CN1035869C - Method for prepn. of ball shaped hydroxy-apatite with homogeneous precipitation - Google Patents
Method for prepn. of ball shaped hydroxy-apatite with homogeneous precipitation Download PDFInfo
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- CN1035869C CN1035869C CN93120052A CN93120052A CN1035869C CN 1035869 C CN1035869 C CN 1035869C CN 93120052 A CN93120052 A CN 93120052A CN 93120052 A CN93120052 A CN 93120052A CN 1035869 C CN1035869 C CN 1035869C
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Abstract
The present invention relates to a method for preparing spherical hydroxyl apatite with homogeneous precipitation. The present invention has the concrete scheme: a precipitation agent or complexing agent and an oxidizing agent are added into aqueous solution containing a certain concentration of calcium ions and phosphate radical ions to carry out homogeneous reaction, and spherical precipitates are generated under a certain reaction condition, wherein the precipitation agent is urea or hexamethylenetetramine, the complexing agent is ethylenediaminetetraacetic acid or EDTA, and the oxidizing agent is hydrogen peroxide. As the present invention does not relate to a pelletizing process, the present invention has the advantages of simple technology and equipment, easy operation and low cost; the spherical precipitates can be directly generated, the spherical particles of various particle diameters can be obtained by the present invention, wherein the spherical hydroxyl apatite particles are used as the filling medium of liquid chromatography, and the effect is good.
Description
The invention relates to a method for preparing spherical hydroxyapatite, in particular to a method for preparing spherical hydroxyapatite by adopting homogeneous precipitation.
Hydroxyapatite is an inorganic salt and also occurs in nature. It is a good artificial dental and orthopaedics material because of its good compatibility to organism.
In 1956 hydroxyapatite was first used as a chromatographic separation medium for proteins by Tiselius et al (arch. biochem.65(1956) 132). In a normal state, hydroxyapatite is an irregular flaky crystal, is not uniformly distributed in a chromatographic column, and is easily broken during chromatography, thereby affecting the separation performance. In order to improve the chromatographic properties of hydroxyapatite, spherical hydroxyapatite has been developed. For example, thousands of others (J.of the Ceramic Society of Japan, 1987, 95(5), 759) use spray pyrolysis technology to produce spherical particles of about 5 um; zongteniming et al (BUNSEKIKAGUAKU, 1989, 38, 34) granulate and sinter hydroxyapatite microcrystals to prepare spherical hydroxyapatite by first adding hydroxyapatite powder into a solution containing a polymer dissolved in an organic solvent and an aqueous solution, emulsifying the mixture by high-speed stirring, removing the organic phase, solidifying the polymer to obtain spherical particles, and sintering the spherical particles to obtain hydroxyapatite spherical particles. These methods all involve a granulation process. The granulation process has complex process and equipment, high cost, difficult control of the granulation operation of the tiny particles and wider particle size distribution.
The invention aims to provide a method which has simple process and equipment; the reaction is carried out in one step to form a sphere, and the sphericity is good; the method for preparing the spherical hydroxyapatite by homogeneous precipitation is easy to operate, can conveniently control the particle size and has low cost.
The concrete solution of the invention is as follows: a method for preparing spherical hydroxyapatite by homogeneous precipitation is characterized in that: adding a precipitator or a complexing agent and an oxidant into an aqueous solution containing calcium ions and phosphate ions with certain concentration, and carrying out homogeneous reaction under certain reaction conditions to generate spherical precipitates. Example 1 thereof: the molar ratio of the reactant calcium ions to the phosphate ions is as follows: 1.2 to 4.5; the precipitating agent is: urea or hexamethylenetetramine, the concentration of the precipitant being: 0.001-10 mol/l; the homogeneous precipitation reagent concentration was: 0.0001-3 mol/l, the reaction temperature is between room temperature and 400 ℃, and the reaction time is between 5 minutes and 20 hours. Example 2 thereof: the molar ratio of the reactant calcium ions to the phosphate ions is as follows: 1.2-4.5: the complexing agent is: ethylene diamine tetraacetic acid or EDTA or citric acid and citrate, the concentration of the complexing agent should be equal to or slightly higher than the concentration of calcium ions in the reaction system; the oxidant is: hydrogen peroxide, oxidant concentration: 1-20%, the concentration of the homogeneous precipitation reactant is 0.0001-3 mol/l, the reaction temperature is between room temperature and 400 ℃, and the reaction time is between 5 minutes and 20 hours.
The principle of the invention is as follows: by homogeneous precipitation reaction, spherical particles are directly generated from soluble calcium salt and phosphate solution under the condition of controlling the generation number of crystal nuclei and the growth speed of crystals. Homogeneous precipitation refers to the simultaneous achievement of supersaturated conditions at a certain point in the reaction system, resulting in uniform precipitated particles. Very early on, analytical chemists used this technique to obtain large particles of precipitate that were easy to wash. The spherical hydroxyapatite is not prepared by utilizing the principle.
The homogeneous reaction conditions provided by the present invention adopt two modes. Firstly, controlling the pH value of a reaction system; and secondly, controlling the concentration of calcium ions in the reaction system.
Controlling the pH value of a reaction system:
the solubility of calcium phosphate in alkaline aqueous solution is very low, the solubility product is 1X 10-115～1×10-110However, as the pH is lowered, the solubility increases, and when the pH is less than 5, it is completely dissolved. Thus, it is possible to precipitate phosphate from an acidic solution containing a certain concentration of calcium ions and phosphate ions by adjusting the pH of the solution. In this system, precipitation of hydroxyapatite can be obtained by alkali neutralization, but the size and shape of the precipitated particles are varied because the degree of supersaturation in the system is not uniform. The present invention is characterized by that in the acidic reaction system containing calcium ion and phosphate radical ion a so-called precipitant is added, and when the reaction condition is changed, the precipitant is decomposed so as to change pH value of reaction system and make calcium phosphate precipitate, and under the condition of said reaction, the calcium phosphate is precipitated in the systemThe supersaturation is achieved at the same time everywhere, namely the homogeneous precipitation is achieved, thus the spherical particle precipitation can be obtained.
The precipitant is a compound which provides precipitation conditions for calcium phosphate such as hydroxyapatite and the like under reaction conditions.
Control of cation concentration:
generally, in order to precipitate calcium phosphate such as hydroxyapatite in a reaction system, it is necessary to supersaturate the concentrations of calcium cations and phosphate ions. In order to provide homogeneous reaction conditions, the invention firstly reacts stoichiometric calcium ions with a complexing agent to form a complex, the calcium ions are masked, phosphate ions and an oxidizing agent are added, when the reaction system is changed, for example, the complex is destroyed by heating, the calcium ions are released and react with the phosphate ions, and when the concentration of the released calcium ions is over-saturated, calcium phosphate precipitation is obtained. Because the release of calcium ions in the reaction system is uniform, homogeneous reaction conditions are formed, and spherical calcium phosphate precipitate is obtained.
In the present invention, the precipitant used is urea or hexamethylenetetramine or formamide.
By heating an aqueous solution of urea, the following reactions can take place:
the released ammonia may change the pH value in the reaction system.
Heating the hexamethylenetetramine aqueous solution can cause the following reactions:
the releasedammonia may change the pH value in the reaction system.
The dosage of the precipitant is preferably 0.001-10 mol/l, the pH value of the reaction system which is lower than 0.001mol/l is not greatly changed and is more than 10mol/l, and the dosage of the precipitant is too large and is uneconomical.
The complexing agent used in the invention is EDTA (ethylene diamine tetraacetic acid disodium salt), ethylene diamine tetraacetic acid or citric acid, citrate, triethanolamine and the like. The reaction principle is illustrated below, taking EDTA as an example:
calcium ions in the reaction system are firstly mixed with EDTA ions Y4-Reacting to form complex, masking calcium ion, i.e. Ca2++Y4-→CaY2-
Then adding stoichiometric phosphate radical ions, and adding a proper amount of oxidant under the alkaline condition to make the system uniform. Heating the reaction system and the oxidizing agent destroys Ca2+The ions react with phosphate radical, and the concentration of the ions reaches supersaturation everywhere in the whole system at the same time to form homogeneous reaction conditions, so that spherical precipitate is generated.
The reaction principle of EDTA is the same as that of EDTA, and the action principle of citric acid and its salt is similar to that of EDTA, except that the calcium complex is formed.
EDTA and the like may be added in stoichiometric amounts, as indicated by the absence of turbidity in the solution. The oxidizing agent is preferably hydrogen peroxide. The amount of the complex to be added is such that the complex is completely destroyed.
In the present invention, the compound for supplying calcium ions is calcium nitrate, calcium chloride, calcium acetate calcium salt having high water solubility, or a calcium compound having poor water solubility, such as calcium oxide, calcium hydroxide, calcium carbonate, etc., but it is preferable to use the compound after dissolving it in an acid. The most suitable concentration of calcium ions in the reaction system is as follows: 0.0001 to 3.5mol, generally speaking, the lower the concentration, the larger the particle, when the concentration is higher than 3.5mol, it is not easy to control the homogeneous reaction condition.
In the present invention, the compound providing phosphate ions is phosphoric acid or a water-soluble salt of a phosphate, such as disodium hydrogenphosphate, dipotassium hydrogenphosphate, sodium dihydrogenphosphate, potassium dihydrogenphosphate, ammonium dihydrogenphosphate, diammonium hydrogenphosphate, sodium pyrophosphate, pyrophosphoric acid, sodium tripolyphosphate, phosphoric acid, etc., and the concentration during the reaction is preferably 0.0001 to 3.5mol/l, and in general, the lower the concentration, the larger the particles, and when the concentration is higher than 3.5mol/l, salting out occurs, and it is not easy to control the homogeneous phase reaction conditions.
The molar ratio of calcium to phosphorus in the molecular composition of hydroxyapatite is 1.67, but the ratio may be suitably varied up and down in the case of homogeneous precipitation reaction.
The precipitation reaction of calcium ions with phosphate ions may generate various forms of calcium phosphate salts other than hydroxyapatite.
The invention does not relate to the granulation process, and can directly prepare the spherical hydroxyapatite. The spherical hydroxyapatite is an excellent liquid chromatography filling material and is also used for other biological materials such as artificial dentistry, orthopaedics and the like.
The invention has the following positive effects:
1. the method can be used for preparing spherical particles of 3-5 um, 5-20 um, 20-60 um and 60-100 um, and is suitable for the filling medium of the column of the liquid chromatography. The appearance of the spherical hydroxyapatite prepared by the invention is shown in figure 1.
2. The X-ray diffraction pattern of the spherical hydroxyapatite prepared by the invention is shown in figure 2. As can be seen from the figure, the spherical particles are hydroxyapatite crystals.
3. The chromatogram of the protein sample separated by the spherical hydroxyapatite-filled chromatographic column prepared by the invention is shown in fig. 3b, and the separation effect of the monoclonal antibody in the mouse ascites is better than that of the chromatographic column filled with the sheet hydroxyapatite (shown in fig. 3a by the product of Bio Rad company) under the parallel condition, and the peak of the monoclonal antibody is not obviously separated.
4. Various spherical calcium phosphate compounds, such as octacalcium phosphate, α -calcium phosphate, β -calcium phosphate, amorphous calcium phosphate, dibasic calcium phosphate dihydrate, dibasic calcium phosphate anhydrous, and the like, can be prepared by the method of the present invention.
Specific examples of the present invention are given below.
A method for preparing spherical hydroxyapatite by homogeneous precipitation is characterized in that: adding a precipitator or a complexing agent and an oxidant into an aqueous solution containing calcium ions and phosphate ions with certain concentration to perform homogeneous reaction, and generating spherical precipitates under certain reaction conditions.
Example 1 thereof: the molar ratio of thereactant calcium ions to the phosphate ions is as follows: 1.5; the precipitating agent is: urea or hexamethylenetetramine, the concentration of the precipitant is: 0.002 mol/l: the concentrations of the homogeneous precipitation reactants were: 0.0002mol/l, reaction temperature: the reaction time is as follows at 50 ℃: for 10 minutes.
Example 2 thereof: the molar ratio of the reactant calcium ions to the phosphate ions is as follows: 1.5; the complexing agent is: ethylene diamine tetraacetic acid or EDTA or citric acid, citrate, the concentration of complexing agent should be equal to or slightly higher than the calcium ion concentration in the reactant; the oxidant is: hydrogen peroxide, oxidant concentration: 5 percent; the homogeneous precipitation reagent concentration was: 0.0002mol/l, reaction temperature: at 75 ℃, the reaction time is as follows: for 10 minutes.
Example 1
Adding 50ml of 3mol/l calcium chloride solution and 50ml of 1.5mol/l disodium hydrogen phosphate solution into a 1000ml flask, diluting with water to 800ml, uniformly stirring, adding urea until the depth of the urea in a reaction system is 3mol/l, uniformly stirring, heating in a water bath at 75 ℃ for 40 minutes, taking out the flask, cooling in water, filtering and washing to obtain spherical particles.
Example 2
Adding 50ml of 3mol/l calcium nitrate solution and 50ml of 1.5mol/l dipotassium phosphate solution into a 1000ml flask, diluting the solution to 800ml with water, uniformly stirring, adding hexamethylene tetramine until the concentration of the hexamethylene tetramine in the reaction system is 3.5mol/l, uniformly stirring, heating the solution in a water bath at 45 ℃ for 240 minutes, taking out the flask, cooling the solution in water, filtering and washing to obtain spherical particles.
Example3
Adding 50ml of 3mol/l calcium nitrate solution and 50ml of 1.5mol/l ammonium dioxyphosphate solution into a 1000ml flask, diluting with water to 800ml, uniformly stirring, adding urea until the concentration of the urea in a reaction system is 10mol/l, uniformly stirring, heating in a water bath at 75 ℃ for 40 minutes, taking out the flask, cooling in water, filtering and washing to obtain spherical particles.
Example 4
Adding 50ml of 3mol/l calcium acetate solution into a 1000ml flask, adding 300ml of 0.5mol/l EDTA solution, stirring uniformly, adding 60ml of 1.5mol/l sodium dihydrogen phosphate solution into water, diluting to 800ml, stirring uniformly, adding 100ml of 30% hydrogen peroxide, stirring uniformly, heating in a water bath at 80 ℃ for 45 minutes, taking out the flask, cooling in water, filtering and washing to obtain spherical particles.
Claims (1)
1. A method for preparing spherical hydroxyapatite by homogeneous precipitation is characterized in that: the content concentration is as follows: calcium ions of 0.0001-3.5 mol/l and the concentration are as follows: 0.0001-3.5 mol/l of phosphate radical ions, wherein the molar ratio of the calcium ions to the phosphate radical ions is as follows: 1.2-4.5, adding a precipitator urea or hexamethylenetetramine into the aqueous solution, wherein the concentration of the precipitator is as follows: 0.001-10 mol/l, or a complexing agent and an oxidant, wherein the complexing agent is EDTA or ethylene diamine tetraacetic acid, the concentration of the complexing agent is equal to or slightly higher than the concentration of calcium ions in the reaction system, the oxidant is hydrogen peroxide, the weight percentage concentration of the hydrogen peroxide is 1-20% of the system, and the reaction temperature is as follows: the reaction time is as follows at room temperature-400 deg.C: and decomposing the precipitant or the complex of the complexing agent and calcium to produce spherical precipitate in the condition of 5 min-20 hr.
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| CN93120052A CN1035869C (en) | 1993-12-15 | 1993-12-15 | Method for prepn. of ball shaped hydroxy-apatite with homogeneous precipitation |
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| CN93120052A CN1035869C (en) | 1993-12-15 | 1993-12-15 | Method for prepn. of ball shaped hydroxy-apatite with homogeneous precipitation |
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| CN1035869C true CN1035869C (en) | 1997-09-17 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100345798C (en) * | 2006-02-17 | 2007-10-31 | 武汉化工学院 | Production process of microporous carbon hydroxyapatite |
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| CN1299369C (en) * | 2005-01-06 | 2007-02-07 | 清华大学 | Method for preparing high-density spherical lithium iron phosphate |
| CN100336719C (en) * | 2006-03-28 | 2007-09-12 | 成都迪康中科生物医学材料有限公司 | Hydrothermal process of preparing nanometer hydroxyapatite colloid |
| US20090175955A1 (en) * | 2006-05-17 | 2009-07-09 | Igor Anatolievich Pomytkin | Hydroperoxylapatite and compositions thereof |
| CN101407316B (en) * | 2007-10-12 | 2012-05-09 | 西南交通大学 | Method for preparing high dispersibility nano-hydroxyapatite |
| EP2242718A2 (en) * | 2007-11-12 | 2010-10-27 | HKPB Scientific Limited | A combustion process for the manufacture of calcium phosphate and calcium phosphate composite particles |
| CN103088383A (en) * | 2011-11-04 | 2013-05-08 | 电子科技大学 | Electrochemical method for preparing citric acid-hydroxyapatite/zirconia transition coating on surface of biomedical titanium |
| CN103159198B (en) * | 2013-04-09 | 2015-04-01 | 厦门合众思创生物工程有限公司 | Preparation method of calcium phosphate |
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| CN105293461B (en) * | 2015-11-18 | 2017-08-29 | 湖北工业大学 | A kind of preparation method of Oil soluble hydroxy apatite nanometer sheet |
| CN106046399A (en) * | 2016-07-20 | 2016-10-26 | 太原理工大学 | Preparation method of surface-mineralized chitosan microsphere |
| CN106966377A (en) * | 2017-04-07 | 2017-07-21 | 上海静妤生物科技有限公司 | Hydroxyapatite micro-sphere and preparation method thereof |
| US11584648B2 (en) * | 2017-10-20 | 2023-02-21 | Hudens Bio Co., Ltd. | Method for preparing octacalcium phosphate and octacalcium phosphate prepared thereby |
| CN109485026B (en) * | 2018-12-28 | 2022-05-10 | 武汉工程大学 | Micron spherical strontium-incorporated hydroxyapatite and homogeneous precipitation synthesis process thereof |
| CN111591969B (en) * | 2020-06-03 | 2021-01-05 | 连云港东泰食品配料有限公司 | Preparation method of hydroxyapatite with high suspension degree |
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|---|---|---|---|---|
| US4335086A (en) * | 1978-07-21 | 1982-06-15 | Michael Spencer | Hydroxyapatite and its preparation |
| JPS60143762A (en) * | 1983-10-03 | 1985-07-30 | Mitsui Toatsu Chem Inc | Hydroxy apatite for chromatography |
| EP0205622A1 (en) * | 1984-12-18 | 1986-12-30 | Kanto Kagaku Kabushiki Kaisha | Calcium-phosphorus type apatite having novel properties and process for its production |
| EP0216621A2 (en) * | 1985-09-23 | 1987-04-01 | Tonen Corporation | Calcium-phosphate type hydroxyapatite and process for producing it |
| US4849193A (en) * | 1988-05-02 | 1989-07-18 | United States Gypsum Company | Process of preparing hydroxylapatite |
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1993
- 1993-12-15 CN CN93120052A patent/CN1035869C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4335086A (en) * | 1978-07-21 | 1982-06-15 | Michael Spencer | Hydroxyapatite and its preparation |
| JPS60143762A (en) * | 1983-10-03 | 1985-07-30 | Mitsui Toatsu Chem Inc | Hydroxy apatite for chromatography |
| EP0205622A1 (en) * | 1984-12-18 | 1986-12-30 | Kanto Kagaku Kabushiki Kaisha | Calcium-phosphorus type apatite having novel properties and process for its production |
| EP0216621A2 (en) * | 1985-09-23 | 1987-04-01 | Tonen Corporation | Calcium-phosphate type hydroxyapatite and process for producing it |
| US4849193A (en) * | 1988-05-02 | 1989-07-18 | United States Gypsum Company | Process of preparing hydroxylapatite |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100345798C (en) * | 2006-02-17 | 2007-10-31 | 武汉化工学院 | Production process of microporous carbon hydroxyapatite |
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