Calcium Phosphate, Dibasic Anhydrous

1 Nonproprietary Names BP: Anhydrous calcium hydrogen phosphate JP: Anhydrous dibasic calcium phosphate PhEur: Calcii hydrogenophosphas anhydricus USP: Dibasic calcium phosphate 2 Synonyms Anhydrous dibasic calcium phosphate is used in toothpaste and dentifrice formulations for its abrasive properties.

Description

A-TAB; calcium monohydrogen phosphate; calcium orthophosphate; Di-Cafos AN; dicalcium orthophosphate; E341; Emcompress Anhydrous; Fujicalin; phosphoric acid calcium salt (1 : 1); secondary calcium phosphate. 3 Chemical Name and CAS Registry Number

Anhydrous dibasic calcium phosphate is a white, odorless, tasteless powder or crystalline solid. It occurs as triclinic crystals. SEM: 1
Excipient: Emcompress Anhydrous Manufacturer: JRS Pharma LP Magnification: 50 Voltage: 5 kV

Dibasic calcium phosphate [7757-93-9] 4 Empirical Formula and Molecular Weight 136.06

CaHPO4 5

Structural Formula

CaHPO4 6 Functional Category

Tablet and capsule diluent. 7 Applications in Pharmaceutical Formulation or Technology

Anhydrous dibasic calcium phosphate is used both as an excipient and as a source of calcium in nutritional supplements. It is used particularly in the nutritional/health food sectors. It is also used in pharmaceutical products because of its compaction properties, and the good flow properties of the coarse-grade material.(15) The predominant deformation mechanism of anhydrous dibasic calcium phosphate coarse-grade is brittle fracture and this reduces the strain-rate sensitivity of the material, thus allowing easier transition from the laboratory to production scale. However, unlike the dihydrate, anhydrous dibasic calcium phosphate when compacted at higher pressures can exhibit lamination and capping. This phenomenon can be observed when the material represents a substantial proportion of the formulation and is exacerbated by the use of deep concave tooling. This phenomenon also appears to be independent of rate of compaction. Anhydrous dibasic calcium phosphate is abrasive and a lubricant is required for tableting, for example 1% w/w magnesium stearate or 1% w/w sodium stearyl fumarate. Two particle-size grades of anhydrous dibasic calcium phosphate are used in the pharmaceutical industry. Milled material is typically used in wet-granulated or roller-compacted formulations. The unmilled or coarse-grade material is typically used in direct-compression formulations. Anhydrous dibasic calcium phosphate is nonhygroscopic and stable at room temperature. It does not hydrate to form the dihydrate.

SEM: 2
Excipient: Emcompress Anhydrous Manufacturer: JRS Pharma LP Magnification: 200 Voltage: 5 kV

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Calcium Phosphate, Dibasic Anhydrous

Pharmacopeial Specifications 12 Incompatibilities

See Table I.
Table I: Pharmacopeial specifications for calcium phosphate, dibasic anhydrous. Test Identification Characters Loss on ignition Loss on drying Acid insoluble substance Heavy metals Chloride Fluoride Sulfate Carbonate Barium Arsenic Organic volatile impurities Iron Assay (dried basis) JP 2001 41.0% 40.05% 431 ppm 40.248% 40.200% 42 ppm 598.0% PhEur 2005 42.0% 440 ppm 4330 ppm 4100 ppm 40.5% 410 ppm 4400 ppm 98.0101.0% USP 28 6.68.5% 40.2% 40.003% 40.25% 40.005% 40.5% 43 mg/g 98.0105.0%

Dibasic calcium phosphate should not be used to formulate tetracyline antibiotics.(6) The surface of milled anhydrous dibasic calcium phosphate is alkaline(2) and consequently it should not be used with drugs that are sensitive to alkaline pH. However, reports(7,8) suggest there are differences in the surface alkalinity/acidity between the milled and unmilled grades of anhydrous dibasic calcium phosphate; the unmilled form has an acidic surface environment. This difference has important implications for drug stability, particularly when reformulating from, e.g. roller compaction to direct compression, when the particle size of the anhydrous dibasic calcium phosphate might be expected to change. Dibasic calcium phosphate dihydrate has been reported to be incompatible with a number of drugs and excipients and many of these incompatibilities are expected to occur with dibasic calcium phosphate, anhydrous; see Calcium phosphate, dibasic dihydrate. 13 Method of Manufacture

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Typical properties

Acidity/alkalinity: pH = 7.3 (20% slurry); pH = 5.1 (20% slurry of A-TAB); pH = 6.17.2 (5% slurry of Fujicalin). Angle of repose: 328 (for Fujicalin) Density: 2.89 g/cm3 Density (bulk): 0.78 g/cm3 for A-TAB; 0.45 g/cm3 for Fujicalin. Density (tapped): 0.82 g/cm3 for A-TAB; 0.46 g/cm3 for Fujicalin. Melting point: does not melt; decomposes at %4258C to form calcium pyrophosphate. Moisture content: 0.10.2%. The anhydrous material contains only surface-adsorbed moisture and cannot be rehydrated to form the dihydrate. Particle size distribution: A-TAB: average particle diameter 180 mm; Encompress Anhydrous: average particle diameter 136 mm; Fujicalin: average particle diameter 94 mm; Powder: average particle diameter: 15 mm. Solubility: practically insoluble in ether, ethanol, and water; soluble in dilute acids. Specific surface area: 2030 m2/g for A-TAB; 35 m2/g for Fujicalin.

Calcium phosphates are usually prepared by reacting very pure phosphoric acid with calcium hydroxide, Ca(OH)2 obtained from limestone, in stoichiometric ratio in aqueous suspension(2) followed by drying at a temperature that will allow the correct hydration state to be achieved. After drying, the coarse-grade material is obtained by means of a classification unit; the fine particle-size material is obtained by milling. Dibasic calcium phosphate, anhydrous, may also be prepared by spraydrying.(9,10) 14 Safety

Dibasic calcium phosphate anhydrous is widely used in oral pharmaceutical products, food products, and toothpastes and is generally regarded as a relatively nontoxic and nonirritant material. 15 Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. The fine-milled grades can generate nuisance dusts and the use of a respirator or dust mask may be necessary. 16 Regulatory Status

GRAS listed. Accepted as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (oral capsules and tablets). Included in nonparenteral medicines licensed in Europe. Included in the Canadian List of Acceptable Non-medicinal Ingredients. 17 Related Substances

Calcium phosphate, dibasic dihydrate; calcium phosphate, tribasic; calcium sulfate. 11 Stability and Storage Conditions 18 Comments

Dibasic calcium phosphate anhydrous is a nonhygroscopic, relatively stable material. Under conditions of high humidity it does not hydrate to form the dihydrate. The bulk material should be stored in a well-closed container in a dry place.

Grades of anhydrous dibasic calcium phosphate available for direct compression include A-TAB (Rhodia), Di-Cafos AN (Chemische Fabrik Budenheim), Emcompress Anhydrous (JRS Pharma LP), and Fujicalin (Fuji Chemical Industry Co. Ltd.). The EINECS number for calcium phosphate is 231-837-1.

Calcium Phosphate, Dibasic Anhydrous

19 Specific References

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1 Fischer E. Calcium phosphate as a pharmaceutical excipient. Manuf Chem 1992; 64(6): 2527. 2 Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical tableting 1: physico-pharmaceutical properties. Pharm World Sci 1993; 15(3): 105115. 3 Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical tableting 2: comparison of tableting properties. Pharm World Sci 1993; 15(3): 116122. 4 Hwang R-C, Peck GR. A systematic evaluation of the compression and tablet characteristics of various types of lactose and dibasic calcium phosphate. Pharm Technol 2001; 25(6): 54, 56, 58, 60, 62, 64, 66, 68. 5 Schlack H, Bauer-Brandl A, Schubert R, Becker D. Properties of Fujicalin, a new modified anhydrous dibasic calcium phosphate for direct compression: comparison with dicalcium phosphate dihydrate. Drug Dev Ind Pharm 2001; 27(8): 789801. 6 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation Agents: A Handbook of Excipients. New York: Marcel Dekker. 1989: 9394. 7 Dulin WA. Degradation of bisoprolol fumarate in tablets formulated with dicalcium phosphate. Drug Dev Ind Pharm 1995; 21(4): 393409. 8 Glombitza BW, Oelkrug D, Schmidt PC. Surface acidity of solid pharmaceutical excipients I. Determination of the surface acidity. Eur J Pharm Biopharm 1994; 40(5): 289293.

9 Takami K, Machimura H, Takado K, Inagaki M, Kawashima Y. Novel preparation of free-flowing spherically granulated dibasic calcium phosphate anhydrous for direct tabletting. Chem Pharm Bull 1996; 44(4): 868870. 10 Schlack H, Bauer-Brandl A, Schubert R, Becker D. Properties of Fujicalin, a new modified anhydrous dibasic calcium phosphate dihydrate. Drug Dev Ind Pharm 2001; 27(9): 789801.

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General References

Bryan JW, McCallister JD. Matrix forming capabilities of three calcium diluents. Drug Dev Ind Pharm 1992; 18(19): 20292047. Carstensen JT, Ertell C. Physical and chemical properties of calcium phosphates for solid state pharmaceutical formulations. Drug Dev Ind Pharm 1990; 16(7): 11211133. Fuji Chemical Industry Co. Ltd. Technical literature: Fujicalin, 1998. Rhodia. Technical literature: Calcium phosphate excipients, 1999.

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Authors

RC Moreton. 22 Date of Revision

30 August 2005.