Corn Starch and Pregelatinized Starch 1 Nonproprietary Names None adopted. 2 Synonyms StarCap 1500.

3 Chemical Name and CAS Registry Number See Section 8. 4 Empirical Formula and Molecular Weight See Section 8. 5 Structural Formula See Section 8. 6 Functional Category Binding agent; compression aid; disintegrant; tablet and capsule diluent; tablet and capsule filler. 7 Applications in Pharmaceutical Formulation or Technology Corn starch and pregelatinized starch can be used in both capsules and tablets to improve flowability, enhance disintegration and improve hardness. 8 Description Corn starch and pregelatinized starch occurs as a white free-flowing powder. It is a coprocessed mixture of predominantly corn starch together with pregelatinized starch. 9 Pharmacopeial Specifications Both corn starch and pregelatinized starch are listed as separate monographs in the JP, PhEur, and USPNF, but the combination is not listed. See Starch, and Starch, Pregelatinized. See also Section 18. 10 Typical Properties Acidity/alkalinity 4.57.0 for StarCap 1500 Iron 40.001% for StarCap 1500 Loss on drying 713% for StarCap 1500 Microbial content Total aerobes count 4100 cfu/g; molds and yeasts 4100 cfu/g (Escherichia coli, Pseudomonas aeruginosa, and Salmonella species absent) for StarCap 1500. Particle size distribution 942% retained on #120 mesh (125 m), 2550% retained on #200 mesh (74 mm), 2055% passing #200 mesh (74 mm) for StarCap 1500 Solubility Insoluble in water for StarCap 1500 Sulfur dioxide 40.005% for StarCap 1500 11 Stability and Storage Conditions Store in sealed containers at below 308C, avoiding high humidity. 12 Incompatibilities See Starch, and Starch, Pregelatinized. 13 Method of Manufacture Corn starch and pregelatinized starch is produced by a proprietary

spray-drying technique. 14 Safety See Starch, and Starch, Pregelatinized. 15 Handling Precautions Observe normal precautions appropriate to the circumstances and quantity of material handled. 16 Regulatory Status Corn starch and pregelatinized starch is a coprocessed mixture of two materials both of which are regarded as nontoxic: Starch GRAS listed. Included in the FDA Inactive Ingredients Database (buccal tablets, oral capsules, powders, suspensions and tablets; topical preparations; and vaginal tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. Pregelatinized starch Included in the FDA Inactive Ingredients Database (oral capsules, suspensions, and tablets; vaginal preparations). Included in non-parenteral medicines licensed in the UK. 17 Related Substances Starch; starch, pregelatinized. 18 Comments Corn starch and pregelatinized starch are two 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 USP32NF27, the General Chapter 5.8 in PhEur 6.0, along with the State of Work document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV. StarCap 1500 is a free-flowing, low-dust excipient with disintegration and dissolution properties independent of medium pH, which help promote deaggregation of the powder mass into primary drug particles and speeds up the dissolution rate of the drug substance, providing rapid disintegration across the pH range present in the human digestive tract.(13) The coprocessed product has been designed specifically for use in capsules and directly compressed tablets, and has enhanced physical properties that cannot be achieved by single blend. It has been reported as having excellent properties for high-dose, high-solubility capsule formulations, with low weight and good content uniformity.(1) The product acts as a compression aid, diluent, and disintegrant, which allows for robust but simple capsule and directly compressible tablet formulations. 19 Specific References 1 Colorcon. Technical datasheet, version 1: StarCap 1500. StarCap 1500 utilized in a direct-fill capsule formulation of a high dose/high solubility active drug gabapentin capsules 300 mg, August 2007. 2 Colorcon. Product information sheet, version 3: Why StarCap 1500 in

capsules? February 2006. 3 Colorcon. AAPS annual meeting and exposition poster reprint: Evaluation of StarCap 1500 in a propranolol hydrochloride capsule formulation, November 2005. 20 General References Colorcon. Product specification: StarCap 1500 co-processed starch, January 2007. Deorkar N. High-functionality excipients: a review. Tablets and Capsules 2008: 2226. http://www.tabletscapsules.com (accessed 3 March 2009). European Directorate for the Quality of Medicines and Healthcare (EDQM). European Pharmacopoeia State Of Work Of International Harmonisation. Pharmeuropa 2009; 21(1): 142143. http://www.edqm. eu/site/-614.html (accessed 3 February 2009). Gohel MC, Jogani PD. A review of co-processed directly compressible excipients. J Pharm Pharm Sci 2005; 8(1): 7693. Nachaegari SK, Bansal AK. Coprocessed excipients for solid dosage forms. Pharm Tech 2004; 28: 5264. 21 Authors ME Quinn, RC Rowe. 22 Date of Revision

Tragacanth 1 Nonproprietary Names BP: Tragacanth JP: Tragacanth PhEur: Tragacanth USP-NF: Tragacanth See also Section 18. 2 Synonyms E413; goats thorn; gum benjamin; gum dragon; gum tragacanth; persian tragacanth; trag; tragant; tragacantha. 3 Chemical Name and CAS Registry Number Tragacanth gum [9000-65-1] 4 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 watersoluble polysaccharides. Bassorin, which constitutes 6070% 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, Dgalactose, 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. 5 Structural Formula See Section 4. 6 Functional Category Suspending agent; viscosity-increasing agent. 7 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 according 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. 8 Description Tragacanth gum occurs as flattened, lamellated, frequently curved fragments, or as straight or spirally twisted linear pieces from 0.52.5mm 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. 9 Pharmacopeial Specifications See Table I. Table I: Pharmacopeial specifications for tragacanth. Test JP XV PhEur 6.3 USP32NF27 Identification Botanical characteristics Microbial limits Flow time Lead 40.001% Heavy metals 420 ppm Methylcellulose Acacia Foreign matter 41.0% Karaya gum Sterculia gum Ash 44.0% 44.0% 10 Typical Properties Acidity/alkalinity pH = 56 for a 1% w/v aqueous dispersion. Acid value 25 Moisture content 415% w/w NIR spectra see Figure 1. 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 1.2501.385 T 744 Tragacanth 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 1004000 mPa s (1004000 cP) at 208C. Viscosity increases with increasing temperature and concentration, 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. 11 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 therefore 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% 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 48, 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. 12 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 compatible with relatively high salt concentrations and most other natural and synthetic suspending agents such as acacia, carboxymethylcellulose, starch, and sucrose. Ayellow colored, stringy, precipitate is formed with 10% w/v ferric chloride solution. 13 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. 14 Safety Tragacanth has been used for many years in oral pharmaceutical 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 15 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. 16 Regulatory Status GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Database (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. 17 Related Substances See Section 18. 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 dispersions 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 XV, contain a specification for powdered tragacanth. 5.0 0.0 6.0 10000 [2nd deriv. log(1/R) 0.5 1388 1166 1435 2246 2481 2365 2326 2222 2010 1886 2349 2261 1921 1721 log(1/R) 0.2 Wavelength/nm 1100 1300 1500 1700 1900 2100 2300 2500 Figure 1: Near-infrared spectrum of tragacanth measured by reflectance. T Tragacanth 745 19 Specific References 1 Taub A et al. Conditions for the preservation of gum tragacanth jellies. J Am Pharm Assoc (Sci) 1958; 47: 235239. 2 Jacobs GP, Simes R. The gamma irradiation of tragacanth: effect on microbial contamination and rheology. J Pharm Pharmacol 1979; 31: 333334. 3 Eisman PC et al. Influence of gum tragacanth on the bactericidal activity of preservatives. J Am Pharm Assoc (Sci) 1957; 46: 144147.

4 Hagiwara A et al. Lack of carcinogenicity of tragacanth gum in B6C3F1 mice. Food Chem Toxicol 1992; 30(8): 673679. 5 Danoff D et al. Big Mac attack [letter]. N Engl J Med 1978; 298: 1095 1096. 6 Rubinger D. Hypersensitivity to tablet additives in transplant recipients on prednisone [letter]. Lancet 1978; ii: 689. 7 Coskey RJ. Contact dermatitis caused by ECG electrode jelly. Arch Dermatol 1977; 113: 839840. 8 FAO/WHO. Evaluation of certain food additives and contaminants. Twenty-ninth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1986; No. 733. 9 Lewis RJ, ed. Saxs Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 3500. 10 Westwood N. Microbial contamination of some pharmaceutical raw materials. Pharm J 1971; 207: 99102. 11 De La Rosa MC et al. Microbiological quality of pharmaceutical raw materials. Pharm Acta Helv 1995; 70: 227232. 20 General References Fairbairn JW. The presence of peroxidases in tragacanth [letter]. J Pharm Pharmacol 1967; 19: 191. Verbeken D et al. Exudate gums: occurence, production, and applications. Appl Microbiol Biotechnol 2003; 63(1): 1021. 21 Author PJ Weller. 22 Date of Revision 12 January 2009.