency in removing Se ranges from 70 to 80%. The efficiency of commercial lanthanum carbonate (4 in table 6) is somewhat lower.

Experiments have shown that lanthanum and titanium compounds prepared according to the method of the invention are also effective in removing Sb, Cr, Pb, Mo from solutions. They also confirm the fact that the discussion in the previous examples is effective in removing phosphorus.

While the invention has been described in conjunction with specific embodiments, it is to be understood that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the aforegoing description. Accordingly, the present invention is intended to embrace all such alternatives, modifications and variances which fall within the spirit and scope of the appended claims.

Claims (12)

1. A method of preparing a rare earth compound comprising:

a. preparing a rare earth chloride solution;

b. mixing a sodium carbonate solution with a rare earth chloride solution at a temperature of 30-90 ℃ to form a precipitate of rare earth oxycarbonate;

c. filtering the precipitate; and

d. the precipitate was dried.

2. The method of claim 1, wherein the precipitate is dried at a temperature of 100-120 ℃.

3. The method of claim 1, wherein the rare earth is lanthanum.

4. The method of claim 1, wherein the rare earth compound is a particle having a porous structure.

5. The method as claimed in claim 4, wherein the precipitate is further heat-treated at a temperature of 400-700 ℃.

6. The method of claim 5, wherein the precipitate is further dried in a spray dryer.

7. A method according to claim 5 or 6, wherein the precipitate comprises spheres or partial spheres.

8. The rare earth compound produced by the process according to any one of claims 1 to 7, wherein the BET specific surface area of the rare earth compound is 10m²G to 40m²In the range of/g and having an adsorption capacity of at least 45mg of phosphate per gram of rare earth compound.

9. Use of a rare earth compound prepared according to any one of claims 1-7 for preparing a composition for binding phosphate in a solution, wherein the compound has an adsorption capacity of at least 45mg of phosphate per gram of compound.

10. Use according to claim 9, wherein the compound binds selectively to phosphate ions.

11. The use according to claim 9, wherein the compound has substantially linear phosphate binding kinetics.

12. Use according to claim 9, wherein the compound is arranged between the inlet and the outlet of the device.