CN103159198A - Preparation method of calcium phosphate - Google Patents
Preparation method of calcium phosphate Download PDFInfo
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- CN103159198A CN103159198A CN2013101215595A CN201310121559A CN103159198A CN 103159198 A CN103159198 A CN 103159198A CN 2013101215595 A CN2013101215595 A CN 2013101215595A CN 201310121559 A CN201310121559 A CN 201310121559A CN 103159198 A CN103159198 A CN 103159198A
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Abstract
The invention provides a preparation of calcium phosphate, relates to calcium phosphate, and provides a preparation method of calcium phosphate, which has the advantages that production is continuous and high in yield stable, required raw materials are simple, reaction conditions are mild and controllable, production cycle is short and product quality is uniform and stable. The method comprises the following steps of: 1) preparing raw materials; 2) delivering clear liquid of phase A and clear liquid of phase B prepared in the step 1) to a microchannel continuous mixing system through a metering pump of a raw material delivery system so that liquid components of each phase are uniformly differentiated, and performing a continuous integral reaction to form a calcium phosphate aggregate; 3) delivering the calcium phosphate aggregate obtained in the step 2) to a heating system; 4) feeding into an insulating system; 5) feeding into a cooling system; and 6) delivering the cooled reaction product to a dehydration cleaning device, and drying the cleaned product to obtain calcium phosphate nano-particle powder.
Description
Technical field
The present invention relates to calcium phosphate, especially relate to the preparation method based on a kind of calcium phosphate of differential reaction technology.
Background technology
Calcium phosphate has better biocompatibility, biological activity, osteoinductive and biodegradability because of it, and is widely used in biomedical bone tissue restoration field.Up-to-date application also comprises water treatment Adsorption of Heavy Metals, drug release, beauty treatment reparation, cosmetics additive and toothpaste additive etc.
Chinese patent 200310105951.7 is take nitrocalcite and Secondary ammonium phosphate and urea as raw material, utilizing multitone chemistry producer to carry out sonochemistry synthesizes, suspension filtered, washing, vacuum-drying are got nano hydroxyapatite powder, and the hydroxy apatite powder granularity that makes is little, particle diameter even, nothing is reunited occurs, because synthesis temperature (40～80 ℃) is relatively low, therefore phase degree of crystallinity is high not enough, and need specific installation multitone chemistry producer.
It is template that Chinese patent 200610055171.X adopts water miscible macromolecular compound polyvinylpyrrolidone (PVP), take nitrocalcite and ammonium phosphate as raw material, under 25 ℃ of ambient room temperature standing 7 days, with the washing of gained throw out, suction filtration, be drying to obtain spherical hydroxide radical phosphorite nanocrystalline product, the method needs long ageing, production cycle is longer, and operation is loaded down with trivial details, is unfavorable for realizing the serialization industrial production.
Chinese patent 03142004.4 and journal article " Journal of Inorganic Materials ", 2004,19 (01): 234-238. has all reported a kind of preparation method of amorphous nano-calcium phosphate, the low scope of the synthesis temperature of these class methods is 0～20 ℃, limited its synthetic application at room temperature or higher temperature, the energy consumption that is used for cooling is higher, and synthesis cycle is longer.
Chinese patent 201110263963.7 discloses a kind of synthetic method of amorphous calcium phosphate, and is synthetic under 0 ℃ of ultrasound environments, therefore can't realize at room temperature synthesizing.In addition, needing increases special ultrasonic device, and generated time is longer, is unfavorable for producing in enormous quantities.
The multiple calcium phosphate of finding at present according to the different chemical metering than classification (the .Angewandte Chemie-International Edition such as Dorozhkin SV, 2002,41 (17): 3130-3146) as shown in table 1.
Table 1
Present studies show that, heterogeneous calcium phosphate, wherein comprise hydroxyapatite (HA) and tricalcium phosphate (TCP) two-phase and consist of, because the inorganic components of its composition and human body hard tissue is basically identical, and combine the biocompatibility of excellence of HA and the biological degradability of TCP.In addition, also have the complex body of type alpha tricalcium phosphate and bata-tricalcium phosphate etc., all show good consistency and degradation property aspect bone tissue restoration.
Take statistical mechanics and quantum mechanics to the research of energy variation in reaction process as foundation, formed the higher activated complex of potential energy between thinking from the reactant to the resultant, the residing state of activated complex is called transition state.Chemical reaction is to rearrange combination between atom from seeing in essence, and in this process, the potential energy of system reduces, and the reaction that makes can go on.Chemical reaction is not just can complete by the simple collision of reactant molecule, but at reactant in the process of resultant, passed through the transition state of a higher-energy.Its reaction scheme model is as follows: A+BC [A...B...C] ≠ → AB+C.
Studies show that of microminiaturized multiplexer spare, in the differential reactive system, due to the characteristic dimension of passage at micron order, along with reducing of yardstick, thermograde, pressure gradient, concentration gradient and density gradient etc. increase very soon, to cause the increase of mass transfer, driving force of heat transfer, thereby shorten diffusion length, enlarge the diffusion flux of unit volume or unit surface.The conventional interchanger of ratio of heat transfer coefficient is large more than 10 times, and mixing time can narrow down to the even little s magnitude of milli s, makes transformation efficiency, controllability and the conversion rate of reaction obviously improve.
Microreactor has the unrivaled superiority of conventional apparatus:
1, little, the quality of equipment requisite space and consuming little energy and corresponding time short, improved the security of equipment and the controllability of reaction process.
What 2, the differential reaction technology was mainly strengthened is transmission characteristic, and linear content is contracted to micron order, the contact gear ratio surface-area increases and volume reduces, and is to the reinforcement of quality and heat transfer process and the improvement of fluid-flow mode.
3, throughput is amplified easily, and the differential conversion unit replaces device geometry to amplify by number amplification flexibly, guarantees that the essential property of each parallel units is consistent, realizes stably producing of product.
4, but the achievement in research rapid conversion is productivity, and low cost realizes industrialization and mass-producing.
Summary of the invention
But the present invention aims to provide serialization and stably produces, and desired raw material is simple, and the reaction conditions gentleness is controlled, and is with short production cycle, the preparation method of a kind of calcium phosphate of product quality stable homogeneous.
Concrete steps of the present invention are as follows:
1) stock liquid preparation: calcium containing compound, 3 kinds of preparation of raw material of P contained compound and trolamine are become A phase clear liquid and B clear liquid mutually, take the concentration of water as the above solution of solvent adjustment, with A phase clear liquid and B mutually clear liquid be contained in respectively in two head tanks; Described A phase clear liquid is that at least a kind of preparation of raw material in above-mentioned 3 kinds of raw materials forms, and described B phase clear liquid is that at least a kind of preparation of raw material in above-mentioned 3 kinds of raw materials forms; Described A phase clear liquid and the B final raw material of clear liquid preparation mutually always plant number and must all contain above-mentioned 3 kinds of raw materials; The calcium phosphorus mol ratio of whole system is: (F
A* C
A-Ca+ F
B* C
B-Ca)/(F
A* C
A-P+ F
B* C
B-P)=1.0～2.0; Two-phase total flux: F
A+ F
B=10～5000mL/min, wherein, F
ABe the A phase flow rate, unit is mL/min; F
BBe the B phase flow rate, unit is mL/min; C
A-CaFor A mutually in the concentration of calcium containing compound, unit is M; C
B-CaFor B mutually in the concentration of calcium containing compound, unit is M; C
A-PFor A mutually in the concentration of P contained compound, unit is M; C
B-PFor B mutually in the concentration of P contained compound, unit is M;
2) volume pump by source material delivery system by the road with the A phase clear liquid in step 1) and B mutually clear liquid be delivered to the microchannel continuous mixing system, make each phase fluid component by even differential, the reaction of serialization integration forms the calcium phosphate aggregate;
3) with step 2) the calcium phosphate aggregate that obtains, be transported to temperature elevation system;
4) enter heat-insulation system;
5) enter again cooling system;
6) reaction product after the cooling is transported to the dehydration washing device, and the product after washing is carried out drying, obtains the nano-calcium phosphate particle powder.
In step 1), the concentration C of described calcium containing compound
CaCan be 0.01～5M; The concentration C of P contained compound
PCan be 0.01～5M; The mol ratio of the add-on of described trolamine and the add-on of calcium ion can be 0.1～10; The temperature of described preparation of raw material process can be 15～50 ℃; Described A phase clear liquid or B phase clear liquid are the transition state complex compound, can place not occur precipitation or suspended substance at least in 1 month;
In step 2) in, described volume pump by source material delivery system with the A phase clear liquid in step 1) and B mutually clear liquid be delivered to the microchannel continuous mixing system can be under 15～50 ℃ of envrionment conditionss by source material delivery system volume pump with the A phase clear liquid in step 1) and B mutually clear liquid steadily be delivered to the microchannel continuous mixing system simultaneously; The size of described microchannel can be 10～200 μ m; The flow reproducibility error of described volume pump is best≤1%, pressure range can be 14.5～1450psi, pressure pulse can≤29psi; The material of pipeline can adopt 316 stainless steels, 316L stainless steel or meet the stainless steel tube of ASTM A269 or equivalent standard, and internal diameter can be 1/16～1 inch, operating pressure can 〉=6000psi.
In step 3), described temperature elevation system rises to 100～300 ℃ with temperature from room temperature through heat exchange in 0.5～10s.
In step 4), described heat-insulation system is realized 100～300 ℃ of constant temperature, and soaking time is 1～30min.
In step 5), described cooling system can be realized in 0.5～10s the temperature of mix products is cooled to 0～90 ℃ from 100～300 ℃ through heat exchange; Pressure-controlling in whole system is before this realized regulating by back pressure apparatus, and the system pressure regulation range is 14.5～1450psi.
In step 6), described drying can adopt conventional oven dry, lyophilize, spraying drying or vacuum-drying etc.
The phase of product calcium phosphate forms can be one or more phase complex bodys in noncrystal calcium phosphate, monocalcium phosphate, calcium monohydrogenphosphate, Calcium Pyrophosphate, tricalcium phosphate, calcium phosphate eight calcium, calcium-deficient apatite and hydroxyapatite.
Traditional stirred autoclave mostly is intermittent process, is difficult to avoid local solubility to occur too high, causes the mass-and heat-transfer inequality to have, the transformation efficiency of impact reaction and the consistence of quality.Little hybrid reaction technology is the stable key of reappearing of product of the present invention, be compared to traditional stirred autoclave, has overcome product exists purity, pattern, size and distribution between different batches difference.The little mixing flow reactor that the present invention relates to is the little mixed structure of a kind of multilayer (Multilamination), dispersed phase fluid is by evenly differential injection, fluid constantly separates repolymerization, physique by micro mixing-reactor becomes n thin layer with fluid well-distributing differential to be mixed, and make its mutual contact, according to the Fick law, will be reduced to diffusion time: t～d
2/ (n
2* D).In formula, t is mixing time; The little diffusion characteristic yardstick of d; N is thin layer quantity; D is spread coefficient.
In the time of in fluid to be mixed is in same microchannel, along with reducing of yardstick, thermograde, pressure gradient, concentration gradient and density gradient etc. increase very soon, to cause the increase of mass transfer, driving force of heat transfer, thereby shorten the molecular diffusion distance, enlarged the diffusion flux of unit volume or unit surface.Therefore rely on molecular diffusion just can (milli s is to little s level) realize evenly mixing completing chemical reaction within the extremely short time, make transformation efficiency, controllability and the conversion rate of reaction obviously improve, reach the effect that micromixing does not have.
Transition state theory(TST) is thought, need through a transition state from the reactant to the product, in this transition state, reactant part scission of link, product part Cheng Jian is referred to as the transition state complex compound, it is not a stable material or the intermediate of a reaction, and be only a stage in the continuous transition of product by reactant, its energy is the extreme point on potential energy surface, the energy difference of itself and reactant is the potential barrier that reaction must overcome.Chemical reaction is not just can complete by the simple collision of reactant molecule, but at reactant in the process of resultant, passed through the transition state of a higher-energy.The reaction model of body series is as follows:
Ca
2++TEA+PO
4 3-□[Ca…TEA…P]
≠→ACP+TEA
This synthetic system is by introducing trolamine as the complex compound medium, it has enough space snappinesies, lone-pair electron on lone-pair electron on N and three-OH make four ligating atoms on a molecule all can be to the Ca ligand complex, and each chelate ring is five-ring (Ca ← HO-CH
2-CH
2-N → Ca) forms co-ordination complex.Make being present in the transition state complex compound that calcium ion can be more stable, reduced on the one hand the energy barrier of reaction formation final product, the existence of trolamine has been played sterically hindered stabilising effect to the synthetic of amorphous state calcium phosphate on the other hand, is difficult to stable synthetic problem thereby solved noncrystal calcium phosphate in room temperature or comparatively high temps.
The present invention is containing trolamine (N (CH
2CH
2OH)
3TEA) in the transition state complex compound system that consists of, make the solution such as calcium ion, phosphate anion realize the differential contact combination reaction of each phase fluid component by the continuous mixing reactor in microchannel, mass transfer and heat transfer process in consolidation system form the calcium phosphate aggregate fast, then through being rapidly heated, insulation and fast cooling, through washing, dehydration, drying, the calcium phosphate powder of acquisition stay in grade homogeneous.
The present invention has following outstanding advantages:
1) process adopts the continuous mixing reactor in microchannel, and each phase fluid component is carried out the differential refinement, has greatly shortened the molecular diffusion distance, realizes mass-and heat-transfer equably on microscopic scale, and enhancing mixed kinetics guarantees that the stable of the finished product can reappear;
2) by introducing trolamine as the complex compound medium, make raw material be in the transition state complex compound than steady state, realize that under normal temperature or comparatively high temps, the stable of (15～50 ℃) calcium phosphate powder synthesizes, particularly solved the difficult problem that non-crystalline state calcium phosphate is difficult to synthesize under this envrionment temperature;
3) adopt preparation technology of the present invention, one of product of calcium phosphate nanometer hydroxyapatite, not only phase purity is high, and degree of crystallinity is high, and size range is controlled at 10～300nm, and size distribution is even;
4) adopt preparation technology of the present invention, obtain first the nanometer hydroxyapatite of two ends indent unique morphology;
5) can obtain the controlled heterogeneous calcium phosphate product of ratio by the adjusting process parameter;
6) raw material type of the present invention is simple, does not especially add other basic materials (as sodium hydroxide or potassium hydroxide etc.) to regulate the pH value, reduces impurity, improves product purity;
7) technical process serialization of the present invention is high, and process is accurately controlled, and is with short production cycle, can realize stably producing of calcium phosphate product.
Description of drawings
Fig. 1 is nanometer hydroxyapatite transmission electron microscope (TEM) picture.In Fig. 1, scale is 100nm.
Fig. 2 is the local TEM picture that amplifies of the recessed special bar-shaped form nanometer hydroxyapatite of inward at both ends.In Fig. 2, scale is 50nm.
Fig. 3 is the nanometer hydroxyapatite size distribution.In Fig. 3, X-coordinate is granularity (d.nm), and ordinate zou is intensity (%).
Fig. 4 is nanometer hydroxyapatite X-ray powder diffraction (XRD) analytical results.In Fig. 4, X-coordinate be diffraction angle (°), ordinate zou is relative intensity (a.u.).
Fig. 5 is the XRD analysis result of nanometer hydroxyapatite after 1150 ℃ of pyroprocessing.In Fig. 5, X-coordinate be diffraction angle (°), ordinate zou is relative intensity (a.u.).
Fig. 6 is non-crystalline state calcium phosphate XRD analysis result.In Fig. 6, X-coordinate be diffraction angle (°), ordinate zou is relative intensity (a.u.).
Fig. 7 is that non-crystalline state calcium phosphate is analyzed by the selected diffraction (SAED) of transmission electron microscope.In Fig. 7, scale is 51nm.
Fig. 8 is the XRD analysis result of non-crystalline state calcium phosphate after 700 ℃ of processing.In Fig. 8, X-coordinate be diffraction angle (°), ordinate zou is relative intensity (a.u.).
Fig. 9 is the XRD analysis result of non-crystalline state calcium phosphate after 950 ℃ of processing.In Fig. 9, X-coordinate be diffraction angle (°), ordinate zou is relative intensity (a.u.).
Figure 10 is the XRD analysis result of α-heterogeneous calcium phosphate of TCP/ β-TCP.In Figure 10, X-coordinate be diffraction angle (°), ordinate zou is relative intensity (a.u.).
Figure 11 is the XRD analysis result of the heterogeneous calcium phosphate of HA/ β-TCP.In Figure 11, X-coordinate be diffraction angle (°), ordinate zou is relative intensity (a.u.).
Figure 12 is the XRD analysis result of β-heterogeneous calcium phosphate of TCP/ β-CDP.In Figure 12, X-coordinate be diffraction angle (°), ordinate zou is relative intensity (a.u.).
Embodiment
1.A phase stock liquid preparation is for the nitrocalcite of 0.2M and the triethanolamine solution of 1M mix;
2.B the preparation of phase stock liquid is the disodium phosphate soln of 0.12M;
3. the backpressure regulation with closed system arrives 2.2MPa, and the flow F of A phase stock liquid transferpump is set
A=75mL/min, the flow F of B phase stock liquid transferpump
B=75mL/min;
4. operation two-phase transferpump, be delivered to the two-phase stock liquid the continuous mixing reactor in microchannel that channel size is 105 μ m simultaneously, carries out even hybrid reaction;
With mix products through the heat exchanger that is rapidly heated, make system temperature reach 145 ℃;
6. enter 145 ℃ of constant temperature 6s, be delivered to the fast cooling interchanger, make system temperature drop to 25 ℃;
7. the reaction product after the cooling is delivered to washing/dehydrating device, the washing secondary, and ethanol is washed once;
8. the product after the dehydration washing to constant weight, gets the nano-calcium phosphate granular powder through 80 ℃ of vacuum-dryings.
Microscopic appearance amplifies from the part of Fig. 1 and Fig. 2 length 100～200nm that transmission electron microscope photo can be found out nanoparticle, width 60～80nm, pattern is the recessed special bar-shaped form of inward at both ends, this structure helps to improve the specific surface area performance of nanoparticle, be expected to be applied to pharmaceutical carrier, in addition from size distribution Fig. 3 about 141.8nm of nano particle median size as can be known, and normal distribution is even.The particle powder XRD analysis of being collected by Fig. 4 its phase as can be known is that pure ha phase (JCPDS:09-0432) is without other dephasigns.High-temperature stability and phase purity for the checking product, it is carried out 1150 ℃ of insulations process 2h, Fig. 5 is that pyroprocessing product X RD analytical results is high-crystallinity, and highly purified hydroxyapatite is without other dephasigns, thereby confirms that also ratio of calcium and phosphorus is approximate stoichiometric ratio 1.67.
Embodiment 2
1.A phase stock liquid preparation is for the nitrocalcite of 0.2M and the triethanolamine solution of 1M mix;
2.B the preparation of phase stock liquid is the disodium phosphate soln of 0.12M;
3. the flow F of A phase stock liquid transferpump is set
A=75mL/min, the flow F of B phase stock liquid transferpump
B=75mL/min under 25 ℃ of room temperature environments of normal pressure, is delivered to the two-phase stock liquid the continuous mixing reactor in microchannel that channel size is 105 μ m simultaneously, and each phase fluid component by even differential, contacts fast chemical combination and forms calcium phosphate aggregate colloidal sol in the microchannel;
4. reaction product mixture calcium phosphate aggregate colloidal sol is delivered to washing/dehydrating device, the washing secondary, ethanol is washed once, in 60 ℃ of vacuum-dryings to constant weight, obtains calcium phosphate powder.
X-ray powder diffraction analytical results such as Fig. 6 are typical non-crystalline state calcium phosphate diffuse peaks.Fig. 7 further determines that it is non-crystalline state calcium phosphate by the selected diffraction analysis of transmission electron microscope.In 700 ℃ of insulation 2h, the XRD phase is α-TCP(JCPDS:09-0348) with the non-crystalline state calcium phosphate powder, and as shown in Figure 8, to prepare this method energy consumption of α-TCP lower for 1300 ℃ of high temperature sinterings relatively in the past.In 950 ℃ of insulation 2h, the XRD phase is β-TCP(JCPDS:09-0169), as shown in Figure 9 with this non-crystalline state calcium phosphate powder.In 800 ℃ of insulation 2h, the XRD phase is α-heterogeneous calcium phosphate of TCP/ β-TCP, as shown in figure 10 with this non-crystalline state calcium phosphate powder.By accurate control sintering temperature and time, can regulate and control each phase content ratio in α-heterogeneous calcium phosphate of TCP/ β-TCP.
Embodiment 3
1.A phase stock liquid preparation is for the nitrocalcite of 0.19M and the triethanolamine solution of 1M mix;
2.B the preparation of phase stock liquid is the disodium phosphate soln of 0.12M;
3. the backpressure regulation with closed system arrives 2.2MPa, and the flow F of A phase stock liquid transferpump is set
A=75mL/min, the flow F of B phase stock liquid transferpump
B=75mL/min;
4. operation two-phase transferpump, be delivered to the two-phase stock liquid the continuous mixing reactor in microchannel that channel size is 105 μ m simultaneously, carries out even hybrid reaction;
With mix products through the heat exchanger that is rapidly heated, make system temperature reach 100 ℃;
6. enter 100 ℃ of constant temperature 6s, be delivered to the fast cooling interchanger, make system temperature drop to 25 ℃;
7. the reaction product after the cooling is delivered to washing/dehydrating device, the washing secondary, and ethanol is washed once;
8. the product after the dehydration washing to constant weight, then carries out the gained powder 950 ℃ of insulation 2h through 80 ℃ of vacuum-dryings, obtains the heterogeneous calcium phosphate of HA/ β-TCP.
Sample X-ray powder diffraction analytical results after pyroprocessing the characteristic peak of HA and β-TCP occurs as shown in figure 11 simultaneously in same spectrogram.
Embodiment 4
1.A the preparation of phase stock liquid contains the nitrocalcite of 1M and the phosphoric acid solution of 0.6M;
2.B the phase stock liquid prepares, and contains the triethanolamine solution of 2M;
3. the flow F of A phase stock liquid transferpump is set
A=50mL/min, the flow F of B phase stock liquid transferpump
B=125mL/min under 30 ℃ of environment, is delivered to the two-phase stock liquid the continuous mixing reactor in microchannel that channel size is 200 μ m simultaneously, and each phase fluid component by even differential, contacts fast chemical combination and forms calcium phosphate aggregate colloidal sol in the microchannel;
4. reaction product mixture calcium phosphate aggregate colloidal sol is delivered to washing/dehydrating device, the washing secondary, ethanol is washed once, in 60 ℃ of vacuum-dryings to constant weight, obtain calcium phosphate powder, then the gained powder is carried out 950 ℃ of insulation 2h, obtain β-heterogeneous calcium phosphate of TCP/ β-CDP, as shown in figure 12.
1.A the preparation of phase stock liquid is the calcium nitrate aqueous solution of 0.1M;
2.B phase stock liquid preparation is for the phosphoric acid of 0.06M and the triethanolamine solution of 0.2M mix;
3. the backpressure regulation with closed system arrives 9MPa, and the flow F of A phase stock liquid transferpump is set
A=50mL/min, the flow F of B phase stock liquid transferpump
B=50mL/min;
4. operation two-phase transferpump, be delivered to the two-phase stock liquid the continuous mixing reactor in microchannel that channel size is 105 μ m simultaneously, carries out even hybrid reaction;
With mix products through the heat exchanger that is rapidly heated, make system temperature reach 300 ℃;
6. enter 300 ℃ of constant temperature 6s, be delivered to the fast cooling interchanger, make system temperature drop to 25 ℃;
7. the reaction product after the cooling is delivered to washing/dehydrating device, the washing secondary, and ethanol is washed once;
8. the product after the dehydration washing to constant weight, gets the nano-calcium phosphate granular powder through 80 ℃ of vacuum-dryings.
Embodiment 6
1.A the preparation of phase stock liquid contains the nitrocalcite of 0.2M and the triethanolamine solution of 2.666M;
2.B the phase stock liquid prepares, and contains the disodium phosphate soln of 0.12M;
3. the flow F of A phase stock liquid transferpump is set
A=10mL/min, the flow F of B phase stock liquid transferpump
B=10mL/min under 50 ℃ of environment, is delivered to the two-phase stock liquid the continuous mixing reactor in microchannel that channel size is 10 μ m simultaneously, and each phase fluid component by even differential, contacts fast chemical combination and forms calcium phosphate aggregate colloidal sol in the microchannel;
4. reaction product mixture calcium phosphate aggregate colloidal sol is delivered to washing/dehydrating device, the washing secondary, ethanol is washed once, in 90 ℃ of vacuum-dryings to constant weight, obtains calcium phosphate powder.
Embodiment 7
1.A the preparation of phase stock liquid contains the calcium acetate of 0.6M and the triethanolamine solution of 1.8M;
2.B the preparation of phase stock liquid contains the phosphoric acid of 0.4M and the triethanolamine solution of 1.2M;
3. the flow F of A phase stock liquid transferpump is set
A=100mL/min, the flow F of B phase stock liquid transferpump
B=100mL/min, under 25 ℃ of room temperature environments of normal pressure, the two-phase stock liquid is delivered to the continuous mixing reactor in microchannel that channel size is 105 μ m simultaneously, and each phase fluid component by even differential, contacts fast chemical combination and forms calcium phosphate aggregate colloidal sol in the microchannel;
4. reaction product mixture calcium phosphate aggregate colloidal sol is delivered to washing/dehydrating device, the washing secondary, ethanol is washed once, in 60 ℃ of vacuum-dryings to constant weight, obtains non-crystalline state calcium phosphate powder.
1.A the preparation of phase stock liquid contains the nitrocalcite of 5M and the phosphoric acid solution of 3M;
2.B the phase stock liquid prepares, and contains the triethanolamine solution of 5M;
3. the flow F of A phase stock liquid transferpump is set
A=50mL/min, the flow F of B phase stock liquid transferpump
B=150mL/min under 25 ℃ of environment, is delivered to the two-phase stock liquid the continuous mixing reactor in microchannel that channel size is 105 μ m simultaneously, and each phase fluid component by even differential, contacts fast chemical combination and forms calcium phosphate aggregate colloidal sol in the microchannel;
4. reaction product mixture calcium phosphate aggregate colloidal sol is delivered to washing/dehydrating device, the washing secondary, ethanol is washed once, in 60 ℃ of vacuum-dryings to constant weight, obtains calcium phosphate powder.
Technical process serialization of the present invention is high, and process is accurately controlled, and phase is controlled, is easy to stably produce.This non-crystalline state, crystallite attitude and heterogeneous calcium phosphate powder are expected to be applied to the fields such as biomedical material, orthopaedics repair materials, cosmetic, beauty and shaping material and nutrient calcium supplementing agent.
Claims (10)
1. the preparation method of a calcium phosphate is characterized in that concrete steps are as follows:
1) stock liquid preparation: calcium containing compound, 3 kinds of preparation of raw material of P contained compound and trolamine are become A phase clear liquid and B clear liquid mutually, take the concentration of water as the above solution of solvent adjustment, with A phase clear liquid and B mutually clear liquid be contained in respectively in two head tanks; Described A phase clear liquid is that at least a kind of preparation of raw material in above-mentioned 3 kinds of raw materials forms, and described B phase clear liquid is that at least a kind of preparation of raw material in above-mentioned 3 kinds of raw materials forms; Described A phase clear liquid and the B final raw material of clear liquid preparation mutually always plant number and must all contain above-mentioned 3 kinds of raw materials; The calcium phosphorus mol ratio of whole system is: (F
A* C
A-Ca+ F
B* C
B-Ca)/(F
A* C
A-P+ F
B* C
B-P)=1.0～2.0; Two-phase total flux: F
A+ F
B=10～5000mL/min, wherein, F
ABe the A phase flow rate, unit is mL/min; F
BBe the B phase flow rate, unit is mL/min; C
A-CaFor A mutually in the concentration of calcium containing compound, unit is M; C
B-CaFor B mutually in the concentration of calcium containing compound, unit is M; C
A-PFor A mutually in the concentration of P contained compound, unit is M; C
B-PFor B mutually in the concentration of P contained compound, unit is M;
2) by the volume pump of source material delivery system (lay the groundwork for later quoting) by the road with the A phase clear liquid in step 1) and B mutually clear liquid be delivered to the microchannel continuous mixing system, make each phase fluid component by even differential, the reaction of serialization integration forms the calcium phosphate aggregate;
3) with step 2) the calcium phosphate aggregate that obtains, be transported to temperature elevation system;
4) enter heat-insulation system;
5) enter again cooling system;
6) reaction product after the cooling is transported to the dehydration washing device, and the product after washing is carried out drying, obtains product nano-calcium phosphate particle powder.
2. a kind of preparation method of calcium phosphate as claimed in claim 1, is characterized in that in step 1) the concentration C of described calcium containing compound
CaBe 0.01～5M; The concentration C of P contained compound
PBe 0.01～5M; The mol ratio of the add-on of described trolamine and the add-on of calcium ion is 0.1～10.
3. a kind of preparation method of calcium phosphate as claimed in claim 1, is characterized in that in step 1), and the temperature of described preparation of raw material process is 15～50 ℃.
4. a kind of preparation method of calcium phosphate as claimed in claim 1, it is characterized in that in step 2) in, described volume pump by source material delivery system with the A phase clear liquid in step 1) and B mutually clear liquid be delivered to the microchannel continuous mixing system be under 15～50 ℃ of envrionment conditionss the volume pump by source material delivery system with the A phase clear liquid in step 1) and B mutually clear liquid steadily be delivered to the microchannel continuous mixing system simultaneously.
5. a kind of preparation method of calcium phosphate as claimed in claim 1, is characterized in that in step 2) in, described microchannel is of a size of 10～200 μ m.
6. a kind of preparation method of calcium phosphate as claimed in claim 1, is characterized in that in step 2) in, the flow reproducibility error of described volume pump is best≤1%, pressure range can be 14.5～1450psi, pressure pulse can≤29psi; The material of pipeline can adopt 316 stainless steels, 316L stainless steel or meet the stainless steel tube of ASTM A269 or equivalent standard, and internal diameter can be 1/16～1 inch, operating pressure can 〉=6000psi.
7. a kind of preparation method of calcium phosphate as claimed in claim 1, is characterized in that in step 3) described temperature elevation system rises to 100～300 ℃ with temperature from room temperature through heat exchange in 0.5～10s.
8. a kind of preparation method of calcium phosphate as claimed in claim 1, is characterized in that in step 4), and described heat-insulation system is realized 100～300 ℃ of constant temperature, and soaking time is 1～30min.
9. a kind of preparation method of calcium phosphate as claimed in claim 1, is characterized in that in step 5), and described cooling system is realized in 0.5～10s the temperature of mix products is cooled to 0～90 ℃ from 100～300 ℃ through heat exchange; Pressure-controlling in whole system is before this realized regulating by back pressure apparatus, and the system pressure regulation range is 14.5～1450psi.
10. a kind of preparation method of calcium phosphate as claimed in claim 1, is characterized in that in step 6), described dry adopt conventional oven dry, lyophilize, spraying drying or vacuum-drying; The phase composition of described product calcium phosphate can be: one or more phase complex bodys in noncrystal calcium phosphate, monocalcium phosphate, calcium monohydrogenphosphate, Calcium Pyrophosphate, tricalcium phosphate, calcium phosphate eight calcium, calcium-deficient apatite and hydroxyapatite.
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| CN104860284A (en) * | 2014-10-11 | 2015-08-26 | 北京大学口腔医学院 | Preparation method for amorphous calcium phosphate nanospheres |
| CN105883742A (en) * | 2016-04-08 | 2016-08-24 | 武汉理工大学 | Preparation method of nano beta-tricalcium phosphate |
| CN106882778A (en) * | 2015-12-15 | 2017-06-23 | 中国科学院大连化学物理研究所 | A kind of method that toothpaste grade calcium hydrophosphate is prepared in micro passage reaction |
| CN111704120A (en) * | 2020-06-18 | 2020-09-25 | 湖南御家化妆品制造有限公司 | Microfluidic-based controllable preparation method of modified hydroxyapatite powder and hydroxyapatite nanoparticles |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104860284A (en) * | 2014-10-11 | 2015-08-26 | 北京大学口腔医学院 | Preparation method for amorphous calcium phosphate nanospheres |
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| CN106882778A (en) * | 2015-12-15 | 2017-06-23 | 中国科学院大连化学物理研究所 | A kind of method that toothpaste grade calcium hydrophosphate is prepared in micro passage reaction |
| CN105883742A (en) * | 2016-04-08 | 2016-08-24 | 武汉理工大学 | Preparation method of nano beta-tricalcium phosphate |
| CN111704120A (en) * | 2020-06-18 | 2020-09-25 | 湖南御家化妆品制造有限公司 | Microfluidic-based controllable preparation method of modified hydroxyapatite powder and hydroxyapatite nanoparticles |
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