med 5

Comments

Xanthan gum is available in several different grades that have varying particle sizes. Fine-mesh grades of xanthan gum are used in applications where high solubility is desirable since they dissolve rapidly in water. However, fine-mesh grades disperse more slowly than coarse grades and are best used dry blended with the other ingredients of a formulation. In general, it is preferable to dissolve xanthan gum in water first and then add the other ingredients of a formulation.

When added to liquid ophthalmics, xanthan gum delays the release of active substances, increasing the therapeutic activity of the pharmaceutical formulations.(24)

Xanthan gum has also been used to produce directly compressed matrices that display a high degree of swelling due to water uptake, and a small amount of erosion due to polymer relaxation.(25)

The USPNF 23 also includes a monograph for xanthan gum solution. A specification for xanthan gum is contained in the Food Chemicals Codex (FCC).

The EINECS number for xanthan gum is 234-394-2.

Xanthan Gum 823

Specific References

Jansson PE, Kenne L, Lindberg B. Structure of extracellular polysaccharide from Xanthamonas campestris. Carbohydr Res 1975; 45: 275–282.

Melton LD, Mindt L, Rees DA, Sanderson GR. Covalent structure of the polysaccharide from Xanthamonas campestris: evidence from partial hydrolysis studies. Carbohydr Res 1976; 46: 245–

257.

Bumphrey G. ‘Extremely useful’ new suspending agent. Pharm J

1986; 237: 665.

Evans BK, Fenton-May V. Keltrol [letter]. Pharm J 1986; 237: 736–737.

Chollet JK, Jozwiakowski MJ, Phares KR, et al. Development of a topically active imiquimod formulation. Pharm Dev Technol 1999; 4(1): 35–43.

Kovacs P. Useful incompatibility of xanthan gum with galacto- mannans. Food Technol 1973; 27(3): 26–30.

Talukdar M, Van der Mooter G, Augustijus P. In vivo evaluation of xanthan gum as a potential excipient for oral controlled-release matrix tablet formulation. Int J Pharm 1998; 169: 105–113.

Lu MF, Woodward L, Borodkin S. Xanthan gum and alginate based controlled release theophylline formulations. Drug Dev Ind Pharm 1991; 17: 1987–2004.

Dhopeshwarkar V, Zatz JL. Evaluation of xanthan gum in the preparation of sustained release matrix tablets. Drug Dev Ind Pharm 1993; 19: 999–1017.

Billa N, Yuen KH, Khader MA, Omar A. Gamma scintigraphic study of the gastrointestinal transit and in vivo dissolution of a controlled release diclofenac sodium formulation in xanthan gum matrices. Int J Pharm 2000; 201: 109–120.

Peh KK, Wong CF. Application of similarity factor in the development of controlled release diltiazem tablet. Drug Dev Ind Pharm 2000; 26: 723–730.

Ceulemans J, Vinckier I, Ludwig A. The use of xanthan gum in an ophthalmic liquid dosage form: rheological characterization of the interaction with mucin. J Pharm Sci 2002; 91(4): 1117–1127.

Patel N, Craddock BL, Staniforth JN, et al. Spray-dried insulin particles retain biological activity in rapid in-vitro assay. J Pharm Pharmacol 2001; 53(10): 1415–1418.

Corveleyn S, Remon JP. Stability of freeze-dried tablets at different relative humidities. Drug Dev Ind Pharm 1999; 25(9): 1005–1013.

Vermani K, Garg S, Zaneveld LJ. Assemblies for in vitro measurement of bioadhesive strength and retention characteristics in simulated vaginal environment. Drug Dev Ind Pharm 2002; 28(9): 1133–1146.

Sinha VR, Kumria R. Binders for colon specific drug delivery: an in vitro evaluation. Int J Pharm 2002; 249(1–2): 23–31.

Howe AM, Flowers AE. Introduction to shampoo thickening.

Cosmet Toilet 2000; 115: 63–66, 68–69.

Walker CV, Wells JI. Rheological synergism between ionic and non-ionic cellulose gums. Int J Pharm 1982; 11: 309–322.

Zatz JL, Figler D, Livero K. Fluidization of aluminum hydroxide gels containing xanthan gum. Drug Dev Ind Pharm 1986; 12: 561–568.

Jeanes AR, Pittsley JE, Senti FR. Polysaccharide B-1459: a new hydrocolloid polyelectrolyte produced from glucose by bacterial fermentation. J Appl Polym Sci 1961; 5(17): 519–526.

Godet P. Fermentation of polysaccharide gums. Process Biochem

1973; 8(1): 33.

FAO/WHO. Evaluation of certain food additives and contami- nants. Twenty-ninth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1986; No. 733.

Booth AN, Hendrickson AP, De Eds F. Physiologic effects of three microbial polysaccharides on rats. Toxicol Appl Pharmacol 1963; 5: 478–484.

Hoepfner E, Reng A, Schmidt PC, eds. Fielder Encyclopedia of Excipients for Pharmaceuticals, Cosmetics and Related Areas, 5th edn. Aulendorf: Edito Cantor Verlag, 2002: 1690.

Munday DL, Cox PJ. Compressed xantham and karaya gum matrices: hydration, erosion and drug release mechanisms. Int J Pharm 2000; 203: 179–192.

General References

Gamini A, De Bleijer J, Leute JC. Physicochemical properties of aqueous solutions of xanthan: an NMR study. Carbohydr Res 1991; 220: 33–47.

Kelco Division of Merck & Co Inc. Technical literature: Xanthan gum—natural biogum for scientific water control, 3rd edn, 1991.

Rhodia. Technical literature: Rhodigel—food grade xanthan gum, 1998.

Shatwell KP, Sutherland IW, Ross-Murphy SB. Influence of acetyl and pyruvate substituents on the solution properties of xanthan polysaccharide. Int J Biol Macromol 1990; 12(2): 71–78.

Vendruscolo CW, Andreazza IF, Ganter JLMS, et al. Xanthan and galactomannan (from M. scabrella) matrix tablets for oral controlled delivery of theophylline. Int J Pharm 2005; 296: 1–11.

Whitcomb PJ. Rheology of xanthan gum. J Rheol 1978; 22(5): 493– 505.

Zatz JL. Applications of gums in pharmaceutical and cosmetic suspensions. Ind Eng Chem Prod Res Dev 1984; 23: 12–16.

BP: Xylitol JP: Xylitol

PhEur: Xylitolum USPNF: Xylitol

Synonyms

E967; Klinit; meso-xylitol; xilitol; Xylifin; Xylisorb; xylit;

Xylitab; xylite; Xylitolo.

Chemical Name and CAS Registry Number

xylo-Pentane-1,2,3,4,5-pentol [87-99-0]

Empirical Formula and Molecular Weight

C5H12O5 152.15

Structural Formula

Functional Category

Antimicrobial preservative; base for medicated confectionery; coating agent; emollient; humectant; sweetening agent; tablet and capsule diluent.

Applications in Pharmaceutical Formulation or Technology

Xylitol is used as a noncariogenic sweetening agent in a variety of pharmaceutical dosage forms, including tablets, syrups, and coatings. It is also widely used as an alternative to sucrose in foods and confectionery. Xylitol is finding increasing applica- tion in chewing gum,(1,2) mouthrinses,(3) and toothpastes(4) as an agent that decreases dental plaque and tooth decay (dental caries). Unlike sucrose, xylitol is not fermented into cariogenic acid end products(5) and it has been shown to reduce dental caries by inhibiting the growth of cariogenic Streptococcus mutans bacteria.(6,7) As xylitol has an equal sweetness intensity to sucrose, combined with a distinct cooling effect upon dissolution of the crystal, it is highly effective in enhancing the flavor of tablets and syrups and masking the unpleasant or bitter flavors associated with some pharmaceutical actives and excipients.

In topical cosmetic and toiletry applications, xylitol is used primarily for its humectant and emollient properties, although it has also been reported to enhance product stability through a combination of potentiation of preservatives and its own bacteriostatic and bactericidal properties.

Granulates of xylitol are used as diluents in tablet formulations, where they can provide chewable tablets with a desirable sweet taste and cooling sensation, without the ‘chalky’ texture experienced with some other tablet diluents. Xylitol solutions are employed in tablet-coating applications at concentrations in excess of 65% w/w. Xylitol coatings are stable and provide a sweet-tasting and durable hard coating.

In liquid preparations, xylitol is used as a sweetening agent and vehicle for sugar-free formulations. In syrups, it has a reduced tendency to ‘cap-lock’ by effectively preventing crystallization around the closures of bottles. Xylitol also has a lower water activity and a higher osmotic pressure than sucrose, therefore enhancing product stability and freshness. In addition, xylitol has also been demonstrated to exert certain specific bacteriostatic and bactericidal effects, particularly against common spoilage organisms.(8,9)

Therapeutically, xylitol is additionally utilized as an energy source for intravenous infusion following trauma.(10)

Description

Xylitol occurs as a white, granular solid comprising crystalline, equidimensional particles having a mean diameter of about 0.4–0.6 mm. It is odorless, with a sweet taste that imparts a cooling sensation. Xylitol is also commercially available in powdered form and several granular, directly compressible forms.(11) See also Section 17.

SEM: 1

Excipient: Xylitol (unsieved)

Magnification: 60×

Xylitol 825

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for xylitol.

Test JP 2001 PhEur2005 USPNF 23

Identification + + +

Characters + + —

Clarity and color of + + —

solution

Water 41.0% 41.0% 40.5%

pH (50% w/w 5.0–7.0 — —

solution)

Melting point 93.0–95.08C 92–968C —

Residue on ignition 40.1% — 40.5%

Heavy metals 45 ppm — 40.001%

Reducing sugars (as + 40.2% 40.2%

dextrose)

Other polyols — — 42.0%

Related substances — 42.0% —

Lead — 40.5 ppm —

Bacterial — 42.5 IU/g —

Organic volatile — — +

impurities

Assay (anhydrous 598.0% 98.0–102.0% 98.5–101.0%

basis)

(a) If intended for use in parenteral products.

Typical Properties

Acidity/alkalinity: pH = 5.0–7.0 (10% w/v aqueous solution).

Boiling point: 215–2178C

Compressibility: see Figure 1. Crystalline xylitol, under the same test conditions as illustrated in Figure 1, produces

12.5 mm tablets of 40 N hardness at 20 kN compression force.

Density (true): 1.52 g/cm3

Density (bulk):

0.8–0.85 g/cm3 for crystalline xylitol;

0.5–0.7 g/cm3 for directly compressible granulated grades.

Flowability: flow characteristics vary depending upon the particle size of xylitol used. Fine-milled grades tend to be relatively poorly flowing, while granulated grades have good flow properties.

Heat of solution: —157.1 kJ/kg (–36.7 cal/g)

Melting point: 92.0–96.08C

Moisture content: xylitol is a moderately hygroscopic powder under normal conditions; see also Figure 2. At 208C and 52% relative humidity, the equilibrium moisture content of xylitol is 0.1% w/w. After drying in a vacuum, over P2O5 at 808C for 4 hours, xylitol loses less than 0.5% w/w water.

Osmolarity: a 4.56% w/v aqueous solution is iso-osmotic with serum.

Particle size distribution: the particle size distribution of xylitol depends upon the grade selected. Normal crystalline material typically has a mean particle size of 0.4–0.6 mm. Milled grades are commercially available that offer mean particle sizes as low as 50 mm. Individual suppliers’ literature

should be consulted for further information. For particle size distributions of granulated xylitol, see Figure 3.

Solubility: see Table II.

Table II: Solubility of xylitol.

Solvent Solubility at 208C

Ethanol 1 in 80

Glycerin Very slightly soluble

Methanol 1 in 16.7

Peanut oil Very slightly soluble

Propan-2-ol 1 in 500

Propylene glycol 1 in 15

Pyridine Soluble

Water 1 in 1.6

Specific rotation: not optically active.

Viscosity (dynamic): see Figure 4.

Figure 1: Compression characteristics of Xylitab 100 and Xylitab 200 (Danisco Sweeteners Ltd.).

⃝: Xylitol with 3.5% polydextrose (Xylitab 100)

□: Xylitol with 2.0% carboxymethylcellulose (Xylitab 200)

Stability and Storage Conditions

Xylitol is stable to heat but is marginally hygroscopic. Caramelization can occur only if it is heated for several minutes near its boiling point. Crystalline material is stable for at least 3 years if stored at less than 65% relative humidity and 258C. Milled and specialized granulated grades of xylitol have a tendency to cake and should therefore be used within 6 months. Aqueous xylitol solutions have been reported to be stable, even on prolonged heating and storage. Since xylitol is not utilized by most microorganisms, products made with xylitol are usually safe from fermentation and microbial spoilage.(8,9)

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

826 Xylitol

Figure 2: Moisture sorption isotherm of xylitol at 208C.

Figure 3: Particle size distribution of granulated xylitol (Xylitab, Danisco Sweeteners Ltd.).

*: Xylitab 100 granulated with 3.5% polydextrose

&: Xylitab 200 granulated with 2.0% carboxymethyl-

cellulose

~: Xylitab 300 wet granulated.

Incompatibilities

Xylitol is incompatible with oxidizing agents.

Method of Manufacture

Xylitol occurs naturally in many fruits and berries, although extraction from such sources is not considered to be

commercially viable. Industrially, xylitol is most commonly derived from various types of hemicellulose obtained from such sources as wood, cane pulp, seed hulls, and shells. These materials usually contain 20–35% xylan, which is readily converted to xylose (wood sugar) by hydrolysis. This xylose is subsequently converted to xylitol via hydrogenation (reduc- tion). Following the hydrogenation step, there are a number of separation and purification steps that ultimately yield high- purity xylitol crystals. The nature of this process, and the stringent purification procedures employed, result in a finished product with a very low impurity content. Potential impurities that may appear in small quantities are mannitol, sorbitol, galactitol, or arabitol.

Less commonly employed methods of xylitol manufacture include the conversion of glucose (dextrose) to xylose followed by hydrogenation to xylitol, and the microbiological conver- sion of xylose to xylitol.

Figure 4: Viscosity of aqueous xylitol solutions at 208C.

Safety

Xylitol is used in oral pharmaceutical formulations, confec- tionery, and food products and is generally regarded as an essentially nontoxic, nonallergenic, and nonirritant material.

Xylitol has an extremely low glycemic index and is metabolized independently of insulin. Following ingestion of xylitol, the blood glucose and serum insulin responses are significantly lower than following ingestion of glucose or sucrose. These factors make xylitol a suitable sweetener for use in diabetic or carbohydrate-controlled diets.(12)

Up to 100 g of xylitol in divided oral doses may be tolerated daily, although, as with other polyols, large doses may have a laxative effect. The laxative threshold depends on a number of factors, including individual sensitivity, mode of ingestion, daily diet, and previous adaptation to xylitol. Single doses of 20–30 g and daily doses of 0.5–1.0 g/kg bodyweight are usually well tolerated by most individuals. Approximately 25–50% of the ingested xylitol is absorbed, with the remaining 50–75% passing to the lower gut, where it undergoes indirect metabolism via fermentative degradation by the intestinal flora.

Xylitol 827

An acceptable daily intake for xylitol of ‘not specified’ has been set by the WHO since the levels used in foods do not represent a hazard to health.(13)

LD50 (mouse, IP): 22.1 g/kg(14,15) LD50 (mouse, IV): 12 g/kg

LD50 (mouse, oral): 12.5 g/kg LD50 (rat, oral): 17.3 g/kg LD50 (rat, IV): 10.8 g/kg

LD50 (rabbit, oral): 16.5 g/kg LD50 (rabbit, IV): 4 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Xylitol may be harmful if ingested in large quantities; and may also be irritant to the eyes. Eye protection and gloves are recommended. Xylitol is flammable, but does not ignite readily.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (oral solution, chewing gum). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

Related Substances

Various directly compressible forms of xylitol that contain other excipients are commercially available, e.g., Xylitab 100, which contains 3.5% polydextrose, and Xylitab 200, which contains 2.0% carboxymethylcellulose (both Danisco Sweet- eners Ltd.). A directly compressible form of pure xylitol is also available, Xylitab 300 (Danisco Sweeteners Ltd.), which is produced via wet granulation.

Pyrogen-free grades of xylitol suitable for parenteral use are also commercially available.

Comments

The sweetening power of xylitol is approximately equal to that of sucrose, although it has been shown to be pH-, concentra- tion-, and temperature-dependent; xylitol is approximately 2.5 times as sweet as mannitol.

Xylitol is highly chemically stable, meaning that it will not interact with pharmaceutical actives or excipients, and can be utilized over a wide pH range (pH 1–11).

The EINECS number for xylitol is 201-788-0.

Xylitol has a negative heat of solution that is far larger than that of other alternative sweetening agents; see Table III. Because of this, xylitol produces an intense cooling effect as the crystalline material dissolves. Xylitol’s combination of sweet- ness and cooling can create product appeal while helping to mask the undesirable taste of many pharmaceutical actives or excipients.

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

Specific References

Tanzer JM. Xylitol chewing gum and dental caries. Int Dent J

1995; 45(1): 65–76.

Soderling E, Trahan L, Tammiala T, Hakkinen L. Effects of xylitol, xylitol-sorbitol, and placebo chewing gums on the plaque of habitual xylitol consumers. Eur J Oral Sci 1997; 105(2): 170–177.

Table III: Comparison of the heat of solution of selected sweetening agents.

Sweetening agent Heat of solution (kJ/kg)

Lactitol (anhydrous) —35.0

Cobanera A, Morasso A, White E, et al. Xylitol-sodium fluoride: effect on plaque. J Dent Res 1987; 66: 814.

Sintes JL, Escalante C, Stewart B, et al. Enhanced anticaries efficacy of a 0.243% sodium fluoride/10% xylitol/silica dentifrice: 3-year clinical results. Am J Dent 1995; 8(5): 231–235.

Trahan L. Xylitol: a review of its action on mutans streptococci and dental plaque – its clinical significance. Int Dent J 1995; 45(1): 77–92.

Hayes C. The effect of non-cariogenic sweeteners on the prevention of dental caries: a review of the evidence. J Dent Educ 2001; 65(10): 1106–1109.

Makinen KK, Chen CCY, Makinen PL, et al. Properties of whole saliva and dental plaque in relation to 40-month consumption of chewing gums containing xylitol, sorbitol and sucrose. Caries Res 1996; 30(3): 180–188.

Emodi A. Xylitol: its properties and food applications. Food Technol 1978; Jan: 28–32.

Makinen KK, Soderling E. Effect of xylitol on some food spoilage microorganisms. J Food Sci 1981; 46(3): 950–951.

Georgieff M, Moldawer LL, Bistrian BR, Blackburn GL. Xylitol, an energy source for intravenous nutrition after trauma. J Parenter Enteral Nutr 1985; 9: 199–209.

Garr JSM, Rubinstein MH. Direct compression characteristics of xylitol. Int J Pharm 1990; 64: 223–226.

Natah SS, Hussien KR, Touminen JA, Koivisto VA. Metabolic response to lactitol and xylitol in healthy men. Am J Clin Nutr 1997; 65(4): 947–950.

FAO/WHO. Evaluation of certain food additives and contami- nants. Twenty-seventh report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1983; No. 696.

Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. Cincinnati: US Department of Health, 1987: 5127–5128.

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

11th edn. New York: Wiley, 2004: 3707.

General References

Counsell JN. Xylitol. London: Applied Science Publishers, 1978. O’Brien Nabors L, Gelardi RC, eds. Alternative Sweeteners, 2nd edn.

New York: Marcel Dekker, 1991.

Thomas SE, Ali MA, Craig DQM, et al. The use of xylitol as a carrier for liquid-filled hard-gelatin capsules. Pharm Technol Int 1991; 3(9): 36–40.

Ylikahri R. Metabolic and nutritional aspects of xylitol. Adv Food Res

Chemical Name and CAS Registry Number

Zein [9010-66-6]

Empirical Formula and Molecular Weight

Zein is a prolamin with a molecular weight of approximately 38 000.

Structural Formula

See Section 8.

Functional Category

Coating agent; extended-release agent; tablet binder.

Applications in Pharmaceutical Formulation or Technology

Zein is used as a tablet binder in wet-granulation processes or as a tablet-coating agent mainly as a replacement for shellac. It is used primarily as an enteric-coating agent or in extended- release oral tablet formulations.(1) Zein is also used in food applications as a coating agent. See Table I.

Table I: Uses of zein.

Use Concentration (%)

Tablet coating agent 15

Tablet sealer 20

Wet granulation binder 30

Description

Zein is a prolamin obtained from corn (Zea mays Linne´ (Fam. Gramineae)). It occurs as a granular, straw- to pale yellow- colored amorphous powder or fine flakes and has a character- istic odor and bland taste.

For amino acid composition, see Section 18.

Pharmacopeial Specifications

See Table II.

Table II: Pharmacopeial specifications for zein.

Test USPNF 23

Identification +

Microbial limits 41000/g

Loss on drying 48.0%

Residue on ignition 42.0%

Heavy metals 40.002%

Organic volatile impurities +

Nitrogen content (dried basis) 13.1–17.0%

Typical Properties

Density: 1.23 g/cm3

Melting point: when completely dry, zein may be heated to 2008C without visible signs of decomposition.

Particle size distribution: 100% less than 840 mm in size.

Solubility: practically insoluble in acetone, ethanol, and water; soluble in aqueous alcohol solutions, aqueous acetone solutions (60–80% v/v), and glycols. Also soluble in aqueous alkaline solutions of pH 11.5 and above.

Stability and Storage Conditions

Zein should be stored in an airtight container, in a cool, dry place. It has not been reported to polymerize.(2,3)

Incompatibilities

Incompatible with oxidizing agents.

Method of Manufacture

Zein is extracted from corn gluten meal with dilute propan-2- ol.

Safety

Zein is used in oral pharmaceutical formulations and food products and is generally regarded as an essentially nontoxic and nonirritant material at the levels employed as an excipient. However, it may be harmful if ingested in large quantities. See also Section 18.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Zein may be irritant to the eyes and may evolve toxic fumes on combustion. Eye- protection and gloves are recommended.

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (oral tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non- medicinal Ingredients.

The EINECS number for zein is 232-722-9.

Zein is a protein derivative that does not contain lysine or tryptophan. For the approximate amino acid content of zein, see Table III.

Zein may be safely consumed by persons sensitive to gluten. A specification for zein is contained in the Food Chemicals

Codex (FCC).

Table III: Approximate amino acid content of zein.

Specific References

Katayama H, Kanke M. Drug release from directly compressed tablets containing zein. Drug Dev Ind Pharm 1992; 18: 2173– 2184.

Porter SC. Tablet coating. Drug Cosmet Ind 1996; May: 46–93.

Seitz JA, Mehta SP, Yeager JL. Tablet coating. In: Lachman L, Liebermann HA, Kanig JL, eds. The Theory and Practice of Industrial Pharmacy. Philadelphia: Lea and Febiger, 1986: 346– 373.

General References

Beck MI, Tomka I, Waysek E. Physico-chemical characterization of zein

comparison with ethyl cellulose.

Glutamic acid 1.5% Serine 5.7%

PhEur: Zinc acetas dihydricus USP: Zinc acetate

Synonyms

Acetic acid, zinc salt; dicarbomethoxy zinc; zinc (II) acetate; zinc diacetate; zinc ethanoate.

Chemical Name and CAS Registry Number

Zinc acetate dihydrate [5970-45-6] Zinc acetate anhydrous [557-34-6]

Empirical Formula and Molecular Weight

C H O Zn·2H O 219.50 (for dihydrate)

Table I: Pharmacopeial specifications for zinc acetate.

4 6 4 2

C4H6O4Zn 183.47 (for anhydrous)

Structural Formula

Functional Category

Emollient; emulsion stabilizer; gelling agent; opacifier; stabiliz- ing agent.

Applications in Pharmaceutical Formulation or Technology

Zinc acetate has been used as an excipient in a variety of pharmaceutical formulations including topical gels, lotions, and solutions, and subcutaneous injections. It has also been investigated for use in an oral controlled-release formulation for water-soluble drugs in combination with sodium alginate and xanthan gum.(1)

Therapeutically, zinc acetate has been used in oral capsules for the treatment of Wilson’s disease.(2,3) Zinc acetate has also been demonstrated to be effective as a spermicide in vaginal contraceptives.(4)

Description

Zinc acetate occurs as white crystalline, lustrous plates with a faint acetic odor and an astringent taste.

Pharmacopeial Specifications

See Table I.

Typical Properties

Acidity/alkalinity: pH = 6.0–8.0 (5% w/v aqueous solution of the dihydrate)

Boiling point: decomposes.

Melting point: 2378C

Solubility: for the dihydrate, see Table II.

Specific gravity: 1.735

Table II: Solubility of zinc acetate dihydrate.

Solvent Solubility at 208C unless otherwise stated

Ethanol (95%) 1 in 30

1 in 1 of boiling ethanol (95%)

Water 1 in 2.3

1 in 1.6 at 1008C

Stability and Storage Conditions

Zinc acetate loses water of hydration above 1008C. Zinc acetate should be stored in a well-closed container in a cool, dry, place.

Incompatibilities

Zinc acetate is incompatible with oxidizing agents, zinc salts, alkalis and their carbonates, oxalates, phosphates, and sulfides.(5)

Method of Manufacture

Zinc acetate is synthesized by reacting zinc oxide with glacial acetic acid, with subsequent crystallization, separation by centrifugation, and drying and milling of the crystals. No organic solvents are used during the synthesis.

Zinc Acetate 831

Safety

Zinc acetate is used in topical pharmaceutical formulations and subcutaneous injections, where it is generally regarded as relatively nontoxic and nonirritant when used as an excipient. However, zinc acetate is poisonous by intravenous and intraperitoneal routes; it is also moderately toxic following oral consumption.(5)

Zinc acetate:

LD50 (rat, oral): 2.510 g/kg(5) LD50 (IP, mouse): 0.057 g/kg

Zinc acetate dihydrate:

LD50 (mouse, IP): 0.108 g/kg LD50 (mouse, oral): 0.287 g/kg LD50 (rat, IP): 0.162 g/kg

LD50 (rat, oral): 0.794 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended. When heated to decomposition, zinc acetate emits toxic fumes of zinc oxide.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (SC injections; topical lotions and solutions). Included in medicines licensed in the UK.

Related Substances

—

Comments

A specification for zinc acetate is included in the Japanese Pharmaceutical Excipients (JPE) 2004.(6) The EINECS number for zinc acetate is 209-170-2.

Specific References

Zeng WM. Oral controlled-release formulation for highly water- soluble drugs: drug–sodium alginate–xanthan gum–zinc acetate matrix. Drug Dev Ind Pharm 2004; 30: 491–495.

Brewer GJ. Zinc acetate for the treatment of Wilson’s disease.

Expert Opin Pharmacother 2001; 2: 1473–1477.

Fahim MS, Wang M. Zinc acetate and lyophilized Aloe barbadensis as vaginal contraceptive. Contraception 1996; 53: 231–236.

European Medicines Evaluation Agency. Summary scientific opinion for the approval of Wilzin (zinc acetate dehydrate). http://www.emea.eu.int/humandocs/PDFs/EPAR/Wilzin/ 099104en6.pdf (accessed 12 April 2005).

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3717–3718.

Japan Pharmaceutical Excipients Council. Japanese Pharmaceu- tical Excipients 2004. Tokyo: Yakuji Nippo, 2004: 945–946.

BP: Zinc stearate PhEur: Zinci stearas USP: Zinc stearate

Synonyms

Cecavon; dibasic zinc stearate; HyQual; stearic acid zinc salt; zinc distearate; zinc soap.

Chemical Name and CAS Registry Number

Octadecanoic acid zinc salt [557-05-1]

Empirical Formula and Molecular Weight

C36H70O4Zn 632.33 (for pure material)

The USP 28 describes zinc stearate as a compound of zinc with a mixture of solid organic acids obtained from fats, and consists chiefly of variable proportions of zinc stearate and zinc palmitate. It contains the equivalent of 12.5–14.0% of zinc oxide (ZnO).

The PhEur 2005 states that zinc stearate [(C17H35COO)2Zn] may contain varying proportions of zinc palmitate [(C15H31COO)2Zn] and zinc oleate [(C17H33COO)2Zn]. It contains not less than 10.0% and not more than 12.0% of zinc.

Structural Formula

See Section 4.

Functional Category

Tablet and capsule lubricant.

Applications in Pharmaceutical Formulation or Technology

Zinc stearate is primarily used in pharmaceutical formulations as a lubricant in tablet and capsule manufacture at concentra- tions up to 1.5% w/w. It has also been used as a thickening and opacifying agent in cosmetic and pharmaceutical creams and as a dusting powder. See Table I.

Table I: Uses of zinc stearate.

Use Concentration (%)

Tablet lubricant 0.5–1.5

Water-repellent ointments 2.5

Description

Zinc stearate occurs as a fine, white, bulky, hydrophobic powder, free from grittiness and with a faint characteristic odor.

Pharmacopeial Specifications

See Table II.

SEM: 1

Excipient: Zinc stearate

Magnification: 600×

SEM: 2

Excipient: Zinc stearate

Magnification: 2400×

Zinc Stearate 833

Table II: Pharmacopeial specifications for zinc stearate.

Test PhEur 2005 USP 28

Identification + +

Characters + —

Acidity or alkalinity + —

Alkalis and alkaline earths — 41.0%

Appearance of solution + —

Acid value of the fatty acids 195–210 — Appearance of solution of fatty acids + —

Organic volatile impurities — +

Assay (as Zn) 10.0–12.0% —

Assay (as ZnO) — 12.5–14.0%

Typical Properties

Autoignition temperature: 4218C

Density: 1.09 g/cm3

Density (tapped): 0.26 g/cm3 for standard grade (Durham Chemicals).

Flash point: 2778C

Melting point: 120–1228C

Particle size distribution: 100% through a 44.5-mm sieve (#325 mesh).

Solubility: practically insoluble in ethanol (95%), ether, water, and oxygenated solvents; soluble in acids, benzene, and other aromatic solvents.

Stability and Storage Conditions

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

Incompatibilities

Zinc stearate is decomposed by dilute acids.

Method of Manufacture

An aqueous solution of zinc sulfate is added to sodium stearate solution to precipitate zinc stearate. The zinc stearate is then washed with water and dried. Zinc stearate may also be prepared from stearic acid and zinc chloride.

Safety

Zinc stearate is used in oral and topical pharmaceutical formulations and is generally regarded as a nontoxic and nonirritant excipient. However, following inhalation, it has been associated with fatal pneumonitis, particularly in infants.(1) As a result, zinc stearate has now been removed from baby dusting powders.

LD50 (rat, IP): 0.25 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended. Zinc stearate may be harmful on inhalation and should be used in a well-ventilated environment; a respirator is recommended. In the UK, the long-term (8-hour TWA) occupational exposure limit for zinc stearate is 10 mg/m3 for total inhalable dust and 4 mg/m3 for respirable dust. The short- term (15-minutes) exposure limit for total inhalable dust is 20 mg/m3.(2) In the US, the OSHA limit is 15 mg/m3 for total dust, 5 mg/m3 respirable fraction for zinc stearate.(3)

When heated to decomposition, zinc stearate emits acrid smoke and fumes of zinc oxide.

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (oral capsules and tablets). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Calcium stearate; magnesium stearate; stearic acid.

Comments

The EINECS number for zinc stearate is 209-151-9.

See Magnesium Stearate for further information and references.

Specific References

Ueda A, Harada K, Ueda T, Nomura S. Experimental study on the pathological changes in lung tissue caused by zinc stearate dust. Ind Health 1984; 22: 243–253.

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

JT Baker (2005). Zinc stearate safety data sheet. http://www.jtbaker.com/msds/englishhtml/z4275.htm (accessed 5

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Wednesday, November 6, 2024

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