# US 2021/0276869 A1 · Stabilized amorphous calcium phosphate doped with fluoride ions and a process for producing the same > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2021/0276869 A1 - Document ID: US20210276869A1 - Status: Published application - Kind: A1 - Application number: 17/255,522 - Filed: 2019-06-27 - Published: 2021-09-09 - Earliest claimed: 2018-06-28 - Assignees: Curasept A.D.S. S.R.L. - Applicants: Curasept A.D.S. S.R.L. - Inventors: Michele IAFISCO; Anna TAMPIERI - Web page: https://patentgrep.com/patent/US20210276869A1 ## CPC - C01B 25/327: {After-treatment} - A61K 6/17: Particle size - A61K 6/54: Filling; Sealing - A61K 6/838: Phosphorus compounds, e.g. apatite - A61K 6/864: Phosphate cements (apatite A61K6/838) - B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery - B82Y 30/00: Nanotechnology for materials or surface science, e.g. nanocomposites - B82Y 40/00: Manufacture or treatment of nanostructures - C01P 2002/01: depicted by a TEM-image - C01P 2002/02: Amorphous compounds - C01P 2004/03: obtained by SEM - C01P 2004/04: obtained by TEM, STEM, STM or AFM - C01P 2004/50: Agglomerated particles - C01P 2004/64: Nanometer sized, i.e. from 1-100 nanometer - C01P 2006/12: Surface area - C01B: NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; {METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C} - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES - C01P: INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS ## Abstract The invention relates to a process for the preparation of a citrate-coated amorphous calcium phosphate nanoparticle which comprises the following steps: 1) providing a first solution of a salt of calcium and a citrate salt wherein the molar ratio of citrate ion to calcium ion is in the range from 1 to 2 thus obtaining a clear first solution; 2) providing a second solution of a salt capable to give phosphate anion and a carbonate salt; 3) mixing together the first and the second solution at a pH in the range from 8 to 11; 4) precipitating the nanoparticle; and 5) drying the nanoparticle obtained from step 4). Preferably and advantageously the invention provides for the addition of a fluoride compound in step 2) for obtaining a fluorine-doped citrate-coated calcium phosphate nanoparticle or a nanoparticle agglomerate. The nanoparticle/nanoparticle agglomerate of the invention has a peculiar superficial area and a diameter that allow to use it as a biomaterial for dentistry application. ## Claims ### Claim 1 A process for the preparation of a citrate-coated amorphous calcium phosphate nanoparticle which comprises the following steps: 1) providing a first solution of a salt of calcium and a citrate salt wherein the molar ratio of citrate ion to calcium ion is in the range from 1 to 2 thus obtaining a clear first solution; 2) providing a second solution of a salt capable to give phosphate anion and a carbonate salt; 3) mixing together the clear first solution and the second solution at a pH in the range from 8 to 11; 4) precipitating the nanoparticle; and 5) drying the nanoparticle obtained from step 4). ### Claim 2 (depends on 1) The process according to claim 1, wherein the salt of calcium is made of an anion selected from the group consisting of chloride, nitrate, hydroxide, acetate, oxalate, lactate, preferably the anion is chloride. ### Claim 3 (depends on 1) The process according to claim 1, wherein the salt of citrate is made of a cation selected from the group consisting of sodium and potassium, preferably the cation is sodium. ### Claim 4 (depends on 1) The process according to claim 1, wherein the molar ratio of citrate ion to calcium ion is about 2. ### Claim 5 (depends on 1) The process according to claim 1, wherein the first solution of step 1) comprises at least one further salt selected from the group of: strontium salt, and magnesium salt. ### Claim 6 (depends on 1) The process according to claim 1, wherein the salt capable to give phosphate anion is a salt of phosphate, hydrogen phosphate or hydrogen phosphate, preferably made of a cation selected from the group consisting of sodium, potassium and ammonium. ### Claim 7 (depends on 1) The process according to claim 1, wherein the pH of step 3) is in the range from 8.5-10.7. ### Claim 8 (depends on 1) The process according to claim 1, wherein in the mixing step 3) the second solution is added to the clear first solution. ### Claim 9 (depends on 1) The process according to claim 1, wherein in step 4) the precipitation is carried out by providing sedimentation cycles by centrifugation removal of supernatant, collecting and washing the precipitate. ### Claim 10 (depends on 1) The process according to claim 1, wherein the drying step 5) is selected from freeze-drying, spray-drying and ventilated oven drying. ### Claim 11 (depends on 1) The process according to claim 1, wherein in step 1) a fluoride compound is added. ### Claim 12 (depends on 11) The process according to claim 11, wherein the fluoride compound is a fluoride of a cation selected from the group consisting of sodium and potassium. ### Claim 13 (depends on 1) A citrate-coated amorphous calcium phosphate nanoparticle obtainable by the process according to claim 1, wherein the drying step 5) is a freeze-drying step, being said nanoparticle characterized by a superficial area from 250 m2 g−1 to 360 m2 g−1 as measured with Brunauer-Emmett-Teller (BET) gas adsorption method and having a round-shaped morphology with a diameter in the range from 30 to 80 nm as measured by transmission electron microscopy (TEM) images. ### Claim 14 (depends on 1) A citrate-coated amorphous calcium phosphate nanoparticle agglomerate obtainable by the process according to claim 1, wherein the drying step 5) is a spray-drying step, being said nanoparticle agglomerate characterized by a superficial area from 2 m2 g−1 to 10 m2 g−1 as measured with Brunauer-Emmett-Teller (BET) gas adsorption method and having a round shaped morphology with a diameter in the range from 2 to 25 μm as measured by scanning electron microscopy (SEM). ### Claim 15 (depends on 1) A fluorine-doped citrate-coated amorphous calcium phosphate nanoparticle obtainable by the process according to claim 1, wherein the drying step 5) is a freeze-drying step, being said nanoparticle characterized by a superficial area from 250 m2 g−1 to 370 m2 g−1 as measured with Brunauer-Emmett-Teller (BET) gas adsorption method and having a round shaped morphology with a diameter in the range from 30 to 80 nm as measured by transmission electron microscopy (TEM) images. ### Claim 16 (depends on 1) A fluorine-doped citrate-coated amorphous calcium phosphate nanoparticle agglomerate obtainable by the process according to claim 1, wherein the drying step 5) is a spray-drying step, being said nanoparticle agglomerate characterized by a superficial area from 3 m2 g−1 to 10 m2 g−1 as measured with Brunauer-Emmett-Teller (BET) gas adsorption method and having a round shape morphology with a diameter in the range from 2 to 25 μm as measured by scanning electron microscopy (SEM). ### Claim 17 (depends on 13) A dentistry application method comprising the use of a nanoparticle or a nanoparticle agglomerate according to claim 13 as a biomaterial. ### Claim 18 (depends on 17) The dentistry application method according to claim 17 wherein the biomaterial is used as remineralization agent or as dentin desensitizer. ### Claim 19 (depends on 14) A dentistry application method comprising the use of a nanoparticle or a nanoparticle agglomerate according to claim 14 as a biomaterial. ### Claim 20 (depends on 19) The dentistry application method according to claim 19 wherein the biomaterial is used as remineralization agent or as dentin desensitizer. ### Claim 21 (depends on 15) A dentistry application method comprising the use of a nanoparticle or a nanoparticle agglomerate according to claim 15 as a biomaterial. ### Claim 22 (depends on 21) The dentistry application method according to claim 21 wherein the biomaterial is used as remineralization agent or as dentin desensitizer. ### Claim 23 (depends on 16) A dentistry application method comprising the use of a nanoparticle or a nanoparticle agglomerate according to claim 16 as a biomaterial. ### Claim 24 (depends on 23) The dentistry application method according to claim 23 wherein the biomaterial is used as remineralization agent or as dentin desensitizer.