Structural Formula

CaHPO4·2H2O

Functional Category

Tablet and capsule diluent.

Applications in Pharmaceutical Formulation or Technology

Dibasic calcium phosphate dihydrate is widely used in tablet formulations both as an excipient and as a source of calcium and phosphorus in nutritional supplements.(1–8) It is one of the more widely used materials, 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. The predominant deformation mechanism of 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, dibasic calcium phosphate dihydrate is abrasive and a lubricant is required  for  tableting,  for  example  about  1%  w/w  of

magnesium stearate or about 1% w/w of sodium stearyl fumarate is commonly used.

Two main particle-size grades of dibasic calcium phosphate dihydrate are used in the pharmaceutical industry. The milled material is typically used in wet-granulated, roller-compacted or slugged formulations. The ‘unmilled’ or coarse-grade material is typically used in direct-compression formulations.

Dibasic calcium phosphate dihydrate is nonhygroscopic and stable at room temperature. However, under certain conditions of temperature and humidity, it can lose water of crystallization below 1008C. This has implications for certain types of packaging and aqueous film coating since the loss of water of crystallization appears to be initiated by high humidity and by implication high moisture vapor concentrations in the vicinity of the dibasic calcium phosphate dihydrate particles.(8)

Dibasic calcium phosphate dihydrate is also used in tooth- paste and dentifrice formulations for its abrasive properties.

Description

Dibasic calcium phosphate dihydrate is a white, odorless, tasteless powder or crystalline solid. It occurs as monoclinic crystals.

SEM: 1

Excipient: Dibasic calcium phosphate dihydrate, coarse grade

Manufacturer: JRS Pharma LP.

Lot No.: W28C

Magnification: 100×

 

Calcium Phosphate, Dibasic Dihydrate 97 

SEM: 2

Excipient: Dibasic calcium phosphate dihydrate, coarse grade

Manufacturer: JRS Pharma LP.

Lot No.: W28C

Magnification: 300×

 



SEM: 4

Excipient: Dibasic calcium phosphate dihydrate, coarse grade

Manufacturer: Rhodia.

Lot No.: 16A-1 (89)

Magnification: 600×

 

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for calcium phosphate, dibasic

 

dihydrate.    

  Test JP 2001 PhEur 2005 USP 28    

SEM: 3 Identification + + +    

Excipient: Dibasic calcium phosphate dihydrate Characters + + —    

Manufacturer: Rhodia. Loss on ignition — — 24.5–26.5%    

Lot No.: 16A-1 (89) Loss on drying 19.5–22.0% — —    

Magnification: 120× Acid insoluble

substances 40.05% — 40.2%    

Heavy metals 431 ppm 440 ppm 40.003%    

Chloride 40.248% 4330 ppm 40.25%    

Fluoride — 4100 ppm 40.005%    

Sulfate 40.160% 40.5% 40.5%    

Carbonate + + +    

Barium + + +    

Arsenic 42 ppm 410 ppm 43 mg/g    

Organic volatile — — +    

impurities    

Iron — 4400 ppm —    

Assay 598.0% 98.0–105.0% 98.0–105.0%  

 Typical Properties

Acidity/alkalinity: pH = 7.4 (20% slurry of DI-TAB)

Angle of repose: 28.38 for Emcompress.(9)

Density (bulk): 0.915 g/cm3 Density (tapped): 1.17 g/cm3 Density (true): 2.389 g/cm3

98 Calcium Phosphate, Dibasic Dihydrate

Flowability:

27.3 g/s for DI-TAB;

11.4 g/s for Emcompress.



(9)

Regulatory Status

GRAS listed. Accepted as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (oral capsules and tablets).

Melting point: dehydrates below 1008C.

Moisture content: dibasic calcium phosphate dihydrate con- tains two molecules of water of crystallization, which can be lost at temperatures well below 1008C.

Particle size distribution: DI-TAB: average particle diameter 180 mm

Fine powder: average particle diameter 9 mm

Solubility: practically insoluble in ethanol, ether, and water; soluble in dilute acids.

Specific surface area: 0.44–0.46 m2/g for Emcompress

Stability and Storage Conditions

Dibasic calcium phosphate dihydrate is a nonhygroscopic, relatively stable material. However, under certain conditions the dihydrate can lose water of crystallization. This has implications for both storage of the bulk material and coating and packaging of tablets containing dibasic calcium phosphate dihydrate.

The bulk material should be stored in a well-closed container in a cool, dry place.

Incompatibilities

Dibasic calcium phosphate dihydrate should not be used to formulate tetracycline antibiotics.(10) Dibasic calcium phos- phate dihydrate has been reported to be incompatible with indomethacin,(11) aspirin,(12) aspartame,(13) ampicillin,(14) cephalexin,(15) and erythromycin.(16) The surface of dibasic calcium phosphate dihydrate is alkaline(16) and consequently it should not be used with drugs that are sensitive to alkaline pH.

Method of Manufacture

Calcium phosphates are usually manufactured by reacting very pure phosphoric acid with calcium hydroxide, Ca(OH)2 obtained from limestone, in stoichiometric ratio in aqueous suspension 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.

Safety

Dibasic calcium phosphate dihydrate is widely used in oral pharmaceutical products, food products, and toothpastes and is generally regarded as a nontoxic and nonirritant material. However, oral ingestion of large quantities may cause abdominal discomfort.

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.

Included in nonparenteral medicines licensed in Europe. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Calcium phosphate, dibasic anhydrous; calcium phosphate, tribasic.

Comments

Grades of dibasic calcium phosphate dihydrate available for direct compression include Calstar (FMC Biopolymer), Di- Cafos (Chemische Fabrik Budenheim), DI-TAB (Rhodia), and Emcompress (JRS Pharma LP).

Accelerated stability studies carried out at elevated tem- peratures on formulations containing significant proportions of dibasic calcium phosphate dihydrate can give erroneous results owing to irreversible dehydration of the dihydrate to the anhydrous form. Depending on the type of packaging and whether or not the tablet is coated, the phenomenon can be observed at temperatures as low as 408C after 6 weeks of storage. As the amount of dibasic calcium phosphate dihydrate in the tablet is reduced, the effect is less easy to observe.

The EINECS number for calcium phosphate is 231-837-1.

Specific References

Lausier JM, Chiang C-W, Zompa HA, Rhodes CT. Aging of tablets made with dibasic calcium phosphate dihydrate as matrix. J Pharm Sci 1977; 66(11): 1636–1637.

Carstensen JT, Ertell C. Physical and chemical properties of calcium phosphates for solid state pharmaceutical formulations. Drug Dev Ind Pharm 1990; 16(7): 1121–1133.

Bryan JW, McCallister JD. Matrix forming capabilities of three calcium diluents. Drug Dev Ind Pharm 1992; 18(19): 2029–2047.

Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical tableting I: physico-pharmaceutical properties. Pharm World Sci 1993; 15(3): 105–115.

Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical tableting II: comparison of tableting properties. Pharm World Sci 1993; 15(3): 116–122.

Land´ın M, Mart´ınez-Pacheco R, Go´ mez-Amoza JL, et al. The effect of country of origin on the properties of dicalcium phosphate dihydrate powder. Int J Pharm 1994; 103: 9–18.

Land´ın M, Mart´ınez-Pacheco R, Go´ mez-Amoza JL, et al. Dicalcium phosphate dihydrate for direct compression: character- ization and intermanufacturer variability. Int J Pharm 1994; 109: 1–8.

Land´ın M, Rowe RC, York P. Structural changes during the dehydration of dicalcium phosphate dihydrate. Eur J Pharm Sci 1994; 2: 245–252.

C¸ elik M, Okutgen E. A feasibility study for the development of a prospective compaction functionality test and the establishment of a compaction data bank. Drug Dev Ind Pharm 1993; 19(17–18): 2309–2334.

Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation Agents: A Handbook of Excipients. New York: Marcel Dekker, 1989: 93–94.

Eerika¨ inen S, Yliruusi J, Laakso R. The behaviour of the sodium salt of indomethacin in the cores of film-coated granules contain- ing various fillers. Int J Pharm 1991; 71: 201–211.

Land´ın M, Perez-Marcos B, Casalderrey M, et al. Chemical stability of acetyl salicylic acid in tablets prepared with different commercial brands of dicalcium phosphate dihydrate. Int J Pharm 1994; 107: 247–249.

Calcium Phosphate, Dibasic Dihydrate 99