MXPA06000116A - Nanoscale calcium phosphate tablets - Google Patents

Abstract

The invention relates to individual calcium phosphate tablets having a length of between 250 nm and 800 nm. The invention also relates to dispersions containing the aforementioned tablets or colloidal dispersions which are obtained by resuspending said tablets in the presence of a dispersing agent. The invention further relates to a method of preparing the inventive tablets. Finally, the invention relates to the use of said tablets as reinforcing fillers, polishing agents, construction materials, additives for dental formulations such as toothpaste or encapsulants.

Description

NANOMETRIC CALCIUM PHOSPHATE PLATELETS The present invention relates to nanometric calcium phosphate platelets, nano-calcium phosphate dispersions and their methods of preparation. Many industries use calcium phosphate under different morphologies. Notably, the morphologies most known and used are the rhombohedral morphologies, needles or large platelets. According to the structures of this calcium phosphate, the morphologies of calcium phosphate will be different. In particular, calcium phosphate platelets are used as a reinforcing filler, notably for reinforcing the polymers or a polymer matrix. This application by reinforcing the calcium phosphate platelets allows to improve the mechanical properties of polymers or their matrix. Or, the currently available technologies do not allow obtaining more than calcium phosphate platelets of which the size is greater than a micron, and which are in the form of aggregates, that is to say, very little individualized. In order to respond to the demands of the industries it is necessary to find calcium phosphate platelets of which the size is less than a micron being individualized. Also the problem proposed to solve the invention is to provide well individualized calcium phosphate platelets and of which the size is of the order of 250 nm to 800 nm.

In this object the invention proposes individualized calcium phosphate platelets and of which the length is between 250 nm and 800 nm. The invention also proposes dispersions containing the platelets according to the invention or colloidal dispersions obtained by suspending said platelets in the presence of a dispersing agent. The invention also relates to the method for preparing platelets according to the invention. Finally, the invention also relates to the use of the above-mentioned platelets as reinforcing fillers, polishing agents, building materials, additives for dental formulations, notably toothpastes or encapsulating agents. The calcium phosphate platelets according to the invention have the advantage of having gas diffusion barrier properties. The calcium phosphate platelets according to the invention still have the advantage of being a good packaging material, notably usable in the food field. Other advantages and features of the present invention will appear clearly on reading the description and the examples provided purely by way of illustration and not limitation, below. The invention relates to individualized calcium phosphate platelets and of which the length is between 250 nm and 800 nm. The individualization of platelets can be shown by granulometric analysis based on a sedimentation principle. It is possible, for example, to use granulometric measuring devices such as the Sedigraph, equipped with an X-ray beam to analyze the sedimentation of the platelets according to the invention. The technique employed may comprise a first dispersion step in the presence of a dispersing agent, of the polyphosphate type, and of an ultrasonic deagglomeration stage, of power of approximately 600 watts, plus or minus 20% > , for 7 minutes. It is also possible to make the measurement directly on a dispersion or on a colloidal dispersion according to the invention, without previous steps. For individualized platelets, it is understood in the sense of the invention that at least 80%, advantageously at least 90%, preferably at least 95%, mass of platelets according to the invention have an equivalent diameter of less than or equal to 200 nm. This equivalent diameter is advantageously greatly less than the length of the platelets visualized by microscopy. By equivalent diameter, it is understood the value determined by the granulometric analysis apparatus based on a sedimentation principle. This value is advantageously calculated on the basis of the diameter of a virtual sphere of a material having the same sedimentation velocity as the platelet sedimentation rate according to the invention.

The platelets according to the invention can present 3 different structures: monetite or majority monetite or apatite deficient. All the platelets according to the invention can have a structure of monetite, well crystallized visible by X-ray diffraction. These platelets can present a chemical shift comprised between -1.4 ppm and -1 ppm measured by MAS NMR of phosphorus 31 that can be attributed to the structure of monetito. In a certain case, the platelets according to the invention may be constituted by a mixture of platelets possessing various structures, in particular a mixture of platelets of monetite, brucite, apatite structure. This mixture is also named in the continuation of the description: calcium phosphate platelets with majority monetite structure. In this mixture, certain platelets can exhibit a chemical shift between 3 ppm and 3.4 ppm as measured by MAS NMR of phosphorus 31 that can be attributed to apatite structure. The platelets according to the invention can also have a deficient, well-crystallized apatite structure visible by X-ray diffraction. In this case, calcium phosphate platelets with a weak apatite structure advantageously have a calcium to phosphorus ratio comprised between 1. 25 and 1 .67, more particularly comprised between 1.3 and 1.6. In addition, the RX spectrum of these calcium phosphate platelets with weak apatite structure advantageously shows the backward stripes towards great distances with respect to an apatite hydroxy structure. Platelet size is preferably visualized by transmission electron microscopy (TEM). In this case, it is possible to analyze images from a dispersion, diluted or not. The platelets according to the invention advantageously have a length between 250 nm and 600 nm, preferably between 250 nm and 400 nm. Advantageously 60% by number of platelets according to the invention have a size less than or equal to 500 nm, preferably 70% and advantageously 80%. The platelets according to the invention advantageously have a thickness between 1 nm and 40 nm, preferably between 1 nm and 15 nm, more particularly between 2 nm and 6 nm. The calcium phosphate platelets according to the invention advantageously have a molar ratio of calcium to phosphorus comprised between: - 0.95 and 1.4 for the monetite structure, preferably between 1.1 and 1.3; 0.95 and 1.4 for the monetite structure mixed with the brucite and apatite structure, preferably between 1.1 and 1.3; - 1 .25 and 1 .67 for the apatite structure deficient, preferably between 1 .3 and 1 .6. The structure of monetite or the deficient apatite structure can be shown by X-ray diffraction. The calcium phosphate platelets with the majority monetite structure present an X-ray spectrum showing a well crystallized apatite, with a parameter c = 6.84A lower than apatite hydroxy parameter c (c = 6.88A). Calcium phosphate platelets with a monetite structure, or with a majority monetite structure or with a weak apatite structure advantageously have BET specific surfaces measured on dry products, between 40 and 100 m2 / g, more particularly between 50 and 80 m2 / g. The calcium phosphate platelets according to the invention may comprise doping elements. Preferably, these doping elements are chosen from alkaline earth elements such as strontium, magnesium, rare earth elements such as trio or elements of atomic number between 57 and 71. Other doping elements can also be contemplated, depending on different applications of dispersions according to the invention. The invention relates according to a first variant to the colloidal dispersions obtained by suspending the calcium phosphate platelets described above in the presence of a dispersing agent. The invention also relates according to a second variant to dispersions containing calcium phosphate platelets described above. In the case of two variants of dispersions according to the invention, at least 80% of the platelets in number have a length comprised between 250 nm and 600 nm, preferably between 250 nm and 400 nm. The dispersions according to the invention, whatever their embodiments, can also contain at least 50% of phosphorus in the form of a monetite structure. The dispersing agent present in the colloidal dispersions according to the first variant can be chosen from polyphosphates, in particular sodium tripolyphosphates. But it is equally possible to choose all the dispersing agents as used in this domain and which are well known to the person skilled in the art. The colloidal dispersions according to the first variant advantageously have a molar ratio Ra of moles of polyphosphate on moles of calcium, Ra being between 0.02 and 0.2, preferably between 0.02 and 0.1. The polyphosphate is preferably present on surfaces of colloids or in the aqueous continuous phase. Another subject of the invention is a method for the synthesis of calcium phosphate platelets according to the invention. The method according to the invention is preferably employed by dissolution after reprecipitation of an appropriate precursor based on brucite, or brucite / apatite mixture, and under dissolution-reprecipitation conditions defined below. The method for preparing calcium phosphate platelets is characterized in that it comprises the following steps: i) preparing a solution of calcium salts of which the pH is comprised between 4 and 6; ii) adding to the solution obtained in step i) a phosphate solution for a duration comprised between 30 minutes and 4 hours and in order to obtain a molar ratio of calcium on phosphate comprised between 1 and 2.5 and keeping the pH constant at a value between 4 and 6; iii) heat treating the dispersion obtained in step ii) at a temperature between 50 ° C and 95 ° C; iv) separating the formed platelets from the dispersion obtained in step ii); and uses in at least one of steps i) or ii) solutions containing an ammonium ion. According to a particular embodiment, steps i) and ii) can be reversed. In this case the first stage of the method is stage ii), and the second stage is stage i). The platelets obtained according to this first variant of the method preferably have a chemical shift comprised between -1.4 ppm and -1 ppm as measured by MAS NMR of phosphorus 31 that can be attributed to the monetite structure.

In certain cases, the platelets obtained according to this first variant of the method can also present a chemical shift comprised between 3 ppm and 3.4 ppm as measured by MAS NMR of phosphorus 31 that can be attributed to the apatite structure. In this specific case, the obtained platelets are made up of a mixture of platelets that have several structures, in particular a mixture of platelets of monetite structure, brucite, apatite. It is a mixture of calcium phosphate platelets with a majority monetite structure, as indicated above. According to another variant, the method for preparing calcium phosphate platelets is characterized in that it comprises the following steps: i) preparing a solution of calcium salts of which the pH is comprised between 4 and 6; ii) adding to the solution obtained in step i) a phosphate solution for a duration comprised between 30 minutes and 4 hours and in order to obtain a molar ratio of calcium on phosphate comprised between 1 and 2.5 and keeping the pH constant at a value between 4 and 6; iii) heat treating the dispersion obtained in step ii) at a temperature between 50 ° C and 95 ° C; iv) adjusting the pH of the dispersion obtained in step iii) to a value between 8 and 9.5; v) separating the platelets formed from the dispersion obtained in step iv); and uses in at least one of steps i) or ii) solutions containing an ammonium ion. According to a particular embodiment, steps i and ii) can be reversed. In this case the first stage of the method is stage ii), and the second stage is stage i). The platelets obtained according to this second variant of the method also preferably have a structure of the apatite-deficient type, as defined above. The following indications are valid whatever the variant of the method of the invention used. Step ii) of the method is preferably performed by continuous addition and not instantaneously of the solution obtained in step i). This addition can also be done drop by drop or a discontinuous addition in a regular time interval. This addition of phosphate solution to the calcium solution is carried out with the continuous addition of OH ions, preferably NH 4 OH, in order to regulate the pH of the solution at the setpoint pH The setpoint pH is preferably between 4 and 6. The OH ion concentration of the solution serving to regulate the pH may preferably vary between 1 M and 6 M, more particularly between 2 M and 4 M. The addition of OH ions "in step ii) can be carried out in such a way as to keep the pH of the regulated dispersion constant at a pH comprised between 4 and 6 (setpoint pH), preferably at pH equal to 5, or in constant yield with The help of a pump By constant pH is meant a pH of which the value has been set at a value between 4 and 6 and of which the pH does not vary more than 0.2 pH units with respect to this value. OH ions discharged is such that the OH7P molar ratio is comprised between 1 and 2.5, preferably between 1.5 and 2. The calcium solution used according to the method of the invention is advantageously a solution of CaCl2 or Ca (NO3) 2. This solution may optionally contain doping salts like those indicated above. Preferably, the concentration of the calcium solution is between 1 M and 2.5 M, preferably between 1.25 M and 1.75 M. The phosphate salt solution used according to the method of the invention is advantageously a solution of ammonium or sodium phosphate, notably of (NH4) 2 (HPO4) or (NH4) (H2PO4). According to the method of the invention, the molar ratio of calcium to phosphorus is advantageously comprised between 1.3 and 1.7, more particularly 1.66. Resulting from step ii), a dispersion in the form of a precipitate is preferably obtained. By X-ray diffraction on the precipitate formed at the exit of this stage, which has been centrifuged and then dried at 20 ° C, a structure of brucite CaHPO4, 2H2O is observed. By microscopy, a platelet morphology of micron-sized object is observed. By nuclear magnetic resonance of phosphorus 31, a brucite structure with a chemical shift can be observed ranging from d ppm = 1.4 to d ppm = 1.8, preferably ranging from 1.6 ppm.; d < 1.8 ppm. The method according to the invention comprises a thermal treatment step, step ii), of which the temperature is preferably between 60 ° C and 90 ° C. This heat treatment is also called maturation and takes place during approximately 3h to 24h, preferably for 3h to 16h. The temperature rise can take place in 5 minutes or in 30 minutes. Step v) according to the first variant or v) according to the second variant of the method according to the invention, platelet separation can be carried out by centrifugation, or filtration. The platelets are then preferably dried at room temperature. Step iv) according to the second variant of the method according to the invention, can be carried out by adding a base to the dispersion obtained in step iii) in order to obtain a pH value comprised between 8 and 9.5. The rise in pH can be carried out by adding a base to the dispersion previously placed under stirring at room temperature. The addition may be instantaneous or be carried out slowly. The addition time may be between 1 minute and 24 hours, preferably between 1 minute and 30 minutes. The dispersion is maintained at pH for a duration which may vary from 5 minutes to 24 hours, preferably between 5 minutes and one hour.

The colloidal dispersions according to the invention can be made, inter alia, according to the method described below. Resulting from step iv) according to the first variant or v) according to the second variant of the method according to the invention, the solid precipitate obtained can be washed using an aqueous solution, preferably demineralized water. This washing is preferably carried out using twice the volume of supernatant of the precipitate to be washed. Then the washed precipitate is separated. The washed precipitate obtained is redispersed with the aid of a dispersing agent solution, in particular with the aid of a tripolyphosphate solution. The concentration of the tripolyphosphate solution is determined by the molar ratio Rb of moles of polyphosphate on a mole of calcium, Rb being between 0.02 and 0.2, preferably between 0.02 and 0.15, and is also determined by the final concentration of calcium of the dispersion. This final concentration of calcium is preferably between 0.25M and 1.5M. After adding the dispersing agent to the solution, the solution is stirred advantageously for 30 minutes to 6 hours. After the addition, the suspension can be purified, for example by ultrafiltration on a 3KD membrane per passage of 2 to 10 volumes of water. A colloidal dispersion and a residue are obtained. The residue is removed, by different techniques known to the person skilled in the art, notably by filtration or by centrifugation. Finally, the invention relates to the use of calcium phosphate platelets or dispersions according to the invention as reinforcing fillers, polishing agents, building materials, additives for tooth formulations, notably toothpastes or encapsulating agents. The following examples illustrate the invention without limiting the scope. EXAMPLES Example 1: Method of preparation of calcium phosphate platelets with monetite structure Step i): A solution A is prepared by dissolving 36.75 g of CaCl2, 2H2O (MW = 147 g / mol) in 150 ml of water. The pH is adjusted to the value of 5 by the addition of 0.3 ml of a 0.01 M HNO3 solution and completed to 250 ml by demineralized water. Stage ii): A solution B is prepared by dissolving 19. 8 g of (NH4) 2 (HPO4) (MW = 132 g / mol) in 200 ml of water. This solution is neutralized at a pH of 5 by the addition of 19 ml of a 12M HNO3 solution. It is then added to 250 ml by the addition of demineralised water. In a stirred reactor, at 20 ° C, calcium salt solution A is poured into the bottom of the tank. Phosphate solution B is added in two hours and at regulated pH. The pH regulation is obtained with the help of a solution of NH4OH at 3M. The amount of 3M ammonia discharged when the maintenance of the pH is 92 ml. At the end of the addition, stirring is allowed 5 minutes. The molar ratio is Ca / P = 1 .66. Stage iii): The dispersion is immediately brought to 80 ° C. The rise in temperature lasts approximately 30 minutes. The ripening time at 80 ° C is 16 hours. Step iv): After cooling the dispersion, the solid product is collected by centrifugation. The solid product is washed by 4 times its volume of water. The product is dried at room temperature. 1.1 RX and RM analysis of a sample taken after the precipitation stage at 20 ° C (stage ii) The characterizations were carried out on the washed product and dried at 20 ° C. The presence of well-crystallized brucite is shown by X-ray diffraction. In certain cases, minority apatite is also formed. By phosphorus NMR 31, a peak chemical shift difference attributable to brucite is observed for the product (d ppm = 1.73 ppm compared to d ppm = 1.28 ppm for classic brucite). 1-2 Analysis of a sample taken after maturing at 80 ° C (stage iii) The individualization of platelets is shown by a granulometric analysis of the product, made with a Sedigraphic type device. The measurement is based on a sedimentation principle with an RX type detector on a 50 ml aliquot of the dispersion obtained after step iii). After cooling the aliquot of the dispersion, the solid product is collected by centrifugation. The solid product is washed by 4 times its volume of water and its volume increases to 50 ml. 0.77 g of tripolyphosphate sodium is added to the dispersion either at a tripolyphosphate / calcium molar ratio = 0.1 and left stirring for 30 minutes. The dispersion is placed under ultrasound for 7 minutes. The ultrasonic tank used is equipped with a probe with a diameter of 7 mm and a maximum power of 800W, which is 80%. The granulomc analysis of the product indicates that 95% of particles have an equivalent diameter of less than 200 nm. This low equivalent diameter size confirms that the platelets observed by transmission electron microscopy are individualized. By microscopy (MET), it is observed platelets of dimensions approximately 300 nm x 50 nm, it being understood that 300 nm is the length and 50 nm is the width. The following characterizations have been made in the washed and dried product at 20 ° C: by X-ray diffraction, the presence of a monetite structure is observed mainly, with a slightly delayed peak towards low angles. The presence of a apatite phase in a minor amount is also observed. This phase of apatite can be indicated on a card corresponding to Ca9.54 P 5.98 O 23.58 Cl - ,. 60 (OH) 2.74.

This structure is deformed with respect to the apatite hydroxy structure with a parameter a higher and a parameter c lower. a b c C 9,432 6,881 0.7295 Ca10 (P04) 6 (OH) 2 (hydroxl apatite) 9.541 6.838 0.7167 CS9.54 P 5.98 O 23.58 Cl 1.60 (0H) 2.74 the values a, b and c are given in Angstrom, and C is the ratio c / a. By X-ray diffraction, and concerning the monetite structure, a very strong intensity diffraction peak corresponding to the OhO direction is also shown, indicating a platelet plane perpendicular to the OhO direction. The determination of the size of crystallites following this direction shows the presence of ordered domains larger than 20 nm in this OhO direction. By phosphorus NMR 31, the presence of brucite and monetite apatite is shown, in respective amounts 35%, 10% and 55%. However, these phases are identified in delayed chemical displacements with respect to the chemical displacements classically attributed to these phases. d ppm classic ppm (product prepared Apatite + 2.9 ppm +3.15 ppm brucite + 1 .28 ppm onetito - 1.60 ppm -1 .15 ppm By infrared, the presence of monetite and non-stoichiometric apatite is observed, but nevertheless well crystallized. By chemical analysis, the overall Ca / P ratio is equal to approximately Ca / Pmo? Ar = 1 .2. Example 2: Method of preparing calcium phosphate platelets with apatite structure deficient: Steps i), ii) and iii) are identical to the steps described in example 1. Step iv): on a 100 ml aliquot of the dispersion after ripening at 80 ° C (step iii), cooled to room temperature and placed under stirring, 27 ml of 1 M ammonia and 10 ml of ammonia are added with a pump. minutes The pH is pH 9. It is left under stirring for 5 nm complementary. Stage v): the product is centrifuged. The product is washed with water then dried. After drying at room temperature, the X-ray diffraction shows apatite hydroxy structure with delayed stripes towards great distances. By transmission electron microscopy, individualized platelets approximately 300 nm in size are observed. Example 3: Method of preparation of colloidal dispersions of calcium phosphate platelets: The conditions of example 1 are taken up to step iii). It is taken after cooling to room temperature and a volume of dispersion corresponding to one third of the total volume is placed under agitation.

The dispersion is placed under centrifugation, the supernatant is removed. The initial volume is completed by demineralized water and placed under agitation. The operation of centrifugation, elimination of supernatant and addition of water to the initial volume is repeated anew. 3.06 g of sodium tripolyphosphate MW = 368 g / mol are added, either a molar ratio Rb = tripolyphosphate / Ca = 0.1. It is homogenized by stirring for two hours and left to stand overnight. A colloidal supernatant is recovered by forming the colloidal dispersion according to the invention.

Claims (1)

CLAIMS 1. Individualized calcium phosphate platelet having a structure of monetite, or majority monetite or apatite deficient and of which the length is between 250 nm and 800 nm. 2. The calcium phosphate plate according to claim 1, characterized in that the length is between 250 nm and 600 nm, preferably between 250 nm and 400 nm. 3. Calcium phosphate plate according to any of the preceding claims, characterized in that its thickness is between 1 nm and 40 nm. 4. Calcium phosphate plate according to any of claims 1 to 3, exhibiting a chemical shift comprised between -1.4 ppm and -1 ppm as measured by MAS NMR of phosphorus 31 attributed to the monetite structure. 5. Calcium phosphate plate according to any of claims 1 to 3, exhibiting a chemical shift comprised between 3 ppm and 3.4 ppm as measured by MAS NMR of phosphorus 31 attributed to the apatite structure. 6. Calcium phosphate plate according to any of claims 1 to 5, characterized in that it has a molar ratio of calcium to phosphorus comprised between 0.95 and 1.4 for the monetite structure, preferably comprised between 1.1 and 1.3. and comprised between 0.95 and 1.4 for the monetite structure mixed with the brucite and apatite structure, preferably comprised between 1.1 and 1.3. The calcium phosphate plate according to any of claims 1 to 3, characterized in that it has a molar ratio of calcium to phosphorus comprised between 1.25 and 1.67 for the apatite structure deficient, preferably comprised between 1.3 and 1 .6. 8. Dispersion containing calcium phosphate platelets according to any of claims 1 to 7. 9. Colloidal dispersion obtained by suspension of calcium phosphate platelets according to one of claims 1 to 7 in the presence of a dispersing agent. 10. Method for preparing platelets according to claims 1 to 6, characterized in that it comprises the following steps: i) preparing a solution of calcium salts of which the pH is comprised between 4 and 6; ii) adding to the solution obtained in step i) a phosphate solution for a duration comprised between 30 minutes and 4 hours and in order to obtain a molar ratio of calcium on phosphate comprised between 1 and 2.5 and keeping the pH constant at a value between 4 and 6; iii) heat treating the dispersion obtained in step ii) at a temperature between 50 ° C and 95 ° C; iv) separating the platelets formed from the dispersion obtained in step iii); and uses in at least one of steps i) or i) solutions containing an ammonium ion. eleven . Method for preparing platelets according to claims 1 to 3 and 7, characterized in that it comprises the following steps: i) preparing a solution of calcium salts of which the pH is comprised between 4 and 6; ii) adding to the solution obtained in step i) a phosphate solution for a duration comprised between 30 minutes and 4 hours and in order to obtain a molar ratio of calcium on phosphate comprised between 1 and 2.5 and keeping the pH constant at a value between 4 and 6; iii) heat treating the dispersion obtained in step ii) at a temperature between 50 ° C and 95 ° C; iv) adjusting the pH of the dispersion obtained in step iii) to a value between 8 and 9.5; v) separating the platelets formed from the dispersion obtained in step iv); and uses in at least one of steps i) or i) solutions containing an ammonium ion. 12. Method according to claim 10 or 11, characterized in that the calcium salt solution is a solution of CaCl2 or of Ca (NO3) 2 13. Method according to one of claims 10 to 12, characterized in that the concentration of the solution of Calcium salts are comprised between 1 M and 2.5 M, preferably between 1.25 M and 1.75 M. Method according to one of claims 10 to 13, characterized in that the phosphate salt solution is a solution of ammonium or sodium phosphate, notably of (NH4) 2 (HPO4) or (NH4) (H2PO4). Method according to one of claims 1 to 14, characterized in that the molar ratio of calcium to phosphorus is between 1.3 and 1.7. Method according to one of claims 10 to 15, characterized in that the molar ratio of calcium to phosphorus is

1 .66. Method according to one of claims 10 to 16, characterized in that the temperature of the heat treatment in step ij) is between 60 ° C and 90 ° C. 18. Use of platelets according to one of the claims 1 to 7 or a dispersion according to claims 8 or 9 as reinforcing filler, polishing agent, building materials, additive for dental formulations, notably toothpastes or encapsulating agent.