CN103159198B - Preparation method of calcium phosphate - Google Patents
Preparation method of calcium phosphate Download PDFInfo
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- CN103159198B CN103159198B CN201310121559.5A CN201310121559A CN103159198B CN 103159198 B CN103159198 B CN 103159198B CN 201310121559 A CN201310121559 A CN 201310121559A CN 103159198 B CN103159198 B CN 103159198B
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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 of a kind of calcium phosphate based on differential reaction technology.
Background technology
Calcium phosphate has more excellent 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 with nitrocalcite and Secondary ammonium phosphate and urea for raw material, multitone chemical generator is utilized to carry out sonochemistry synthesis, suspension filtered, washing, vacuum-drying are obtained nano hydroxyapatite powder, and obtained hydroxy apatite powder granularity is little, uniform particle sizes, soilless sticking occur, because synthesis temperature (40 ~ 80 DEG C) is relatively low, therefore phase degree of crystallinity is high not enough, and need specific installation multitone chemical generator.
Chinese patent 200610055171.X adopts water miscible macromolecular compound polyvinylpyrrolidone (PVP) to be template, with nitrocalcite and ammonium phosphate for raw material, 7 days are left standstill under 25 DEG C of ambient room temperature, by the washing of gained throw out, suction filtration, be drying to obtain the nanocrystalline product of spherical hydroxyapatite, the method needs long ageing, production cycle is longer, and operation is loaded down with trivial details, is unfavorable for realizing serialization industrial production.
Chinese patent 03142004.4 and journal article " Journal of Inorganic Materials ", 2004,19 (01): the 234-238. preparation methods all reporting a kind of amorphous nano-calcium phosphate, the lower scope of synthesis temperature of these class methods is 0 ~ 20 DEG C, limit its synthesis application at room temperature or higher temperature, energy consumption for lowering the temperature is higher, and synthesis cycle is longer.
Chinese patent 201110263963.7 discloses a kind of synthetic method of amorphous calcium phosphate, synthesizes under 0 DEG C of ultrasound environments, therefore cannot realize at room temperature synthesizing.In addition, need to increase special ultrasonic device, and generated time is longer, is unfavorable for producing in enormous quantities.
The multiple calcium phosphate of current discovery is according to different chemical metering .Angewandte Chemie-International Edition such as (, 2002,41 (17): 3130-3146) Dorozhkin SV more as shown in table 1 than classification.
Table 1
Current research shows, heterogeneous calcium phosphate, wherein comprise hydroxyapatite (HA) and tricalcium phosphate (TCP) two-phase formation, because the inorganic components of its composition and human body hard tissue is basically identical, and combine the biocompatibility of the excellence of HA and the biological degradability of TCP.In addition, also have the complex body etc. of type alpha tricalcium phosphate and bata-tricalcium phosphate, in bone tissue restoration, all show excellent consistency and degradation property.
With statistical mechanics and quantum mechanics to the research of energy variation in reaction process for foundation, think and define the higher activated complex of potential energy between reactant to resultant, the state residing for activated complex is called transition state.Chemical reaction inherently sees it is rearrange combination between atom, and in the process, the potential energy of system reduces, and the reaction made can go on.Chemical reaction is not just can be completed by the simple collision of reactant molecule, but in the process of reactant to resultant, have passed through the transition state of a higher-energy.Its reaction scheme model is as follows: A+BC [A...B...C] ≠ → AB+C.
The research of microminiaturized multiplexer part shows, in differential reactive system, because the characteristic dimension of passage is at micron order, along with the reduction of yardstick, thermograde, pressure gradient, concentration gradient and density gradient etc. increase very soon, to the increase of mass transfer, driving force of heat transfer be caused, thus shorten diffusion length, expand the diffusion flux of unit volume or unit surface.Large more than 10 times of ratio of heat transfer coefficient usual heat exchanger, mixing time can narrow down to the even micro-s magnitude of milli s, and transformation efficiency, controllability and the conversion rate of reacting is significantly improved.
Microreactor has the unrivaled superiority of conventional apparatus:
1, little, the quality of equipment requisite space and consuming little energy and the corresponding time short, improve the security of equipment and the controllability of reaction process.
What 2, differential reaction technology was mainly strengthened is transmission characteristic, and linear content is contracted to micron order, contact gear ratio surface-area increases and volume reduces, and is to quality and the strengthening of heat transfer process and the improvement of fluid-flow mode.
3, throughput is amplified easily, and differential conversion unit replaces device geometry to amplify by number amplification flexibly, ensures that the essential property of each parallel units is consistent, realizes stably producing of product.
4, achievement in research can be rapidly converted into productivity, and low cost realizes industrialization and mass-producing.
Summary of the invention
The present invention aims to provide and can serialization stably produce, and desired raw material is simple, and reaction conditions gentleness is controlled, with short production cycle, the preparation method of a kind of calcium phosphate of product qualities stable homogeneous.
Concrete steps of the present invention are as follows:
1) stock liquid preparation: calcium containing compound, P contained compound and trolamine 3 kinds of preparation of raw material are become A phase clear liquid and B phase clear liquid, take water as the concentration of the above solution of solvent adjustment, A phase clear liquid and B phase clear liquid are contained in two head tanks respectively; 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; Number always planted by the final raw material of described A phase clear liquid and the preparation of B phase clear liquid all must 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
afor A phase flow rate, unit is mL/min; F
bfor B phase flow rate, unit is mL/min; C
a-Cafor the concentration of calcium containing compound in A phase, unit is M; C
b-Cafor the concentration of calcium containing compound in B phase, unit is M; C
a-Pfor the concentration of P contained compound in A phase, unit is M; C
b-Pfor the concentration of P contained compound in B phase, unit is M;
2) by the road the A phase clear liquid in step 1) and B phase clear liquid are delivered to microchannel continuous mixing system by the volume pump of source material delivery system, make each phase fluid component by homogeneous differential, the reaction of serialization integration forms calcium phosphate aggregate;
3) by step 2) the calcium phosphate aggregate that obtains, be transported to temperature elevation system;
4) heat-insulation system is entered;
5) cooling system is entered again;
6) reaction product after cooling is transported to dehydration washing device, and the product after washing is carried out drying, obtains 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 DEG C; Described A phase clear liquid or B phase clear liquid are transition state complex compound, can place and within least 1 month, not occur precipitation or suspended substance;
In step 2) in, the A phase clear liquid in step 1) and B phase clear liquid are delivered to microchannel continuous mixing system by the described volume pump by source material delivery system can steadily be delivered to microchannel continuous mixing system by the volume pump of source material delivery system by the A phase clear liquid in step 1) and B phase clear liquid under 15 ~ 50 DEG C of envrionment conditionss simultaneously; The size of described microchannel can be 10 ~ 200 μm; 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 DEG C by temperature from room temperature through heat exchange in 0.5 ~ 10s.
In step 4), described heat-insulation system realizes constant temperature 100 ~ 300 DEG C, and soaking time is 1 ~ 30min.
In step 5), described cooling system, can be implemented in 0.5 ~ 10s through heat exchange and the temperature of mix products is cooled to 0 ~ 90 DEG C from 100 ~ 300 DEG C; Pressure-controlling in whole system is before this realized regulating by back pressure apparatus, and system pressure regulation range is 14.5 ~ 1450psi.
In step 6), described drying can adopt conventional oven dry, lyophilize, spraying dry or vacuum-drying etc.
The thing phase composite of product phosphoric acid calcium can be: one or more thing 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 there will be local solubility too high, causes mass-and heat-transfer inequality to have, the transformation efficiency of impact reaction and the consistence of quality.Microring array reaction technology is the key that product of the present invention stablizes reproduction, is compared to traditional stirred autoclave, overcomes the difference that product exists purity, pattern, size and distribution between different batches.The microring array flow reactor that the present invention relates to is a kind of multilayer microring array structure (Multilamination), dispersed phase fluid is injected by homogeneous differential, fluid constantly separates repolymerization, by the physique of micro mixing-reactor, fluid well-distributing differential to be mixed is become n thin layer, and make its brought into interactive contact, according to Fick law, diffusion time will be reduced to: t ~ d
2/ (n
2× D).In formula, t is mixing time; The micro-diffusion characteristic yardstick of d; N is thin layer quantity; D is spread coefficient.
When fluid to be mixed is in same microchannel, along with the reduction of yardstick, thermograde, pressure gradient, concentration gradient and density gradient etc. increase very soon, the increase of mass transfer, driving force of heat transfer will be caused, thus shorten molecular diffusion distance, expand the diffusion flux of unit volume or unit surface.Therefore rely on molecular diffusion just can (milli s to micro-s level) realize Homogeneous phase mixing and complete chemical reaction within the extremely short time, the transformation efficiency of reaction, controllability and conversion rate are significantly improved, reaches the effect that micromixing does not have.
Transition state theory(TST) is thought, need through a transition state from reactant to product, in this transition state, reactant part scission of link, product section Cheng Jian, is referred to as transition state complex compound, it is not the intermediate of a stable material or a reaction, and be only by reactant to the stage of in the continuous transition of product, its energy is the extreme point in potential energy surface, and the energy difference of itself and reactant reacts the potential barrier that must overcome.Chemical reaction is not just can be completed by the simple collision of reactant molecule, but in the process of reactant to resultant, have 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 complex compound medium, it has enough spatial flexibility, lone-pair electron on lone-pair electron on N and three-OH make four ligating atoms on a molecule all can to Ca ligand complex, and each chelate ring is five-ring (Ca ← HO-CH
2-CH
2-N → Ca) form co-ordination complex.What make that calcium ion can be more stable is present in transition state complex compound, reduce the energy barrier that reaction forms final product on the one hand, on the other hand the synthesis of existence to amorphous state calcium phosphate of trolamine serves sterically hindered stabilising effect, thus solves noncrystal calcium phosphate is difficult to stable synthesis problem in room temperature or comparatively high temps.
The present invention is containing trolamine (N (CH
2cH
2oH)
3tEA) in the transition state complex system formed, the solution such as calcium ion, phosphate anion is made to realize the differential contacts combination reaction of each phase fluid component by the continuous mixing reactor in microchannel, mass transfer in consolidation system and heat transfer process, form calcium phosphate aggregate fast, then through being rapidly heated, being incubated and fast cooling, through washing, dehydration, dry, obtain the calcium phosphate powder that stay in grade is homogeneous.
The present invention has following outstanding advantages:
1) process adopts the continuous mixing reactor in microchannel, carries out differential refinement, greatly shortens molecular diffusion distance, realize mass-and heat-transfer equably on the microscale level, enhancing mixed kinetics to each phase fluid component, ensures that the stable of the finished product can reappear;
2) by introducing trolamine as complex compound medium, raw material is made to be in the comparatively steady state of transition state complex compound, the stable synthesis of (15 ~ 50 DEG C) calcium phosphate powder under realizing normal temperature or comparatively high temps, particularly solves the difficult problem that non-crystalline state calcium phosphate under this envrionment temperature is difficult to synthesize;
3) adopt preparation technology of the present invention, one of product of calcium phosphate nanometer hydroxyapatite, not only thing phase purity is high, and degree of crystallinity is high, and size range is controlled at 10 ~ 300nm, even particle size distribution;
4) adopt preparation technology of the present invention, obtain the nanometer hydroxyapatite of two ends indent unique morphology first;
5) the controlled heterogeneous calcium-phosphate product of ratio can be obtained by 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.) and carrys out adjust ph, reduces impurity, improves product purity;
7) technical process serialization of the present invention is high, and process controllable precise is with short production cycle, can realize stably producing of calcium phosphate product.
Accompanying drawing explanation
Fig. 1 is nanometer hydroxyapatite transmission electron microscope (TEM) picture.In FIG, scale is 100nm.
Fig. 2 is the TEM picture of the special rod-like morphology nanometer hydroxyapatite partial enlargement that inward at both ends is recessed.In fig. 2, scale is 50nm.
Fig. 3 is nanometer hydroxyapatite size distribution.In figure 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 the diagram, X-coordinate is diffraction angle (°), and ordinate zou is relative intensity (a.u.).
Fig. 5 is the XRD analysis result of nanometer hydroxyapatite after 1150 DEG C of pyroprocessing.In Figure 5, X-coordinate is diffraction angle (°), and ordinate zou is relative intensity (a.u.).
Fig. 6 is non-crystalline state calcium phosphate XRD analysis result.In figure 6, X-coordinate is diffraction angle (°), and 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 the figure 7, scale is 51nm.
Fig. 8 is the XRD analysis result of non-crystalline state calcium phosphate after 700 DEG C of process.In fig. 8, X-coordinate is diffraction angle (°), and ordinate zou is relative intensity (a.u.).
Fig. 9 is the XRD analysis result of non-crystalline state calcium phosphate after 950 DEG C of process.In fig .9, X-coordinate is diffraction angle (°), and ordinate zou is relative intensity (a.u.).
Figure 10 is the XRD analysis result of the heterogeneous calcium phosphate of α-TCP/ β-TCP.In Fig. 10, X-coordinate is diffraction angle (°), and ordinate zou is relative intensity (a.u.).
Figure 11 is the XRD analysis result of the heterogeneous calcium phosphate of HA/ β-TCP.In fig. 11, X-coordinate is diffraction angle (°), and ordinate zou is relative intensity (a.u.).
Figure 12 is the XRD analysis result of the heterogeneous calcium phosphate of β-TCP/ β-CDP.In fig. 12, X-coordinate is diffraction angle (°), and ordinate zou is relative intensity (a.u.).
Embodiment
Embodiment 1
Prepared by 1.A phase stock liquid, for the nitrocalcite of 0.2M and the triethanolamine solution of 1M mix;
Prepared by 2.B phase stock liquid, be the disodium phosphate soln of 0.12M;
3. by the backpressure regulation of closed system to 2.2MPa, the flow F of A phase stock liquid transferpump is set
athe flow F of=75mL/min, B phase stock liquid transferpump
b=75mL/min;
4. run two-phase transferpump, two-phase stock liquid is delivered to the continuous mixing reactor in microchannel that channel size is 105 μm simultaneously, carries out Homogeneous phase mixing reaction;
5. by mix products through the heat exchanger that is rapidly heated, make system temperature reach 145 DEG C;
6. enter 145 DEG C of constant temperature 6s, be delivered to fast cooling interchanger, make system temperature drop to 25 DEG C;
7. the reaction product after cooling is delivered to washing/dehydrating device, washing secondary, and ethanol is washed once;
8. the product after dehydration washing to constant weight, obtains nano-calcium phosphate granular powder through 80 DEG C of vacuum-dryings.
Microscopic appearance can find out the length 100 ~ 200nm of nanoparticle from the partial enlargement transmission electron microscope photo of Fig. 1 and Fig. 2, width 60 ~ 80nm, pattern is the special rod-like morphology that inward at both ends is recessed, this structure contributes to the specific surface area performance improving nanoparticle, be expected to be applied to pharmaceutical carrier, be about 141.8nm from the known nano particle median size of size distribution Fig. 3 in addition, and normal distribution is even.The particle powder XRD analysis of being collected by Fig. 4 its thing known is mutually for pure ha phase (JCPDS:09-0432) is without other dephasigns.For verifying high-temperature stability and the thing phase purity of product, 1150 DEG C of isothermal holding 2h are carried out to it, Fig. 5 is pyroprocessing product X RD analytical results is high-crystallinity, and highly purified hydroxyapatite without other dephasigns, thus also confirms that ratio of calcium and phosphorus is that approximate stoichiometry is than 1.67.
Embodiment 2
Prepared by 1.A phase stock liquid, for the nitrocalcite of 0.2M and the triethanolamine solution of 1M mix;
Prepared by 2.B phase stock liquid, be the disodium phosphate soln of 0.12M;
3. the flow F of A phase stock liquid transferpump is set
athe flow F of=75mL/min, B phase stock liquid transferpump
b=75mL/min, under normal pressure 25 DEG C of room temperature environments, is delivered to the continuous mixing reactor in microchannel that channel size is 105 μm simultaneously by two-phase stock liquid, each phase fluid component is by homogeneous differential in microchannel, and Rapid contact chemical combination forms calcium phosphate aggregate colloidal sol;
4. reaction product mixture calcium phosphate aggregate colloidal sol is delivered to washing/dehydrating device, washing secondary, ethanol is washed once, in 60 DEG C of vacuum-dryings to constant weight, obtains calcium phosphate powder.
X-ray powder diffraction analytical results, as Fig. 6, is typical non-crystalline state calcium phosphate diffuse peaks.Fig. 7, by the selected diffraction analysis of transmission electron microscope, determines that it is non-crystalline state calcium phosphate further.By non-crystalline state calcium phosphate powder in 700 DEG C of insulation 2h, XRD things be α-TCP(JCPDS:09-0348 mutually), as shown in Figure 8, to prepare this method energy consumption of α-TCP lower for 1300 DEG C of high temperature sinterings relatively in the past.It is β-TCP(JCPDS:09-0169 mutually that this non-crystalline state calcium phosphate powder is incubated 2h, XRD things in 950 DEG C), as shown in Figure 9.It is the heterogeneous calcium phosphate of α-TCP/ β-TCP mutually that this non-crystalline state calcium phosphate powder is incubated 2h, XRD things in 800 DEG C, as shown in Figure 10.By accurately controlling sintering temperature and time, can regulate and control each phase content ratio in the heterogeneous calcium phosphate of α-TCP/ β-TCP.
Embodiment 3
Prepared by 1.A phase stock liquid, for the nitrocalcite of 0.19M and the triethanolamine solution of 1M mix;
Prepared by 2.B phase stock liquid, be the disodium phosphate soln of 0.12M;
3. by the backpressure regulation of closed system to 2.2MPa, the flow F of A phase stock liquid transferpump is set
athe flow F of=75mL/min, B phase stock liquid transferpump
b=75mL/min;
4. run two-phase transferpump, two-phase stock liquid is delivered to the continuous mixing reactor in microchannel that channel size is 105 μm simultaneously, carries out Homogeneous phase mixing reaction;
5. by mix products through the heat exchanger that is rapidly heated, make system temperature reach 100 DEG C;
6. enter 100 DEG C of constant temperature 6s, be delivered to fast cooling interchanger, make system temperature drop to 25 DEG C;
7. the reaction product after cooling is delivered to washing/dehydrating device, washing secondary, and ethanol is washed once;
8. gained powder to constant weight through 80 DEG C of vacuum-dryings, is then carried out 950 DEG C of insulation 2h, obtains the heterogeneous calcium phosphate of HA/ β-TCP by the product after dehydration washing.
As shown in figure 11, in same spectrogram, there is the characteristic peak of HA and β-TCP in the sample X-ray powder diffraction analytical results after pyroprocessing simultaneously.
Embodiment 4
Prepared by 1.A phase stock liquid, containing the nitrocalcite of 1M and the phosphoric acid solution of 0.6M;
Prepared by 2.B phase stock liquid, containing the triethanolamine solution of 2M;
3. the flow F of A phase stock liquid transferpump is set
athe flow F of=50mL/min, B phase stock liquid transferpump
b=125mL/min, under 30 DEG C of environment, is delivered to the continuous mixing reactor in microchannel that channel size is 200 μm simultaneously by two-phase stock liquid, each phase fluid component is by homogeneous differential in microchannel, and Rapid contact chemical combination forms calcium phosphate aggregate colloidal sol;
4. reaction product mixture calcium phosphate aggregate colloidal sol is delivered to washing/dehydrating device, washing secondary, ethanol is washed once, in 60 DEG C of vacuum-dryings to constant weight, obtain calcium phosphate powder, then gained powder is carried out 950 DEG C of insulation 2h, obtain the heterogeneous calcium phosphate of β-TCP/ β-CDP, as shown in figure 12.
Embodiment 5
Prepared by 1.A phase stock liquid, be the calcium nitrate aqueous solution of 0.1M;
Prepared by 2.B phase stock liquid, for the phosphoric acid of 0.06M and the triethanolamine solution of 0.2M mix;
3. by the backpressure regulation of closed system to 9MPa, the flow F of A phase stock liquid transferpump is set
athe flow F of=50mL/min, B phase stock liquid transferpump
b=50mL/min;
4. run two-phase transferpump, two-phase stock liquid is delivered to the continuous mixing reactor in microchannel that channel size is 105 μm simultaneously, carries out Homogeneous phase mixing reaction;
5. by mix products through the heat exchanger that is rapidly heated, make system temperature reach 300 DEG C;
6. enter 300 DEG C of constant temperature 6s, be delivered to fast cooling interchanger, make system temperature drop to 25 DEG C;
7. the reaction product after cooling is delivered to washing/dehydrating device, washing secondary, and ethanol is washed once;
8. the product after dehydration washing to constant weight, obtains nano-calcium phosphate granular powder through 80 DEG C of vacuum-dryings.
Embodiment 6
Prepared by 1.A phase stock liquid, containing the nitrocalcite of 0.2M and the triethanolamine solution of 2.666M;
Prepared by 2.B phase stock liquid, containing the disodium phosphate soln of 0.12M;
3. the flow F of A phase stock liquid transferpump is set
athe flow F of=10mL/min, B phase stock liquid transferpump
b=10mL/min, under 50 DEG C of environment, is delivered to the continuous mixing reactor in microchannel that channel size is 10 μm simultaneously by two-phase stock liquid, each phase fluid component is by homogeneous differential in microchannel, and Rapid contact chemical combination forms calcium phosphate aggregate colloidal sol;
4. reaction product mixture calcium phosphate aggregate colloidal sol is delivered to washing/dehydrating device, washing secondary, ethanol is washed once, in 90 DEG C of vacuum-dryings to constant weight, obtains calcium phosphate powder.
Embodiment 7
Prepared by 1.A phase stock liquid, containing the calcium acetate of 0.6M and the triethanolamine solution of 1.8M;
Prepared by 2.B phase stock liquid, containing 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
athe flow F of=100mL/min, B phase stock liquid transferpump
b=100mL/min, under normal pressure 25 DEG C of room temperature environments, two-phase stock liquid is delivered to simultaneously the continuous mixing reactor in microchannel that channel size is 105 μm, each phase fluid component is by homogeneous differential in microchannel, and Rapid contact chemical combination forms calcium phosphate aggregate colloidal sol;
4. reaction product mixture calcium phosphate aggregate colloidal sol is delivered to washing/dehydrating device, washing secondary, ethanol is washed once, in 60 DEG C of vacuum-dryings to constant weight, obtains non-crystalline state calcium phosphate powder.
Embodiment 8
Prepared by 1.A phase stock liquid, containing the nitrocalcite of 5M and the phosphoric acid solution of 3M;
Prepared by 2.B phase stock liquid, containing the triethanolamine solution of 5M;
3. the flow F of A phase stock liquid transferpump is set
athe flow F of=50mL/min, B phase stock liquid transferpump
b=150mL/min, under 25 DEG C of environment, is delivered to the continuous mixing reactor in microchannel that channel size is 105 μm simultaneously by two-phase stock liquid, each phase fluid component is by homogeneous differential in microchannel, and Rapid contact chemical combination forms calcium phosphate aggregate colloidal sol;
4. reaction product mixture calcium phosphate aggregate colloidal sol is delivered to washing/dehydrating device, washing secondary, ethanol is washed once, in 60 DEG C of vacuum-dryings to constant weight, obtains calcium phosphate powder.
Technical process serialization of the present invention is high, and process accurately controls, and thing is mutually controlled, is easy to stably produce.This non-crystalline state, crystallite state 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 (9)
1. a preparation method for calcium phosphate, is characterized in that concrete steps are as follows:
1) stock liquid preparation: calcium containing compound, P contained compound and trolamine 3 kinds of preparation of raw material are become A phase clear liquid and B phase clear liquid, take water as the concentration of the above solution of solvent adjustment, A phase clear liquid and B phase clear liquid are contained in two head tanks respectively; 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; Number always planted by the final raw material of described A phase clear liquid and the preparation of B phase clear liquid all must 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
afor A phase flow rate, unit is mL/min; F
bfor B phase flow rate, unit is mL/min; C
a-Cafor the concentration of calcium containing compound in A phase, unit is M; C
b-Cafor the concentration of calcium containing compound in B phase, unit is M; C
a-Pfor the concentration of P contained compound in A phase, unit is M; C
b-Pfor the concentration of P contained compound in B phase, unit is M; 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;
2) by the volume pump of source material delivery system by the road by step 1) in A phase clear liquid and B phase clear liquid be delivered to microchannel continuous mixing system, make each phase fluid component by homogeneous differential, the reaction of serialization integration forms calcium phosphate aggregate;
3) by step 2) the calcium phosphate aggregate that obtains, be transported to temperature elevation system;
4) heat-insulation system is entered;
5) cooling system is entered again;
6) reaction product after cooling is transported to dehydration washing device, and the product after washing is carried out drying, obtains product nano calcium phosphate granules powder.
2. the preparation method of a kind of calcium phosphate as claimed in claim 1, is characterized in that in step 1) in, the temperature of described preparation of raw material process is 15 ~ 50 DEG C.
3. the preparation method of a kind of calcium phosphate as claimed in claim 1, it is characterized in that in step 2) in, the described volume pump by source material delivery system is by step 1) in A phase clear liquid and B phase clear liquid be delivered to microchannel continuous mixing system be under 15 ~ 50 DEG C of envrionment conditionss by the volume pump of source material delivery system by step 1) in A phase clear liquid and B phase clear liquid be simultaneously steadily delivered to microchannel continuous mixing system.
4. the preparation method of a kind 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 μm.
5. the preparation method of a kind of calcium phosphate as claimed in claim 1, is characterized in that in step 2) in, flow reproducibility error≤1% of described volume pump, pressure range is 14.5 ~ 1450psi, pressure pulse≤29psi; The material of pipeline adopts 316 stainless steels, 316L stainless steel or meets the stainless steel tube of ASTM A269 or equivalent standard, and internal diameter is 1/16 ~ 1 inch, operating pressure >=6000psi.
6. the preparation method of a kind of calcium phosphate as claimed in claim 1, is characterized in that in step 3) in, described temperature elevation system, rises to 100 ~ 300 DEG C by temperature from room temperature through heat exchange in 0.5 ~ 10s.
7. the preparation method of a kind of calcium phosphate as claimed in claim 1, is characterized in that in step 4) in, described heat-insulation system realizes constant temperature 100 ~ 300 DEG C, and soaking time is 1 ~ 30min.
8. the preparation method of a kind of calcium phosphate as claimed in claim 1, is characterized in that in step 5) in, described cooling system, realizes, in 0.5 ~ 10s, the temperature of mix products is cooled to 0 ~ 90 DEG C from 100 ~ 300 DEG C through heat exchange; Pressure-controlling in whole system is before this realized regulating by back pressure apparatus, and system pressure regulation range is 14.5 ~ 1450psi.
9. the preparation method of a kind of calcium phosphate as claimed in claim 1, is characterized in that in step 6) in, described drying adopts conventional oven dry, lyophilize, spraying dry or vacuum-drying; The thing phase composite of described product phosphoric acid calcium is: one or more thing 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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| 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 |
| CN105883742B (en) * | 2016-04-08 | 2018-04-27 | 武汉理工大学 | A kind of preparation method of nano-β-tricalcium phosphate |
| CN111704120B (en) * | 2020-06-18 | 2022-03-01 | 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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