96 Calcium Phosphate, Dibasic Dihydrate

15 Handling Precautions 3 Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical tableting 2: comparison of tableting properties. Pharm World Sci Observe normal precautions appropriate to the circumstances and 1993; 15(3): 116–122. quantity of material handled. The fine-milled grades can generate 4 Hwang R-C, Peck GR. A systematic evaluation of the compression and nuisance dusts and the use of a respirator or dust mask may be tablet characteristics of various types of lactose and dibasic calcium necessary. phosphate. Pharm Technol 2001; 25(6): 54, 56, 58, 60, 62, 64, 66, 68. 5 Schlack H et al. Properties of Fujicalin, a new modified anhydrous C 16 Regulatory Status dibasic calcium phosphate for direct compression: comparison with dicalcium phosphate dihydrate. Drug Dev Ind Pharm 2001; 27(8): GRAS listed. Accepted as a food additive in Europe. Included in the 789–801. FDA Inactive Ingredients Database (oral capsules and tablets). 6 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation Included in nonparenteral medicines licensed in Europe. Included in Agents: A Handbook of Excipients. New York: Marcel Dekker, 1989; the Canadian List of Acceptable Non-medicinal Ingredients. 93–94. 7 Dulin WA. Degradation of bisoprolol fumarate in tablets formulated 17 Related Substances with dicalcium phosphate. Drug Dev Ind Pharm 1995; 21(4): 393–409. 8 Glombitza BW et al. Surface acidity of solid pharmaceutical excipients I. Calcium phosphate, dibasic dihydrate; calcium phosphate, tribasic; Determination of the surface acidity. Eur J Pharm Biopharm 1994; calcium sulfate. 40(5): 289–293. 9 Kiyoshi T et al. Novel preparation of free-flowing spherically 18 Comments granulated dibasic calcium phosphate anhydrous for direct tabletting. Chem Pharm Bull 1996; 44(4): 868–870. Anhydrous dibasic calcium phosphate is one of the materials that 10 Ayorinde JO et al. The survival of B. subtilis spores in dicalcium have been selected for harmonization by the Pharmacopeial phosphate, lactose, and corn starch. Pharmaceutical Technology 2005; Discussion Group. For further information see the General 29(12): 56–67. Information Chapter <1196> in the USP32–NF27, the General ‘ ’ Chapter 5.8 in PhEur 6.0, along with the State of Work document 20 General References on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV. Bryan JW, McCallister JD. Matrix forming capabilities of three calcium Grades of anhydrous dibasic calcium phosphate available for diluents. Drug Dev Ind Pharm 1992; 18(19): 2029–2047. direct compression include A-TAB (Innophos), Di-Cafos AN Carstensen JT, Ertell C. Physical and chemical properties of calcium phosphates for solid state pharmaceutical formulations. Drug Dev Ind (Chemische Fabrik Budenheim), Emcompress Anhydrous (JRS Pharm 1990; 16(7): 1121–1133. Pharma LP), and Fujicalin (Fuji Chemical Industry Co. Ltd.). A European Directorate for the Quality of Medicines and Healthcare study has examined the use of calcium phosphate in reducing (EDQM). European Pharmacopoeia – State Of Work Of International (10) microbial contamination during direct compression in tableting. Harmonisation. Pharmeuropa 2009; 21(1): 142–143. http://www.edq- The EINECS number for calcium phosphate is 231-837-1. The m.eu/site/-614.html (accessed 3 February 2009). PubChem Compound ID (CID) for anhydrous dibasic calcium Fuji Chemical Industry Co. Ltd. Technical literature: Fujicalin, 1998. phosphate is 24441. Innophos Inc. Product datasheet: Calcium Phosphates, 2008.

19 Specific References 21 Author 1 Fischer E. Calcium phosphate as a pharmaceutical excipient. Manuf RC Moreton. Chem 1992; 64(6): 25–27. 2 Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical 22 Date of Revision tableting 1: physico-pharmaceutical properties. Pharm World Sci 1993; 15(3): 105–115. 3 February 2009.

Calcium Phosphate, Dibasic Dihydrate

1 Nonproprietary Names 3 Chemical Name and CAS Registry Number BP: Calcium Hydrogen Phosphate Dibasic calcium phosphate dihydrate [7789-77-7] JP: Dibasic Calcium Phosphate Hydrate PhEur: Calcium Hydrogen Phosphate Dihydrate 4 Empirical Formula and Molecular Weight USP: Dibasic Calcium Phosphate Dihydrate CaHPO42H2O 172.09

2 Synonyms 5 Structural Formula Calcii hydrogenophosphas dihydricus; calcium hydrogen orthopho- See Section 4. sphate dihydrate; calcium monohydrogen phosphate dihydrate; Di- Cafos; dicalcium orthophosphate; DI-TAB; E341; Emcompress; phosphoric acid calcium salt (1 : 1) dihydrate; secondary calcium 6 Functional Category phosphate. Tablet and capsule diluent. Calcium Phosphate, Dibasic Dihydrate 97

7 Applications in Pharmaceutical Formulation or SEM 1: Excipient: dibasic calcium phosphate dihydrate, coarse grade; Technology manufacturer: JRS Pharma LP; lot no.: W28C; magnification: 100. 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 C 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 SEM 2: Excipient: dibasic calcium phosphate dihydrate, coarse grade; manufacturer: JRS Pharma LP; lot no.: W28C; magnification: 300. moisture vapor concentrations in the vicinity of the dibasic calcium phosphate dihydrate particles.(8) Dibasic calcium phosphate dihydrate is also used in toothpaste and dentifrice formulations for its abrasive properties.

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

9 Pharmacopeial Specifications See Table I. See also Section 18.

Table I: Pharmacopeial specifications for calcium phosphate, dibasic dihydrate. Test JP XV PhEur 6.4 USP 32 Identification þþ þ Characters þþ — Loss on ignition — 24.5–26.5% 24.5–26.5% Loss on drying 19.5–22.0% — — Acid-insoluble substances 40.05% 40.2% 40.2% Heavy metals 431 ppm 440 ppm 40.003% Chloride 40.248% 40.25% 40.25% Fluoride — 4100 ppm 40.005% Sulfate 40.160% 40.5% 40.5% Carbonate þþ þ Barium þþ þ Arsenic 42 ppm 410 ppm 43 mg/g Moisture content Dibasic calcium phosphate dihydrate contains Iron — 4400 ppm — two molecules of water of crystallization, which can be lost at Assay 598.0% 98.0–105.0% 98.0–105.0% temperatures well below 1008C. NIR spectra see Figure 1. Particle size distribution DI-TAB: average particle diameter 180 mm; fine powder: average particle diameter 9 mm. 10 Typical Properties Solubility Practically insoluble in ethanol, ether, and water; Acidity/alkalinity pH = 7.4 (20% slurry of DI-TAB) soluble in dilute acids. 8 (9) Angle of repose 28.3 for Emcompress. Specific surface area 0.44–0.46 m2/g for Emcompress. Density (bulk) 0.915 g/cm3 Density (tapped) 1.17 g/cm3 Density (true) 2.389 g/cm3 11 Stability and Storage Conditions Flowability 27.3 g/s for DI-TAB;11.4 g/s for Emcompress.(9) Dibasic calcium phosphate dihydrate is a nonhygroscopic, relatively Melting point Dehydrates below 1008C. stable material. However, under certain conditions the dihydrate 98 Calcium Phosphate, Dibasic Dihydrate

SEM 3: Excipient: dibasic calcium phosphate dihydrate; manufacturer: 1.5 0.8 Innophos; lot no.: 16A-1 (89); magnification: 120. 1945

1911 1969 1408 1514 0.0 1499 1994 C 1425 1475 1956 log(1/R)

1930

1000 × [2nd deriv. log(1/R)] −3.0 −0.2 1100 1300 1500 1700 1900 2100 2300 2500 Wavelength/nm

Figure 1: Near-infrared spectrum of dibasic calcium phosphate dihydrate measured by reflectance.

13 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 SEM 4: Excipient: dibasic calcium phosphate dihydrate, coarse grade; by drying at a temperature that will allow the correct hydration manufacturer: Innophos; lot no.: 16A-1 (89); magnification: 600. 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.

14 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. How- ever, oral ingestion of large quantities may cause abdominal discomfort.

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 Database (oral capsules and tablets). Included in nonparenteral medicines licensed in Europe. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

17 Related Substances can lose water of crystallization. This has implications for both storage of the bulk material and coating and packaging of tablets Calcium phosphate, dibasic anhydrous; calcium phosphate, triba- sic. containing dibasic calcium phosphate dihydrate. The bulk material should be stored in a well-closed container in a cool, dry place. 18 Comments Dibasic calcium phosphate dihydrate is one of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter <1196> in the USP32–NF27, the General ‘ ’ 12 Incompatibilities Chapter 5.8 in PhEur 6.0, along with the State of Work document on the PhEur EDQM website, and also the General Information Dibasic calcium phosphate dihydrate should not be used to Chapter 8 in the JP XV. (10) formulate tetracycline antibiotics. Dibasic calcium phosphate Grades of dibasic calcium phosphate dihydrate available for dihydrate has been reported to be incompatible with indometha- direct compression include Calstar (FMC Biopolymer), Di-Cafos (11) (12) (13) (14) (15) cin, aspirin, aspartame, ampicillin, cephalexin, and (Chemische Fabrik Budenheim), DI-TAB (Innophos), and Emcom- erythromycin.(16) The surface of dibasic calcium phosphate press (JRS Pharma LP). dihydrate is alkaline(16) and consequently it should not be used Accelerated stability studies carried out at elevated temperatures with drugs that are sensitive to alkaline pH. on formulations containing significant proportions of dibasic Calcium Phosphate, Tribasic 99 calcium phosphate dihydrate can give erroneous results owing to 10 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation irreversible dehydration of the dihydrate to the anhydrous form. Agents: A Handbook of Excipients. New York: Marcel Dekker, 1989; Depending on the type of packaging and whether or not the tablet is 93–94. coated, the phenomenon can be observed at temperatures as low as 11 Eerika¨inen S et al. The behaviour of the sodium salt of indomethacin in 8 the cores of film-coated granules containing various fillers. Int J Pharm 40 C after 6 weeks of storage. As the amount of dibasic calcium 1991; 71: 201–211. phosphate dihydrate in the tablet is reduced, the effect is less easy to 12 Landı´n M et al. Chemical stability of acetyl salicylic acid in tablets observe. prepared with different commercial brands of dicalcium phosphate C The EINECS number for calcium phosphate is 231-837-1. The dihydrate. Int J Pharm 1994; 107: 247–249. PubChem Compound ID (CID) for dibasic calcium phosphate 13 El-Shattawy HH et al. Aspartame direct compression excipients: dibydrate is 104805. preformulation stability screening using differential scanning calorime- try. Drug Dev Ind Pharm 1981; 7(5): 605–619. 14 El-Shattaway HH. Ampicillin direct compression excipients: preformu- 19 Specific References lation stability screening using differential scanning calorimetry. Drug 1 Lausier JM et al. Aging of tablets made with dibasic calcium phosphate Dev Ind Pharm 1982; 8(6): 819–831. dihydrate as matrix. J Pharm Sci 1977; 66(11): 1636–1637. 15 El-Shattaway HH et al. Cephalexin I direct compression excipients: 2 Carstensen JT, Ertell C. Physical and chemical properties of calcium preformulation stability screening using differential scanning calorime- phosphates for solid state pharmaceutical formulations. Drug Dev Ind try. Drug Dev Ind Pharm 1982; 8(6): 897–909. Pharm 1990; 16(7): 1121–1133. 16 El-Shattaway HH et al. Erythromycin direct compression excipients: 3 Bryan JW, McCallister JD. Matrix forming capabilities of three calcium preformulation stability screening using differential scanning calorime- diluents. Drug Dev Ind Pharm 1992; 18(19): 2029–2047. try. Drug Dev Ind Pharm 1982; 8(6): 937–947. 4 Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical tableting I: physico-pharmaceutical properties. Pharm World Sci 20 General References 1993; 15(3): 105–115. European Directorate for the Quality of Medicines and Healthcare 5 Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical (EDQM). European Pharmacopoeia – State Of Work Of International tableting II: comparison of tableting properties. Pharm World Sci Harmonisation. Pharmeuropa 2009; 21(1): 142–143. http://www.edq- 1993; 15(3): 116–122. m.eu/site/-614.html (accessed 3 February 2009). 6 Landı´nMet al. The effect of country of origin on the properties of Green CE et al. R-P trials calcium excipient. Manuf Chem 1996; 67(8): 55, dicalcium phosphate dihydrate powder. Int J Pharm 1994; 103: 9–18. 57. 7 Landı´n M et al. Dicalcium phosphate dihydrate for direct compression: Innophos Inc. Product data sheet: Calcium Phosphates, 2008. characterization and intermanufacturer variability. Int J Pharm 1994; 109: 1–8. 8 Landı´n M et al. Structural changes during the dehydration of dicalcium 21 Author phosphate dihydrate. Eur J Pharm Sci 1994; 2: 245–252. RC Moreton. 9C¸ 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– 22 Date of Revision 2334. 3 February 2009.

Calcium Phosphate, Tribasic

1 Nonproprietary Names See also Sections 4 and 8. BP: Calcium Phosphate PhEur: Calcium Phosphate 4 Empirical Formula and Molecular Weight USP-NF: Tribasic Calcium Phosphate Ca3(PO4)2 310.20 Ca5(OH)(PO4)3 502.32 2 Synonyms 5 Structural Formula Calcium orthophosphate; E341(iii); hydroxylapatite; phosphoric acid calcium salt (2 : 3); precipitated calcium phosphate; tertiary See Sections 3 and 4. calcium phosphate; Tri-Cafos; tricalcii phosphas; tricalcium diorthophosphate; tricalcium orthophosphate; tricalcium phos- 6 Functional Category phate; TRI-CAL WG; TRI-TAB. Anticaking agent; buffering agent; dietary supplement; glidant; tablet and capsule diluent. 3 Chemical Name and CAS Registry Number Tribasic calcium phosphate is not a clearly defined chemical entity 7 Applications in Pharmaceutical Formulation or but is a mixture of calcium phosphates. Several chemical names, Technology CAS Registry Numbers, and molecular formulas have therefore Tribasic calcium phosphate is widely used as a capsule diluent and been used to describe this material. Those most frequently cited are tablet filler/binder in either direct-compression or wet-granulation shown below. processes. The primary bonding mechanism in compaction is plastic Calcium hydroxide phosphate [12167-74-7] deformation. As with dibasic calcium phosphate, a lubricant and a Tricalcium orthophosphate [7758-87-4] disintegrant should usually be incorporated in capsule or tablet