med 11

Exposure to light, moisture, and heat causes discoloration and a loss of activity. Butylated hydroxytoluene should be stored in a well-closed container, protected from light, in a cool, dry place.

Incompatibilities

Butylated hydroxytoluene is phenolic and undergoes reactions characteristic of phenols. It is incompatible with strong oxidizing agents such as peroxides and permanganates. Contact with oxidizing agents may cause spontaneous combus- tion. Iron salts cause discoloration with loss of activity. Heating with catalytic amounts of acids causes rapid decomposition with the release of the flammable gas isobutene.

Method of Manufacture

Prepared by the reaction of p-cresol with isobutene.

Safety

Butylated hydroxytoluene is readily absorbed from the gastro- intestinal tract and is metabolized and excreted in the urine mainly as glucuronide conjugates of oxidation products. Although there have been some isolated reports of adverse skin reactions, butylated hydroxytoluene is generally regarded as nonirritant and nonsensitizing at the levels employed as an antioxidant.(3,4)

The WHO has set a temporary estimated acceptable daily intake for butylated hydroxytoluene at up to 125 mg/kg body- weight.(5)

Ingestion of 4 g of butylated hydroxytoluene, although causing severe nausea and vomiting, has been reported to be nonfatal.(6)

LD50 (guinea pig, oral): 10.7 g/kg(7) LD50 (mouse, IP): 0.14 g/kg

LD50 (mouse, IV): 0.18 g/kg LD50 (mouse, oral): 0.65 g/kg LD50 (rat, oral): 0.89 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Butylated hydroxytoluene may be irritant to the eyes and skin and on inhalation. It should be handled in a well-ventilated environment; gloves and eye

protection are recommended. Closed containers may explode owing to pressure build-up when exposed to extreme heat.

Regulatory Status

GRAS listed. Accepted as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (IM and IV injections, nasal sprays, oral capsules and tablets, rectal, topical, and vaginal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Butylated hydroxyanisole.

Comments

A specification for butylated hydroxytoluene is contained in the Food Chemicals Codex (FCC).

The EINECS number for butylated hydroxytoluene is 204- 881-4.

Specific References

Snipes W, Person S, Keith A, Cupp J. Butylated hydroxytoluene inactivates lipid-containing viruses. Science 1975; 188: 64–66.

Freeman DJ, Wenerstrom G, Spruance SL. Treatment of recurrent herpes simplex labialis with topical butylated hydroxytoluene. Clin Pharmacol Ther 1985; 38: 56–59.

Roed-Peterson J, Hjorth N. Contact dermatitis from antioxidants: hidden sensitizers in topical medications and foods. Br J Dermatol 1976; 94: 233–241.

Juhlin L. Recurrent urticaria: clinical investigation of 330 patients.

Br J Dermatol 1981; 104: 369–381.

FAO/WHO. Evaluation of certain food additives and contami- nants. Thirty-seventh report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1991; No. 806.

Shlian DM, Goldstone J. Toxicity of butylated hydroxytoluene. N Engl J Med 1986; 314: 648–649.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 430.

General References

Verhagen H. Toxicology of the food additives BHA and BHT. Pharm Weekbl (Sci) 1990; 12: 164–166.

BP: Butyl hydroxybenzoate

JP: Butyl parahydroxybenzoate PhEur: Butylis parahydroxybenzoas USPNF: Butylparaben

Synonyms

4-Hydroxybenzoic acid butyl ester; Lexgard B; Nipabutyl; Tegosept B; Trisept B; Uniphen P-23; Unisept B.

Chemical Name and CAS Registry Number

Butyl-4-hydroxybenzoate [94-26-8]

Empirical Formula and Molecular Weight

C11H14O3 194.23

Structural Formula

Functional Category

Antimicrobial preservative.

Applications in Pharmaceutical Formulation or Technology

Butylparaben is widely used as an antimicrobial preservative in cosmetics and pharmaceutical formulations; see Table I.

It may be used either alone or in combination with other paraben esters or with other antimicrobial agents. In cosmetics, it is the fourth most frequently used preservative.(1)

As a group, the parabens are effective over a wide pH range and have a broad spectrum of antimicrobial activity, although they are most effective against yeasts and molds; see Section 10. Owing to the poor solubility of the parabens, paraben salts, particularly the sodium salt, are frequently used in formula- tions. However, this may raise the pH of poorly buffered

formulations.

See Methylparaben for further information.

Table I: Uses of butylparaben.

Use Concentration (%)

Oral suspensions 0.006–0.05

Topical preparations 0.02–0.4

SEM: 1

Excipient: Butylparaben

Magnification: 240×

SEM: 2

Excipient: Butylparaben

Magnification: 2400×

Description

Butylparaben occurs as colorless crystals or a white, crystalline, odorless or almost odorless, tasteless powder.

Pharmacopeial Specifications

See Table II.

84 Butylparaben

Table II: Pharmacopeial specifications for butylparaben.

Butylparaben is thus more active than methylparaben. Activity may be improved by using combinations of parabens since synergistic effects occur. Activity has also been reported to be improved by the addition of other excipients; see Methylparaben for further information.

Density (bulk): 0.731 g/cm3 Density (tapped): 0.819 g/cm3 Melting point: 68–728C

Partition coefficients: values for different vegetable oils vary considerably and are affected by the purity of the oil; see Table IV.(3)

Solubility: see Table V.

substances Parahydroxybenzoic

acid and salicylic acid

Organic volatile impurities

+ — —

— — +

Table IV: Partition coefficients for butylparaben between oils and water.(3)

Solvent Partition coefficient oil : water

Mineral oil 3.0

Peanut oil 280

Soybean oil 280

Assay (dried basis) 599.0% 98.0–102.0% 99.0–100.5%

Typical Properties

Antimicrobial activity: butylparaben exhibits antimicrobial activity between pH 4–8. Preservative efficacy decreases with increasing pH owing to the formation of the phenolate anion. Parabens are more active against yeasts and molds than against bacteria. They are also more active against Gram-positive than against Gram-negative bacteria; see Table III.(2)

The activity of the parabens increases with increasing chain length of the alkyl moiety, but solubility decreases.

Table III: Minimum inhibitory concentrations (MICs) for butylparaben in aqueous solution.(2)

Microorganism MIC (mg/mL)

Aerobacter aerogenes ATCC 8308 400

Aspergillus niger ATCC 9642 125

Aspergillus niger ATCC 10254 200

Bacillus cereus var. mycoides ATCC 6462 63

Bacillus subtilis ATCC 6633 250

Candida albicans ATCC 10231 125

Enterobacter cloacae ATCC 23355 250

Escherichia coli ATCC 8739 5000

Escherichia coli ATCC 9637 5000

Klebsiella pneumoniae ATCC 8308 250

Penicillium chrysogenum ATCC 9480 70

Penicillium digitatum ATCC 10030 32

Proteus vulgaris ATCC 13315 125

Pseudomonas aeruginosa ATCC 9027 >1000

Pseudomonas aeruginosa ATCC 15442 >1000

Pseudomonas stutzeri 500

Rhizopus nigricans ATCC 6227A 63

Saccharomyces cerevisiae ATCC 9763 35

Salmonella typhosa ATCC 6539 500

Serratia marcescens ATCC 8100 500

Staphylococcus aureus ATCC 6538P 125

Staphylococcus epidermidis ATCC 12228 250

Trichophyton mentagrophytes 35

Table V: Solubility of butylparaben.

Solvent Solubility at 208C unless otherwise stated

Acetone Freely soluble

Mineral oil 1 in 1000

Peanut oil 1 in 20

Propylene glycol 1 in 1

Water 1 in >5000

1 in 670 at 808C

Stability and Storage Conditions

Aqueous butylparaben solutions at pH 3–6 can be sterilized by autoclaving, without decomposition.(4) At pH 3–6, aqueous solutions are stable (less than 10% decomposition) for up to about 4 years at room temperature, while solutions at pH 8 or above are subject to rapid hydrolysis (10% or more after about 60 days at room temperature).(5)

Butylparaben should be stored in a well-closed container, in a cool, dry place.

Incompatibilities

The antimicrobial activity of butylparaben is considerably reduced in the presence of nonionic surfactants as a result of micellization.(6) Absorption of butylparaben by plastics has not been reported but appears probable given the behavior of other parabens. Some pigments, e.g., ultramarine blue and yellow iron oxide, absorb butylparaben and thus reduce its preserva- tive properties.(7)

Butylparaben is discolored in the presence of iron and is subject to hydrolysis by weak alkalis and strong acids.

See also Methylparaben.

Alginic acid; calcium salt; Algin; CA33; calc algin; calcium polymannuronate; Calginate; E404; Kaltostat.

Chemical Name and CAS Registry Number

Calcium alginate [9005-35-0]

Empirical Formula and Molecular Weight

[(C6H7O6)2Ca]n 195.16 (calculated)

219.00 (actual, average)

Each calcium ion binds with two alginate molecules. The molecular weight of 195.16 relates to one alginate molecule, and the equivalent of half a calcium ion, therefore n = 1/2.

Calcium alginate is a polyuronide made up of a sequence of two hexuronic acid residues, namely D-mannuronic acid and L- guluronic acid. The two sugars form blocks of up to 20 units along the chain, with the proportion of the blocks dependent on the species of seaweed and also the part of the seaweed used. The number and length of the blocks are important in determining the physical properties of the alginate produced; the number and sequence of the mannuronate and guluronate residues varies in the naturally occurring alginate.

It has a typical macromolecular weight between 10 000 and 600 000.

Structural Formula

See Section 4.

Functional Category

Emulsifiying agent; stabilizing agent; tablet disintegrant; thickener.

Applications in Pharmaceutical Formulation or Technology

In pharmaceutical formulations, calcium alginate and calcium- sodium alginate have been used as tablet disintegrants.(1) The use of a high concentration (10%) of calcium-sodium alginate has been reported to cause slight speckling of tablets.(1)

A range of different types of delivery systems intended for oral administration have been investigated. These exploit the gelling properties of calcium alginate.(2) Calcium alginate beads have been used to prepare floating dosage systems(3,4) contain- ing amoxicillin,(5) frusemide,(6) and barium sulfate;(7) and as a means of providing a sustained or controlled-release action for sulindac,(8) diclofenac,(9,10) tiaramide,(11) insulin,(12) and ampi- cillin.(13) The use of calcium alginate beads, reinforced with chitosan, may be useful for the controlled release of protein drugs to the gastro-intestinal tract.(14) The bioadhesive proper- ties of calcium alginate beads have also been investigated.(15)

A series of studies investigating the production,(16) formula- tion,(17) and drug release(18) from calcium alginate matrices for oral administration have been published. The release of diltiazem hydrochloride from a polyvinyl alcohol matrix was shown to be controlled by coating with a calcium alginate membrane; the drug release profile could be modified by increasing the coating thickness of the calcium alginate layer.(19) The microencapsulation of live attenuated Bacillus Calmette– Gue´rin (BCG) cells within a calcium alginate matrix has also been reported.(20)

It has been shown that a modified drug release can be obtained from calcium alginate microcapsules,(21) pellets,(22,23) and microspheres.(24) When biodegradable bone implants composed of calcium alginate spheres and containing genta- micin were introduced into the femur of rats, effective drug levels in bone and soft tissue were obtained for 30 days and 7 days, respectively.(25)

Therapeutically, the gelling properties of calcium alginate are utilized in wound dressings in the treatment of leg ulcers, pressure sores, and other exuding wounds. These dressings are highly absorbent and are suitable for moderately or heavily exuding wounds. Calcium alginate dressings also have hemo- static properties, with calcium ions being exchanged for sodium ions in the blood; this stimulates both platelet activation and whole blood coagulation. A mixed calcium–sodium salt of alginic acid is used as fibers in dressings or wound packing material.

Sterile powder consisting of a mixture of calcium and sodium alginates has been used in place of talc in glove powders.

In foods, calcium alginate is used as an emulsifier, thickener, and stabilizer.

Description

Calcium alginate is an odorless or almost odorless, tasteless, white to pale yellowish-brown powder or fibers.

Pharmacopeial Specifications

See Section 18.

Typical Properties

Moisture content: loses not more than 22% of its weight on drying.

Solubility: practically insoluble in chloroform, ethanol, ether, water, and other organic solvents. Soluble in dilute solutions of sodium citrate and of sodium bicarbonate and in sodium chloride solution. Soluble in alkaline solutions or in solutions of substances that combine with calcium.

Stability and Storage Conditions

Calcium alginate can be sterilized by autoclaving at 1158C for 30 minutes or by dry heat at 1508C for 1 hour. Calcium alginate should be stored in airtight containers.

Calcium Alginate 87

Incompatibilities

Calcium alginate is incompatible with alkalis and alkali salts. Propranolol hydrochloride has been shown to bind to alginate molecules, suggesting that propranolol and calcium ions share common binding sites in the alginate chains; the formation of the calcium alginate gel structure was impeded in the presence of propranolol molecules.(26)

Method of Manufacture

Calcium alginate can be obtained from seaweed, mainly species of Laminaria.

Solutions of sodium alginate interact with an ionized calcium salt, resulting in the instantaneous precipitation of insoluble calcium alginate, which can then be further processed. Introducing varying proportions of sodium ions during manufacture can produce products having different absorption rates.

Safety

Calcium alginate is widely used in oral and topical formula- tions, and in foods.

In 1974, the WHO set an estimated acceptable daily intake of calcium alginate of up to 25 mg, as alginic acid, per kilogram body-weight.(27)

When heated to decomposition, it emits acrid smoke and irritating fumes.

LD50 (rat, IP): 1.41 g/kg(28)

LD50 (rat, IV): 0.06 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of the material handled.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (oral tablets). Included in nonparenteral medicines licensed in the UK.

Related Substances

Alginic acid; potassium alginate; sodium alginate; propylene glycol alginate.

Comments

Although not included in any pharmacopeias, a specification for calcium alginate is contained in the Food Chemicals Codex (FCC),(29) and has been included in the British Pharmaceutical Codex (BPC);(30) see Table I.

Table I: FCC(29) and BPC(30) specifications for calcium alginate.

Test FCC 1996 BPC 1973

Arsenic 43 ppm 4 3ppm

Ash 12–18% —

Heavy metals 40.004% (as lead) —

Iron — 4530 ppm

Lead 410 ppm 410 ppm

Loss on drying 415% 22.00%

Sulfated ash — 31.0–34.0%

Assay 89.6–104.5% —

Specific References

Khan KA, Rhodes CT. A comparative evaluation of some alginates as tablet disintegrants. Pharm Acta Helv 1972; 47: 41–50.

Tonnesen HH, Karlsen J. Alginate in drug delivery systems. Drug Dev Ind Pharm 2002; 28(6): 621–630.

Iannuccelli V, Coppi G, Bernabei MT, Cameroni R. Air compart- ment multiple-unit system for prolonged gastric residence. Part 1 Formulation study. Int J Pharm 1998; 174: 47–54.

Whitehead L, Fell JT, Collett JH, Sharma HL, Smith AM. Floating dosage forms: in vivo study demonstrating prolonged gastric retention. J Control Release 1998; 55: 3–12.

Whitehead L, Collett JH, Fell JT. Amoxicillin release from a floating dosage form based on alginates. Int J Pharm 2000; 210: 45–49.

Iannuccelli V, Coppi G, Leo E. PVP solid dispersions for the controlled release of frusemide from a floating multiple-unit system. Drug Dev Ind Pharm 2000; 26(6): 595–603.

Iannuccelli V, Coppi G, Sansone R, Ferolla G. Air compartment multiple-unit system for prolonged gastric residence. Part 2. In vivo evaluation. Int J Pharm 1998; 174: 55–62.

Abd-Elmageed A. Preparation and evaluation of sulindac alginate beads. Bull Pharm Sci Assiut Univ 1999; 22(1): 73–80.

Mirghani A, Idkaidek NM, Salem MS, Najib NM. Formulation and release behavior of diclofenac sodium in Compritol 888 matrix beads encapsulated in alginate. Drug Dev Ind Pharm 2000; 26(7): 791–795.

Turkoglu M, Gursoy A, Eroglu L, Okar I. Effect of aqueous polymer dispersions on properties of diclofenac/alginate beads and in vivo evaluation in rats. STP Pharm Sci 1997; 7(2): 135–140.

Fathy M, Safwat SM, El-Shanawany SM, Tous SS, Otagiri M. Preparation and evaluation of beads made of different calcium alginate compositions for oral sustained release of tiaramide. Pharm Dev Tech 1998; 3(3): 355–364.

Rasmussen MR, Snabe T, Pedersen LH. Numerical modelling of insulin and amyloglucosidase release from swelling Ca-alginate beads. J Controlled Release 2003; 91(3): 395–405.

Torre ML, Giunchedi P, Maggi L, et al. Formulation and characterization of calcium alginate beads containing ampicillin. Pharm Dev Tech 1998; 3(2): 193–198.

Anal AK, Bhopatkar D, Tokura S, Tamura H, Stevens WF. Chitosan-alginate multilayer beads for gastric passage and controlled intestinal release of protein. Drug Dev Ind Pharm 2003; 29(6): 713–724.

Gaserod O, Jolliffe IG, Hampson FC, Dettmar PW, Skjak-Braek G. Enhancement of the bioadhesive properties of calcium alginate gel beads by coating with chitosan. Int J Pharm 1998; 175: 237–246.

Ostberg T, Graffner C. Calcium alginate matrices for oral multiple unit administration. Part 1. Pilot investigations of production method. Acta Pharm Nord 1992; 4(4): 201–208.

Ostberg T, Vesterhus L, Graffner C. Calcium alginate matrices for oral multiple unit administration. Part 2. Effect of process and formulation factors on matrix properties. Int J Pharm 1993; 97: 183–193.

Ostberg T, Lund EM, Graffner C. Calcium alginate matrices for oral multiple unit administration. Part 4. Release characteristics in different media. Int J Pharm 1994; 112: 241–248.

88 Calcium Alginate

Coppi G, Iannuccelli V, Cameroni R. Polysaccharide film-coating for freely swellable hydrogels. Pharm Dev Tech 1998; 3(3): 347– 353.

Esquisabel A, Hernandez RM, Igartua M, et al. Production of BCG alginate-PLL microcapsules by emulsification/internal gelation. J Microencapsul 1997; 14(5): 627–638.

El-Gibaly I, Anwar MM. Development, characterization and in vivo evaluation of polyelectrolyte complex membrane gel micro- capsules containing melatonin-resin complex for oral use. Bull Pharm Sci Assiut Univ 1998; 21(2): 117–139.

Pillay V, Fassihi R. In vitro modulation from cross-linked pellets for site-specific drug delivery to the gastrointestinal tract. Part 1. Comparison of pH-responsive drug release and associated kinetics. J Control Release 1999; 59: 229–242.

Pillay V, Fassihi R. In vitro release modulation from cross-linked pellets for site-specific drug delivery to the gastrointestinal tract. Part 2. Physicochemical characterization of calcium-alginate, calcium-pectinate and calcium-alginate-pectinate pellets. J Control Release 1999; 59: 243–256.

Chickering DE, Jacob JS, Desai TA, et al. Bioadhesive micro- spheres. Part 3. In vivo transit and bioavailability study of drug loaded alginate and poly (fumaric–co-sebacic anhydride) micro- spheres. J Control Release 1997; 48: 35–46.

Iannuccelli V, Coppi G, Bondi M, et al. Biodegradable intraopera- tive system for bone infection treatment. Part 2. In vivo evaluation. Int J Pharm 1996; 143: 187–194.

Lim LY, Wan LSC. Propranolol hydrochloride binding in calcium alginate beads. Drug Dev Ind Pharm 1997; 23(10): 973–980.

FAO/WHO. Toxicological evaluation of certain food additives with a review of general principles and of specifications. Seventeenth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1974; No. 539.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 668.

Food Chemicals Codex, 4th edn. Washington, DC: National Academy Press, 1996: 54.

British Pharmaceutical Codex. London: Pharmaceutical Press, 1973: 66.

BP: Calcium carbonate

JP: Precipitated calcium carbonate PhEur: Calcii carbonas

USP: Calcium carbonate

Table I: Pharmacopeial specifications for calcium carbonate.

Test JP 2001 PhEur 2005 USP 28

Identification + + +

Characters — + —

Loss on drying 41.0% 42.0% 42.0%

Synonyms

Substances

insoluble in acetic acid

40.2% 40.2% 40.2%

Calcium carbonate (1 : 1); carbonic acid calcium salt 1:1; creta preparada; Destab; E170; MagGran CC; Micromite; Pharma- Carb; precipitated carbonate of lime; precipitated chalk; Vivapress Ca; Witcarb.

Chemical Name and CAS Registry Number

Fluoride — — 40.005%

Arsenic 45 ppm 44 ppm 43 ppm

Barium + + +

Chlorides — 4330 ppm —

Lead — — 43 ppm

Iron — 4200 ppm 40.1% Heavy metals 420 ppm 420 ppm 40.002%

Carbonic acid, calcium salt (1 : 1) [471-34-1]

Magnesium and

alkali (metals) salts

40.5% 41.5% 41.0%

Empirical Formula and Molecular Weight

Sulfates — 40.25% —

Mercury — — 40.5 mg/g

Assay (dried basis) 5 98.5% 98.5%–100.5% 98.0%–100.5%

Structural Formula

CaCO3

Functional Category

Buffering agent; coating agent; opacifier; tablet and capsule diluent; therapeutic agent.

Applications in Pharmaceutical Formulation or Technology

Calcium carbonate, employed as a pharmaceutical excipient, is mainly used in solid-dosage forms as a diluent.(1–6) It is also used as a base for medicated dental preparations, as a buffering agent, and as a dissolution aid in dispersible tablets. Calcium carbonate is used as a bulking agent in tablet sugar-coating processes and as an opacifier in tablet film-coating.

Calcium carbonate is also used as a food additive and therapeutically as an antacid and calcium supplement.

Description

Calcium carbonate occurs as an odorless and tasteless white powder or crystals.

Pharmacopeial Specifications

See Table I.

SEM: 1

Excipient: Calcium carbonate Manufacturer: Whittaker, Clark & Daniels Lot No.: 15A-3

Excipient: Calcium carbonate Manufacturer: Whittaker, Clark & Daniels Lot No.: 15A-3

Magnification: 2400×

Voltage: 20 kV

SEM: 3

Excipient: Calcium carbonate Manufacturer: Whittaker, Clark & Daniels Lot No.: 15A-4

Magnification: 600×

Voltage: 20 kV

SEM: 4

Excipient: Calcium carbonate Manufacturer: Whittaker, Clark & Daniels Lot No.: 15A-4

Magnification: 2400×

Voltage: 20 kV

SEM: 5

Excipient: Calcium carbonate Manufacturer: Whittaker, Clark & Daniels Lot No.: 15A-2

Excipient: Calcium carbonate Manufacturer: Whittaker, Clark & Daniels Lot No.: 15A-2

Magnification: 2400×

Voltage: 20 kV

Typical Properties

Acidity/alkalinity: pH = 9.0 (10% w/v aqueous dispersion)

Density (bulk): 0.8 g/cm3 Density (tapped): 1.2 g/cm3 Flowability: cohesive.

Hardness (Mohs): 3.0 for Millicarb. Melting point: decomposes at 8258C. Moisture content: see Figure 1.

Particle size: see Figure 2.

Refractive index: 1.59

Solubility: practically insoluble in ethanol (95%) and water. Solubility in water is increased by the presence of ammonium salts or carbon dioxide. The presence of alkali hydroxides reduces solubility.

Specific gravity: 2.7

Specific surface area: 6.21–6.47 m2/g

Stability and Storage Conditions

Calcium carbonate is stable and should be stored in a well- closed container in a cool, dry place.

Incompatibilities

Incompatible with acids and ammonium salts (see also Sections 10 and 18).

Method of Manufacture

Calcium carbonate is prepared by double decomposition of calcium chloride and sodium bicarbonate in aqueous solution. Density and fineness are governed by the concentrations of the solutions. Calcium carbonate is also obtained from the naturally occurring minerals aragonite, calcite, and vaterite.

Safety

Calcium carbonate is mainly used in oral pharmaceutical formulations and is generally regarded as a nontoxic material. However, calcium carbonate administered orally may cause constipation and flatulence. Consumption of large quantities (4–60 g daily) may also result in hypercalcemia or renal impairment.(7) Therapeutically, oral doses of up to about

1.5 g are employed as an antacid. In the treatment of hyperphosphatemia in patients with chronic renal failure, oral daily doses of 2.5–17 g have been used. Calcium carbonate may interfere with the absorption of other drugs from the gastrointestinal tract if administered concomitantly.

LD50 (rat, oral): 6.45 g/kg

Figure 1: Moisture sorption–desorption isotherm of calcium carbo- nate.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Calcium carbonate may be irritant to the eyes and on inhalation. Eye protection, gloves, and a dust mask are recommended. Calcium carbonate should be handled in a well-ventilated environment. In the UK, the long-term (8-hour TWA) occupational exposure limit for calcium carbonate is 10 mg/m3 for total inhalable dust and 4 mg/m3 for respirable dust.(8)

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (oral capsules and tablets; otic solutions). Included in nonparenteral medi- cines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

—

92 Calcium Carbonate

Figure 2: Particle-size distribution of calcium carbonate (Sturcal, Rhodia).

When calcium carbonate is used in tablets containing aspirin and related substances, traces of iron may cause discoloration. This may be overcome by inclusion of a suitable chelating agent. Grades with reduced lead levels are commercially available for use in antacids and calcium supplements.

Directly compressible tablet diluents containing calcium carbonate and other excipients are commercially available. Examples of such grades are Barcroft CS90 (containing 10% starch), Barcroft CX50 (containing 50% sorbitol), and Barcroft CZ50 (containing 50% sucrose) available from SPI Pharma. Available from DMV International, are Cal-Carb 4450 PG (containing maltodextrin), and Cal-Carb 4457 and Cal-Carb 4462 (both containing pregelatinized corn starch).

Two directly compressible grades containing only calcium carbonate are commercially available (Vivapress Ca 740 and Vivapress Ca 800, J. Rettenmaier and So¨ hne).

A specification for calcium carbonate is contained in the Food Chemicals Codex (FCC).

The EINECS number for calcium carbonate is 207-439-9.

Specific References

Haines-Nutt RF. The compression properties of magnesium and calcium carbonates. J Pharm Pharmacol 1976; 28: 468–470.

Ejiofor O, Esezebo S, Pilpel N. The plasto-elasticity and compressibility of coated powders and the tensile strength of their tablets. J Pharm Pharmacol 1986; 38: 1–7.

Gorecki DKJ, Richardson CJ, Pavlakidis P, Wallace SM. Dissolu- tion rates in calcium carbonate tablets: a consideration in product selection. Can J Pharm 1989; 122: 484–487, 508.

Allen LV. Featured excipient: capsule and tablet diluents. Int J Pharm Compound 2000; 4(4): 306–310, 324–325.

Mattsson S, Nystrom C. Evaluation of strength-enhancing factors of a ductile binder in direct compression of sodium bicarbonate and calcium carbonate powders. Eur J Pharm Sci 2000; 10(1): 53–

66.

Serra MD, Robles LV. Compaction of agglomerated mixtures of calcium carbonate and microcrystalline cellulose. Int J Pharm 2003; 258(1–2): 153–164.

Orwoll ES. The milk-alkali syndrome: current concepts. Ann Intern Med 1982; 97: 242–248.

Health and Safety Executive. EH40/2002: Occupational Exposure Limits 2002. Sudbury: Health and Safety Executive, 2002.

General References

Armstrong NA. Tablet manufacture. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 3. New York: Marcel Dekker, 2002: 2713–2732.

Ciancio SG. Dental products. In: Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical Technology, 2nd edn, vol. 3. New York: Marcel Dekker, 2002: 691–701.

Roberts DE, Rogers CM, Richards CE, Lee MG. Calcium carbonate mixture. Pharm J 1986; 236: 577.

Calcium Phosphate, Dibasic Anhydrous

Nonproprietary Names

BP: Anhydrous calcium hydrogen phosphate JP: Anhydrous dibasic calcium phosphate PhEur: Calcii hydrogenophosphas anhydricus USP: Dibasic calcium phosphate

Synonyms

A-TAB; calcium monohydrogen phosphate; calcium ortho- phosphate; Di-Cafos AN; dicalcium orthophosphate; E341; Emcompress Anhydrous; Fujicalin; phosphoric acid calcium salt (1 : 1); secondary calcium phosphate.

Chemical Name and CAS Registry Number

Dibasic calcium phosphate [7757-93-9]

Empirical Formula and Molecular Weight

Tablet and capsule diluent.

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.(1–5) 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.

Anhydrous dibasic calcium phosphate is used in toothpaste and dentifrice formulations for its abrasive properties.

Description

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

SEM: 2

Excipient: Emcompress Anhydrous Manufacturer: JRS Pharma LP Magnification: 200×

Voltage: 5 kV

94 Calcium Phosphate, Dibasic Anhydrous

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for calcium phosphate, dibasic anhydrous.

Test JP 2001 PhEur 2005 USP 28

Identification + + +

Characters + + —

Loss on ignition — — 6.6–8.5%

Loss on drying 41.0% 42.0% —

Acid insoluble substance 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 40.200% 40.5% 40.5%

Carbonate + + +

Barium + + +

Arsenic 42 ppm 410 ppm 43 mg/g

Organic volatile impurities — — +

Iron — 4400 ppm —

Assay (dried basis) 598.0% 98.0–101.0% 98.0–105.0%

Typical properties

Acidity/alkalinity:

pH = 7.3 (20% slurry);

pH = 5.1 (20% slurry of A-TAB);

pH = 6.1–7.2 (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: 0.1–0.2%. 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: 20–30 m2/g for A-TAB; 35 m2/g for Fujicalin.

Stability and Storage Conditions

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.

Incompatibilities

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 environ- ment. 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.

Method of Manufacture

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 spray- drying.(9,10)

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.

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.

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.

Related Substances

Calcium phosphate, dibasic dihydrate; calcium phosphate, tribasic; calcium sulfate.

Comments

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 95

Specific References

Fischer E. Calcium phosphate as a pharmaceutical excipient.

Manuf Chem 1992; 64(6): 25–27.

Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical tableting 1: physico-pharmaceutical properties. Pharm World Sci 1993; 15(3): 105–115.

Schmidt PC, Herzog R. Calcium phosphates in pharmaceutical tableting 2: comparison of tableting properties. Pharm World Sci 1993; 15(3): 116–122.

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.

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 dihyd- rate. Drug Dev Ind Pharm 2001; 27(8): 789–801.

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

Dulin WA. Degradation of bisoprolol fumarate in tablets formulated with dicalcium phosphate. Drug Dev Ind Pharm 1995; 21(4): 393–409.

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): 289–293.

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): 868–870.

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): 789–801.

General References

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

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.

Fuji Chemical Industry Co. Ltd. Technical literature: Fujicalin, 1998. Rhodia. Technical literature: Calcium phosphate excipients, 1999.

Calcium Phosphate, Dibasic Dihydrate

Nonproprietary Names

BP: Calcium hydrogen phosphate JP: Dibasic calcium phosphate

PhEur: Calcii hydrogenophosphas dihydricus USP: Dibasic calcium phosphate

Synonyms

Calcium hydrogen orthophosphate dihydrate; calcium mono- hydrogen phosphate dihydrate; Di-Cafos; dicalcium ortho- phosphate; DI-TAB; E341; Emcompress; phosphoric acid calcium salt (1 : 1) dihydrate; secondary calcium phosphate.

Chemical Name and CAS Registry Number

Dibasic calcium phosphate dihydrate [7789-77-7]

Empirical Formula and Molecular Weight

CaHPO4·2H2O 172.09

med 11

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