~" ' MM II II II MM II II III I Ml II I II J European Patent Office _ _ _ -•#»>■ © Publication number: 0 533 724 B1 Office_„. europeen des brevets © EUROPEAN PATENT SPECIFICATION © Date of publication of patent specification: 26.04.95 © Int. CI.6: C07C 59/265, A61 K 31/1 9, C07C 59/245, C07C 51/41 © Application number: 91910588.2 @ Date of filing: 30.05.91 © International application number: PCT/US91/03779 © International publication number: WO 91/19692 (26.12.91 91/29) Q») CALCIUM CITRATE MALATE COMPOSITION. © Priority: 14.06.90 US 537313 © Proprietor: THE PROCTER & GAMBLE COM- 31.10.90 US 608055 PANY One Procter & Gamble Plaza @ Date of publication of application: Cincinnati 31.03.93 Bulletin 93/13 Ohio 45202 (US) © Publication of the grant of the patent: @ Inventor: FOX, Mary, Mora 26.04.95 Bulletin 95/17 13 Applewood Dr. Fairfield, OH 45014 (US) © Designated Contracting States: Inventor: HECKERT, David, Clinton AT BE DE FR GB IT NL 3561 Kehr Road Oxford, OH 45056 (US) © References cited: Inventor: LUHRSEN, Kenneth, Ray EP-A- 0 297 679 Route 1, Box 11 EP-A- 0 304 987 Aurora, IN 47001 (US) © Representative: Canonlcl, Jean-Jacques et al Procter & Gamble European Technical Cen- ter N.V. 00 Temselaan 100 ^ B-1853 Strombeek-Bever (BE) CM 00 00 w Note: Within nine months from the publication of the mention of the grant of the European patent, any person ® may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition CL shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee LU has been paid (Art. 99(1) European patent convention). Rank Xerox (UK) Business Services (3. 10/3.09/3.3.3) EP 0 533 724 B1 Description This invention relates to a soluble calcium source comprising specific molar ratios of calcium, citrate and malate. The composition is more soluble than calcium citrate or calcium malate alone, and when 5 prepared by the process herein, consists of a metastable complex salt which is distinct from either pure calcium citrate or pure calcium malate. BACKGROUND OF THE INVENTION io Calcium is a mineral that is important for building bones and teeth. One of the problems with supplementation of the diet with calcium is that all sources of calcium are not equally soluble or bioavailable. In addition, some calcium sources are not as pure as other sources. For example, calcium carbonate derived from bone meal, oyster shell, or other biological origins contains trace amounts of lead and other minerals. Some calcium carbonates also contain silica. Therefore, it is necessary to take 75 additional amounts of these materials to achieve the same calcium level as those taken from synthetic sources which are essentially pure calcium carbonate. Calcium citrate is poorly soluble in water; 1 gram of calcium citrate dissolves per 1050 grams of cold water. Calcium malate exhibits a similar solubility. Calcium hydroxide is only slightly soluble in water, and it absorbs carbon dioxide from the air readily forming calcium carbonate. 20 In addition, calcium salts readily hydrate even when stored in dry cool places. Therefore, the amount of calcium being delivered may be even less than expected because of the large amount of water absorbed by the salts. Therefore a calcium salt which is readily bioavailable and which is readily soluble in neutral solutions as well as acidic solutions is highly desirable. This would allow the calcium salt to be added to neutral as well 25 as acid foods in a soluble form and to be an effective supplement. Granular salts can produce a gritty taste in foods and beverages if they are not soluble or are too large in particle size. It is therefore an object of this invention to produce a calcium salt which is highly bioavailable and which is readily soluble in water. 30 BACKGROUND ART Japanese patent application Sho 56/097,248 (Tanaka, 1981) discloses a calcium citrate malate salt of increased solubility. This salt is a 5:2:2 ratio of calcium:citrate:malate. The applicant suggests that 2 molecules of calcium malate are associated with 1 molecule of calcium citrate. The product is described as 35 a white crystalline powder which is soluble at 0.5 g/100 ml of water at 20 ° C and which has a pH of 6 to 6.5. The product is formed by mixing calcium carbonate with citric and malic acids in water at 50 ° C to 60 ° C and separating the white crystalline material from the mother liquor. When the product is dry (oven drying is used) the temperature is raised to 110°C-120°C to sterilize the powder. Alternatively a product is made using calcium chloride, sodium citrate and sodium malate. 40 Calcium citrate malate has been made in beverages. U.S. 4,737,375 issued to Nakel et al describes beverages nutritionally supplemented with calcium to which citric and malic acids are added. U.S. 4,722,847 issued to Heckert (1988) describes calcium citrate malate in beverages and the preparation of the material in a beverage format. European Patent to Jacobs entitled "Novel Calcium Supplements", 304,987 (1989), discloses calcium 45 citrate malate materials that have a 6:2:3 molar ratio. SUMMARY OF THE INVENTION A process for forming a metastable calcium citrate malate having a solubility in water at about 20 ° C of 50 75% or more weight percent calcium per calcium citrate malate on a 100 mg basis comprising: (a) adding a calcium source selected from the group consisting of calcium hydroxide, calcium carbonate, or calcium oxide to citric and malic acid in water, preferably wherein the mole ratios of calcium is from 2 to 10, of citric is from 1 to 3 and of malic acid is from 1 to 5; (b) mixing this solution at 20 °C to about 80 °C until the citric and malic acids are neutralized by the 55 calcium, preferably at a temperature of from 30 ° C to 80 ° C; (c) drying the mixture at a temperature of less than 100°C; and (d) grinding the resultant solid to particles less than 1 millimeter in size. 2 EP 0 533 724 B1 The drying can be done by freeze drying, spray drying oven drying, convection or forced air drying. The calcium:citrate:malate ratio can vary. DETAILED DESCRIPTION OF THE INVENTION 5 As used herein the term, "calcium citrate malate" refers to a mixture of calcium, citrate and malate. The specific ratios will be defined as the ratio of calcium to citrate to malate. All ratios of calcium, citrate and malate are on a mole basis. The calcium citrate malate is referred to herein as CCM. As used herein, the term "malic acid" refers to the mixture of the D and the L isomers, i.e. malic acid is io optically active and the racemic mixture is used herein. D-malic acid and L-malic acid can be used. As used herein the term "metastable" means that the material is not at equilibrium, and is a mixture of various crystalline and non-crystalline forms and solid solutions of the calcium ions, citrate ions and malate ions as well as salts of these materials. While the reaction kinetics would indicate that the calcium neutralizes all of the acid groups of citric and malic acid, or partially neutralizes depending on the ratio of is the calcium to citric acid to malic acid, a molecular complex consisting of 2 moles of citrate and 3 moles of malate with 6 moles of calcium apparently does not form. But rather, an equilibrium is established between the salts and, when prepared by the process herein, a complex salt is formed. This complex salt is distinct from pure calcium citrate or pure calcium malate or simple mixtures thereof. The salt may be crystalline or micro crystalline, but may also represent an amorphous form or may contain solid solutions of calcium, 20 citrate and malate ions. This complex is thermodynamically an intermediate formed in the preparation of a dry form. Occasion- ally this reaction produces a product which is the most thermodynamically stable and is practically insoluble. The exact reason for this is not known. The metastable materials probably have more than 1 crystalline state reflected by the presence of 25 multiple hydration states. In addition, there are likely to be significantly different arrangements of the citrate and malate within the material. The physical and chemical data of these salts are consistent with the theory that there are non-crystalline regions within the powdered material which can hydrate to the point of behaving like a solution. It is important for the solubility characteristics of the calcium citrate malate that the apparent metastable structure be achieved. 30 Therefore, while the X-ray diffraction pattern indicates that there is some crystallinity, and that this material is different from calcium citrate or calcium malate, the exact structure of the material is not known. The calcium citrate malate herein can exist in several states of hydration with from 2 to as many as 16 to 20 water molecules (e.g. a 6:2:3:8H20 moiety exists). 35 A. Process for Making Metastable Calcium Citrate Malate The calcium citrate malate is prepared by adding a calcium salt, as a powder or as an aqueous solution, to an aqueous solution of citric acid and malic acid in the mole ratio necessary to make the desired calcium citrate malate material. When calcium carbonate is used, carbon dioxide evolves as the 40 calcium carbonate is neutralized by the citric and malic acids.