2-Pyrrolidone

Nonproprietary Names

None adopted.

Synonyms

g-Aminobutyric acid lactam; 4-aminobutyric acid lactam; g- aminobutyric lactam; g-aminobutyrolactam; g-butyrolactam; butyrolactam; 2-oxopyrrolidine; 2-Pyrol; a-pyrrolidinone; pyr- rolidone; a-pyrrolidone; Soluphor P.

Chemical Name and CAS Registry Number

Pyrrolidinone [616-45-5]

Empirical Formula and Molecular Weight

C4H7NO 85.11

Structural Formula

 

Functional Category

Penetration enhancer; plasticizer; solvent; solubilizing agent.

Applications in Pharmaceutical Formulation or Technology

Pyrrolidones such as 2-pyrrolidone and N-methylpyrrolidone (see Section 17) are mainly used as solvents in veterinary injections.(1,2) They have also been suggested for use in human pharmaceutical formulations as solvents in parenteral, oral, and topical applications. In topical applications, pyrrolidones appear to be effective penetration enhancers.(1–7) Pyrrolidones have also been investigated for their application in controlled- release depot formulations.(8)

Description

2-Pyrrolidone occurs as a colorless or slightly colored liquid that solidifies at room temperature and has a characteristic odor.

Pharmacopeial Specifications

—

Typical Properties

Acidity/alkalinity: pH = 8.2—10.8 for a 10% v/v aqueous solution.

Boiling point: 2458C

�Dipole moment: 2.3 Debye at 258C

Enthalpy of vaporization: 48.21  3.0 kJ/mol

Flash point (open cup): 548C

Melting point: 2.68C

Refractive index: n25 = 1.480–1.490

Solubility: miscible with ethanol (95%), propan-2-ol, and water. Also miscible with other organic solvents such as aromatic hydrocarbons.

Specific gravity: 1.11 at 258C

Viscosity (dynamic): 13.3 mPa s (13.3 cP) at 258C

Stability and Storage Conditions

2-Pyrrolidone is chemically stable and, if it is kept in unopened original containers, the shelf-life is approximately one year. 2- Pyrrolidone should be stored in a well-closed container protected from light and oxidation, at temperatures below 208C.

Incompatibilities

2-Pyrrolidone is incompatible with oxidizing agents and strong acids.

Method of Manufacture

2-Pyrrolidone is prepared from butyrolactone by a Reppe process, in which acetylene is reacted with formaldehyde.

Safety

Pyrrolidones are mainly used in veterinary injections and have also been suggested for use in human oral, topical, and parenteral pharmaceutical formulations. In mammalian spe- cies, pyrrolidones are biotransformed to polar metabolites that are excreted via the urine.(9,10) 2-Pyrrolidone is mildly toxic by ingestion and subcutaneous routes; mutagenicity data have been reported.(11) 2-Pyrrolidone appears to be nonirritant when applied to skin and mucous membranes.(1)

LD50 (guinea pig, oral): 6.5 g/kg(11) LD50 (rat, oral): 6.5 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Some pyrrolidones in their pure state are considered toxic, corrosive, and flammable; contact with skin and eyes should be avoided. Vapors or sprays should not be inhaled. Suitable eye and skin protection and a respirator are recommended. When heated to decomposition, 2-pyrrolidone emits toxic fumes of NOx.

Regulatory Status

—

634 2-Pyrrolidone

Related Substances

N-Methylpyrrolidone.

N-Methylpyrrolidone

Synonyms: 1-methyl-2-pyrrolidinone; 1-methyl-5-pyrrolidi- none; N-methyl-2-pyrrolidinone; methylpyrrolidone; N- methylpyrrolidonum; NMP; Pharmasolve; m-Pyrol.

Empirical formula: C5H9NO

Molecular weight: 99.14

CAS number: [872-50-4]

Description: N-methylpyrrolidone occurs as a clear, hygro- scopic liquid with a mild amine odor.

Typical properties: Boiling point: 2028C Dielectric constant: 32.2 at 258C Dipole moment: 4.9 Debye at 258C

Enthalpy of evaporation: 43.82  3.0 kJ/mol

Flash point (closed cup): 938C Flash point (open cup): 968C Freezing point: —248C

Heat of combustion: 719 kcal/mol

Melting point: —178C

Refractive index: n25 = 1.4690

Solubility: miscible with ethanol (95%), water, and most other organic solvents.

Specific gravity: 1.028 at 258C

Surface tension: 40.7 mN/m (40.7 dyne/cm) at 258C

Vapor pressure: 0.33 mmHg at 23.28C; 5.00 mmHg at 65.08C.

Viscosity: 1.65 mPa s (1.65 cP) at 258C

Safety: N-methylpyrrolidone is considered a poison by the intravenous route. It is moderately toxic by ingestion, skin contact, and intraperitoneal routes. It is an experimental teratogen; mutagenicity data have been reported.(12)

LD50 (mouse, IP): 3.05 g/kg(12) LD50 (mouse, IV): 0.155 g/kg LD50 (mouse, oral): 5.13 g/kg LD50 (rabbit, SC): 8.0 g/kg LD50 (rat, IP): 2.472 g/kg

LD50 (rat, IV): 0.0805 g/kg LD50 (rat, oral): 3.914 g/kg

Handling precautions: in the UK, the occupational exposure limits for N-methylpyrrolidone are 103 mg/m3 (25 ppm) long-term (8-hour TWA) and 309 mg/m3 (75 ppm) short- term (15 minutes).(13)

Comments: N-methylpyrrolidone is produced by the condensa- tion of butyrolactone with methylamine. The EINECS number for N-methylpyrrolidone is 212-828-1. A specifica- tion for N-methylpyrrolidone is included in the PhEur 2005 and Japanese Pharmaceutical Excipients (JPE) 2004.(14)

�Comments

The EINECS number for 2-pyrrolidone is 204-648-7.

Specific References

BASF. Soluphor P. http://www.pharma-solutions.basf.com (accessed 31 May 2005).

International Specialty Products. http://www.ispcorp.com/ products/pharma/index.html (accessed 31 May 2005).

Bhatia KS, Singh J. Percutaneous absorption of LHRH through porcine skin: effect of N-methyl 2-pyrrolidone and isopropyl myristate. Drug Dev Ind Pharm 1997; 23: 1111–1114.

Bhatia KS, Singh J. Effect of dimethylacetamide and 2-pyrrolidone on the iontophoretic permeability of LHRJ through porcine skin. Drug Dev Ind Pharm 1997; 23: 1215–1218.

Ryatt KS, Stevenson JM, Maibach RH, Guy RH. Pharmacody- namic measurement of percutaneous enhancement in vivo. J Pharm Sci 1986; 75: 374–377.

Southwell D, Barry BW. Penetration enhancement in human skin: effect of 2-pyrrolidone, dimethylformamide and increased hydra- tion on finite dose permeation of aspirin and caffeine. Int J Pharm 1984; 22: 291–298.

Alberti I, Kalia YN, Naik A, et al. In vivo assessment of enhancement topical delivery of terbinafine to human stratum corneum. J Control Release 2001; 71: 319–327.

Ravivarapu HB, Dunn RL. Parameters affecting the efficacy of a sustained release polymeric implant of leuprolide. Int J Pharm 2000; 194: 181–191.

Bandle EF, Wendt G, Ranalder UB, Trautmann KH. 2-Pyrrolidi- none and succinimide endogenously present in several mammalian species. Life Sci 1984; 35: 2205–2212.

Akesson B, Jonsson BA. Major metabolic pathway for N-methyl- 2-pyrrolidone in humans. Drug Metab Dispos 1997; 25: 267–269.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3122.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2523.

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

Japan Pharmaceutical Excipients Council. Japanese Pharmaceu- tical Excipients 2004. Tokyo: Yakuji Nippo, 2004: 547–548.

General References

—

Authors

RK Chang, AJ Shukla, Y Sun.

Date of Revision

26 August 2005.

Raffinose

Nonproprietary Names

None adopted.

Synonyms

Gossypose; melitose; melitriose; D-raffinose; D-(+)-raffinose.

Chemical Name and CAS Registry Number

b-D-Fructofuranosyl-O-a-D-galactopyranosyl-(1→6)-a-D- glucopyranoside, anhydrous [512-69-6]

b-D-Fructofuranosyl-O-a-D-galactopyranosyl-(1→6)-a-D- glucopyranoside pentahydrate [17629-30-0]

Empirical Formula and Molecular Weight

�Typical Properties

Collapse temperature: –268C(2)

Decomposition temperature: 1308C (pentahydrate)(7)

Density (bulk): 0.67 g/cm3 (pentahydrate) Density (tapped): 0.98 g/cm3 (pentahydrate) Density (true): 1.465 g/cm3 (anhydrous)

Diffusion coefficient (infinite dilution): 0.33 × 10—5 cm2/s (water at 158C)(8)

Glass transition temperature: 1148C (amorphous)(9)

Heat of solution at infinite dilution (258C): 52 kJ/mol (crystal- line pentahydrate); –38 kJ/mol (amorphous)(1)

Melting point: 808C (pentahydrate);(7) 1188C (anhydrous)(10) Optical rotation: 1058 (pentahydrate); 1238 (anhydrous)(11) Specific gravity: 1.465 (pentahydrate)(7)

Solubility in methanol: 0.10 g/mL(11)

Solubility in water: 0.14 g/mL(7)

Solubility: soluble 1 in 10 of methanol, in pyridine and 1 in 7.1

C18

�H32

�O16

�504.44 (for anhydrous)

�of water; slightly soluble in ethanol (95%); insoluble in diethyl ether.

C18H32O16·5H2O   594.52 (for pentahydrate)

Structural Formula

 

D-Raffinose anhydrous

Functional Category

Blood substitute stabilizer; stabilizer for freeze-dried formula- tions; sucrose crystallization modifier.

Applications in Pharmaceutical Formulation or Technology

Raffinose is a trisaccharide carbohydrate that is used as a bulking agent, stabilizer, and water scavenger in freeze- drying.(1,2) It is also used as a crystallization inhibitor in sucrose solutions.(3–5)

Description

Raffinose is a white crystalline powder. It is odorless and has a sweet taste approximately 10% that of sucrose.(6)

Pharmacopeial Specifications

—

�The data for the crystal structure,(12,13) NMR struc- ture,(14) powder x-ray diffraction pattern,(15) water vapor sorption isotherms, (15,16) glass transition temperature as a function of water,(15) heat capacity,(1) heat of solution properties,(1) vapor pressure,(17) and osmotic pressure(18) are described in the literature.

SEM: 1

Excipient: D-(+)-Raffinose pentahydrate Manufacturer: Sigma-Aldrich (Lot No. 092K01211) Magnification: 100×

 

Stability and Storage Conditions

Raffinose is stable under ordinary conditions of use and storage. Excessive heat should be avoided to prevent degrada- tion. Thermal decomposition products are carbon monoxide and carbon dioxide.(19,20)

636 Raffinose

SEM: 2

Excipient: D-(+)-Raffinose pentahydrate Manufacturer: Sigma-Aldrich (Lot No. 092K01211) Magnification: 500×

 

Incompatibilities

Raffinose is incompatible with strong oxidizers.(21)

Method of Manufacture

Raffinose occurs naturally in Australian manna, cottonseed meal, and seeds of various food legumes. It can be isolated from beet sugar molasses through sucrose separation, seed-crystal- lization, and filtration.(13,22)

Safety

Raffinose is a naturally occurring trisaccharide investigated for use in freeze-dried pharmaceutical formulations. It occurs in a number of plants that are consumed widely (see Section 13).

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Gloves and safety glasses are recommended. Dust generation should be kept to reasonable levels to avoid ignition or explosion. Short-term exposure has caused respiratory and eye irritation. Long-term exposure has shown adverse reproductive effects in animals. No occupa- tional exposure limits have been established. Dust or air mixtures may ignite or explode.(19,20)

Regulatory Status

Raffinose is a naturally occurring trisaccharide and is consumed as part of a normal diet.

Related Substances

Raffinose is composed of three monosaccharides: galactose, glucose, and fructose. It shares related structures with sucrose and melibiose. It is also related to stachyose, which possesses an additional (1→6)-linked a-D-galactopyranosyl unit.

�Two solvated forms(22) and an amorphous form(14,23,24) of raffinose can be synthesized.

Comments

Raffinose has been shown to accumulate in organisms that can survive extreme desiccation, and has therefore been examined as an excipient in stabilizing co-lyophilized protein and labile preparations during storage at elevated temperatures.(25,26)

When exposed to elevated relative humidity (RH) of 75% at 258C, raffinose has been shown to form different hydrate levels.(27)

Raffinose is indigestible by humans because of a lack of an a-galactosidase and undergoes fermentation in the colon, causing production of carbon dioxide, hydrogen, and methane gases.(10)

Specific References

Miller DP, de Pablo JJ. Calorimetric solution properties of simple saccharides and their significance for the stabilization of biological structure and function. J Phys Chem 2000; B104: 8876–8883.

Mackenzie AP. Basic principles of freeze-drying for pharmaceu- ticals. Bull Parenter Drug Assoc 1966; 20(4): 101–129.

Caffrey M, Fonseca V, Leopold AC. Lipid–sugar interactions: relevance to anhydrous biology. Plant Physiol 1988; 86: 754–758.

Liang B, Hartel RW, Berglund KA. Effects of raffinose to anhydrous biology. AIChE J 1989; 35(12): 2053–2057.

Van Scoik KG, Carstensen JT. Nucleation phenomena in amor- phous sucrose systems. Int J Pharm 1990; 58: 185–196.

Halsam E, ed. Comprehensive Organic Chemistry: The Synthesis and Reactions of Organic Compounds, vol. 5. Oxford: Pergamon Press, 1979; 749.

Perry RH, Green DW. Perry’s Chemical Engineer’s Handbook, 7th edn. New York: McGraw Hill, 1997.

Lide DR. Handbook of Chemistry and Physics, 83rd edn. Boca Raton, FL: CRC Press, 2002.

Taylor LS, Zografi G. Sugar–polymer hydrogen bond interactions in lyophilized amorphous mixtures. J Pharm Sci 1998; 87(12): 1615–1621.

Kirk-Othmer Encyclopedia of Chemical Technology, vol. 22, 4th edn. New York: Wiley, 1992; 903.

O’Neil MJ, ed. Merck Index, 13th edn. Whitehouse Station, NJ: Merck, 2001: 1452.

Van Alsenoy C, French AD, Cao M, et al. Ab initio-MIA and molecular mechanics studies of the distorted sucrose linkage of raffinose. J Am Chem Soc 1994; 116: 9590–9595.

Berman, HM. The crystal structure of a trisaccharaide, raffinose pentahydrate. Acta Crystallogr 1970; B26: 290–299.

Neubauer H, Meiler J, Peti W, Griesinger C. NMR structure determination of saccharose and raffinose by means of homo- and heteronuclear dipolar couplings. Helv Chim Acta 2001; 84(1): 243–258.

Saleki-Gerhardt A, Stowell JG, Burn SR, Zografi G. Hydration and dehydration of crystalline and amorphous forms of raffinose. J Pharm Sci 1995; 84(3): 318–323.

Saleki-Gerhardt A. Role of water in the solid state properties of crystalline and amorphous form of sugars. Doctor of Philosophy Thesis, University of Wisconsin-Madison 1993; 104–108.

Cooke SA, Jonsdottir SO. The vapour pressure of water as a function of solute concentration above aqeous solutions of fructose, sucrose, raffinose, erythitol, xylitol, and sorbitol. J Chem Thermodynam 2002; 34(10): 1545–1555.

Kiyosawa K. The volumes of hydrated glucose, sucrose and raffinose molecules, and the osmotic pressures of these aqueous saccharide solutions as measured by the freezing-point-of-depres- sion method. Bull Chem Soc Jpn 1988; 61: 633–642.

Mallinckrodt Baker, Inc. Material Safety Data Sheet. No R0300:

Raffinose, 5-hydrate, 29 October 2001.

Acros Organics N.V. Material Safety Data Sheet. No 93702:

D-Raffinose pentahydrate, 2 August 2000.

Raffinose 637

MDL Information Systems, Inc. Material Safety Data Sheet:

D-Raffinose pentahydrate, 22 March 2001.

Hungerford EH, Nees AR. Raffinose preparation and properties.

Ind Eng Chem 1934; 26(4): 462–464.

Collins PM, ed. Carbohydrates. London: Chapman and Hall, 1997: 431.

Jeffrey GA, Huang D. The hydrogen bonding in the crystal structure of raffinose pentahydrate. Carbohydr Res 1990; 206: 173–182.

Davidson P, Sun QW. Effect of sucrose/raffinose mass ratios on the stability of co-lyophilized protein during storage above the Tg. Pharm Res 2001; 18(4): 474–479.

Kazuhito K, Franks F, Echlin P, Greer AL. Structural and dynamic properties of crystalline and amorphous phases in raffinose–water mixtures. Pharm Res 1999; 16(9): 1441–1448.

�

Hogan SE, Buckton G. Water sorption/desorption—near IR and calorimetric study of crystalline and amorphous raffinose. Int J Pharm 2001; 227: 57–69.

General References

—

Authors

BC Hancock, MP Mullarney.

Date of Revision

25 August 2005.

Saccharin

Nonproprietary Names

BP: Saccharin PhEur: Saccharinum USPNF: Saccharin

Synonyms

1,2-Benzisothiazolin-3-one 1,1-dioxide; benzoic sulfimide; benzosulfimide; 1,2-dihydro-2-ketobenzisosulfonazole; 2,3- dihydro-3-oxobenzisosulfonazole; E954; Garantose; gluside; Hermesetas; sacarina; saccharin insoluble; o-sulfobenzimide; o-sulfobenzoic acid imide.

Chemical Name and CAS Registry Number

1,2-Benzisothiazol-3(2H)-one 1,1-dioxide [81-07-2]

Empirical Formula and Molecular Weight

C7H5NO3S 183.18

Structural Formula

 

Functional Category

Sweetening agent.

Applications in Pharmaceutical Formulation or Technology

Saccharin is an intense sweetening agent used in beverages, food products, table-top sweeteners, and oral hygiene products such as toothpastes and mouthwashes. In oral pharmaceutical formulations, it is used at a concentration of 0.02–0.5% w/w. It has been used in chewable tablet formulations as a sweetening agent.(1,2)

Saccharin can be used to mask some unpleasant taste characteristics or to enhance flavor systems. Its sweetening power is approximately 500 times that of sucrose.

Description

Saccharin occurs as odorless white crystals or a white crystal- line powder. It has an intensely sweet taste, with a metallic aftertaste that at normal levels of use can be detected by approximately 25% of the population.

�SEM: 1

Excipient: Saccharin

Magnification: 600×

 

SEM: 2

Excipient: Saccharin

Magnification: 2400×

 

Pharmacopeial Specifications

See Table I.

Saccharin 639

Table I: Pharmacopeial specifications for saccharin.

 

Test PhEur 2005 USPNF 23    

Identification + +    

Characters + —    

Appearance of solution + —    

Melting range 226–2308C 226–2308C    

Loss on drying 41.0% 41.0%    

Residue on ignition — 40.2%    

Sulfated ash 40.1% —    

Toluenesulfonamides + 40.0025%    

Selenium — 40.003%    

Heavy metals 420 ppm 40.001%    

Readily carbonizable substances — +    

Benzoic and salicylic acids — +    

Organic volatile impurities — +    

Related substances — —    

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

Typical Properties

Acidity/alkalinity: pH = 2.0 (0.35% w/v aqueous solution)

Density (bulk): 0.7–1.0 g/cm3

Density (tapped): 0.9–1.2 g/cm3

Dissociation constant: pKa = 1.6 at 258C

Heat of combustion: 3644.3 kJ/mol (871 kcal/mol)

Moisture content: 0.1%

Solubility: readily dissolved by dilute ammonia solutions, alkali hydroxide solutions, or alkali carbonate solutions (with the evolution of carbon dioxide). See Table II.

Table II: Solubility of saccharin.

Solvent Solubility at 208C unless otherwise stated

Acetone 1 in 12

Chloroform Slightly soluble

Ethanol (95%) 1 in 31

Ether Slightly soluble

Glycerin 1 in 50

Water 1 in 290

1 in 25 at 1008C

Stability and Storage Conditions

Saccharin is stable under the normal range of conditions employed in formulations. In the bulk form it shows no detectable decomposition and only when it is exposed to a high temperature (1258C) at a low pH (pH 2) for over 1 hour does significant decomposition occur. The decomposition product formed is (ammonium-o-sulfo)benzoic acid.(3)

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

Incompatibilities

Saccharin can react with large molecules, resulting in a precipitate being formed.

Method of Manufacture

Saccharin is prepared from toluene by a series of reactions known as the Remsen–Fahlberg method. Toluene is first

�

reacted with chlorosulfonic acid to form o-toluenesulfonyl chloride, which is reacted with ammonia to form the sulfonamide. The methyl group is then oxidized with dichro- mate, yielding o-sulfamoylbenzoic acid, which forms the cyclic imide saccharin when heated.

An alternative method involves a refined version of the Maumee process. Methyl anthranilate is initially diazotized to form 2-carbomethoxybenzenediazonium chloride; sulfonation followed by oxidation then yields 2-carbomethoxybenzenesul- fonyl chloride. Amidation of this material, followed by acidification, forms insoluble acid saccharin.

Safety

There has been considerable controversy concerning the safety of saccharin, which has led to extensive studies since the mid- 1970s.

Two-generation studies in rats exposed to diets containing 5.0–7.5% total saccharin (equivalent to 175 g daily in humans) suggested that the incidence of bladder tumors was significantly greater in saccharin-treated males of the second generation than in controls.(4,5) Further experiments in rats suggested that a contaminant of commercial saccharin, o-toluene sulfonamide, might also account for carcinogenic effects. In view of these studies, a ban on the use of saccharin was proposed in several countries. However, in 1977 a ban by the FDA led to a Congressional moratorium that permitted the continued use of saccharin in the USA.

From the available data it now appears that the development of tumors is a sex-, species-, and organ-specific phenomenon and extensive epidemiological studies have shown that saccharin intake is not related to bladder cancer in humans.(6,7) The WHO has set a temporary acceptable daily intake for saccharin, including its calcium, potassium, and sodium salts, at up to 2.5 mg/kg body-weight.(8) In the UK, the Committee on Toxicity of Chemicals in Food, Consumer Products, and the Environment (COT) has set an acceptable daily intake for saccharin and its calcium, potassium, and sodium salts (expressed as saccharin sodium) at up to 5 mg/kg body-

weight.(9)

Adverse reactions to saccharin, although relatively few in relation to its widespread use, include: urticaria with pruritus following ingestion of saccharin-sweetened beverages(10) and photosensitization reactions.(11)

LD50 (mouse, oral): 17.5 g/kg(12) LD50 (rat, IP): 7.10 g/kg

LD50 (rat, oral): 14.2 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and a dust mask are recommended.

Regulatory Status

Accepted for use as a food additive in Europe. Note that the EU number ‘E954’ is applied to both saccharin and saccharin salts. Included in the FDA Inactive Ingredients Guide (oral solutions, syrups, tablets, and topical preparations). Included in nonpar- enteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

640 Saccharin

Related Substances

Alitame; saccharin ammonium; saccharin calcium; saccharin sodium.

Saccharin ammonium

Empirical formula: C7H8N2O3S

Molecular weight: 200.2

CAS number: [6381-61-9]

Saccharin calcium

Empirical formula: C14H8CaN2O6S2·3H2O

Molecular weight: 467.48

CAS number:

[6381-91-5] for the hydrated form [6485-34-3] for the anhydrous form

Synonyms: Syncal CAS.

Appearance: white, odorless crystals or crystalline powder with an intensely sweet taste.

Solubility: 1 in 4.7 ethanol (95%); 1 in 2.6 of water.

Comments

The perceived intensity of sweeteners relative to sucrose depends upon their concentration, temperature of tasting, and pH, and on the flavor and texture of the product concerned.

Intense sweetening agents will not replace bulk, textural, or preservative characteristics of sucrose if sucrose is removed from a formulation.

Synergistic effects for combinations of sweeteners have been reported. Saccharin is often used in combination with cyclamates and aspartame since the saccharin content may be reduced to minimize any aftertaste. A specification for saccharin is contained in the Food Chemicals Codex (FCC).

The EINECS number for saccharin is 201-321-0.

Specific References

Suzuki H, Onishi H, Hisamatsu S, et al. Acetaminophen-contain- ing chewable tablets with suppressed bitterness and improved oral feeling. Int J Pharm 2004; 278(1): 57–61.

Mullarney MP, Hancock BC, Carlson GT, et al. The powder flow and compact mechanical properties of sucrose and three high-

�density sweetners used in chewable tablets. Int J Pharm 2003;

257(1–2): 227–236.

DeGarmo O, Ashworth GW, Eaker CM, Munch RH. Hydrolytic stability of saccharin. J Am Pharm Assoc (Sci) 1952; 41: 17–18.

Arnold DL, Moodie CA, Grice HC, et al. Long-term toxicity of ortho-toluenesulfonamide and sodium saccharin in the rat. Toxicol Appl Pharmacol 1980; 52: 113–152.

Arnold DL. Two-generation saccharin bioassays. Environ Health Perspect 1983; 50: 27–36.

Council on Scientific Affairs. Saccharin: review of safety issues. J Am Med Assoc 1985; 254: 2622–2624.

Morgan RW, Wong O. A review of epidemiological studies on artificial sweeteners and bladder cancer. Food Chem Toxicol 1985; 23: 529–533.

FAO/WHO. Evaluation of certain food additives and contami- nants. Twenty-eighth report of the FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1984; No. 710.

Food Advisory Committee. FAC further advice on saccharin. FdAC/REP/9. London: MAFF, 1990.

Miller R, White LW, Schwartz HJ. A case of episodic urticaria due to saccharin ingestion. J Allergy Clin Immunol 1974; 53: 240–242.

Gordon HH. Photosensitivity to saccharin. J Am Acad Dermatol

1983; 8: 565.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3277.

General References

Anonymous. Saccharin is safe. Chem Br 2001; 37(4): 18.

Lindley MG. Sweetener markets, marketing and product development. In: Marie S, Piggott JR, eds. Handbook of Sweeteners. Glasgow: Blackie, 1991: 186.

Zubair MU, Hassan MMA. Saccharin. In: Florey K, ed. Analytical Profiles of Drug Substances, vol. 13. Orlando, FL: Academic Press, 1984: 487–519.

Authors

SC Owen.

Date of Revision

11 August 2005.

Saccharin Sodium

Nonproprietary Names

BP: Saccharin sodium JP: Saccharin sodium

PhEur: Saccharinum natricum USP: Saccharin sodium

Synonyms

1,2-Benzisothiazolin-3-one 1,1-dioxide, sodium salt; Crystal- lose; E954; sodium o-benzosulfimide; soluble gluside; soluble saccharin; sucaryl sodium.

Chemical Name and CAS Registry Number

1,2-Benzisothiazol-3(2H)-one 1,1-dioxide, sodium salt [6155-57-3] for the dihydrate

[128-44-9] for the anhydrous material

See also Section 8.

Empirical Formula and Molecular Weight

C7H4NNaO3S 205.16

C7H4NNaO3S·2/3H2O (84%) 217.24

C7H4NNaO3S·2H2O (76%) 241.19

Structural Formula

 

Functional Category

Sweetening agent.

Applications in Pharmaceutical Formulation or Technology

Saccharin sodium is an intense sweetening agent used in beverages, food products, table-top sweeteners,(1) and pharma- ceutical formulations such as tablets, powders, medicated confectionery, gels, suspensions, liquids, and mouthwashes;(2) see Table I. It is also used in vitamin preparations.

Saccharin sodium is considerably more soluble in water than saccharin, and is more frequently used in pharmaceutical

�formulations. Its sweetening power is approximately 300 times that of sucrose. Saccharin sodium enhances flavor systems and may be used to mask some unpleasant taste characteristics.

Injection of saccharin sodium has been used to measure the arm-to-tongue circulation time.

Table I: Uses of saccharin sodium.

Use Concentration (%)

Dental paste/gel 0.12–0.3

IM/IV injections 0.9

Oral solution 0.075–0.6

Oral syrup 0.04–0.25

Description

Saccharin sodium occurs as a white, odorless or faintly aromatic, efflorescent, crystalline powder. It has an intensely sweet taste, with a metallic aftertaste that at normal levels of use can be detected by approximately 25% of the population. Saccharin sodium can contain variable amounts of water.

SEM: 1

Excipient: Saccharin sodium Magnification: 35× Voltage: 5 kV

 

Pharmacopeial Specifications

See Table II.

642 Saccharin Sodium

Table II: Pharmacopeial specifications for saccharin sodium.

Test JP 2001 PhEur 2005 USP 28

Identification + + +

Characters + + —

�Stability and Storage Conditions

Saccharin sodium is stable under the normal range of conditions employed in formulations. Only when it is exposed to a high temperature (1258C) at a low pH (pH 2) for over 1 hour does significant decomposition occur. The 84% grade is

Clarity and color of solution

�+ + —

�the most stable form of saccharin sodium since the 76% form will dry further under ambient conditions.

Acidity or alkalinity + + +

Water 415.0%  415.0% 415.0%

Benzoate and salicylate + — +

Arsenic 42 ppm — —

Selenium — — 40.003%

Acidity or alkalinity + + +

Toluenesulfonamides + + +

Heavy metals 420 ppm 420 ppm 40.001%

�Saccharin sodium should be stored in a well-closed container in a cool, dry place.

Incompatibilities

—

Method of Manufacture

Readily carbonizable substances

Organic volatile impurities

�+ — +

— — +

�Saccharin is produced by the oxidation of o-toluene sulfon- amide by potassium permanganate in a solution of sodium

hydroxide. Acidification of the solution precipitates saccharin, which is then dissolved in water at 508C and neutralized by

Assay (anhydrous basis)  598.0%  99.0–101.0%  98.0–101.0%

Typical Properties

Unless stated, data refer to either 76% or 84% saccharin sodium.

Acidity/alkalinity: pH = 6.6 (10% w/v aqueous solution)

Density (bulk):

0.8–1.1 g/cm3 (76% saccharin sodium);

�addition of sodium hydroxide. Rapid cooling of the solution initiates crystallization of saccharin sodium from the liquors.

Safety

There has been considerable controversy concerning the safety of saccharin and saccharin sodium in recent years; however, it is now generally regarded as a safe, intense sweetener. See Saccharin for further information.

The WHO has set a temporary acceptable daily intake of up

0.86 g/cm3 (84% saccharin sodium).

Density (particle): 1.70 g/cm3 (84% saccharin sodium)

Density (tapped):

0.9–1.2 g/cm3 (76% saccharin sodium);

0.96 g/cm3 (84% saccharin sodium).

Melting point: decomposes upon heating.

Moisture content: saccharin sodium 76% contains 14.5% w/w water; saccharin sodium 84% contains 5.5% w/w water. During drying, water evolution occurs in two distinct phases. The 76% material dries under ambient conditions to approximately 5.5% moisture (84% saccharin sodium); the remaining moisture is then removed only by heating.

Solubility: see Table III.

Table III: Solubility of saccharin sodium.

Solvent Solubility at 208C

unless otherwise stated

Buffer solutions:

pH 2.2 (phthalate) 1 in 1.15

1 in 0.66 at 608C

pH 4.0 (citrate–phosphate) 1 in 1.21

1 in 0.69 at 608C

pH 7.0 (citrate–phosphate) 1 in 1.21

1 in 0.66 at 608C

pH 9.0 (borate) 1 in 1.21

1 in 0.69 at 608C

Ethanol 1 in 102

Ethanol (95%) 1 in 50

Propylene glycol 1 in 3.5

Propan-2-ol Practically insoluble

Water 1 in 1.2