Specific References

Nabors LO, Miller WT. Cyclamate: a toxicological review.

Commen Toxicol 1989; 3(4): 307–315.

Lecos C. The sweet and sour history of saccharin, cyclamate and aspartame. FDA Consumer 1981; 15(7): 8–11.

Anonymous. Cyclamate alone not a carcinogen. Am Pharm 1985;

NS25(9): 11.

Kojima S, Ichibagase H. Studies on synthetic sweetening agents

VIII. Cyclohexylamine, a metabolite of sodium cyclamate. Chem Pharm Bull 1966; 14: 971–974.

D’Arcy PF. Adverse reactions to excipients in pharmaceutical formulations. In: Florence AT, Salole EG, eds. Formulation Factors in Adverse Reactions. London: Wright, 1990: 1–22.

Schma¨ hl D, Habs M. Investigations on the carcinogenicity of the artificial sweeteners sodium cyclamate and sodium saccharin in rats in a two-generation experiment. Arzneimittelforschung 1984; 34: 604–606.

Yong JM, Sanderson KV. Photosensitive dermatitis and renal tubular acidosis after ingestion of calcium cyclamate. Lancet 1969; ii: 1273–1274.

FAO/WHO. Evaluation of certain food additives and contami- nants. Twenty-sixth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep Ser 1982; No. 683.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3243.

680 Sodium Cyclamate

Benavente-Garcia O, Castillo J, Del Bano MJ, Lorente J. Improved water solubility of neohesperidin dihydrochalcone in sweetener blends. J Agric Food Chem 2001; 49(1): 189–191.

General References

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

Schiffman SS, Sattely-Miller EA, Graham BG, et al. Effect of temperature, pH, and ions on sweet taste. Physiol Behav 2000; 68(4): 469–481.

Authors

SC Owen.

Date of Revision

11 August 2005.

Sodium Hyaluronate

Nonproprietary Names

BP: Sodium hyaluronate PhEur: Natrii hyaluronas

Synonyms

Hyaluronan; hyaluronate sodium; RITA HA C-1-C.

Chemical Name and CAS Registry Number

Sodium hyaluronate [9067-32-7]

Empirical Formula and Molecular Weight

(C14H20NO11Na)n (401.3)n

Structural Formula

 

Functional Category

Humectant; lubricant; matrix for sustained release.

Applications in Pharmaceutical Formulation or Technology

Sodium hyaluronate is the predominant form of hyaluronic acid at physiological pH. The name hyaluronan is used when the polysaccharide is mentioned in general terms, and in the literature the terms hyaluronic acid and sodium hyaluronate are used interchangeably.

Hyaluronan is used therapeutically to treat osteoarthritis in the knee, and is an effective treatment for arthritic pain.(1) Crosslinked hyaluronan gels are used as drug delivery systems.(2)

Hyaluronan is the most common negatively charged glycosaminoglycan in the human vitreous humor, and is known to interact with polymeric and liposomal DNA complexes,(3) where hyaluronan solutions have been shown to decrease the cellular uptake of complexes.(4) This is useful for enhancing the availability and retention time of drugs administered to the eye. It is immunoneutral, which makes it useful for the attachment of biomaterials for use in tissue engineering and drug delivery

systems;(5) it also has important applications in the fields of vascosurgery and vascosupplementation.(6)

Description

The PhEur 2005 describes sodium hyaluronate as the sodium salt of hyaluronic acid, a glycosaminoglycan consisting of D- glucuronic acid and N-acetyl-D-glucosamine disaccharide units.

Sodium hyaluronate occurs as white to off-white powder or granules. It is very hygroscopic.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specification for sodium hyaluronate.

Test PhEur 2005

Characters +

Identification +

Appearance of solution +

pH 5.0–8.5

Intrinsic viscosity +

Sulfated glycosaminoglycans 41%

Nucleic acids 40.5

Protein 40.3%(a)

Chlorides 40.5%

Iron 480 ppm

Loss on drying 420.0%

Microbial contamination 4102/g

Bacterial endotoxins 40.05 IU/mg(b)

Assay 95.0–105.0%

(a) <0.1% for parenteral dosage forms.

(b) 40.5 IU/mg for parenteral dosage forms.

Typical Properties

Acidity/alkalinity: pH = 5.0–8.5 (0.5% w/v aqueous solution) Solubility: soluble in water, although speed of dissolution depends upon molecular weight (higher molecular weights are slower to dissolve, although this process can be increased

by gentle agitation). Slightly soluble in mixtures of organic solvents with water.(7)

Stability and Storage Conditions

Sodium hyaluronate should be stored in a cool, dry place in tightly sealed containers. The powder is stable for three years if stored in unopened containers.

Incompatibilities

—

682 Sodium Hyaluronate

Method of Manufacture

Sodium hyaluronate occurs naturally in vitreous humor, serum, chicken combs, shark skin, and whale cartilage; it is usually extracted and purified from chicken combs. It may also be manufactured by fermentation of selected Streptococcus zooepidemicus bacterial strains; sodium hyaluronate is removed from the fermentation medium by filtration and purified by ultrafiltration. It is then precipitated with an organic solvent and dried.

Safety

Sodium hyaluronate is used in cosmetics and in topical, parenteral, and ophthalmic pharmaceutical formulations. It is generally regarded as a relatively nontoxic and nonirritant material. Sodium hyaluronate has been reported to be an experimental teratogen.(8)

LD50 (mouse, IP): 1.5 g/kg(8) LD50 (rabbit, IP): 1.82 g/kg LD50 (rat, IP): 1.77 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. When heated to decomposi- tion, sodium hyaluronate emits toxic fumes of Na2O.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (topical gel preparation).

Related Substances

Hyaluronic acid.

Hyaluronic acid

Molecular weight: hyaluronic acid molecules have a molecular weight of 300–2000 kDa as the number of repeating disaccharide units in each molecule is variable. In its natural form, hyaluronic acid exists as a high-molecular-weight polymer of 106–107 Da.

CAS number: [9067-32-7]

Appearance: hyaluronic acid appears as a white to off-white powder or granules.

Comments: hyaluronic acid is used as an adjuvant for ophthalmic drug delivery,(9) and has been found to enhance the absorption of drugs and proteins via mucosal tissue.(10) It has also been used experimentally in controlled-release films that are suitable for application to surgical sites for the prevention of adhesion formation,(11) and in matrix formulations used in gene delivery systems.(12) The EINECS number for hyaluronic acid is 232-678-0.

Comments

Microspheres prepared from hyaluronan esters have been evaluated for the vaginal administration of calcitonin in the treatment of postmenopausal osteoporosis.(13) Microspheres prepared from hyaluronan esters have also been used experi- mentally as delivery devices for nerve growth factors,(14) and as a nasal delivery system for insulin.(15)

An N-(2-hydroxypropyl)methacrylamide (HPMA)–hyalur- onan polymeric drug delivery system has been used for the

targeted delivery of doxorubicin to cancer cells. This copolymer exhibited increased toxicity due to hyaluronan receptor- mediated uptake of the macromolecular drug.(16)

The EINECS number for sodium hyaluronate is232-678-0.

Specific References

Castellacci E, Polieri T. Antalgesic effect and clinical tolerability of hyaluronic acid in patients with degenerative diseases of knee cartilage: an outpatient treatment survey. Drugs Exp Clin Res 2004; 30(2): 67–73.

Dehayza P, Cheng L. Sodium hyaluronate microspheres. US Patent No. 2,004,127,459; 2004.

Pitka¨ nen L, Ruponen M, Nieminen J, Urtti A. Vitreous is a barrier in nonviral gene transfer by cationic lipids and polymers. Pharm Res 2003; 20(4): 576–583.

Ruponen M, Yla¨ -Herttuala S, Urtti A. Interactions of polymeric and liposomal gene delivery systems with extracellular glycosami- noglycans: physicochemical and transfection studies. Biochim Biophys Acta 1999; 1415: 331–341.

Vercruysse KP, Prestwich GD. Hyaluronate derivatives in drug delivery. Crit Rev Ther Carrier Syst 1998; 15: 513–555.

Balazs EA, Denlinger JL. Clinical uses of hyaluronan. In: Evered D, Whelan J, eds: The Biology of Hyaluronan. Chichester: Wiley, 1989: 265–280.

Contipro C a.s. Sodium hyaluronate. http://www.cpn-contipro.com (accessed 26 May 2005).

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 1970.

Saettone MF, Monti D,Tarracca MT, Chetoni P. Mucoadhesive ophthalmic vehicles: evaluation of polymeric low-viscosity for- mulations. J Ocul Pharm 1994; 10: 83–92.

Cho KY, Chung TW, Kim BC, et al. Release of ciprofloxacin from polymer-graft-hyaluronic acid hydrogels in vitro. Int J Pharm 2003; 260(1): 83–91.

Jackson JK, Skinner KC, Burgess L, et al. Paclitaxel-loaded crosslinked hyaluronic acid films for the prevention of postsurgical adhesions. Pharm Res 2002; 19(4): 411–417.

Kim A, Checkla DM, Dehazya P, et al. Characterization of DNA- hyaluronan matrix for sustained gene transfer. J Control Release 2003; 90(1): 81–75.

Rochira M, Miglietta MR, Richardson JL, et al. Novel vaginal delivery systems for calcitonin II. Preparation and characterisation of HYAFF1 microspheres containing calcitonin. Int J Pharm 1996; 144: 19–26.

Ghezzo E, Beredetti LM, Rochira M, et al. Hyaluronan derivative microspheres as NGF delivery devices: preparation methods and in vitro release characterization. Int J Pharm 1992; 29: 133–141.

Illum L, Farray NF, Fisher AN, et al. Hyaluronic acid ester microspheres as a nasal delivery system for insulin. J Control Release 1994; 29: 133–141.

Luo Y, Bernshaw NJ, Lu ZR, et al. Targetted delivery of doxorubicin by HPMA copolymer–hyaluronan bioconjugates. Pharm Res 2002; 19(4): 396–402.

General References

—

Authors

SC Owen.

Date of Revision

26 May 2005.

Sodium Hydroxide

Nonproprietary Names

BP: Sodium hydroxide JP: Sodium hydroxide

PhEur: Natrii hydroxidum USPNF: Sodium hydroxide

Synonyms

Caustic soda; E524; lye; soda lye; sodium hydrate.

Chemical Name and CAS Registry Number

Sodium hydroxide [1310-73-2]

Empirical Formula and Molecular Weight

NaOH 40.00

Structural Formula

NaOH

Functional Category

Alkalizing agent; buffering agent.

Applications in Pharmaceutical Formulation or Technology

Sodium hydroxide is widely used in pharmaceutical formula- tions to adjust the pH of solutions.(1) It can also be used to react with weak acids to form salts.

Description

Sodium hydroxide occurs as a white or nearly white fused mass. It is available in small pellets, flakes, sticks, and other shapes or forms. It is hard and brittle and shows a crystalline fracture. Sodium hydroxide is very deliquescent and on exposure to air it rapidly absorbs carbon dioxide and water.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for sodium hydroxide.

 

Test JP 2001 PhEur 2005 USPNF 23    

Identification + + +    

Characters — + —    

Appearance of + + —    

solution    

Insoluble substances — — +    

and organic matter    

Sodium carbonate 42.0% 42.0% —    

Sulfates — 450 ppm —    

Chlorides 40.05% 450 ppm —    

Iron — 410 ppm —    

Mercury + — —    

Heavy metals 430 ppm 420 ppm 40.003%    

Potassium + — +    

Assay (total alkali 595.0% 97.0–100.5% 95.0–100.5%  

calculated as NaOH)

Typical Properties

Acidity/alkalinity:

pH ≈ 12 (0.05% w/w aqueous solution); pH ≈ 13 (0.5% w/w aqueous solution); pH ≈ 14 (5% w/w aqueous solution).

Melting point: 3188C

Solubility: see Table II.

Table II: Solubility of sodium hydroxide.

Solvent Solubility at 208C

unless otherwise stated

Ethanol 1 in 7.2

Ether Practically insoluble

Glycerin Soluble

Methanol 1 in 4.2

Water 1 in 0.9

1 in 0.3 at 1008C

Stability and Storage Conditions

Sodium hydroxide should be stored in an airtight nonmetallic container in a cool, dry place. When exposed to air, sodium hydroxide rapidly absorbs moisture and liquefies, but sub- sequently becomes solid again owing to absorption of carbon dioxide and formation of sodium carbonate.

Incompatibilities

Sodium hydroxide is a strong base and is incompatible with any compound that readily undergoes hydrolysis or oxidation. It will react with acids, esters, and ethers, especially in aqueous solution.

684 Sodium Hydroxide

Method of Manufacture

Sodium hydroxide is manufactured by electrolysis of brine using inert electrodes. Chlorine is evolved as a gas at the anode and hydrogen is evolved as a gas at the cathode. The removal of chloride and hydrogen ions leaves sodium and hydroxide ions in solution. The solution is dried to produce the solid sodium hydroxide.

A second method uses the Kellner–Solvay cell. Saturated sodium chloride solution is electrolyzed between a carbon anode and a flowing mercury cathode. In this case the sodium is produced at the cathode rather than the hydrogen because of the readiness of sodium to dissolve in the mercury. The sodium– mercury amalgam is then exposed to water and a sodium hydroxide solution is produced.

Safety

Sodium hydroxide is widely used in the pharmaceutical and food industries and is generally regarded as a nontoxic material at low concentrations. At high concentrations it is a corrosive irritant to the skin, eyes, and mucous membranes.

LD50 (mouse, IP): 0.04 g/kg(2) LD50 (rabbit, oral): 0.5 g/kg

Handling Precautions

Observe normal handling precautions appropriate to the quantity and concentration of material handled. Gloves, eye protection, a respirator, and other protective clothing should be worn.

Sodium hydroxide is a corrosive irritant to the skin, eyes, and mucous membranes. The solid and solutions cause burns, often with deep ulceration. It is moderately toxic on ingestion and harmful on inhalation.

In the UK, the occupational exposure limit for sodium hydroxide has been set at 2 mg/m3 short-term.(3)

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (dental preparations; injections; inhalations; nasal, ophthalmic, oral, otic, rectal, topical, and vaginal preparations). Included in

nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Potassium hydroxide.

Comments

Sodium hydroxide is most commonly used in solutions of fixed concentration. Sodium hydroxide has some antibacterial and antiviral properties and is used as a disinfectant in some applications.(4–6) A specification for sodium hydroxide is contained in the Food Chemicals Codex (FCC).

The EINECS number for sodium hydroxide is 215-185-5.

Specific References

Zhan X, Yin G, Ma B. Improved stability of 25% vitamin C parenteral formulation. Int J Pharm 1998; 173: 43–49.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3254–3255.

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

Brown P, Rohmer RG, Gajduseck DC. Sodium hydroxide decontamination of Creutzfeldt–Jakob disease virus. N Engl J Med 1984; 320: 727.

Gasser G. Creutzfeldt–Jakob disease [letter]. Br Med J 1990; 300: 1523.

Perkowski CA. Operational aspects of bioreactor contamination control. J Parenter Sci Technol 1990; 44: 113–117.

General References

—

Authors

AH Kibbe.

Date of Revision

12 August 2005.