WO2005003028A2

WO2005003028A2 - Calcium phosphate particles and production thereof

Info

Publication number: WO2005003028A2
Application number: PCT/FR2004/001666
Authority: WO
Inventors: Jean-Yves Chane-Ching; Cédric BOISSIERE; Stephen Mann
Original assignee: Rhodia Chimie
Priority date: 2003-06-30
Filing date: 2004-06-29
Publication date: 2005-01-13
Also published as: WO2005003028A3; FR2856673A1

Abstract

The invention relates to particles of calcium phosphate platelets with a monetite structure, the thickness of the platelets being 0.005 µm to 0.2 µm, the porous volume, corresponding to pores with a diameter less than 1 µm, measured with mercury, is at least 0.30 ml/g and having a mean diameter, d50, of 5 µm to 15 µm. Also disclosed are particles of calcium phosphate fibres with apatite structure, the porous volume of which, measured by mercury porosimetry and corresponding to the pores with diameter less than 1 micron, is at least 0.40 ml/g, the specific surface of which is at least 150 m2/g and the means diameter, d50, is 5 µm to 15 µm. The invention further relates to a method for the production of said particles of calcium phosphate and the use of said particles, whereby the particles obtained are used as reinforcing filler, thermal insulation filler, pharmaceutical excipient, polishing agent, support material, construction materials, and additive for bucco-dental formulations such as toothpastes or as encapsulating agent.

Description

CALCIUM PHOSPHATE PARTICLES AND PROCESS FOR THE PREPARATION THEREOF

The subject of the present invention is particles, platelets or fibers, of calcium phosphate, as well as their methods of preparation. Many manufacturers use calcium phosphate, developing different morphologies, different pore volumes and different specific surfaces. In particular, products with a high specific surface area and pore volume are of great interest for applications in reinforcement, thermal insulation agent, pharmaceutical excipient developing high compressibility. However, obtaining products in solid form developing high specific surfaces is generally obtained for products of nanometric size developing dust phenomena, which make them difficult to handle. In order to meet the requirements of manufacturers, it has become necessary to find calcium phosphate particles with high pore volumes as well as good specific surfaces while not developing dust phenomena. Also the problem which the invention proposes to solve is to provide particles of calcium phosphates having large pore volumes and / or large specific surfaces while having a micron size. For this purpose, the invention provides particles of calcium phosphate platelets with a monetite structure, the thickness of the platelets of which is between 0.005 μm and 0.2 μm, the pore volume corresponding to the pores with a diameter of less than 1 μm, measured at mercury, is at least 0.30 ml / g, and having an average diameter, do, of between 5 μm and 15 μm. The invention also provides particles of calcium phosphate fibers with apatite structure, the pore volume of which, measured with a mercury porosimeter and corresponding to the pores of diameter less than 1 micron, is at least 0.40 ml / g, the specific surface is at least 150 m ² / g and whose average diameter, d ₅₀ , is between 5 μm and 15 μm. The BET specific surface area determined by nitrogen adsorption is determined according to standard ASTM D 3663-78 established from the BRUNEAU-EMMETT-TELLER method described in the periodical "The Journal of American Society 60.309 (1938)". For the determination of the pore volume, it can be done according to the mercury porosimeter method (for example by following standard ASTM-D 4284-83). The invention also relates to a process for preparing the calcium phosphate particles according to the invention. Finally, the subject of the invention is also the use of the particles according to the invention or of particles obtained according to the process of the invention as reinforcing filler, thermal insulation filler, pharmaceutical excipient, polishing agent, support agent, building materials, additive for oral formulations, in particular toothpaste or encapsulation agent. The particles according to the invention advantageously have significant calcium phosphate / polymer interfaces when the particles are used as reinforcement in polymer matrices. Another advantage of the particles according to the invention is their large pore volumes, which can be of great interest when the particles are used as a vectoring agent for liquid active materials. Advantageously, the high pore volume of the particles according to the invention also facilitates the compressibility of the particles. The particles according to the invention also have the advantage of developing high specific surfaces, and high pore volumes in a micrometric and non-nanometric form, which allows a better presentation of the product for the user. Other advantages and characteristics of the present invention will become clear on reading the description and examples given by way of purely illustrative and nonlimiting description, which will follow. The invention relates first of all to particles of calcium phosphate platelets with a monetite structure, the thickness of the platelets of which is between 0.005 μ and 0.2 μm, the pore volume corresponding to the pores of diameter less than 1 μm, measured with mercury, is at least 0.30 ml / g, and having an average diameter, d ₅₀ , of between 5 μm and 15 μm. Preferably, the platelet particles according to the invention have an average diameter, d _δ o, of between 8 μm and 12 μm. This average diameter can be viewed on photographs obtained by scanning electron microscopy. Preferably, the platelet particles according to the invention have a monodisperse particle size distribution. This distribution advantageously shows that 80% of the population of particles have the same mean diameter, dso, varying to plus or minus 2 μm, preferably 90% of the population of particles have the same mean diameter, d ₅₀ , varying to plus or minus minus 2 μm. The platelet particles according to the invention are preferably formed by a weakly compact entanglement of platelets, also called lamellae. These plates are visible for example in scanning electron microscopy (SEM) and have dimensions L, I, such that the length, L, is between 0.1 μm and 5 μm, and the width, I, is between 0 , 1 μm and 5 μm. The platelet particles according to the invention may also contain a small proportion of particles whose thickness of the platelets can reach up to 0.5 μm. The platelet particles according to the invention advantageously have a low compactness of the entanglement of the platelets. This low compactness can be characterized by the pore volume, determined by measurement with nitrogen or mercury. The platelet particles according to the invention have a pore volume, measured with nitrogen, which is at least 0.04 ml / g. By mercury porosimetry, the pore volume corresponding to pores of diameter less than 1 micron is advantageously at least 0.35 ml / g, preferably between 0.35 and 0.60 ml / g and even more preferably between 0.35 and 0.50 ml / g. The platelet particles according to the invention advantageously have a large specific surface, which is determined by nitrogen adsorption / desorption curves. Advantageously, the platelet particles according to the invention have a specific surface of between 20 m ² / g and 50 m ² / g. These particles according to the invention have a low content of organic compounds. In particular, these organic compounds can be a calcium complexing agent and / or a polymer, or breakdown products of these, these 2 compounds being described later in the text. Advantageously, the particles according to the invention have a carbon content of between 0.01 and 3%, percentage expressed by weight. The invention then relates to particles of calcium phosphate fibers with apatite structure, the pore volume of which, measured with a mercury porosimeter and corresponding to the pores of diameter less than 1 micron, is at least 0.40 ml / g, the specific surface is at least 150 m ² / g and whose average diameter, d ₅ o, is between 5 μm and 15 μm. Advantageously, the fiber particles according to the invention have an apatite structure of the following formula: Ca ι ₀ - _x (HPO ₄ ) _x (PO ₄ ) 6- (OH) ₂ . _x with x varying from 0 to 2, inclusive. When x is equal to zero, the fiber particles according to the invention have a hydroxyapatite structure. Advantageously, the fiber particles according to the invention have an average diameter, d ₅₀ , of between 8 μm and 12 μm. This average diameter can be viewed on photographs obtained by scanning electron microscopy. Preferably, these fiber particles according to the invention have a monodisperse particle size distribution. This distribution advantageously shows that 80% of the population of particles have the same mean diameter, d ₅₀ , varying to more or less 3 μm, preferably 90% of the population of particles have the same mean diameter, d ₅₀ , varying to more or less 3 μm. The fiber particles according to the invention are preferably formed by a weakly compact entanglement of fibers, also called fibrils. These fibers are visible for example in scanning electron microscopy (SEM) and have dimensions such that the length of the fibers, L, is between 0.1 μm and 3 μm and the average diameter of the fibers, d ₅₀ is between 0 , 05 μm and 0.2 μm. The fiber particles according to the invention advantageously have a low compactness of the entanglement of the fibers. This low compactness can be characterized by the pore volume, determined by measurement with nitrogen or mercury. The fiber particles according to the invention have a pore volume, measured with nitrogen, which is at least 0.10 ml / g. By mercury porosimetry, the pore volume corresponding to the pores of diameter less than 1 micron is at least 0.40 ml / g, preferably between 0.50 and 0.70 ml / g and more preferably between 0 , 50 and 0.60 ml / g. The fiber particles according to the invention advantageously have a large specific surface, which is determined by adsorption / desorption curves with nitrogen. Advantageously, the fiber particles according to the invention have a specific surface of at least 150 m ² / g, preferably between 170 m ² / g and 220 m ² / g and more preferably comprised between 170 m ² / g and 200 m ² / g. These fiber particles according to the invention have a low content of organic compounds. In particular, these organic compounds can be a calcium complexing agent and / or a polymer, or breakdown products of these, these 2 compounds being described later in the text. Advantageously, the particles according to the invention have a carbon content of between 0.01 and 3%, percentage expressed by weight. The invention also relates to a process for preparing the particles of calcium phosphate platelets according to the invention. The process for preparing the calcium phosphate platelet particles, described above, comprises the following stages: i) bringing into contact a solution of calcium salts, at least one calcium complexing agent, a solution of phosphate salts, and at least one polymer, and at a pH below 3.5; ii) precipitate the solution obtained in step i); iii) separate and wash the solid obtained in step ii), with a washing solution whose pH is less than 7.5. Then the process for preparing the calcium phosphate fiber particles, described above, comprises the following stages: i) bringing into contact a solution of calcium salts, at least one calcium complexing agent, a solution of phosphate salts , and at least one polymer, and at a pH below 3.5; ii) precipitate the solution obtained in step i); iii) separating and washing the solid obtained in step ii), with a washing solution whose pH is less than 7.5; iv) bringing the solid obtained in step iii) into contact with a solution of calcium salts whose pH is greater than 7; v) separating the solid obtained in step iv). The method according to the invention comprises steps i) ii) and iii) when it is a question of producing the particles of platelets and further comprises steps iv) and v) when it is a question of producing the particles of fibers according to the invention. Steps i) ii) and iii) are common to both processes. First, during step i) an ionic solution containing calcium salts, at least one Ca ²⁺ complexing agent, phosphate salts and at least one polymer is prepared. The calcium salts which may be suitable are preferably CaC. ₂ , CaC- ₂ , 2H ₂ O, Ca (NO ₃ ) ₂ . Advantageously, the concentration of the calcium salt solution in step i) is between 0.15M and 1M. Preferably, during step i) a complexing agent of the

Ca ²⁺ . The complexing agents which are particularly suitable according to the process of the invention are organic acids such as malonic acid or maleic acid. Preferably maleic acid will be used, but other organic acids may also be suitable. The complexing agent is added in step i) in an amount such that the molar ratio, R1, moles of calcium complexing agent to moles of calcium added is preferably between 0.05 and 1.5. Also added during step i) a phosphate salt solution. This solution is preferably a solution of ammonium or sodium phosphate, in particular of (NH) ₂ (HPO) or (NH ₄ ) (H ₂ PO ₄ ) or NaH ₂ PO or (Na) ₂ HPO. Advantageously, the concentration of the phosphate salt solution in step i) is between 0.1 M and 0.85M. Finally, a polymer is also added during step i). The polymer which is particularly suitable for the process according to the invention has anionic functions, preferably carboxylate (COO ^" ), phosphate or phosphonate functions. Among the preferred polymers according to the process of the invention, this is chosen from polymers with a peptide backbone of polyaspartic, polyglutamic acid, polylysine, polyglycine, casein type or else among the homopolymers and copolymers of acrylic or methacrylic acid, of polyacrylic or polymethacrylic acid or else among copolymers of the polyacrylic-polymethacrylic, polyacrylic type polyhydroxyethylacrylic, polyacrylic-polyacrylamide or among natural and / or modified polysaccharide polymers such as guar, carboxymethylcellulose, xanthan gum or among modified polysaccharide polymers having phosphate or phosphonate functions or among peptide polymers containing phosphate functions . The polymer according to the invention preferably has a molecular weight, PM, of less than 2000 g / mole. During step i), the order of addition of the components and the solutions is indifferent. Advantageously, step i) of the method according to the invention is carried out so as to obtain a molar ratio, R2, moles of anionic functions present within the polymer on moles of added calcium of between 0.01 and 0.5, of preferably 0.01 and 0.15. Preferably step i) of the process according to the invention is carried out so as to obtain a molar ratio, R, moles of calcium on moles of phosphorus of between 0.5 and 2, preferably between 1 and 1, 7. The pH of the solution during step i) is preferably kept constant at a pH value of less than 3.5, more particularly less than 3. This pH is obtained or maintained by pre-adjusting the pH of the different solutions used and optionally by post acidification of the mixture. Then during step ii), the solution obtained in step i) is precipitated. Preferably, this precipitation is carried out in a homogeneous manner, for example by adding alcohol to the solution prepared in step i). The alcohol which is particularly suitable according to the process of the invention is an alcohol chosen from propanol, isopropanol, ethanol. Water-soluble alcohols are also suitable. The volume ratio, V, Volume of alcohol over volume of water is generally between 2 and 5. This addition of alcohol is preferably carried out at room temperature.

It can be done instantly. The precipitate is preferably left to mature. Curing can also be carried out at room temperature. The ripening time can vary from 30 minutes to 24 hours. A precipitate forms over time. During step iii), the solid obtained in the previous step (ii) is separated and washed. The solid formed can be recovered by any solid / liquid separation method known to those skilled in the art. It can be obtained by simple filtration, centrifugation. The product is then preferably washed. This washing can be carried out with water or with a solvent, for example an alcohol, so as to remove the incorporated polymer. Several washes may be necessary. When the pH of the washing solution is less than pH 7.5, preferably less than pH 7, the particles of calcium phosphate platelets according to the invention, with monetite structure, are obtained. The product obtained can be dried, by any method known to those skilled in the art. Optionally, the method according to the invention can be followed by a step iv) and a step v). Step iv) consists in bringing the solid obtained in step iii) into contact with a solution of calcium salts whose pH is greater than 7. Advantageously, the quantity of calcium ions added during this step iv) allows to obtain a molar ratio, R, moles of calcium over moles of phosphorus greater than 1.5, preferably greater than 1.67. This contacting can be carried out for a period of 5 minutes to 10 hours at room temperature, preferably without or with very little stirring. Step v) consists in separating the solid obtained in the previous step (iv). The solid formed can be recovered by any solid / liquid separation method known to those skilled in the art. The particles of calcium phosphate fibers according to the invention are obtained, with an apatite structure. The product obtained can be dried, by any method known to those skilled in the art. Finally, the invention also relates to the use of the particles according to the invention or of the particles obtained according to the process of the invention as reinforcing filler, thermal insulation filler, pharmaceutical excipient, polishing agent, support agent, construction, additive for oral formulations including toothpaste or encapsulation agent.

The following examples illustrate the invention without, however, limiting its scope. It should be noted that the specific surface and the pore volumes of the products given in the description and in the examples correspond to measurements carried out on a sample which has been treated until a constant weight is obtained. Thus, before analysis, the product was dried in air, and at atmospheric pressure, for two hours at 200 ° C. in an oven.

EXAMPLES

Example 1: Obtaining particles of calcium phosphate platelets with a monetite structure: A solution A is prepared by dissolving 8.1 g of CaC. ₂ , 2H ₂ O, and 5.8 g of maleic acid in 200 ml of water. A solution B is prepared by dissolving 5.1 g of NaH ₂ PO in 50 ml of water. 1.5 g of sodium polyaspartate acid are added to this solution.

40% by weight (coming from Aldrich, PM = 3000 g / mol) Solutions A and B are mixed instantly. The pH is 2. This solution is left to stand overnight. 1000 ml of 95% ethanol by volume are always added at room temperature. The solution becomes turbid over time. A powder is recovered after 16 hours which is separated by centrifugation. The product is washed with 1.5 liters of ethanol, centrifuged and then washed again with 1.5 liters of deionized water previously adjusted to pH 6. The washing operation is repeated once with pH 6.

By scanning electron microscopy, spherical particles of calcium phosphate platelets, about 8 μm in diameter, are observed. These particles are formed by a tangle of crystallites with a thickness of less than 0.1 μm. By X-ray diffraction, a monetite structure is observed. The specific surface of the product is 35 m ² / g. The pore volume determined by measurement with nitrogen is 0.05 ml / g with a spread of pores. By mercury porosimetry, the porogram shows a pore volume of 0.36 ml / g corresponding to the population of pores with a diameter of less than 1 micron.

Example 2: Obtaining particles of calcium phosphate fibers with hvdroxyapatite structure: A recrystallization solution is prepared by dissolving 1.43 g of

CaCI ₂ , 2H ₂ θ in one liter of demineralized water. 0.5 ml of 1 M NH ₄ OH solution is then added, then 3 ml of 5M NaOH solution and the mixture is made up to 2 liters with demineralized water. The mixture is stirred for one hour and the solution is left to stand. 2 g of monetite powder, washed and dried at 20 ° C., as previously prepared in Example 1, are added. It is left for 24 hours without agitation. The powder is then recovered by centrifugation and washed with demineralized water. The powder is dried at 20 ° C for several days.

By scanning electron microscopy, particles formed by entanglement of fibers are observed. By X-ray diffraction, a hydroxyapatite structure is observed. The pore volume determined by measurement with nitrogen is 0.26 ml / g. By mercury porosimetry, the porogram indicates a pore volume of 0.58 ml / g corresponding to the population of pores of equivalent diameter less than 1 micron. By nitrogen adsorption / desorption, the specific surface of the product is determined equal to 173 m ² / g.

EXAMPLE 3 Obtaining particles of calcium phosphate platelets with a monetite structure in the presence of casein: A solution A is prepared by dissolving 0.61 g of CaCl 2, 0.58 g of maleic acid in 20 ml of water . A solution B is prepared by dissolving 1.17 g of NaH ₂ PO ₄ , 12H ₂ O in 5 ml of aqueous solution at 1% by weight of casein. Solutions A and B are mixed instantly. The pH is pH 1.86. We let it rest overnight. 100 ml of 95% ethanol by volume are always added at room temperature. A powder is recovered after 16 hours which is separated by centrifugation. The product is washed with 500 ml of 95% ethanol, centrifuged and then washed again with 500 ml of deionized water previously adjusted to pH 6. The washing operation is repeated once with water at pH 6.

By scanning electron microscopy, spherical particles of the order of 12 μm in diameter are observed. These particles are formed by a tangle of low compactness of crystallites with a thickness of about 0.1 μm. By X-ray diffraction, a monetite structure is observed.

Claims

1. Particles of calcium phosphate platelets with a monetite structure, the thickness of the platelets of which is between 0.005 μm and 0.2 μm, the pore volume corresponding to pores with a diameter of less than 1 μm, measured with mercury, is at least minus 0.30 ml / g, and having an average diameter, dso, of between 5 μm and 15 μm.

2. Particles of calcium phosphate platelets according to claim 1, characterized in that they have a monodisperse particle size distribution, showing that 80% of the population of particles have the same mean diameter, d ₅ o, varying to more or less 2 .mu.m.

3. Particles of calcium phosphate platelets according to one of the preceding claims, characterized in that they have platelets whose length is between 0.1 μm and 5 μm, and the width is between 0.1 μm and 5 μm.

4. Particles of calcium phosphate platelets according to one of the preceding claims, characterized in that they have a specific surface of between 20 m ² / g and 50 m ² / g.

5. Particles of calcium phosphate platelets according to one of the preceding claims, characterized in that they have a carbon content of between 0.01 and 3%, percentage expressed by weight.

6. Particles of calcium phosphate fibers with apatite structure, the pore volume of which, measured with a mercury porosimeter and corresponding to pores with a diameter of less than 1 micron, is at least 0.40 ml / g, the specific surface area is at least minus 150 m ² / g and whose average diameter, d _δ o, is between 5 μ and 15 μm.

7. Particles of calcium phosphate fibers according to claim 6, characterized in that they have a monodisperse particle size distribution showing that 80% of the population of particles have the same mean diameter, d ₅₀ , varying to more or less 3 μm.

8. Particles of calcium phosphate fibers according to one of claims 6 or 7 characterized in that they have a specific surface of between 170 m ² / g and 220 m ² / g, preferably between 170 m ² / g and 200 m ² / g.

9. Particles of calcium phosphate fibers according to one of claims 6 to 8 characterized in that they have fibers whose length is between 0.1 μm and 3 μm and whose average diameter, so, is included between 0.05 μm and 0.2 μm.

10. Particles of calcium phosphate fibers according to one of claims 6 to 9 characterized in that they have a carbon content of between 0.01 and 3%, percentage expressed by weight.

11. A method of preparing the particles according to claims 1 to 5 characterized in that it comprises the following steps: i) bringing into contact a solution of calcium salts, at least one calcium complexing agent, a solution of phosphate salts , and at least one polymer, and at a pH below 3.5; ii) precipitate the solution obtained in step i); iii) separate and wash the solid obtained in step ii), with a washing solution whose pH is less than 7.5.

12. A method of preparing the particles according to claims 6 to 10 characterized in that it comprises the following steps: i) bringing into contact a solution of calcium salts, at least one calcium complexing agent, a solution of phosphate salts , and at least one polymer, and at a pH below 3.5; ii) precipitate the solution obtained in step i); iii) separating and washing the solid obtained in step ii), with a washing solution whose pH is less than 7.5; iv) bringing the solid obtained in step iii) into contact with a solution of calcium salts whose pH is greater than 7; v) separating the solid obtained in step iv).

13. Method according to claims 11 or 12 characterized in that the calcium salt solution is a solution of CaC, CaC. ₂ , 2H ₂ O or Ca (NOs) ₂ .

14. Method according to claims 11 to 13 characterized in that the calcium complexing agent is an organic acid such as malonic acid or maleic acid.

15. Method according to claims 11 to 14 characterized in that the phosphate salt solution is a solution of ammonium or sodium phosphate, in particular of (NH ₄ ) ₂ (HPO ₄ ) or (NH ₄ ) (H ₂ PO ₄ ) or NaH ₂ PO ₄ or (Na) ₂ HPO ₄ or (Na ₂ ) HPO ₄ .

16. Method according to claims 11 to 15 characterized in that the polymer has anionic functions, preferably carboxylate, phosphate or phosphonate functions.

17. The method of claim 16 characterized in that the polymer is chosen from polymers with a peptide backbone of polyaspartic, polyglutamic acid, polylysine, polyglycine, casein type or even from homopolymers and copolymers of acrylic or methacrylic acid, of polyacrylic or polymethacrylic acid or among copolymers of the polyacrylic-polymethacrylic, polyacrylic-polyhydroxyethylacrylic, polyacrylic-polyacrylamide type or among natural and / or modified polysaccharide polymers such as guar, carboxymethylcellulose, or xanthan gum or modified polysaccharides having phosphate or phosphonate functions or else among peptide polymers containing phosphate functions.

18. Method according to claims 16 or 17 characterized in that the polymer has a molecular weight, PM, less than 2000 g / mol.

19. Method according to claims 11 to 18 characterized in that step i) is carried out so as to obtain a molar ratio, R1, moles of calcium complexing agent on moles of calcium added of between 0.05 and 1, 5.

20. Method according to claims 11 to 19 characterized in that step i) is carried out so as to obtain a molar ratio, R2, moles of anionic functions present within the polymer on moles of added calcium of between 0.01 and 0.5, preferably 0.01 and 0.15.

21. Method according to claims 11 to 20 characterized in that the concentration of the solution of calcium salts in step i) is between 0.15M and 1M.

22. Method according to claims 11 to 21 characterized in that the concentration of the phosphate salt solution in step i) is between 0.1M and 0.85M.

23. Method according to claims 11 to 22 characterized in that step i) is carried out so as to obtain a molar ratio, R ₃ , moles of calcium on moles of phosphorus between 0.5 and 2, preferably between 1 and 1, 7-

24. Method according to claims 11 to 23 characterized in that the precipitation step ii) is carried out in a homogeneous manner, for example by addition of alcohol.

25. The method of claim 24 characterized in that the alcohol is an alcohol chosen from propanol, isopropanol, pethanol.

26. Method according to claims 11 to 25 characterized in that step iii) is carried out at a pH below 7.

27. The method as claimed in claims 12 to 26, characterized in that the quantity of calcium ions added in step iv) makes it possible to obtain a molar ratio, R ₄ , moles of calcium over moles of phosphorus greater than 1.5, preferably greater than 1.67.

28. Use of the particles according to one of claims 1 to 10 or of the particles obtained according to claims 11 to 27 as reinforcing filler, thermal insulation filler, pharmaceutical excipient, polishing agent, support agent, building materials, additive for oral formulations including toothpaste or encapsulation agent.