Process for Producing Calcium Phosphate

Europaisches Patentamt European Patent Office © Publication number: 0 265 945 Office europeen des brevets A2

® Priority: 31.10.86 JP 260196/86 © Applicant: ASAHI KOGAKU KOGYO KABUSHIKI KAISHA © Date of publication of application: 36-9, Maeno-cho 2-Chome Itabashi-ku 04.05.88 Bulletin 88/18 Tokyo 174(JP)

0 Representative: Hansen, Bernd, Dr.rer.nat et al Hoffmann, Eitle & Partner Patentanwalte Arabellastrasse 4 Postfach 81 04 20 D-8000 MUnchen 81 (DE)

@ Process for producing calcium phosphate.

© A process for producing a calcium phosphate comprising the steps of (a) dissolving at least one member selected from the group consisting of calcium hydroxide and calcium oxide in water with at least one member selected from the group consisting of a sugar, a sugar alcohol, and a polyhydric alcohol; (b) and adding phosphoric acid to the solution obtained to precipitate a calcium phosphate.

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PROCESS FOR PRODUCING CALCIUM PHOSPHATE

SUMMARY OF THE INVENTION HELD OF THE INVENTION An object of the present invention is to provide The present invention relates to a process for a process for producing a calcium phosphate in producing a calcium phosphate, and more particu- 5 which a high quality calcium phosphate can be larly to a process for producing a calcium phos- obtained in a simplified manner without disadvan- phate by reacting calcium hydroxide and phos- tages such as precipitation and solidification of phoric acid in an aqueous solution, that is, by a wet calcium hydroxide. method. It has now been found that the above and other io objects of the present invention are attained by a process for producing a calcium phosphate com- BACKGROUND OF THE INVENTION prising the steps of (a) dissolving at least one member selected from the group consisting of cal- Calcium phosphates are now widely used as cium hydroxide and calucium oxide in water with at food additives, dental materials, for artificial bones, 75 least one member selected from the group consist- etc. ing of a sugar, a sugar alcohol, and a polyhydric In the production of calcium phosphates, a wet alcohol; and (b) adding phosphoric acid to the method in which calcium hydroxide and phosphoric solution obtained to precipitate a calcium phos- acid are reacted in an aqueous solution is generally phate. employed. In accordance with the wet method, 20 calcium hydroxide or calcium oxide is added to water to prepare a suspension (hereinafter referred BRIEF DESCRIPTION OF THE DRAWINGS to as "lime milk"), and an aqueous phosphoric acid solution is added thereto dropwise and reacted with Fig. 1 is a photograph showing the state of the lime milk to precipitate a calcium phosphate. 25 the aqueous calcium hydroxide solution used in the In the wet method, however, calcium hydroxide Example 1 and that of the aqueous suspension of is present chiefly in solid form in the lime milk calcium hydroxide used in the Comparative Exam- because the solubility of calcium hydroxide in wa- ple. ter is extremely low (solubility at 20 °C: 0.126 g per Fig. 2 is a photograph showing the state just 100 g of water). For this reason, even if phosphoric 30 after the stirring for precipitation of calcium phos- acid is added with vigorous stirring, it is difficult to phate through addition of phosphoric acid to the consistently obtain a high quality product under the above aqueous solution and the aqueous suspen- influences of granularity, form, and the like of solid sion. calcium hydroxide. Moreover, during the storage of Fig. 3 is a photograph showing the state the lime milk, precipitation and solidification occur 35 when the above calcium phosphate precipitated unless vigorous stirring is continuously applied. For solution is allowed to stand for 2 minutes after example, in the conventional wet method, since stirring. both calcium hydroxide in solid form and that in Fig. 4 is an X-ray diffraction pattern of a dissolved form react with phosphoric acid, un- sintered material of calcium phosphate prepared in homogeneous calcium phosphate having different 40 Example 2. diameters and properties is obtained. Another problem is that in transporting the lime milk by means of e.g., a pump, adhesion to the DETAILED DESCRIPTION OF THE INVENTION pipe and solidification occur. Thus, there has been proposed a method in 45 According to the present invention, calcium hy- which a water-soluble calcium salt such as calcium droxide is dissolved in an aqueous solution contain- chloride or calcium nitrate, is used in place of the ing at least one of sugars, sugar alcohols, and lime milk and is reacted with sodium phosphate, polyhydric alcohols, and phosphoric acid or an ammonium phosphate and the like in an aqueous aqueous solution thereof is added to the resultant solution to produce a calcium phosphate. so solution to precipitate calcium phosphate. This method, however, has the disadvantage Addition of at least one of sugars, sugar al- that undesirable compounds are produced as well cohols, and polyhydric alcohols increases the solu- as the desired calcium phosphate, requiring an bility of calcium hydroxide in water, thereby permit- additional step for removing the byproducts and ting the dissolution of calcium hydroxide in water. complicating the process. Thus, the problem of precipitation and solidification

2 3 0 265 945 4 during storage or transportation can be overcome, The ratio of calcium hydroxide to phosphoric and handling and operation can be simplified. acid (Ca/P atomic ratio) is determined depending Moreover, since phosphoric acid is reacted with on the composition of the desired calcium phos- calcium hydroxide which is dissolved, calcium phate. Examples of the desired calcium phosphate phosphate is precipitated in a fine particulate form 5 includes hydroxy apatite (Caio(P04)6(OH)2) and further is of high quality. Sugars, sugar al- (Ca/P = 10/6), fluorine apatite (Ca^PO^) cohols, and polyhydric alcohols used to increase (Ca/P = 10/6), and tricalcium phosphate (Ca3(P04)2) the solubility of calcium hydroxide in water are (Ca/P = 3/2). inexpensive, and since they are composed of only The calcium phosphate precipitated by the re- carbon, hydrogen, and oxygen, they can be re- 10 action can be withdrawn in a powder form by any moved by evaporation in the form of carbon diox- conventional techniques such as filtration, cen-. ide gas and steam by heating. trigual separation, and spray drying. The solution of calcium hydroxide in an aque- The calcium phosphate obtained can be used ous solution containing at least one of sugars, as a material for production of various products sugar alcohols and polyhydric alcohols can be pre- 15 such as artificial bone and column fillers. Particu- pared, for example, by any of the following meth- larly, a high density sintered material can be pre- ods: (1) a method in which an aqueous solution of pared from the calcium phosphate obtained ac- at least one of sugars, sugar alcohols, and poly- cording to the present invention, and such a sin- hydric alcohols is prepared and calcium hydroxide tered material can be used as a bio-ceramics of or calcium oxide is added to and dissolved in the 20 high quality. aqueous solution; (2) a method in which calcium The present invention is described in greater hydroxide or calcium oxide is added to water to detail with reference to the following examples, prepare lime milk and at least one of sugars, sugar which are not to be construed as limiting the alcohols, and polyhydric alcohols is added to and present invention. Unless otherwise indicated, all dissolved in the lime milk; and (3) a method in 2s parts, percents, and ratios are by weight. which water, at least one of sugars, sugar alcohols, and polyhydric alcohols, and calcium hydroxide or calcium oxide are mixed at the same time. EXAMPLE 1 Examples of at least one of sugars, sugar alcohols, and polyhydric alcohols which can be used 30 50 g of glycerine and 100 g of water were in the present invention include glucose, fructose, placed in a 200 itU flask and mixed to prepare 150 galactose, maltose, saccharose, mannose, sorbose, g of an aqueous glycerine solution. To this aque- ribose, xylose, arabinose, lactose, sorbitol, man- ous glycerine solution, 2 g of calcium oxide was nitol, glycerine, erithritol, etc. added. Upon stirring the resultant mixture with a The concentration of sugars, sugar alcohols, 35 magnetic stirrer, a transparent solution was ob- and polyhydric alcohols in the aqueous solution is tained. The state of the solution is shown in Fig. 1 preferably 10 wt% or more. At a lower concentra- on the left side. tion of less than 10 wt%, it is relatively difficult to A necessary amount of a 4% aqueous phos- satisfactorily dissolve calcium hydroxide in the so- phoric acid solution for forming hydroxy apatite (2.1 lution. It is not necessary, however, to add the 40 g as phosphoric acid) was added dropwise to the sugars, sugar alcohols, and polyhydric alcohols till above aqueous solution and mixed. Then the solu- the saturated concentration is attained. tion became turbid and hydroxy apatite precipitat- The desired calcium phosphate can be ed. The state of the suspension just after stirring is precipitated by adding phosphoric acid to the shown in Fig. 2 on the left side. The stirring was aqueous calcium hydroxide solution and reacting 45 stopped and the suspension was allowed to stand them therein. In this case, it is preferred that phos- for 2 minutes. The suspension was still turbid at phoric acid be added as an aqueous solution hav- this time since the precipitated hydroxy apatite is ing a concentration of 80 wt% or less under stir- in a form of super fine particles. The state of the ring. For this operation, the phosphoric acid drop- suspension at this time is shown in Fig. 3 on the ping method which is widely used in the art may 50 left side. The hydroxy apatite thus precipitated was be employed, or the continuous contact preparation in a super fine particle form and was excellent in method as disclosed in Japanese Patent Applica- dispersibility, and even after standing for 2 minutes tion (OPI) No. 152009/79 (the term "OPI" as used after stirring, almost no precipitation occurred. herein means a "published unexamined Japanese patent application") and British Patent Application 55 1, 586,91 5A may be employed. During the addition of phosphoric acid, any of water-soluble com- pound, e.g., a fluoride, may be present.

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COMPARATIVE EXAMPLE aqueous solution, a calcium pnospnaie wmcn is in a very fine particulate form and of high purity can of 150 g of water was placed in a 200 ml flask, be obtained. Furthermore, the process produc- and 2 g of calcium oxide was added thereto and tion is greatly simplified. stirred with a magnetic stirrer. The mixture became > While the invention has been described in de- /vhitely turbid and lime milk was obtained. The tail and with reference to specific examples thereof, state is shown in Fig. 1 on the right side. it will be apparent to one skilled in the art that A necessary amount of a 4% aqueous phos- various changes and modifications can be made Dhoric acid solution for forming hydroxy apatite (2.1 therein without departing from the spirit and scope g as phosphoric acid) was added to the above o thereof. solution and mixed. Then, the solution became turbid, and hydroxy apatite precipitated. The state Df the suspension just after the stopping of stirring Claims is shown in Fig. 2 on the right side. The state of the suspension 2 minutes after the stopping of rs 1. A process for producing a calcium phos- stirring is shown in Fig. 3 on the right side. The phate comprising the steps of lower half of the suspension was turbid, and the (a) dissolving at least one member selected and upper half of the suspension was transparent. This from the group consisting of calcium hydroxide is because the hydroxy apatite thus precipitated is calcium oxide in water with at least one member a coarse particle form, and on standing it for 2 20 selected from the group consisting of a sugar, a minutes after the stopping of stirring, considerable sugar alcohol, and a polyhydric alcohol; precipitation occurred. (b) and adding phosphoric acid to the solution obtained to precipitate a calcium phosphate. 2. A process for producing a calcium phos- EXAMPLE 2 25 phate as claimed in Claim 1 , wherein said sugar is selected from the group consisting of glucose, 200 g of saccharose was added to 1 kg of furactose, galactose, maltose, saccharose, man- water to prepare 1.2 kg of an aqueous saccharose nose, sorbose, ribose, xylose, arabinose, and lac- solution. 34.8 g of calcium oxide was added to the tose. above solution. Upon stirring the resulting mixture, 30 3. A process for producing a calcium phos- a transparent solution was obtained. phate as claimed in Claim 1, wherein said sugar Upon dropwise adding a necessary amount of alcohol is selected from the group consisting of a 4% aqueous phosphoric acid solution for forming sorbitol and mannitol. calcium triphosphate (40.5 g as phosphoric acid) to 4. A process for producing a calcium phos- the above solution, the mixture became turbid and 35 phate as claimed in Claim 1, wherein said poly- calcium triphosphate precipitated. hydric alcohol is selected from the group consist- The turbid solution obtained was dried using a ing of glycerin and erythritol. spray drier. The powder thus obtained was molded 5. A process for producing a calcium phos- in a pellet form and fired at 1,100°C to obtain a phate as claimed in Claim 1 , wherein said step (a) sintered material of high density. The X-ray diffrac- 40 comprises first preparing an aqueous solution of tion pattern of the sintered material is shown in Fig. said sugar, sugar alcohol, or polyhydric alcohol, 4. This X-ray diffraction pattern showed that the and thereafter adding said calcium hydroxide or sintered material was /S-tricalcium phosphate. calcium oxide. In accordance with the present invention, as 6. A process for producing a calcium phos- described above, calcium hydroxide is dissolved in 45 phate as claimed in Claim 1, wherein said step (a) an aqueous soulution containing at least one of comprises first adding said calcium hydroxide or sugars, sugar alcohols, and polyhydric alcohols, calcium oxide to water to prepare lime milk, and and phosphoric acid is added to the aqueous cal- thereafter adding said sugar, sugar alcohol, or poly- cium hydroxide solution to precipitate calcium hydric alcohol to said lime milk. phosphate. Thus, there is no chance of precipita- so 7. A process for producing a calcium phos- tion and solidifying of calcium hydroxide during the phate as claimed in Claim 1, wherein said step (a) storage and transportation, and the handling opera- comprises simultaneously adding said sugar, sugar tion thereof is simplified. Moreover, in accordance alcohol, or polyhydric alcohol, and said calcium with the present invention, since the desired cal- hydroxide or calcium oxide to water. cium phosphate is precipitated by adding phos- 55 8. A process for producing a calcium phosphoric acid to calcium hydroxide in the state of an phate as claimed in Claim 1, wherein the total concentration of said sugar, sugar alcohol, or polyhydric alcohol in said solution is at least 10 wt%.

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a. a process for producing a calcium phosphate as claimed in Claim 1, wherein said calcium phosphate is selected from the group consisting of Caio(P04)6

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