01 Excipients Prelims 1..9

Sucralose 701 recommended. Stearyl alcohol is not a fire hazard, although it will 10 Weller PJ. Stearyl alcohol. Kibbe AH, ed. Handbook of Pharmaceutical burn and may give off noxious fumes containing carbon monoxide. Excipients, 3rd edn. London and Washington, DC: Pharmaceutical Press and American Pharmaceutical Association, 2000; 537–538. 11 Gaul LE. Dermatitis from cetyl and stearyl alcohols. Arch Dermatol 16 Regulatory Status 1969; 99: 593. Included in the FDA Inactive Ingredients Database (oral tablets, 12 Fisher AA. Contact dermatitis from stearyl alcohol and propylene rectal topical, and vaginal preparations). Included in nonparenteral glycol. Arch Dermatol 1974; 110: 636. medicines licensed in the UK. Included in the Canadian List of 13 Black H. Contact dermatitis from stearyl alcohol in Metosyn Acceptable Non-medicinal Ingredients. (flucinonide) cream. Contact Dermatitis 1975; 1: 125. 14 Cronin E. Contact Dermatitis. Edinburgh: Churchill Livingstone, 1980; 808. 17 Related Substances 15 Yesudian PD, King CM. Allergic contact dermatitis from stearyl alcohol Cetostearyl alcohol; cetyl alcohol. in Efudix cream. Contact Dermatitis 2001; 45: 313–314. 16 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004; 2758. 18 Comments The EINECS number for stearyl alcohol is 204-017-6. The 20 General References PubChem Compound ID (CID) for stearyl alcohol is 8221. Barry BW. Continuous shear, viscoelastic and spreading properties of a new topical vehicle, FAPG base. J Pharm Pharmacol 1973; 25: 131–137. 19 Specific References Cognis. Product literature: Speziol C18 Pharma, 2004. 1 Egan RR, Portwood O. Higher alcohols in skin lotions. Cosmet Perfum Cognis. Product literature: Drug-Delivery Agents – Pharmaline, 2008. 1974; 89(3): 39–42. Japan Pharmaceutical Excipients Council. Japanese Pharmaceutical Exci- 2 Alexander P. Organic rheological additives. Manuf Chem 1986; 57(9): pients Directory 1996. Tokyo: Yakuji Nippo, 1996; 527. 49, 52. Madan PL et al. Microencapsulation of a waxy solid: wall thickness and 3 Cao DY et al. Preparation of tetramethylpyrazine phosphate pulsed- surface appearance studies. J Pharm Sci 1974; 63: 280–284. release tablets. Chin J New Drugs 2005; 14(6): 723–726. Rowe RC. A quantitative assessment of the reactivity of the fatty alcohols 4 Cao QR et al. Photoimages and the release characteristics of lipophilic with cetrimide using immersion calorimetry. J Pharm Pharmacol 1987; matrix tablets containing highly water-soluble potassium citrate with 39: 50–52. high drug loadings. Int J Pharm 2007; 339(1–2): 19–24. Sasol. Product literature: Sasol olefins and surfactants, 2005. 5 Kaiho F et al. Application of fatty alcohols to pharmaceutical dosage Schott H, Han SK. Effect of inorganic additives on solutions of nonionic forms. Yakuzaigaku 1984; 44: 99–102. surfactants II. J Pharm Sci 1975; 64: 658–664. 6 Tanabe K et al. Effect of additives on release of ibuprofen from Wan LSC, Poon PKC. The interfacial activity of sodium lauryl sulfate in the suppositories. Yakuzaigaku 1988; 48: 262–269. presence of alcohols. Can J Pharm Sci 1970; 5: 104–107. 7 Passerini N et al. Controlled release of verapamil hydrochloride from waxy microparticles prepared by spray congealing. J Control Release 2003; 88(2): 263–275. 21 Author 8 Liggins RT, Burt HM. Paclitaxel loaded poly(L-lactic acid) micro- RT Guest. spheres: properties of microspheres made with low molecular weight polymers. Int J Pharm 2001; 222(1): 19–33. 9 Takahashi Yet al. Trial for transdermal administration of sulfonylureas. 22 Date of Revision J Pharm Soc Japan 1997; 117: 1022–1027. 12 February 2009.

S Sucralose

1 Nonproprietary Names 5 Structural Formula USP-NF: Sucralose

2 Synonyms Splenda; sucralosa; sucralosum; SucraPlus; TGS; 10,40,60-trichloro- galactosucrose; 4,10,60-trichloro-4,10,60-trideoxy-galacto-sucrose.

3 Chemical Name and CAS Registry Number 1,6-Dichloro-1,6-dideoxy-b-D-fructofuranosyl-4-chloro-4-deoxy- a-D-galactopyranoside [56038-13-2]

4 Empirical Formula and Molecular Weight 6 Functional Category

C12H19Cl3O8 397.64 Sweetening agent. 702 Sucralose

SEM 1: Excipient: sucralose; manufacturer: Tate & Lyle; magnification: Solubility Freely soluble in ethanol (95%), methanol, and water; 1000; voltage 3.0 kV. slightly soluble in ethyl acetate. 20 Specific rotation [a]D = þ84.08 to þ87.58 (1% w/v aqueous solution); þ68.28 (1.1% w/v solution in ethanol). Viscosity 0.6–3.8 mPa s (0.6–3.8 cP).

11 Stability and Storage Conditions Sucralose is a relatively stable material. In aqueous solution, at highly acidic conditions (pH < 3), and at high temperatures (4358C), it is hydrolyzed to a limited extent, producing 4-chloro-4- deoxygalactose and 1,6-dichloro-1,6-dideoxyfructose. In food products, sucralose remains stable throughout extended storage periods, even at low pH. However, it is most stable at pH 5–6. Sucralose should be stored in a well-closed container in a cool, dry place, at a temperature not exceeding 218C. Sucralose, when heated at elevated temperatures, may break down with the release of carbon dioxide, carbon monoxide, and minor amounts of hydrogen chloride.

7 Applications in Pharmaceutical Formulation or 12 Incompatibilities Technology — Sucralose is used as a sweetening agent in beverages, foods, and pharmaceutical applications. It has a sweetening power approxi- 13 Method of Manufacture mately 300–1000 times that of sucrose and has no aftertaste. It has Sucralose may be prepared by a variety of methods that involve the no nutritional value, is noncariogenic, does not promote dental selective substitution of three sucrose hydroxyl groups by chlorine. caries, and produces no glycemic response. See also Table I. Sucralose can also be synthesized by the reaction of sucrose (or an acetate) with thionyl chloride. Table I: Uses of sucralose. Use Concentration (%) 14 Safety Sucralose is generally regarded as a nontoxic and nonirritant Food products 0.03–0.24 material and is approved, in a number of countries, for use in food products. Following oral consumption, sucralose is mainly unab- sorbed and is excreted in the feces.(1–3) 8 Description The WHO has set an acceptable daily intake for sucralose of up to 15 mg/kg body-weight.(4) Sucralose is a white to off-white colored, free-flowing, crystalline powder. LD50 (mouse, oral): > 16 g/kg

LD50 (rat, oral): > 10 g/kg 9 Pharmacopeial Specifications 15 Handling Precautions See Table II. S Observe normal precautions appropriate to the circumstances and Table II: Pharmacopeial specifications for sucralose. quantity of material handled.

Test USP32–NF27 16 Regulatory Status Identification þ The FDA, in April 1998, approved sucralose for use as a tabletop Specific rotation þ84.08 to þ87.58 sweetener and as an additive in a variety of food products. In the Water 42.0% 4 UK, sucralose was fully authorized for use in food products in Residue on ignition 0.7% 2005.(5) It is also accepted for use in many other countries Heavy metals 40.001% Limit of hydrolysis products 40.1% worldwide. Included in the Canadian List of Acceptable Non- Limit of methanol 40.1% medicinal Ingredients. Related compounds 40.5% Assay (dried basis) 98.0–102.0% 17 Related Substances Sucrose.

10 Typical Properties 18 Comments Acidity/alkalinity pH = 5–6 (10% w/v aqueous solution at 208C) The sweetening effect of sucralose is not reduced by heating, and Density (bulk) 0.35 g/cm3 food products containing sucralose may be subjected to high- Density (tapped) 0.62 g/cm3 temperature processes such as pasteurization, sterilization, UHT Density (true) 1.63 g/cm3 processing and baking. Sucralose is often blended with maltodex- Melting point 1308C (for anhydrous crystalline form); 36.58C trin or dextrose as bulking agents in its granular form. (for pentahydrate). A specification for sucralose is contained in the Food Chemicals Particle size distribution 90% < 12 mm in size. Codex (FCC).(6) Partition coefficient log10 P = 0.51 (octanol : water) The EINECS number for sucralose is 259-952-2. The PubChem Refractive index 1.33 to 1.37 Compound ID (CID) for sucralose includes 71485 and 5066234. Sucrose 703

19 Specific References Anonymous. Artificial sweeteners. Can Pharm J 1996; 129(Apr): 22. 1 Grice HC, Goldsmith LA. Sucralose – an overview of the toxicity data. Anonymous. Sucralose – a new artificial sweetener. Med Lett Drugs Ther Food Chem Toxicol 2000; 38(Suppl. 2): S1–S6. 1998; 40: 67–68. 2 Roberts A et al. Sucralose metabolism and pharmacokinetics in man. Jenner MR, Smithson A. Physicochemical properties of the sweetener Food Chem Toxicol 2000; 38(Suppl. 2): S31–S41. sucralose. J Food Sci 1989; 54(6): 1646–1649. 3 Mclean Baird I et al. Repeated dose study of sucralose tolerance in Kloesel L. Sugar substitutes. Int J Pharm Compound 2000; 4(2): 86–87. human subjects. Food Chem Toxicol 2000; 38(Suppl. 2): S123–S129. Knight I. The development and applications of sucralose, a new high- 4 FAO/WHO. Evaluation of certain food additives and contaminants. intensity sweetener. Can J Physiol Pharmacol 1994; 72(4): 435–439. Thirty-seventh report of the joint FAO/WHO expert committee on food Kroschwiz JI, Howe-Grant M, eds. Kirk-Othmer Encyclopedia of Chemical additives. World Health Organ Tech Rep Ser 1991; No. 806: 21–23. Technology, 4th edn, vol. 11: New York: John Wiley & Sons, 1994; 295. 5 Statutory Instrument (SI) 2005: No. 1156. The Sweeteners in Food McNeil Nutritionals. Splenda: the online guide to cooking, eating and living (Amendment) (Wales) Regulations 2005. London: Stationery Office, well. http://www.splenda.com (accessed 19 February 2009). 2005. Tate and Lyle. Technical literature: Sucralose, 2001. 6 Food Chemicals Codex, 6th edn. Bethesda, MD: United States Pharmacopeia, 2008; 930. 21 Authors BA Langdon, MP Mullarney. 20 General References American Dietetic Association. Position of the American Dietetic Associa- tion: use of nutritive and nonnutritive sweetners. J Am Diet Assoc 2004; 22 Date of Revision 104: 255–275. 19 February 2009.

Sucrose

1 Nonproprietary Names 5 Structural Formula BP: Sucrose JP: Sucrose PhEur: Sucrose USP-NF: Sucrose

S 2 Synonyms Beet sugar; cane sugar; a-D-glucopyranosyl-b-D-fructofuranoside; refined sugar; saccharose; saccharum; sugar.

6 Functional Category Confectionery base; coating agent; granulation aid; suspending agent; sweetening agent; tablet binder; tablet and capsule diluent; 3 Chemical Name and CAS Registry Number tablet filler; therapeutic agent; viscosity-increasing agent. b-D-fructofuranosyl-a-D-glucopyranoside [57-50-1] 7 Applications in Pharmaceutical Formulation or Technology Sucrose is widely used in oral pharmaceutical formulations. Sucrose syrup, containing 50–67% w/w sucrose, is used in tableting as a binding agent for wet granulation. In the powdered form, sucrose serves as a dry binder (2–20% w/w) or as a bulking agent and sweetener in chewable tablets and lozenges.(1–3) Tablets 4 Empirical Formula and Molecular Weight that contain large amounts of sucrose may harden to give poor C12H22O11 342.30 disintegration.