WO2017082811A1 - Procédé de fabrication de particules sphériques constituées de phosphate et de calcium - Google Patents

Procédé de fabrication de particules sphériques constituées de phosphate et de calcium Download PDF

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WO2017082811A1
WO2017082811A1 PCT/SE2016/051121 SE2016051121W WO2017082811A1 WO 2017082811 A1 WO2017082811 A1 WO 2017082811A1 SE 2016051121 W SE2016051121 W SE 2016051121W WO 2017082811 A1 WO2017082811 A1 WO 2017082811A1
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Prior art keywords
particles
ions
phosphate
solution
weight
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Inventor
Torbjörn MELLGREN
Wei Xia
Erik UNOSSON
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PSILOX AB
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PSILOX AB
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B25/00—Phosphorus; Compounds thereof
    • C01B25/16—Oxyacids of phosphorus; Salts thereof
    • C01B25/26—Phosphates
    • C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0241—Containing particulates characterized by their shape and/or structure
    • A61K8/025—Explicitly spheroidal or spherical shape
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0241—Containing particulates characterized by their shape and/or structure
    • A61K8/0279—Porous; Hollow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/24—Phosphorous; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns

Definitions

  • the present invention relates to an improved method of producing spherical calcium phosphate particles containing magnesium.
  • the invention further relates to a
  • composition comprising said particles and its use in dental and medical applications.
  • CaP Calcium phosphates
  • Caio(P04) 6(OH) 2 hydroxyapatite
  • HA hydroxyapatite
  • Resorbable micro- or nanoparticles i.e. particles that can be dissolved in vivo
  • bone void fillers such as bone void fillers, drug delivery vehicles, desensitization agents of dentinal tubules, etc.
  • CaP particles can influence their properties in above-mentioned applications. Particles with spherical shape and large pore volume are good candidates for drug delivery vehicles, protein and ion adsorption, and bone and teeth fillers. Hence, they have recently attracted increased attention. CaP, such as HA, spontaneously grow like flakes, fibers or rods by wet chemical methods. Spherical CaP has previously been prepared using structure directing agents, such as ion substituents, surfactants and biomolecules.
  • a present inventor showed in WO2011/016772 that strontium ions affected the morphology of CaP to form hollow spheres, and showed further in WO2014/148997 that CaP hollow spheres can also be formed in the absence of strontium ions. But there still exists a need for a more efficient method of preparing hollow spherical CaP particles.
  • the object of the present invention is to provide CaP particles that are essentially spherical, and porous, and a method of preparing said particles.
  • the method of the present invention is simpler, faster, more cost effective, and results in a higher particle yield per unit volume mixture than methods disclosed by prior art
  • the present invention relates to a spherical particle wherein the particle comprises 40-70 weight% such as 50-65 weight% of calcium, 20-40weight% such as 25- 40 weight% of phosphate and 5-30 weight% magnesium, and wherein the Ca/P molar ratio is in the range of 1.10 to 1.90, and wherein the particle size is less than 1 ⁇ , preferably less than 600nm.
  • the present invention relates to a method of preparing the particles according to the present invention wherein the method comprises:
  • aqueous buffer solution of purified water having a pH of 2 to 10 comprising sodium, potassium and phosphate ions, wherein the concentration of said ions are 100 to 400 mM for sodium, 0-10 mM for potassium and 8-25mM such as 12-25 mM for phosphate;
  • step b) heating the mixture of step b) at 60 to 120° C for at least 2 minutes;
  • the present invention relates to a bleaching chewing gum comprising particles according to the present invention and a paste forming compound, and wherein the particles further comprises a bleaching agent such as a peroxide.
  • the present invention relates to particles obtained from the method of the present invention.
  • the present invention relates to a chewing gum comprising the particles or the composition according to the present invention.
  • the present invention relates to a composition
  • a composition comprising spherical particles and, a paste forming compound; wherein the particles comprises 40-70 weight% such as 50-65 weight% of calcium, 20-40weight% such as 25-40 weight% of phosphate and 5-30 weight% magnesium, and wherein the Ca/P weight ratio is in the range of 1.10 to 1.90, and wherein the particle size is less than ⁇ preferably less than 600 nm.
  • FIGURES Figure 1. SEM image of calcium phosphate hollow spheres. Figure 2. SEM image of calcium phosphate hollow spheres. Figure 3. SEM image of calcium phosphate hollow spheres. Figure 4. SEM image of calcium phosphate particles.
  • FIG. 5 SEM image of calcium phosphate hollow spheres.
  • Figure 6. SEM image of calcium phosphate hollow spheres.
  • Figure 7 SEM image of calcium phosphate hollow spheres.
  • Figure 8 SEM image of calcium phosphate hollow spheres.
  • Figure 9 SEM image of calcium phosphate hollow spheres.
  • Figure 10 SEM image of calcium phosphate hollow spheres.
  • FIG 11 Illustration of continuous mode process for synthesis of calcium phosphate hollow spheres.
  • Figure 12 SEM image of calcium phosphate hollow spheres.
  • Figure 13 SEM image of calcium phosphate hollow spheres.
  • Figure 14 SEM image of calcium phosphate hollow spheres.
  • paste forming compound relates to compounds that may be mixed with the particles of the present invention to make a paste.
  • the paste forming compound increases the viscosity of the mixture when added to the particles.
  • Non-limiting examples of paste forming compounds are glycerol, polyethylene glycol, polyvinyl alcohol and polysaccharides such as cellulose, hyaluronan and chitosan.
  • the chemical formula for stoichiometric hydroxyapatite (HA) is Caio(P04) 6(OH) 2, but for the purpose of this application many variations can be used.
  • the present invention is mainly described in terms calcium phosphates (CaP), which includes but is not limited to: ⁇ -tricalcium phosphate ( ⁇ -TCP) dicalcium phosphate dihydrate (DCPD), octacalcium phosphate (OCP), tricalcium phosphate (TCP), and amorphous calcium phosphate (ACP) or any derivative thereof.
  • the present application discloses a method of preparing spherical particles of CaP without the use of templates or sintering steps. Instead the present invention is a method that is driven by ion concentration, time, and temperature. Compared to previous ion doped CaP spheres, the present invention discloses a method to produce spheres that are smaller in size and at a higher yield point per unit volume of mixture. By developing a method that produces more CaP spheres per unit volume of mixture, the present inventors facilitates a production method of CaP spheres that is more cost and energy effective than what has been described in the prior art.
  • the particles according to the present invention have a hollow core and a shell.
  • the core part may be described as a void not comprising any calcium phosphate material.
  • the shell of the particle is porous, in another embodiment the shell is dense.
  • the particles of the present invention comprise 40-70 weight% of calcium (Ca), 20-40 weight% of phosphate (PC ) and 5-30 weight% magnesium (Mg).
  • the particles may contain other ions as well.
  • the concentration of magnesium is 3-15 weight%. In another embodiment the concentration of magnesium is 1-10 weight%. In one embodiment the particles comprise 55-65 weight% of calcium, 25-35 weight% of phosphate and 3-15 weight% of magnesium.
  • the Ca/P molar ratio may be between 1.10 and 1.90, for example 1.10 and 1.70. In one embodiment the ratio is 1.30 to 1.70. In one embodiment the ratio is 1.40 to 1.50.
  • the particles may contain trace amounts of potassium and/or sodium since they are used in the buffer solution as counter ions.
  • the mean particle size, the diameter, should be small, not more than ⁇ preferably less than 600 nm. This provides a higher surface area per unit mass, which also makes it easier to fill voids for example dentinal tubules.
  • the size should not be too small since it makes it harder to make a formulation suitable as e.g. a chewing gum. Without being bound by theory, the size is also believed to influence the particles ability to stick to the teeth.
  • the particles are 600 nm or less, or 400 nm or less (mean particle size).
  • the mean particle size is 200 to 600 nm.
  • the particles are 10 nm or more, or 50 nm or more, or 100 nm or more, or 300 nm or more, or 450 nm or more.
  • the mean particle size is between 200-500 nm such as 200-300nm or 220-280nm. Mean particle size is determined by measuring the diameter of at least three representative particles from a sample using SEM.
  • the particles have a hollow core and a shell and wherein the particle (i.e. the shell of the particle) comprises 50-65 weight% of calcium, 25-40 weight% of phosphate and 5-30 weight% magnesium, and wherein the Ca/P weight ratio is in the range of 1.10 to 1.90, preferably 1.10 to 1.70, and wherein more than 80 % of the particles have a particle size between 200 to lOOOnm such as 200- 600 nm.
  • the particles comprises 55-65weight% of calcium such as 60- 65weight%, 30-40weight% of phosphate such as 35-40weight% and 15-25weight% of magnesium such as 20-25weight%.
  • the particles comprises calcium, phosphate and magnesium in a total amount of at least 95 weigh t%, or at least 98 weight%, or at least 99weight%, or at least 99.9weight%.
  • the synthesis is performed in an aqueous buffer solution having a pH of 2-10, preferably a pH of 6-10, or pH 6-9, preferably 6.5 to 8 or more preferably a pH of 7.0-7.5, comprising calcium, phosphate, magnesium, potassium and sodium ions.
  • a pH of 2-10 preferably a pH of 6-10, or pH 6-9, preferably 6.5 to 8 or more preferably a pH of 7.0-7.5, comprising calcium, phosphate, magnesium, potassium and sodium ions.
  • the pH value of the solutions before and after precipitation is stable.
  • the concentration of calcium ions may be in the range of 1.5-10 mM, the concentration of magnesium ions may be in the range of 1-15 mM, and the concentration of phosphate ions can be in the range 8-25 mM.
  • the calcium ion concentration is 1.5 to less than 5 mM, or 1.5 to 3 mM, and in another embodiment the magnesium ion concentration is 1 to less than 5 mM, or 1.5 to 3 mM
  • the Ca:Mg molar ratio is from 1:6 to 4:1 such as 1:3 to 4:1, for example 1:2 to 3:1 , or 1:1 to 2:1, or 1:4 to 1:6.
  • the concentration of sodium ions in the solution is in the range of 0.01-1420 mM and the concentration of potassium ions is in the range of 0.01-1420 mM, preferably 170-200 mM of sodium and 0.08-0.5 mM of potassium.
  • the concentration of sodium may be 100 to 400mM and the concentration of potassium ions may be 0.08 to 10 mM, or 0.5 to 5 mM.
  • the sodium ions may be added as NaCl or Na 2 HPC>4 or as a combination, and potassium ions may be added as KCl or KH2PO4 or as a combination.
  • the Na:K molar ratio is more than 23:1, preferably more than 30:1, more preferably more than 35:1.
  • sodium:potassium:phosphate is 100-400:0-10:8-25. In another embodiment the molar ratio is 100-400:0-10:12-25. In yet another embodiment the molar ratio is 170- 200:0.08-0.5:12-16.
  • the molar ratio between Ca and P should be close to 1:10, for example 1:9.0 to 1:11, or 1:9.5 to 1:10.7, or 1:10 to 1:10.5.
  • the water used to prepare the aqueous buffer solution should be purified water.
  • the water may be deionized, distilled, double distilled or ultra-pure water.
  • the water may be Milli-Q ® .
  • the method of the present invention is driven by ion concentration and temperature. This means that if the ion concentrations are wrong or the
  • the aqueous buffer solution in the present invention may be prepared and mixed at or around room temperature for subsequent heating.
  • a preferred temperature for preparation of the buffer solution is from about 15°C to 30°C, or from about 20°C to 25°C.
  • the reaction temperature in the present invention is at least 60°C, or at least 70°C, or at least 80°C.
  • the reaction temperature may be 90°C or more, 100°C or more, or 120°C or less.
  • a preferred reaction temperature range is from about 60°C to 120°C, or 70°C to 110°C, or from about 80°C to 100°C.
  • Sphere formation is also sensitive to heating rate of the mixture. If the heating rate is too slow, spheres and especially hollow spheres will not form. In one
  • the heating rate is at least 1.3°C per minute, or at least 1.5°C per minute, or at least 2°C per minute. In one embodiment the heating rate is 3°C per minute or more, or 6°C per minute or more. In another embodiment the heating rate is 15°C per minute or less, or 12°C per minute or less, or 10°C per minute or less, or 8°C per minute or less.
  • a non limiting heating rate range is 1-5°C per minute such as 1.2 to 2°C per minute or 1.3 to 1.5°C per minute.
  • the method could be a static process, stirring or shaking process, a turbulent flow process, or a hydrothermal process.
  • the particles may be isolated using any suitable technique for example filtering, evaporation, centrifugation or combinations thereof.
  • the method of the present invention facilitates a very short synthesis time but it is also believed that time will influence the particle size distribution.
  • the synthesis time may be 1 minute, but it may be a couple of hours. In one embodiment the synthesis time is at least 2 minutes, or at least 5 minutes, or at least 10 minutes, or at least 30 minutes, or at least 1 hour, or at least 2 hours, or at least 6 hours. In one embodiment the synthesis time is 20-180 minutes or 30-120 minutes.
  • the obtained particles will have essentially a TCP structure, such as ⁇ -TCP, or magnesium substituted HA structure or a mixture thereof.
  • the particles formed are not spherical. They will instead form flakes or rods.
  • the inventors however surprisingly found that by increasing the amount of sodium and magnesium ions in the solution, an increased amount of phosphate and calcium ions could be added and the reaction still formed spheres.
  • the reaction time was also significantly reduced and the yield (amount of particles per unit volume of mixture) of spherical particles was increased. This in total makes the present invention a more cost and time efficient method than what has been described in prior art.
  • the present invention results in a higher degree of HA structure without the need of any further treatments. This is an advantage since HA is an approved material or structure partly due to its natural occurrence in bone and teeth.
  • the particles obtained from the present method without any further treatment has at least 30%, or at least 40%, or at least 50%, or at least 75%, or at least 90% of the crystal structure is that of hydroxyapatite as determined using Rietfeld refinement from XRD spectra.
  • Some of the major costs for the preparation of the particles are the raw materials used to prepare the buffer solution and the energy required to heat the solution. The present inventors have therefore developed the method so that the buffer solution with the counter ions may be recycled and/or reused without compromising with the result to any major extent, Example 6.
  • Figure 11 discloses an illustrative set up and method of the recycling of the buffer solution. After precipitation of the particles, the buffer solution still has an adequate concentration of counter ions (sodium and potassium) which may be reused.
  • the solution is preferably first cooled down for example to room temperature (20-25C), and may then be supplemented with
  • phosphate, calcium and magnesium ions preferably corresponding to the amount consumed in the precipitation of particles.
  • the recycling step can be performed as many times as the concentration range of the ions allow formation of spherical hollow particles.
  • the concentration of sodium ions in the recycled buffer solution may be 100 to 400 mM and the concentration of potassium ions may be 0.08 to lOmM.
  • the concentration of phosphate ions in the supplemented recycled solution may be 8-25 mM, the
  • concentration of calcium ions may be 1.5-10 mM, and the concentration of magnesium ions may be 1-15 mM.
  • the phosphate ion concentration is from 10 to less than 25 mM, or 10 to 16 mM.
  • calcium ion concentration is 1.5 to less than 5 mM, or 1.5 to 3 mM.
  • the magnesium ion concentration is 1 to less than 5 mM, or 1.5 to 3 mM.
  • the Ca:Mg molar ratio is from 1:6 to 4:1 such as 1:3 to 4:1, for example 1:2 to 3: 1 , or 1:1 to 2:1, or 1:4 to 1:6.
  • the inventors have further developed the method so that a continuous process may be used to prepare the particles, which results in significant time saving.
  • two chemical reactor vessels are used in series, where one is held at lower temperature and the other at higher temperature.
  • the buffer solution is circulated between these reactors and supplemented with phosphate, calcium, and magnesium ions in the reactor vessel held at lower temperature.
  • the supplement of phosphate, calcium and magnesium ions is made periodically, and in another embodiment the supplement of said ions is made continuously.
  • the particles are circulated with the buffer solution and isolated by for example filtration at the end of the process.
  • the particles are isolated continuously by for example a filtration unit placed in line between the two reactor vessels.
  • the particles of the present invention may be used in a bleaching agent or paste or chewing gum for teeth.
  • a problem with prior art has been that the bleaching also degrades the enamel, resulting in increased tooth sensitivity and gingival irritation.
  • the present invention aims at delivering a bleaching agent locally using the particles of the present invention, which will act to remineralize the tooth during and/or after the bleaching step.
  • the preparation of a bleaching agent with the particles of the present invention comprises: -Providing particles of the present invention and a solution of a bleaching additive, for example a peroxide solution;
  • the peroxide used may be hydrogen peroxide or carbamide peroxide or a mixture thereof.
  • tooth bleaching additives include; sodium percarbonate, sodium chlorite, sodium perborate, peroxymonosulphate, peroxide plus metal catalysts and oxireductase enzymes.
  • the concentrations of peroxides in the solution may be 0.1-60weight% such as 1 weight% or more, or 5 weight% or more, or 10 weight% or more, or 15 weight% or more, or 20 weight% or more, or 25 weight% or more, but 55 weigh t% or less, or 50 weigh t% or less, or 45 weigh t% or less, or 40 weight% or less.
  • the concentration may be 10-60weight% for carbamide peroxide, or 0.1-35 weight% hydrogen peroxide, such as 10-35wt% hydrogen peroxide.
  • Example 1 CaP particles were prepared as follows: NaCl, KC1, CaCl 2 , MgCl 2 , KH2PO4, and Na 2 HPC>4 were dissolved in water at a molar ratio of 185:0.29:2:1.25:2.231: 12.05 to form a phosphate buffered saline solution at 25°C. The solution was heated under stirring at a rate of 1.4°C per minute to a temperature of 85°C, where it was held for 40 min. During this time the CaP particles will precipitate from the solution. The particles were then filtered out of solution and dried before examination in SEM. At this ion concentration and under the described process parameters, spherical particles with a mean diameter of roughly 300 nm were produced. See Figure 1.
  • CaP particles were prepared as follows: NaCl, KC1, CaCl 2 , MgCl 2 , KH2PO4, and Na 2 HPC>4 were dissolved in water at a molar ratio of 170:0.08: 1.5:1.5:1.5:8.1 to form a phosphate buffered saline solution at 25°C. The solution was heated under stirring at a rate of 1.4°C per minute to a temperature of 85°C, where it was held for 40 min. During this time the CaP particles will precipitate from the solution. The particles were then filtered out of solution and dried before examination in SEM. At this ion concentration and under the described process parameters, spherical particles with a mean diameter of roughly 560 nm were produced. See Figure 2.
  • Example 3 Example 3:
  • CaP particles were prepared as follows: NaCl, KC1, CaCl 2 , MgCl 2 , KH2PO4, and Na 2 HPC>4 were dissolved in water at a molar ratio of 200:0.5:2.5:1.5:2.963:16 to form a phosphate buffered saline solution at 25°C. The solution was heated under stirring at a rate of 1.4°C per minute to a temperature of 85°C, where it was held for 40 min. During this time the CaP particles will precipitate from the solution. The particles were then filtered out of solution and dried before examination in SEM. At this ion concentration and under the described process parameters, spherical particles with a mean diameter of roughly 230 nm were produced. See Figure 3.
  • CaP particles were prepared as follows: NaCl, KCl, CaCl 2 , MgCl 2 , KH2PO4, and Na 2 HPC>4 were dissolved in water at designated molar
  • concentrations to form a phosphate buffered saline solution at 25°C The molar concentrations varied as follows: NaCl: 100-170 mM; KCl: 0.1-5 mM; CaCl 2 : 0.9-1.8 mM; MgCl 2 : 0.1-1 mM; Na 2 HP0 4 : 8.1-16 mM; KH 2 P0 4 : 1.5-2.963 mM.
  • the solution was heated under stirring at a rate of 1.4°C per minute to a temperature of 85°C, where it was held for 40 min. During this time the CaP particles precipitated from the solution. The particles were then filtered out of solution and dried before examination in SEM.
  • CaP particles were prepared as follows: NaCl, KCl, CaCl 2 , MgCl 2 , KH2PO4, and Na 2 HP04 were dissolved in water at designated molar concentrations to form a phosphate buffered saline solution at 25°C.
  • the molar concentrations varied as follows: NaCl: 170-200 mM; KCl: 0.08-0.5 mM; CaCl 2 : 1.5-2.5 mM; MgCl 2 : 1-1.5 mM; Na 2 HP0 4 : 8.1-16 mM; KH 2 P0 4 : 1.5-2.963 mM..
  • the solution was heated under stirring at a rate of 1.4°C per minute to a temperature of 85°C, where it was held for 40 min. During this time the CaP particles precipitated from the solution. The particles were then filtered out of solution and dried before examination in SEM. The particles from each experiment were rated according to size and morphology, i.e. if spheres were formed or not. See Table 1. The data was evaluated in the DOE software to identify statistically verified trends. The results of the evaluation revealed that, within the ion concentration design space, spheres were formed in nearly all areas, but having different sizes. It also revealed an increase in yield of spheres, primarily according to the amount of calcium added.
  • CaP particles were prepared as follows: NaCl, KCl, CaCl 2 , MgCl 2 , KH 2 PC>4, and Na 2 HPC>4 were dissolved in water at a molar ratio of
  • Example 8 The effect of a yet further increase in magnesium content was evaluated.
  • CaP particles were prepared as follows: NaCl, KCl, CaCl 2 , MgCl 2 , KH 2 PC>4, and Na 2 HPC>4 were dissolved in water at a molar ratio of 200:0.08:2.5:10:2.231:16 to form a phosphate buffered saline solution at 25°C. The solution was heated under stirring at a rate of 1.4°C per minute to a temperature of 85°C, where it was held for 40 min. The particles were then filtered out of solution and dried before examination in SEM, see Figure 9. The experiment revealed that spheres were formed also with this further elevated
  • CaP particles were prepared as follows: NaCl, KCl, CaCl 2 , MgCl 2 , KH 2 PC>4, and Na 2 HPC>4 were dissolved in water at a molar ratio of
  • a continuous process with recycling of process water and counter ions has also been developed in pilot scale, where two 50 L reactors are placed in series, one held at 25°C and the other at 85°C. Briefly, the continuous process was carried out as follows: The first reactor was charged with NaCl, KC1, CaCl 2 , MgCl 2 , KH2PO4, and Na 2 HP04, in this case at a molar ratio of 200:0.5:2.5:1.5:2.963:16 to form a phosphate buffered saline solution at 25°C. The solution was then pumped through a heat exchanger and collected in the second reactor where it was continually heated at 85°C. The first reactor was then charged again with an identical buffer solution at 25°C.
  • a pilot scale continuous process with recycling of process water and counter ions, where the precipitated particles are filtered directly in-line has also been developed.
  • two SO L reactors and a filter were placed in series. Briefly, the continuous process was carried out as follows: The first reactor was charged with NaCl, KC1, CaCl 2 , MgCl 2 , KH2PO4, and Na 2 HP0 4 , in this case at a molar ratio of 200:0.5:2.5: 1.5:2.963:16 to form a phosphate buffered saline solution at 25°C. The solution was then pumped through a heating heat exchanger and received in the second reactor where it was heated at 85°C. The first reactor was then charged again with an identical buffer solution.
  • a semi-continuous batch process has also been developed in pilot scale, where two 50 L reactors and a filter are placed in series. Briefly, the process was carried out as follows: The first reactor was charged with NaCl, KC1, CaCl 2 , MgCl 2 , KH2PO4, and Na 2 HP04, in this case at a molar ratio of 200:0.5:2.5:1.5:2.963:16 to form a phosphate buffered saline solution at 25°C. The solution was then pumped through a heating heat exchanger and received in the second reactor where it was heated at 85°C. The first reactor was then charged again with an identical buffer solution.

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Abstract

La présente invention concerne des particules. Une particule selon l'invention comprend 50 à 65 % en poids de calcium, 25 à 40 % en poids de phosphate, et 5 à 30 % en poids de magnésium, le rapport pondéral Ca/P se trouvant dans la plage de 1,10 à 1,90, et plus de 80 % des particules ont une granulométrie comprise entre 200 et 600 nm. La présente invention concerne également le procédé de préparation de ces particules.
PCT/SE2016/051121 2015-11-12 2016-11-14 Procédé de fabrication de particules sphériques constituées de phosphate et de calcium Ceased WO2017082811A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
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CN114395521A (zh) * 2022-02-18 2022-04-26 南充市中心医院 一种空心磁性磷酸钙细胞微载体及其制备方法
US20220296477A1 (en) * 2019-10-30 2022-09-22 Psilox Ab Stabilized amorphous calcium magnesium phosphate particle compositions

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