SEM: 3

Excipient: Sodium chloride, granular Manufacturer: Van Waters & Rogers, Inc. Magnification: 600×

 

 

Figure 1: Compression characteristics of sodium chloride (cubic crystals).(3) Tablet diameter = 12 mm.

Incompatibilities

Aqueous sodium chloride solutions are corrosive to iron. They also react to form precipitates with silver, lead, and mercury salts. Strong oxidizing agents liberate chlorine from acidified solutions of sodium chloride. The solubility of the antimicro- bial preservative methylparaben is decreased in aqueous sodium chloride solutions(23) and the viscosity of carbomer gels and solutions of hydroxyethyl cellulose or hydroxypropyl cellulose is reduced by the addition of sodium chloride.



Method of Manufacture

Sodium chloride occurs naturally as the mineral halite. Commercially, it is obtained by the solar evaporation of sea water, by mining, or by the evaporation of brine from underground salt deposits.

Safety

Sodium chloride is the most important salt in the body for maintaining the osmotic tension of blood and tissues. About 5–12 g of sodium chloride is consumed daily, in the normal adult diet, and a corresponding amount is excreted in the urine. As an excipient, sodium chloride may be regarded as an essentially nontoxic and nonirritant material. However, toxic effects following the oral ingestion of 0.5–1.0 g/kg body-weight in adults may occur. The oral ingestion of larger quantities of sodium chloride, e.g. 1000 g in 600 mL of water,(24) is harmful and can induce irritation of the gastrointestinal tract, vomiting, hypernatremia, respiratory distress, convulsions, or death.

In rats, the minimum lethal intravenous dose is 2.5 g/kg body-weight.

LD50 (mouse, IP): 6.61 g/kg(25) LD50 (mouse, IV): 0.65 g/kg LD50 (mouse, oral): 4.0 g/kg LD50 (mouse, SC): 3.0 g/kg LD50 (rat, oral): 3.0 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. If heated to high tempera- tures, sodium chloride evolves a vapor irritating to the eyes.

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (injections; inhalations; nasal, ophthalmic, oral, otic, rectal, and topical preparations). Included in nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Potassium chloride.

Comments

Domestic table salt may contain sodium iodide (as a prophylactic substance against goiter) and agents such as magnesium carbonate, calcium phosphate, or starch, which reduce the hygroscopic characteristics of the salt and maintain the powder in a free-flowing state.

Food-grade dendritic salt, which is porous, can be used as an absorbent for liquid medications, and as a tablet diluent in specific formulations.

Each gram of sodium chloride represents approximately

17.1 mmol of sodium and 17.1 mmol of chloride; 2.54 g of sodium chloride is approximately equivalent to 1 g of sodium. A saturated solution of sodium chloride can be used as a constant-humidity solution; at 258C, a relative humidity of 75% is produced. A specification for sodium chloride is

contained in the Food Chemicals Codex (FCC).

The EINECS number for sodium chloride is 231-598-3.

674 Sodium Chloride

Specific References

Leigh S, Carless JE, Burt BW. Compression characteristics of some pharmaceutical materials. J Pharm Sci 1967; 56: 888–892.

Rees JE, Shotton E. Some observations on the ageing of sodium chloride compacts. J Pharm Pharmacol 1970; 22: 17S–23S.

Shotton E, Obiorah BA. The effect of particle shape and crystal habit on the properties of sodium chloride. J Pharm Pharmacol 1973; 25: 37P–43P.

Roberts RJ, Rowe RC, Kendall K. Brittle-ductile transitions in die compaction of sodium chloride. Chem Eng Sci 1989; 44: 1647– 1651.

Hammouda Y, Eshra AG, El-Banna HM. The use of sodium chloride as a directly compressible filler. Part III: Drug-to-filler ratio. Pharm Ind 1978; 40(9): 987–992.

Gonza´lez-Rodriguez ML, Ferna´ndez-Herva´s MJ, Caraballo I, Rabasco AM. Design and evaluation of a new central core matrix tablet. Int J Pharm 1997; 146: 175–180.

Korsatko-Wabnegg B. Development of press-coated tablets with controlled release effect using poly-D-(–)-3-hydroxybutyric acid [in German]. Pharmazie 1990; 45: 842–844.

Moussa IS, Cartilier LH. Evaluation of crosslinked amylose press- coated tablets for sustained drug delivery. Int J Pharm 1997; 149: 139–149.

O¨ zdemir N, Sahin J. Design of a controlled release osmotic pump system of ibuprofen. Int J Pharm 1997; 158: 91–97.

Shivanand P, Sprockel OL. A controlled porosity drug delivery system. Int J Pharm 1998; 167: 83–96.

Tirkkonen S, Paronen P. Enhancement of drug release from ethylcellulose microcapsules using solid sodium chloride in the wall. Int J Pharm 1992; 88: 39–51.

Tirkkonen S, Paronen P. Release of indomethacin from tabletted ethylcellulose microcapsules. Int J Pharm 1993; 92: 55–62.

Yuasa H, Nakano T, Kanaya Y. Suppression of agglomeration in fluidized bed coating I. Suppression of agglomeration by adding sodium chloride. Int J Pharm 1997; 158: 195–201.

Pandit NK, Wang D. Salt effects on the diffusion and release rate of propranolol from poloxamer 407 gels. Int J Pharm 1998; 167: 183–189.

Mishra B, Pandit JK. Multiple water-oil-water emulsions as prolonged release formulations of pentazocine. J Control Release 1990; 14: 53–60.

Shah D, Ecanow B, Balagot R. Coacervate formation by inorganic salts with benzalkonium chloride. J Pharm Sci 1973; 62: 1741– 1742.

Richard AJ. Ultracentrifugal study of effect of sodium chloride on micelle size of fusidate sodium. J Pharm Sci 1975; 64: 873–875.

McDonald C, Richardson C. The effect of added salts on solubilization by a non-ionic surfactant. J Pharm Pharmacol 1981; 33: 38–39.

Mattha AG. Rheological studies on Plantago albicans (Psyllium) seed gum dispersions II: effect of some pharmaceutical additives. Pharm Acta Helv 1977; 52: 214–217.

Okor RS. The effect of phenol on the electrolyte flocculation of certain polymeric dispersions to thixotropic gels. Pharm Res 1993; 10: 220–222.

Elamin AA, Alderborn G, Ahlneck C. The effect of pre-compaction processing and storage conditions on powder and compaction properties of some crystalline materials. Int J Pharm 1994; 108: 213–224.

Ahlneck C, Alderborn G. Moisure adsorption and tabletting. II. The effect on tensile strength and air permeability of the relative humidity during storage of tablets of 3 crystalline materials. Int J Pharm 1989; 56: 143–150.

McDonald C, Lindstrom RE. The effect of urea on the solubility of methyl p-hydroxybenzoate in aqueous sodium chloride solution. J Pharm Pharmacol 1974; 26: 39–45.

Calam J, Krasner N, Haqqani M. Extensive gastrointestinal damage following a saline emetic. Dig Dis Sci 1982; 27: 936–940.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 3238–3239.

General References

Heng PW, Hao JS, Chan LW, Chen SH. Influence of osmotic agents in diffusion layer on drug release from multilayer coated pellets. Drug Dev Ind Pharm 2004; 30(2): 213–220.

Authors

SC Owen.

Date of Revision

8 June 2005.

Sodium Citrate Dihydrate

Nonproprietary Names

BP: Sodium citrate JP: Sodium citrate PhEur: Natrii citras USP: Sodium citrate

Synonyms

Citric acid trisodium salt; E331; sodium citrate tertiary; trisodium citrate.

Chemical Name and CAS Registry Number

Trisodium 2-hydroxypropane-1,2,3-tricarboxylate dihydrate [6132-04-3]

Empirical Formula and Molecular Weight

C6H5Na3O7·2H2O 294.10

Structural Formula

 

Functional Category

Alkalizing agent; buffering agent; emulsifier; sequestering agent.

Applications in Pharmaceutical Formulation or Technology

Sodium citrate, as either the dihydrate or anhydrous material, is widely used in pharmaceutical formulations; see Table I.

It is used in food products, primarily to adjust the pH of solutions. It is also used as a sequestering agent. The anhydrous material is used in effervescent tablet formulations.(1) Sodium citrate is additionally used as a blood anticoagulant either alone or in combination with other citrates such as disodium hydrogen citrate.

Therapeutically, sodium citrate is used to relieve the painful irritation caused by cystitis, and also to treat dehydration and acidosis due to diarrhea; see Section 14.

Table I: Uses of sodium citrate dihydrate.

Use Concentration (%)

Buffering agent 0.3–2.0

Injections 0.02–4.0

Ophthalmic solutions 0.1–2.0

Sequestering agent 0.3–2.0

Description

Sodium citrate dihydrate consists of odorless, colorless, monoclinic crystals, or a white crystalline powder with a cooling, saline taste. It is slightly deliquescent in moist air, and in warm dry air it is efflorescent. Although most pharmacopeias specify that sodium citrate is the dihydrate, the USP 28 states that sodium citrate may be either the dihydrate or anhydrous material.

Pharmacopeial Specifications

See Table II.

Typical Properties

Acidity/alkalinity: pH = 7.0–9.0 (5% w/v aqueous solution)

Density (bulk): 1.12 g/cm3 Density (tapped): 0.99 g/cm3 Density (true): 1.19 g/cm3

Melting point: converts to the anhydrous form at 1508C.

SEM: 1

Excipient: Sodium citrate dihydrate (granular)

Manufacturer: Pfizer Ltd

Magnification: 60×

 

676 Sodium Citrate Dihydrate

SEM: 2

Excipient: Sodium citrate dihydrate (granular)

Manufacturer: Pfizer Ltd

Magnification: 600×

 

Table II: Pharmacopeial specifications for sodium citrate dihydrate.

 

Test JP 2001 PhEur 2005 USP 28    

Identification + + +    

Characters — + —    

pH 7.5–8.5 — —    

Appearance of + + —    

solution    

Acidity or alkalinity + + +    

Loss on drying 10.0–13.0% — —    

Water — 11.0–13.0% 10.0–13.0%    

Oxalate + 4300 ppm —    

Sulfate 40.048% 4150 ppm —    

Heavy metals 410 ppm 410 ppm 40.001%    

Arsenic 42 ppm — —    

Chloride 40.015% 450 ppm —    

Tartrate + — +    

Readily carbonizable + + —    

substances

Pyrogens

—

+(a)

—    

Assay (anhydrous 599.0% 99.0–101.0% 99.0–100.5%    

basis)  

(a) If intended for use in large-volume preparations for parenteral use, compliance with a test for pyrogens may be required.

Osmolarity: a 3.02% w/v aqueous solution is iso-osmotic with serum.

Particle size distribution: various grades of sodium citrate dihydrate with different particle sizes are commercially available.

Solubility: soluble 1 in 1.5 of water, 1 in 0.6 of boiling water; practically insoluble in ethanol (95%).

Stability and Storage Conditions

Sodium citrate dihydrate is a stable material. Aqueous solutions may be sterilized by autoclaving. On storage, aqueous solutions may cause the separation of small, solid particles from glass containers.

The bulk material should be stored in an airtight container in a cool, dry place.

Incompatibilities

Aqueous solutions are slightly alkaline and will react with acidic substances. Alkaloidal salts may be precipitated from their aqueous or hydro-alcohol solutions. Calcium and strontium salts will cause precipitation of the corresponding citrates. Other incompatibilities include bases, reducing agents, and oxidizing agents.

Method of Manufacture

Sodium citrate is prepared by adding sodium carbonate to a solution of citric acid until effervescence ceases. The resulting solution is filtered and evaporated to dryness.

Safety

After ingestion, sodium citrate is absorbed and metabolized to bicarbonate. Although it is generally regarded as a nontoxic and nonirritant excipient, excessive consumption may cause gastrointestinal discomfort or diarrhea. Therapeutically, in adults, up to 15 g daily of sodium citrate dihydrate may be administered orally, in divided doses, as an aqueous solution to relieve the painful irritation caused by cystitis.

Citrates and citric acid enhance intestinal aluminum absorption in renal patients, which may lead to increased, harmful serum aluminum levels. It has therefore been suggested that patients with renal failure taking aluminum compounds to control phosphate absorption should not be prescribed citrate- or citric acid-containing products.(2)

See Section 17 for anhydrous sodium citrate animal toxicity data.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Sodium citrate dihydrate dust may be irritant to the eyes and respiratory tract. Eye protection and gloves are recommended. Sodium citrate should be handled in a well-ventilated environment or a dust mask should be worn.

Regulatory Status

GRAS listed. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Guide (inhalations, injections, ophthalmic products, oral solutions, suspensions, syrups and tablets, nasal, otic, rectal, topical, transdermal, and vaginal preparations). Included in nonparenteral and parent- eral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Anhydrous sodium citrate; citric acid monohydrate.

Sodium Citrate Dihydrate 677

Anhydrous sodium citrate Empirical formula: C6H5Na3O7 Molecular weight: 258.07

CAS number: [68-04-2]

Synonyms: anhydrous trisodium citrate; citric acid trisodium salt anhydrous; trisodium 2-hydroxy-1,2,3-propane- tricarboxylic acid.

Appearance: colorless crystals or a white crystalline powder.

Safety:

LD50 (mouse, IP): 1.36 g/kg(3) LD50 (mouse, IV): 0.17 g/kg LD50 (rabbit, IV): 0.45 g/kg LD50 (rat, IP): 1.55 g/kg

Comments

Each gram of sodium citrate dihydrate represents approxi- mately 10.2 mmol of sodium and 3.4 mmol of citrate. Each gram of anhydrous sodium citrate represents approximately

11.6 mmol of sodium and 3.9 mmol of citrate.

The EINECS number for sodium citrate is 200-675-3.



Specific References

Anderson NR, Banker GS, Peck GE. Quantitative evaluation of pharmaceutical effervescent systems II: stability monitoring of reactivity and porosity measurements. J Pharm Sci 1982; 71: 7–13.

Main J, Ward MK. Potentiation of aluminum absorption by effervescent analgesic tablets in a haemodialysis patient. Br Med J 1992; 304: 1686.

Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th edn. New York: Wiley, 2004: 2572.

General References

—

Authors

GE Amidon.

Date of Revision

19 August 2005.

Sodium Cyclamate

Nonproprietary Names

BP: Sodium cyclamate PhEur: Natrii cyclamas

Synonyms

Cyclohexylsulfamic acid monosodium salt; E952; sodium cyclohexanesulfamate.

Chemical Name and CAS Registry Number

Sodium N-cyclohexylsulfamate [139-05-9]

Empirical Formula and Molecular Weight

C6H12NNaO3S 201.22

Structural Formula

 

Functional Category

Sweetening agent.

Applications in Pharmaceutical Formulation or Technology

Sodium cyclamate is used as an intense sweetening agent in pharmaceutical formulations, foods, beverages, and table-top sweeteners. In dilute solution, up to about 0.17% w/v, the sweetening power is approximately 30 times that of sucrose. However, at higher concentrations this is reduced and at a concentration of 0.5% w/v a bitter taste becomes noticeable. Sodium cyclamate enhances flavor systems and can be used to mask some unpleasant taste characteristics. In most applica- tions, sodium cyclamate is used in combination with saccharin.

Description

Sodium cyclamate occurs as white, odorless or almost odorless crystals or as a crystalline powder with an intensely sweet taste.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for sodium cyclamate.

Test PhEur 2005

Identification +

Characters +

Appearance of solution +

pH (10% w/v aqueous solution) 5.5–7.5

Absorbance at 270 nm 40.10

Sulfamic acid +

Aniline 41 ppm

Cyclohexylamine 410 ppm

Dicyclohexylamine 41 ppm

Sulfates 40.1%

Heavy metals 410 ppm

Loss on drying 41.0%

Assay (dried basis) 98.5–101.0%

Typical Properties

Acidity/alkalinity: pH = 5.5–7.5 for a 10% w/v aqueous solution.

Solubility: see Table II.

Table II: Solubility of sodium cyclamate.

Solvent Solubility at 208C unless otherwise stated

Benzene Practically insoluble

Chloroform Practically insoluble

Ethanol (95%) 1 in 250

Ether Practically insoluble

Propylene glycol 1 in 25

Water 1 in 5

1 in 2 at 458C

Stability and Storage Conditions

Sodium cyclamate is hydrolyzed by sulfuric acid and cyclo- hexylamine at a very slow rate that is proportional to the hydrogen ion concentration. Therefore, for all practical considerations, it can be regarded as stable. Solutions are also stable to heat, light, and air over a wide pH range.

Samples of tablets containing sodium cyclamate and saccharin have shown no loss in sweetening power following storage for up to 20 years.

The bulk material should be stored in a well-closed container in a cool, dry place.

Incompatibilities

—

Method of Manufacture

Cyclamates are prepared by the sulfonation of cyclohexylamine in the presence of a base. Commercially, the sulfonation can

Sodium Cyclamate 679

involve sulfamic acid, a sulfate salt, or sulfur trioxide. Tertiary bases such as triethylamine or trimethylamine may be used as the condensing agent. The amine salts of cyclamate that are produced are converted to the sodium, calcium, potassium, or magnesium salt by treatment with the appropriate metal oxide.

Safety

There has been considerable controversy concerning the safety of cyclamate following the FDA decision in 1970 to ban its use in the USA.(1–3) This decision resulted from a feeding study in rats that suggested that cyclamate could cause an unusual form of bladder cancer. However, that study has been criticized because it involved very high doses of cyclamate administered with saccharin, which has itself been the subject of controversy concerning its safety; see Saccharin. Although excreted almost entirely unchanged in the urine, a potentially harmful metabolite of sodium cyclamate, cyclohexylamine, has been detected in humans.(4)

Extensive long-term animal feeding studies and epidemio- logical studies in humans have failed to show any evidence that cyclamate is carcinogenic or mutagenic.(5,6) As a result, sodium cyclamate is now accepted in many countries for use in foods and pharmaceutical formulations. See also Section 16.

Few adverse reactions to cyclamate have been reported, although its use has been associated with instances of photosensitive dermatitis.(7)

The WHO has set an estimated acceptable daily intake for sodium and calcium cyclamate, expressed as cyclamic acid, at up to 11 mg/kg body-weight.(8) In Europe, a temporary acceptable daily intake for sodium and calcium cyclamate, expressed as cyclamic acid, has been set at up to 1.5 mg/kg body-weight.

LD50 (mouse, IP): 1.15 g/kg(9) LD50 (mouse, IV): 4.8 g/kg LD50 (mouse, oral): 17 g/kg LD50 (rat, IP): 1.35 g/kg

LD50 (rat, IV): 3.5 g/kg LD50 (rat, oral): 15.25 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection is recom- mended.

Regulatory Status

The use of cyclamates as artificial sweetners in food, soft drinks, and artificial sweetening tablets was at one time prohibited in the UK and some other countries owing to concern about the metabolite cyclohexylamine. However, this is no longer the case, and cyclamates are now permitted for use as a food additive in Europe.

Included in the FDA Inactive Ingredients Guide (oral powder, solutions and suspensions). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Alitame; calcium cyclamate; cyclamic acid.

Calcium cyclamate

Empirical formula: C12H24CaN2O6S2·2H2O



Molecular weight: 432.57

CAS number:

[5897-16-5] for the dihydrate;

[139-06-0] for the anhydrous form.

Synonyms: calcium N-cyclohexylsulfamate dihydrate; Cyclan; cyclohexanesulfamic acid calcium salt; cyclohexylsulfamic acid calcium salt; E952; Sucaryl calcium.

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

Acidity/alkalinity: pH = 5.5–7.5 for a 10% w/v aqueous solution.

Solubility: freely soluble in water; practically insoluble in benzene, chloroform, ethanol (95%), and ether.

Cyclamic acid

Empirical formula: C6H13NO3S

Molecular weight: 179.23

CAS number: [100-88-9]

Synonyms: cyclamate; cyclohexanesulfamic acid; N-cyclo- hexylsulfamic acid; E952; hexamic acid; Sucaryl.

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

Melting point: 169–1708C

Solubility: slightly soluble in 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 the bulk, textural, or preservative characteristics of sucrose if sucrose is removed from a formulation.

Synergistic effects for combinations of sweeteners have been reported, e.g., sodium cyclamate with saccharin sodium or acesulfame potassium.

Sodium cyclamate has also been used to increase the solubility of neohesperidin dihydrochalcone in sweetener blends.(10)