United States Patent (19) (11) 4,247,526 Jarvis et al. 45) Jan. 27, 1981 (54) METHOD FOR PRE PARING DICALCIUM Primary Examiner-O. R. Vertiz PHOSPHATE DHYDRATE WITH Assistant Examiner-Gregory A. Heller IMPROVED STABILITY Attorney, Agent, or Firm-S. M. Tarter; W. H. Duffey; (75) Inventors: William M. Jarvis, Webster Groves; F. D. Shearin Keun. Y. Kim, Clayton, both of Mo. 57 ABSTRACT (73) Assignee: Monsanto Company, St. Louis, Mo. Dicalcium phosphate dihydrate containing a sufficient amount of trimagnesium phosphate and/or tetrasodium 21) Appl. No.: 43,412 pyrophosphate to inhibit spontaneous hydrolysis and /or decomposition of the dicalcium phosphate dihy (22) Filed: May 29, 1979 drate is widely used as a dental polishing agent with and (51) int. Cl...... COB 00/00; C01B 15/16; without added fluoride. Now it has been found that COB 25/26 dicalcium phosphate dihydrate containing a sufficient (52) U.S. C...... 423/266; 423/267; amount of pyrophosphate to provide hydrolytic stabil 423/308; 423/311; 424/57 ity to the dicalcium phosphate can have improved fluo (58) Field of Search ...... 423/265, 266, 267, 307, ride stability when about 0.1 weight percent to about 5 423/308,309, 311, 313; 424/57 weight percent of trimagnesium phosphate, and about 0.1 weight percent to about 3 weight percent of at least (56) References Cited one pharmaceutically acceptable condensed phosphate U.S. PATENT DOCUMENTS salt is added to the formulation. In the preferred em 2,852,341 9/1958 Bell et al. .... 8 was 423/308 bodiment less than 2 percent sodium tripolyphosphate 3,012,852 12/1961 Nelson ...... a a 423/267 provides satisfactory results. 3,066,056 11/1962 Schlaeger et al. .. 423/267 3,464,786 9/1969 Harnisch et al...... 423/313 10 Claims, No Drawings 4,247,526 1. 2 (A) providing dicalcium phosphate dihydrate con METHOD FOR PREPARING DICALCUM taining a sufficient amount of pyrophosphate com PHOSPHATE DHYDRATE WITH IMPROVED plex to provide at least some hydrolytic stability to STABILITY the DCPD; 5 (B) adding to the dicalcium phosphate dihydrate BACKGROUND OF THE INVENTION from about 0.1 weight percent to about 5 weight The present invention relates to a method of prepar percent trimagnesium phosphate, based on the ing dentifrice abrasives, and more particularly to dical weight of the dicalcium phosphate dihydrate; and cium phosphate dihydrate with improved stability. (C) adding to the dicalcium phosphate dihydrate 10 from about 0.1 weight percent to about 3 weight Dicalcium orthophosphate dihydrate (CahPO4.2- percent of a pharmaceutically acceptable con H2O) that has been stabilized against spontaneous hy densed phosphate salt, based on the weight of the drolysis and/or decomposition with a small amount of dicalcium phosphate dihydrate. tetrasodium pyrophosphate in accordance with the The term "DCPD' as it is used in the specification processes such as those described by Moss et al in U.S. 15 and claims shall mean dicalcium phosphate dihydrate. Pat. No. 2,287,699 or with trimagnesium orthophos The term "pyrophosphate complex' shall mean the phate and the like has been utilized in dental prepara chemical composition that is formed when a salt of a tions for many years. Indeed, dicalcium phosphate dihy soluble pyrophosphate or calcium-alkali metal pyro drate frequently is stabilized against spontaneous hydro phosphate is added to DCPD during the precipitation lysis and/or decomposition with a small amount of both 20 stage to provide conventional hydrolytic stability to the tetrasodium pyrophosphate and trimagnesium phos DCPD. The term “hydrolytic stability” with respect to phate in dental preparations. DCPD shall mean DCPD that has been stabilized Furthermore, as is known to those skilled in the art, against spontaneous hydrolysis and/or decomposition. dentifrice formulations using dicalcium phosphate dihy DCPD containing the pyrophosphate complex can drate frequently contain sodium or potassium mono 25 be prepared by any number of techniques known to fluorophosphate as a source of fluoride ion to inhibit or those skilled in the art. Generally, a basic calcium-con retard the formation of dental caries. Thus, the use of taining material such as calcium carbonate, calcium dicalcium phosphate dihydrate with sodium or potas oxide, calcium hydroxide and mixtures thereof, includ sium monofluorophosphate and stabilized against spon ing mixtures commonly known as slaked lime, quick taneous hydrolysis and/or decomposition with tetraso 30 lime and hydrated lime, are added to dilute aqueous dium pyrophosphate and/or trimagnesium phosphate, solutions of orthophosphoric acid to precipitate DCPD. either with or without other polishing agents, are well Then, hydrolytic stability of the DCPD from the pyro known to those skilled in the art. phosphate complex is achieved by adding a calcium/- Although satisfactory results are obtained using the sodium pyrophosphate or a soluble pyrophosphate salt dental formulations as set forth above, it has been found 35 to the DCPD such as is disclosed in U.S. Pat. Nos. that over a period of time the soluble fluoride is lost 2,287,699; 3,012,852; 3,169,096; 3,411,873 and the like. from the dental formulations. For example, it has been In the preferred embodiment, the DCPD is prepared found that dental formulations containing dicalcium by adding 0.3 weight percent P2Os equivalent of tet phosphate dihydrate stabilized with tetrasodium pyro raalkali metal pyrophosphate to an aqueous mixture phosphate at up to 1 weight percent by weight P2O5, as containing DCPD having a pH from about 5.5 to about pyrophosphate, or about 2 weight percent trimagne 6.5 and then adding a sufficient amount of lime to the sium phosphate octahydrate, and sufficient sodium DCPD slurry to provide a pH from about 6.5 to about monofluorophosphate to provide about 1,000 parts per 8.0. million soluble fluoride will lose a substantial amount of The soluble pyrophosphate salts useful for preparing the soluble fluoride after prolonged storage. Only a 45 the pyrophosphate complex are well known to those small improvement is seen when both trimagnesium skilled in the art. Tetraalkali metal pyrophosphates such phosphate and tetrasodium pyrophosphate are used as tetrasodium pyrophosphate and tetrapotassium pyro together with respect to soluble fluoride stability. phosphate are preferred, and tetrasodium pyrophos Although Applicants do not wish to be bound by any phate is especially preferred to form the pyrophosphate particular theory, it is believed that the loss of soluble 50 complex. The amount of soluble pyrophosphate salt to fluoride in the formulation is related to the hydrolytic be added to the DCPD to provide partial hydrolytic instability of the dicalcium phosphate dihydrate. It is stability ranges from about 0.1 to about 5 percent by believed that fluoride ion catalyzes the formation of weight of P2O5, as pyrophosphate, based on the weight calcium hydroxyapatite which then reacts with the of the DCPD. It is preferred to add the soluble pyro soluble fluoride to form water-insoluble calcium 55 phosphate salt in an amount corresponding to an addi fluoroapatite and/or calcium fluoride. Hence, it can be tion of from about 0.5 to about 2.5 percent by weight of seen that improved fluoride stability of dicalcium phos P2O5, as pyrophosphate, based on the weight of the phate dihydrate may improve stability against spontane DCPD. On yet another basis, the soluble pyrophos ous hydrolysis and/or decomposition. phate salt is added in an amount which results in a In any event, it can be seen that there is a need for a DCPD containing from about 0.2 to about 2.5 percent method of preparing dicalcium phosphate dihydrate by weight of pyrophosphate P2O5, which would repre which will provide greater amounts of soluble fluoride sent typical stabilized DCPD. after prolonged storage. Now, a method to meet this After the DCPD containing the pyrophosphate com need is provided. plex is recovered from the slurry and dried, trimagne 65 sium phosphate is added by techniques known to the SUMMARY OF THE INVENTION art, as for example, blending powdered trimagnesium These and other needs are achieved by a method phosphate with the DCPD. The amount of trimagne which comprises: sium phosphate that can be used in the composition of 4,247,526 3 4 the present invention can vary within wide limits. The Pharmaceutically acceptable salts of a compound beneficial effects of the trimagnesium phosphate are having only one phosphorous atom, such as an ortho generally not observed at concentrations less than about phosphate, does not provide as much stability to the 0.1 weight percent, based on the weight of the DCPD, DCPD as provided by condensed phosphates, although and additional stability is not seen at concentrations 5 their presence in the DCPD prepared by the method of above about 5 weight percent, based on the weight of the present invention is not harmful. Indeed, it may be the DCPD. It is preferred to add between about 0.5 desirable to add such a compound along with the con weight percent and about 3 weight percent, based on densed phosphate to obtain maximum fluoride stability. the weight of the DCPD. The amount of the pharmaceutically acceptable con In addition, the trimagnesium phosphate used in the 10 densed phosphate salt can vary within wide limits. Al method of the present invention is generally added as though beneficial effects are observed at concentrations the octahydrate. However, other hydrates of magne as low as about 0.1 percent, based on the weight of the sium phosphate may be equivalent since the exact form DCPD, it is preferred to use higher concentrations, say of the effective magnesium phosphate after it has been greater than about 0.3 weight percent. There does not incorporated into a DCPD-based toothpaste formula- 15 seem to be a beneficial effect in using more than about tion is not known. Hence, anhydrous trimagnesium 3 weight percent, based on the weight of the DCPD, phosphate or trimagnesium phosphates containing 8 to and the presence of higher concentrations of condensed 22 waters of hydration, or even dimagnesium phosphate phosphates may degrade soluble fluoride stability to hydrates, are deemed to be equivalent for purposes of some degree. The exact concentration of the pharma this invention, although the use of trimagnesium phos- 20 ceutically acceptable condensed phosphate salts will phate with 8 waters of hydration is preferred. depend upon a number of factors, as will occur to those According to the process of the present invention skilled in the art in view of the present disclosure, such there is also added to the DCPD from about 0.1 weight as the amount of trimagnesium phosphate and the percent to about 3 weight percent, based on the weight amount of the pyrophosphate complex, the grade of the of the DCPD, of at least one pharmaceutically accept- 25 DCPD, the particular condensed phosphate salt used able condensed phosphate salt. The pharmaceutically and the like. However, it is preferred to add between acceptable condensed phosphate salt can be added to about 0.3 weight percent and about 2 weight percent, the DCPD by techniques known to the art, such as by based on the weight of the DCPD. blending the powdered condensed phosphate salt with The mechanism by which the pyrophosphate com the DCPD. 30 plex and the trimagnesium phosphate and the con In the method of the present invention, the pharma densed phosphate salts provide the superior soluble ceutically acceptable condensed phosphate salt and the fluoride stability to DCPD is not understood. At first, it trimagnesium phosphate can be added to the DCPD was believed that since the condensed phosphate salts containing the pyrophosphate complex at any stage are known to be strong calcium sequestering agents, the before the DCPD is incorporated into a toothpaste 35 superior results were achieved by this action. However, formulation. The order of addition is not believed to be when a DCPD composition containing the pyrophos important, but we prefer to add the trimagnesium phos phate complex and trimagnesium complex was admixed phate to the DCPD before we add the pharmaceutically with trisodium nitrilotriacetate or tetrasodium ethylene acceptable condensed phosphate salt. diamine tetraacetate, the hydrolytic stability of the re Any number of pharmaceutically acceptable con- 40 sulting DCPD was not as good as the stability obtained densed phosphate salts known to those skilled in the art by the present method. can be used in the method of the present invention. The DCPD prepared by the present method can be Sodium, ammonium and potassium salts, either singly or used in toothpaste formulations with alkali metal mono admixed together or with other elements such as cal fluorophosphates such as sodium monofluorophos cium and the like, are generally considered to be phar- 45 phate, potassium monofluorophosphate and the like. maceutically acceptable. Hence, suitable condensed Sodium monofluorophosphate is preferred for use with phosphate salts include the pharmaceutically acceptable DCPD. salts of pyrophosphates, such as tetrasodium pyrophos The DCPD prepared by the present method can be phate, tetrapotassium pyrophosphate, disodium dihy combined with other dental polishing agents, as will drogen pyrophosphate (commonly called sodium acid 50 occur to those skilled in the art. Such dental polishing pyrophosphate), anhydrous or the hexahydrate, triso agents include, but are not limited to, insoluble meta dium or tripotassium pyrophosphate, and the like; poly phosphates, silica gels, alumina, chalk and the like. Al phosphates such as pentasodium tripolyphosphate, pen though satisfactory results are achieved using the tapotassium tripolyphosphate and hydrogen containing DCPD prepared by the present method, it may be desir sodium or potassium tripolyphosphates (Na4HP3O 10, 55 able to add an additional polishing agent such as anhy K3H2P3O10) and the like; ultraphosphates; metaphos drous dicalcium orthophosphate, i.e., precipitated anhy phates, such as sodium metaphosphate and potassium drous dicalcium orthophosphate, in order to clean teeth metaphosphate and the like. Pentasodium tripolyphos that are very heavily coated with discoloring material, phate is preferred. food particles, tartar and the like. The preparation of In addition to the above condensed phosphate salts, 60 such DCPD containing a minor amount of such addi amorphous condensed phosphates can be used in the tional polishing agents is known to those skilled in the present method, such as the sodium phosphate glasses art, such as described in U.S. Pat. No. 3,334,979. which extend from pure P2O5 to a composition near a In the formation of finished dentifrice compositions Na2O/P2O5 mole ratio of 1.7. The glass with the mole containing DCPD prepared by the present method, ratio of 1.0 is called hexametaphosphate (sometimes 65 practically any of the auxiliary agents that are conver Graham's salt) and other glasses have been called poly tionally utilized in toothpastes and/or tooth powder phosphates with the degree of polymerization given by formulations can be used. Toothpastes, for example, proximate analysis. will generally contain: a source of fluoride ion, such as 4,247,526 5 6 sodium monofluorophosphate; a sweetener, such as Samples of the above paste are transferred to plastic saccharin; a humectant, such as sorbitol or glycerine; a bottles. Thereafter, the plastic bottles are stoppered and binding agent, such as hydroethyl cellulose, carboxy placed in an oven at 50° C. for six weeks as an acceler methyl cellulose, and the like; a sudsing agent, such as ated test to simulate two years storage at ambient tem sodium lauryl sulfate, sucrose monolaurate or tridecyl perature. After the six weeks storage, the bottles are alcohol that has been reacted with from about 3 to removed from the oven and the soluble fluoride concen about 10 moles of ethylene oxide per mole of alcohol; tration of the formulation is measured potentiometri and a flavoring agent. cally. The results of the storage after six weeks are In toothpastes, the level of the DCPD that is utilized shown in Table 1. can generally be varied from about 20 to about 60 10 weight percent, and preferably from about 30 to about TABLE 1 45 weight percent of the formulation. As noted above, FLUORIDE STABILITY the DCPD prepared by the present method need not be POWDERED SOLUBLE F the only polishing agent in the dentifrice formulation, ADDITIVE TO OCPD REMAINING although it is generally preferred that DCPD represents 15 RUN Identity Wt 7, (ppm) - - 190 at least about half of all of the polishing agents in the 2 Sodium Tripolyphosphate 1 290 dentifrice formulation. , 3 Trimagnesium Phosphate 2 390 4. Trimagnesium Phosphate 3 390 DESCRIPTION OF THE PREFERRED 5 Trimagnesium Phosphate 2 430 EMBODIMENTS Glassy Sodium Poly 20 phosphate This invention is illustrated by, but not limited to, the 6 Trimagnesium Phosphate 2 455 following Examples wherein all percentages are by Sodium Hexametaphosphate 1 7 Trimagnesium. Phosphate 2 490 weight unless otherwise indicated. Sodium Trimetaphosphate 1 8 Trimagnesium Phosphate 2 490 EXAMPLE I 25 SQ Glassy Phosphate An aqueous slurry containing DCPD is prepared by 9 Trimagnesium Phosphate 2 49S Tetrasodium Pyrophos the reaction of phosphoric acid and lime in an aqueous phate l media. The resulting slurry contains approximately 30 10 Trimagnesium Phosphate 2 565 percent DCPD and the slurry pH is 5.8. Pentasodium Tripoly A 2780 gram sample of the DCPD aqueous slurry 30 phosphate 1 with pH adjusted to 6.5 using lime slurry (13.5 percent DCPD containing 0.5 percent pyrophosphate complex CaO) is charged to a one gallon reactor equipped with containing about 200 phosphorus atoms stirrer. There is added to this slurry 188 grams of a 9 available commercially from Monsanto Company, St. Louis, Missouri percent TSPP aqueous solution (2 percent TSPP based on the DCPD present) and the mixture is stirred for 45 35 EXAMPLE II minutes at about 29 C. The pH is then adjusted to about 7.7 with aqueous lime slurry (13.5 percent CaO) The procedure of Example I is repeated. The added and the solid DCPD product is separated from the soluble fluoride content of the toothpaste formulation is slurry, dried and milled. A small portion of the sample about 1,000 ppm. The results are shown in Table 2. was separated and the P2O5 levels corresponding to the TABLE 2. pyrophosphate complex present is determined substan FLUORIDE STABILITY tially in accordance with the well known ion exchange POWDERED method for analysis of sodium triphosphate ASTM ADDITIVE TO DCPD SOLUBLE F D-2671-70 (reapproved 1975), entitled "Standard Wt REMAINING Method for Analysis of Sodium Triphosphate by the 45 RUN Identity % (ppm) 11 Trimagnesium Phosphate 2 510 Simplified Ion Exchange Method). The pyrophosphate 12 Trimagnesium Phosphate 5 480 complex content is found to be about 0.5 percent. 13 Pentasodium Tripolyphosphate 0.5 330 Portions of the above DCPD containing the pyro Sodium Metaphosphate 0.5 phosphate complex, after drying and milling, are 14 Pentasodium Tripolyphosphate 0.5 290 50 Disodium Dihydrogen Pyro blended with powdered trimagnesium phosphate and phosphate 0.5 /or powdered condensed phosphates, and used to pre 15 Trimagnesium Phosphate 2 570 pare a toothpaste formulation similar to that disclosed in Pentasodium Tripolyphosphate 2 U.S. Pat. No. 3,308,029 issued Mar. 7, 1967 which is 16 Trimagnesium Phosphate 2 550 Pentasodium Tripolyphosphate 1.5 typical of those that are commercially available, except 55 17 Trimagnesium Phosphate 2 570 for flavor. It contains about 1,000 ppm added fluoride. Pentasodium Tripolyphosphate l The formulation is set forth below: 18 Trimagnesium Phosphate 2 600 Pentasodium Tripolyphosphate 0.5 Sodium Hexametaphosphate 0.5 Parts by Weight 19 Trimagnesium Phosphate 2 590 60 . . Pentasodium Tripolyphosphate 0.5 Glycerine 21.8 Disodium Dihydrogen Pyrophos DCPD 49.6 phate 0.5 Sodium Lauryl Sulfate 1.5 Saccharin 0.2 Water 25.2 Sodium Monofluorophosphate 0.8 65 EXAMPLE III Carboxymethyl Cellulose 0.9 A sample of the DCPD from Example II is blended 00.0 with 2 percent trimagnesium phosphate, 1 percent pen tasodium tripolyphosphate and 0.05 percent monoso 4,247,526 7 8 dium phosphate. When the DCPD is used in the tooth phate complex, based on the weight of the dicalcium paste formulation of Example II containing about 1,000 phosphate dihydrate. 3. A method of claim 2 wherein the stabilizing ppm soluble fluoride and stored for six weeks at 50° C., amount of pyrophosphate complex is from about 0.5 about 610 ppm soluble fluoride remains after the test. weight percent to about 2.5 weight percent P2O5 equiv Although the invention has been described in terms alent of pyrophosphate complex. of specified embodiments which are set forth in consid 4. A method of claim 3 wherein there is added to the erable detail, it should be understood that this is by way dicalcium phosphate dihydrate from about 0.5 weight of illustration only and that the invention is not neces percent to about 2.5 weight percent trimagnesium phos sarily limited thereto since alternative embodiments and 10 phate. operating techniques will become apparent to those 5. A method of claim 4 wherein there is added to the skilled in the art in view of the disclosure. Accordingly, dicalcium phosphate dihydrate from about 0.3 weight modifications are contemplated which can be made percent to about 2 weight percent of at least one phar without departing from the spirit of the described in maceutically acceptable condensed phosphate salt. 5 6. A method of claim 5 wherein the pharmaceutically vention. acceptable condensed phosphate salt is selected from What is claimed is: the group consisting of pentasodium tripolyphosphate, 1. A method which comprises: sodium trimetaphosphate, disodium dihydrogen meta (A) providing dicalcium phosphate dihydrate con phosphate, tetrasodium pyrophosphate, and mixtures taining a sufficient amount of pyrophosphate com 20 thereof. plex to provide at least some hydrolytic stability to 7. A method of claim 6 wherein the pharmaceutically the DCPD; acceptable condensed phosphate salt is pentasodium (B) adding to the dicalcium phosphate dihydrate tripolyphosphate. from about 0.1 weight percent to about 5 weight 8. A method of claim 6 wherein the pharmaceutically percent trimagnesium phosphate, based on the 25 acceptable condensed phosphate salt is a mixture of weight of the dicalcium phosphate dihydrate; and sodium tripolyphosphate and sodium hexametaphos (C) adding to the dicalcium phosphate dihydrate phate. 9. A method of claim 6 wherein the pharmaceutically from about 0.1 weight percent to about 3 weight acceptable condensed phosphate salt is a mixture of percent of a pharmaceutically acceptable con 30 pentasodium tripolyphosphate and disodium dihydro densed phosphate salt, based on the weight of the gen pyrophosphate. dicalcium phosphate dihydrate. 10. A method of claim 6 wherein the pharmaceuti 2. A method of claim 1 wherein the amount of pyro cally acceptable phosphate salt is pentasodium tripoly phosphate complex is from about 0.1 weight percent to phosphate mixed with monosodium phosphate. about 5 weight percent P2O5 equivalent of pyrophos 35

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