med 5

Doliwa A, Santoyo S, Ygartua P. Effect of passive and iontophore- tic skin pretreatments with terpenes on the in vitro skin transport of piroxicam. Int J Pharm 2001; 229(1-2): 37–44.

Songkro S, Rades T, Becket G. The effects of p-menthane monoterpenes and related compounds on the percutaneous absorption of propranolol hydrochloride across newborn pig skin I. In vitro skin permeation and retention studies. STP Pharma Sci 2003; 13(5): 349–357.

Ray S, Ghosal SK. Release and skin permeation studies of naproxen from hydrophilic gels and effect of terpenes as enhancers on its skin permeation. Boll Chim Farm 2003; 142(3): 125–129.

Gao S, Singh J. In vitro percutaneous absorption enhancement of the lipophilic drug tamoxifen by terpenes. J Control Release 1998; 51: 193–199.

Kang L, Jun HW, Mani N. Preparation and characterisation of two-phase melt systems of lignocaine. Int J Pharm 2001; 222(1): 35–44.

Kang L, Jun HW. Formulation and efficacy studies of new topical anaesthetic creams. Drug Dev Ind Pharm 2003; 29(5): 505–512.

Blake KD. Dangers of common cold treatments in children. Lancet 1993; 341: 640.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials,

LD50

(guinea pig, oral): 0.88 g/kg(11)

11th edn. New York: Wiley, 2004: 3462–3463.

LD50 (mouse, IP): 0.11 g/kg LD50 (mouse, IV): 0.1 g/kg LD50 (mouse, oral): 0.64 g/kg LD50 (mouse, SC): 0.243 g/kg LD50 (rat, oral): 0.98 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Special precautions should be taken to avoid inhalation, or contact with the skin or eyes. Eye protection and gloves are recommended. When thymol is

BP: Titanium dioxide JP: Titanium oxide PhEur: Titanii dioxidum USP: Titanium dioxide

Synonyms

Anatase titanium dioxide; brookite titanium dioxide; color index number 77891; E171; Kronos 1171; pigment white 6; rutile titanium dioxide; Tioxide; TiPure; titanic anhydride; Tronox.

Chemical Name and CAS Registry Number

Titanium oxide [13463-67-7]

Empirical Formula and Molecular Weight

Coating agent; opacifier; pigment.

Applications in Pharmaceutical Formulation or Technology

Titanium dioxide is widely used in confectionery, cosmetics, and foods, in the plastics industry, and in topical and oral pharmaceutical formulations as a white pigment.

Owing to its high refractive index, titanium dioxide has light-scattering properties that may be exploited in its use as a white pigment and opacifier. The range of light that is scattered can be altered by varying the particle size of the titanium dioxide powder. For example, titanium dioxide with an average particle size of 230 nm scatters visible light, while titanium dioxide with an average particle size of 60 nm scatters ultraviolet light and reflects visible light.(1)

In pharmaceutical formulations, titanium dioxide is used as a white pigment in film-coating suspensions,(2,3) sugar-coated tablets, and gelatin capsules. Titanium dioxide may also be admixed with other pigments.

Titanium dioxide is also used in dermatological prepara- tions and cosmetics, such as sunscreens.(1,4)

SEM: 1

Excipient: Titanium dioxide

Magnification: 1200×

Voltage: 10 kV

Description

White, amorphous, odorless, and tasteless nonhygroscopic powder. Although the average particle size of titanium dioxide powder is less than 1 mm, commercial titanium dioxide generally occurs as aggregated particles of approximately 100 mm diameter.

Titanium dioxide may occur in several different crystalline forms: rutile; anatase; and brookite. Of these, rutile and anatase are the only forms of commercial importance. Rutile is the more thermodynamically stable and is used more frequently than the other crystalline forms.

Pharmacopeial Specifications

See Table I.

Typical Properties

Density (bulk): 0.4–0.62 g/cm3(5) Density (tapped): 0.625–0.830 g/cm3(6) Density (true):

3.8–4.1 g/cm3 for Anatase;

3.9–4.2 g/cm3 for Rutile.

Melting point: 18558C

Table I: Pharmacopeial specifications for titanium dioxide.

Test JP 2001 PhEur 2005 USP 28

Identification + + +

Characters — + —

Appearance of solution — + —

Acidity or alkalinity — + —

Water-soluble

substances 45.0 mg 425 mg 40.25%

Heavy metals — 420 ppm —

Iron — + —

Loss on drying 40.5% — 40.5%

Loss on ignition — — 413%

Acid-soluble substances — — 40.5%

Organic volatile — — +

impurities

Lead

— 460 ppm —

Assay 598.5% 98.0–100.5% 99.0–100.5%

Moisture content: 0.44%

Particle size distribution: average particle size = 1.05 mm.(5) See also Figures 1 and 2.

0.71 J/g (0.17 cal/g) for Anatase;

0.71 J/g (0.17 cal/g) for Rutile.

Specific surface area: 9.90–10.77 m2/g

Solubility: practically insoluble in dilute sulfuric acid, hydro- chloric acid, nitric acid, organic solvents, and water. Soluble in hydrofluoric acid and hot concentrated sulfuric acid. Solubility depends on previous heat treatment; prolonged heating produces a less-soluble material.

Figure 1: Particle-size distribution of titanium dioxide (fine powder).

Titanium Dioxide 783

Figure 2: Particle-size distribution of titanium dioxide (agglomerated particles).

Tinting strength (Reynolds):

1200–1300 for Anatase;

1650–1900 for Rutile.

Stability and Storage Conditions

Titanium dioxide is extremely stable at high temperatures. This is due to the strong bond between the tetravalent titanium ion and the bivalent oxygen ions. However, titanium dioxide can lose small, unweighable amounts of oxygen by interaction with radiant energy. This oxygen can easily recombine again as a part of a reversible photochemical reaction, particularly if there is no oxidizable material available. These small oxygen losses are important because they can cause significant changes in the optical and electrical properties of the pigment.

Titanium dioxide should be stored in a well-closed container, protected from light, in a cool, dry place.

Incompatibilities

Owing to a photocatalytic effect, titanium dioxide may interact with certain active substances, e.g. famotidine.(7) Studies have shown that titanium dioxide monatonically degrades film mechanical properties and increases water vapor permeability of polyvinyl alcohol coatings when used as an inert filler and whitener.(6)

Titanium dioxide has also been shown to induce photo- oxidation of unsaturated lipids.(8)

Method of Manufacture

Titanium dioxide occurs naturally as the minerals rutile (tetragonal structure), anatase (tetragonal structure), and brookite (orthorhombic structure).

Titanium dioxide may be prepared commercially by direct combination of titanium and oxygen; by treatment of titanium salts in aqueous solution; by the reaction of volatile inorganic

784 Titanium Dioxide

titanium compounds with oxygen; and by the oxidation or hydrolysis of organic compounds of titanium.

Safety

Titanium dioxide is widely used in foods and oral and topical pharmaceutical formulations. It is generally regarded as an essentially nonirritant and nontoxic excipient.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection, gloves, and a dust mask are recommended. Titanium dioxide is regarded as a relatively innocuous nuisance dust,(9) that may be irritant to the respiratory tract. In the UK, the long-term (8-hour TWA) exposure limit is 10 mg/m3 for total inhalable dust and 4 mg/m3 for respirable dust.(10)

Titanium dioxide particles in the 500 nm range have been reported to translocate to all major body organs after oral administration in the rat.(11)

Regulatory Status

Accepted as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (dental paste; intrauterine supposi- tories; ophthalmic preparations; oral capsules, suspensions, tablets; topical and transdermal preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Coloring agents.

Comments

Titanium dioxide is a hard, abrasive material. Coating suspensions containing titanium dioxide have been reported to cause abrasion and wear of a steel-coated pan surface, which led to white tablets being contaminated with black specks.(12)

If titanium dioxide is used as a pigment it should conform to the appropriate food standards specifications, which are more demanding than the pharmacopeial specifications.

When mixed with methylcellulose, titanium dioxide can reduce the elongation and tensile strength of the film but slightly increase the adhesion between pigmented film and the tablet surface.(13) A specification for titanium dioxide is contained in the Food Chemicals Codex (FCC).

The EINECS number for titanium dioxide is 236-675-5.

Specific References

Hewitt JP. Titanium dioxide: a different kind of sunshield. Drug Cosmet Ind 1992; 151(3): 26, 28, 30, 32.

Rowe RC. Quantitative opacity measurements on tablet film coatings containing titanium dioxide. Int J Pharm 1984; 22: 17– 23.

Be´chard SR, Quraishi O, Kwong E. Film coating: effect of titanium dioxide concentration and film thickness on the photostability of nifedipine. Int J Pharm 1992; 87: 133–139.

Alexander P. Ultrafine titanium dioxide makes the grade. Manuf Chem 1991; 62(7): 21, 23.

Brittain HG, Barbera G, DeVincentis J, Newman AW. Titanium dioxide. In: Brittain HG, ed. Analytical Profiles of Drug Substances and Excipients, volume 21. San Diego: Academic Press, 1992: 659–691.

Hsu ER, Gebert MS, Becker NT, Gaertner AL. Effects of plasticizers and titanium dioxide on the properties of poly(vinyl alcohol) coatings. Pharm Dev Technol 2001; 6(2): 277–284.

Kakinoki K, Yamane K, Teraoka R, et al. Effect of relative humidity on the photocatalytic activity of titanium dioxide and photostability of famotidine. J Pharm Sci 2004; 93(3): 582–589.

Sayre RM, Dowdy JC. Titanium dioxide and zinc oxide induce photooxidation of unsaturated lipids. Cosmet Toilet 2000; 115; 75–80, 82.

Driscoll KE, Maurer JK, Lindenschmidt RC, et al. Respiratory tract responses to dust: relationships between dust burden, lung injury, alveolar macrophage fibronectin release, and the develop- ment of pulmonary fibrosis. Toxicol Appl Pharmacol 1990; 106: 88–101.

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

Jani PU, McCarthy DE, Florence AT. Titanium dioxide (rutile) particle uptake from the rat GI tract and translocation to systemic organs after oral administration. Int J Pharm 1994; 105(May 2); 157–168.

Rosoff M, Sheen P-C. Pan abrasion and polymorphism of titanium dioxide in coating suspensions. J Pharm Sci 1983; 72: 1485.

Lehtola VM, Heinamaki JT, Nikupaavo P, Yliruusi JK. Effect of titanium dioxide on mechanical, permeability and adhesion properties of aqueous-based hydroxypropyl methylcellulose films. Boll Chim Farm 1994; 133(Dec): 709–714.

General References

Judin VPS. The lighter side of TiO2. Chem Br 1993; 29(6): 503–505.

Loden M, Akerstrom U, Lindahl K, Berne B. Novel method for studying photolability of topical formulations: a case study of titanium dioxide stabilization of ketoprofen. J Pharm Sci 2005; 94(4): 781– 787.

Ortyl TT, Peck GE. Surface charge of titanium dioxide and its effect on dye adsorption and aqueous suspension stability. Drug Dev Ind Pharm 1991; 17: 2245–2268.

Rowe RC. Materials used in the film coating of oral dosage forms. In: Florence AT, ed. Critical Reports on Applied Chemistry, volume 6. Oxford: Blackwell Scientific, 1984: 1–36.

BP: Tragacanth JP: Tragacanth

PhEur: Tragacantha USPNF: Tragacanth See also Section 18.

Synonyms

E413; goat’s thorn; gum benjamin; gum dragon; gum tragacanth; persian tragacanth; trag; tragant.

Chemical Name and CAS Registry Number

Tragacanth gum [9000-65-1]

Empirical Formula and Molecular Weight

Tragacanth is a naturally occurring dried gum obtained from Astragalus gummifer Labillardie`re and other species of Astragalus grown in Western Asia; see Section 13.

The gum consists of a mixture of water-insoluble and water- soluble polysaccharides. Bassorin, which constitutes 60–70% of the gum, is the main water-insoluble portion, while the remainder of the gum consists of the water-soluble material tragacanthin. On hydrolysis, tragacanthin yields L-arabinose, L-fucose, D-xylose, D-galactose, and D-galacturonic acid. Tragacanth gum also contains small amounts of cellulose, starch, protein, and ash.

Tragacanth gum has an approximate molecular weight of 840 000.

Structural Formula

See Section 4.

Functional Category

Suspending agent; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Tragacanth gum is used as an emulsifying and suspending agent in a variety of pharmaceutical formulations. It is used in creams, gels, and emulsions at various concentrations accord- ing to the application of the formulation and the grade of gum used.

Tragacanth gum is also used similarly in cosmetics and food products, and has been used as a diluent in tablet formulations.

Description

Tragacanth gum occurs as flattened, lamellated, frequently curved fragments, or as straight or spirally twisted linear pieces from 0.5–2.5 mm in thickness; it may also be obtained in a powdered form. White to yellowish in color, tragacanth is a

translucent, odorless substance, with an insipid mucilaginous taste.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for tragacanth.

Test JP 2001 PhEur 2005 USPNF 23

Identification + + +

Characters — + —

Botanical characteristics — — +

Microbial limits — + +

Flow time — + —

Lead — — 40.001%

Heavy metals — — 420 ppm

Methylcellulose — + —

Acacia — + —

Foreign matter — 41.0% —

Karaya gum + — +

Sterculia gum — + —

Organic volatile impurities — — +

Ash 44.0% 44.0% —

Typical Properties

Acidity/alkalinity: pH = 5–6 for a 1% w/v aqueous dispersion.

Acid value: 2–5

Moisture content: 415% w/w

Particle size distribution: for powdered grades 50% w/w passes through a 73.7 mm mesh.

Solubility: practically insoluble in water, ethanol (95%), and other organic solvents. Although insoluble in water, tragacanth gum swells rapidly in 10 times its own weight of either hot or cold water to produce viscous colloidal sols or semigels. See also Section 18.

Specific gravity: 1.250–1.385

Viscosity (dynamic): the viscosity of tragacanth dispersions varies according to the grade and source of the material. Typically, 1% w/v aqueous dispersions may range in viscosity from 100–4000 mPa s (100–4000 cP) at 208C. Viscosity increases with increasing temperature and con- centration, and decreases with increasing pH. Maximum initial viscosity occurs at pH 8, although the greatest stability of tragacanth dispersions occurs at about pH 5. See also Sections 11 and 12.

Stability and Storage Conditions

Both the flaked and powdered forms of tragacanth are stable. Tragacanth gels are liable to exhibit microbial contamination with enterobacterial species, and stock solutions should there- fore contain suitable antimicrobial preservatives. In emulsions, glycerin or propylene glycol are used as preservatives; in gel formulations, tragacanth is usually preserved with either 0.1% w/v benzoic acid or sodium benzoate. A combination of 0.17%

786 Tragacanth

w/v methylparaben and 0.03% w/v propylparaben is also an effective preservative for tragacanth gels;(1) see also Section 12. Gels may be sterilized by autoclaving. Sterilization by gamma irradiation causes a marked reduction in the viscosity of tragacanth dispersions.(2)

Tragacanth dispersions are most stable at pH 4–8, although stability is satisfactory at higher pH or as low as pH 2.

The bulk material should be stored in an airtight container in a cool, dry place.

Incompatibilities

At pH 7, tragacanth has been reported to considerably reduce the efficacy of the antimicrobial preservatives benzalkonium chloride, chlorobutanol, and methylparaben, and to a lesser extent that of phenol and phenylmercuric acetate.(3) However, at pH < 5 tragacanth was reported to have no adverse effects

on the preservative efficacy of benzoic acid, chlorobutanol, or

methylparaben.(1)

The addition of strong mineral and organic acids can reduce the viscosity of tragacanth dispersions. Viscosity may also be reduced by the addition of alkali or sodium chloride, particularly if the dispersion is heated. Tragacanth is compa- tible with relatively high salt concentrations and most other natural and synthetic suspending agents such as acacia, carboxymethylcellulose, starch, and sucrose. A yellow colored, stringy, precipitate is formed with 10% w/v ferric chloride solution.

Method of Manufacture

Tragacanth gum is the air-dried gum obtained from Astragalus gummifer Labillardie`re and other species of Astragalus grown principally in Iran, Syria, and Turkey. A low-quality gum is obtained by collecting the natural air-dried exudate from Astragalus bushes. A higher-grade material is obtained by making incisions in the trunk and branches of the bush, which are held open with variously sized wooden pegs. The exudate is left to drain from the incision and dry naturally in the air before being collected. The size and position of the wooden wedges determine the physical form of the exudate, while the drying conditions determine the color of the gum. After collection, the tragacanth gum is sorted by hand into various grades, such as ribbons or flakes.

Safety

Tragacanth has been used for many years in oral pharmaceu- tical formulations and food products, and is generally regarded as an essentially nontoxic material. Tragacanth has been shown to be noncarcinogenic.(4) However, hypersensitivity reactions, which are occasionaly severe, have been reported following ingestion of products containing tragacanth.(5,6) Contact dermatitis has also been reported following the topical use of tragacanth formulations.(7)

The WHO has not specified an acceptable daily intake for tragacanth gum, as the daily intake necessary to achieve a desired effect, and its background levels in food, were not considered to be a hazard to health.(8)

LD50 (hamster, oral): 8.8 g/kg(9) LD50 (mouse, oral): 10 g/kg LD50 (rabbit, oral): 7.2 g/kg LD50 (rat, oral): 16.4 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Tragacanth gum may be irritant to the skin and eyes. Eye protection, gloves, and a dust mask are recommended.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (buccal/ sublingual tablets, oral powders, suspensions, syrups, and tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

See Section 18.

Comments

Tragacanth gum is a naturally occurring material whose physical properties vary greatly according to the grade and source of the material. Samples can contain relatively high levels of bacterial contamination.(10,11)

Hog gum (caramania gum), obtained from species of Prunus, and sterculia gum have been used in industrial applications as substitutes for tragacanth.

Powdered tragacanth gum tends to form lumps when added to water and aqueous dispersions should therefore be agitated vigorously with a high-speed mixer. However, aqueous disper- sions are more readily prepared by first prewetting the tragacanth with a small quantity of a wetting agent such as ethanol (95%), glycerin, or propylene glycol. If lumps form, they usually disperse on standing. Dispersion is generally complete after 1 hour. If other powders, such as sucrose, are to be incorporated into a tragacanth formulation the powders are best mixed together in the dry state.

Some pharmacopeias, such as JP 2001, contain a specifica- tion for powdered tragacanth.

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

Specific References

Taub A, Meer WA, Clausen LW. Conditions for the preservation of gum tragacanth jellies. J Am Pharm Assoc (Sci) 1958; 47: 235– 239.

Jacobs GP, Simes R. The gamma irradiation of tragacanth: effect on microbial contamination and rheology. J Pharm Pharmacol 1979; 31: 333–334.

Eisman PC, Cooper J, Jaconia D. Influence of gum tragacanth on the bactericidal activity of preservatives. J Am Pharm Assoc (Sci) 1957; 46: 144–147.

Hagiwara A, Boonyaphiphat P, Kawabe M, et al. Lack of carcinogenicity of tragacanth gum in B6C3F1 mice. Food Chem Toxicol 1992; 30(8): 673–679.

Danoff D, Lincoln L, Thomson DMP, Gold P. Big Mac attack [letter]. N Engl J Med 1978; 298: 1095–1096.

Rubinger D, Friedlander M, Superstine E. Hypersensitivity to tablet additives in transplant recipients on prednisone [letter]. Lancet 1978; ii: 689.

Coskey RJ. Contact dermatitis caused by ECG electrode jelly. Arch Dermatol 1977; 113: 839–840.

FAO/WHO. Evaluation of certain food additives and contami- nants. Twenty-ninth report of the joint FAO/WHO expert

Tragacanth 787

committee on food additives. World Health Organ Tech Rep Ser

1986; No. 733.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3500.

Westwood N. Microbial contamination of some pharmaceutical raw materials. Pharm J 1971; 207: 99–102.

De La Rosa MC, Del Rosario Medina M, Vivar C. Microbiological quality of pharmaceutical raw materials. Pharm Acta Helv 1995; 70: 227–232.

General References

Fairbairn JW. The presence of peroxidases in tragacanth [letter]. J Pharm Pharmacol 1967; 19: 191.

Verbeken D, Dierckx S, Dewettinck K. Exudate gums: occurence, production, and applications. Appl Microbiol Biotechnol 2003; 63(1): 10–21.

C*Ascend; (a-D-glucosido)-a-D-glucoside; mycose; natural tre- halose; a,a-trehalose; trehalose dihydrate.

Chemical Name and CAS Registry Number

a-D-Glucopyranosyl-a-D-glucopyranoside anhydrous [99-

20-7]

a-D-Glucopyranosyl-a-D-glucopyranoside dihydrate [6138-

23-4]

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