176 Edetic Acid
`
`Edetic Acid
`
`1. Nonproprietary Names
`USPNF: Edetic acid
`
`2. Synonyms
`Edathamil; EDTA; ethylenediaminetetraacetic acid; (ethyle(cid:173)
`nedinitrilo )tetraacetic acid; Questric acid 5286; Sequestrene
`AA; Versene Acid.
`
`3. Chemical Name and CAS Registry Numbers
`N,N' -1,2-Ethanediy1bis[N-( carboxymethy1)glycine]
`[60-00-4]
`
`4. Empirical Formula
`CIOHI6N208
`
`Molecular Weight
`292.24
`
`5. Structural Formula
`(HOOCCH2)2NCH2CH2N(CH2COOH)2
`
`6. Functional Category
`Chelating agent; therapeutic agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Edetic acid and edetate salts are used in pharmaceutical
`formulations, cosmetics and foods as chelating agents; that is,
`they form stable water-soluble complexes (chelates) with
`alkaline earth and heavy metal ions. The chelated form has
`few of the properties of the free ion, and for this reason
`chelating agents are often described as 'removing' ions from
`solution; this process is also called sequestering. The stability
`of the metal-edetate complex depends on the metal ion
`involved and also on the pH. The calcium chelate is relatively
`weak and will preferentially chelate heavy metals, such as iron,
`copper and lead, with the release of calcium ions. For this
`reason, edetate calcium disodium is used therapeutically in
`cases of lead poisoning, see also Section 19.
`Edetic acid and edetates are primarily used as antioxidant
`synergists by sequestering trace amounts of metal ions,
`particularly copper, iron and manganese, which might
`otherwise catalyze autoxidation reactions. Edetic acid and
`edetates may be used alone or in combination with true
`antioxidants, the usual concentration employed being in the
`range 0.005-0.1% wjv. Edetates have been used to stabilize:
`ascorbic acid; corticosteroids; epinephrine; folic acid; formal(cid:173)
`dehyde; gums and resins; hyaluronidase; hydrogen peroxide;
`oxytetracycline; penicillin; salicylic acid and unsaturated fatty
`acids. Essential oils may be washed with a 2% wjv solution of
`edetate to remove trace metal impurities.
`Edetic acid and edetates possess some antimicrobial activity
`but are most frequently used in combination with other
`antimicrobial preservatives due to their synergistic effects.
`Many solutions used for the cleaning, storage and wetting of
`contact lenses thus contain disodium edetate. Typically, edetic
`acid and edetates are used in concentrations of0.01-0.1% wjv
`as antimicrobial preservative synergists, see Section 10.
`Edetic acid and disodium edetate may also be used as water
`softeners since they will chelate the calcium and magnesium
`ions present in hard water; edetate calcium disodium is not
`
`effective. Many cosmetic and toiletry products, e.g. soaps,
`contain edetic acid as a water softener.
`Disodium edetate is also used as an anticoagulant since it will
`chelate calcium and prevent the coagulation of blood in Vitro.
`Concentrations of 0.1% wjv are used in small volumes for
`hematological testing and 0.3% wjv in transfusions.
`
`8. Description
`Edetic acid occurs as a white crystalline powder.
`
`9. Pharmacopeial Specifications
`
`Test
`
`Identification
`Residue on ignition
`Heavy metals
`Nitrilotriacetic acid
`Iron
`Assay
`
`USPNFXVII
`+
`:s; 0.2%
`:s; 0.003%
`:s; 0.3%
`:s; 0.005%
`98.0-100.5%
`
`10. Typical Properties
`Acidity/alkalinity:
`pH = 2.2 for a 0.2% wjv aqueous solution.
`Antimicrobial activity: edetic acid has some antimicrobial
`aCtivity against Gram-negative microorganisms, Pseudomonas
`aeruginosa, some yeasts and fungi, although this activity is
`insufficient for edetic acid to be used effectively as an
`antimicrobial preservative on its own.0·2
`) However, when used
`with other antimicrobial preservatives edetic acid demonstrates
`a marked synergistic effect in its antimicrobial activity. Edetic
`acid and edetates are therefore frequently used in combination
`with such preservatives as: benzalkonium chloride; bronopo1;
`cetrimide; imidurea; parabens and phenols, especially chlorox(cid:173)
`ylenol. Typically, edetic acid is used at a concentration of0.1-
`0.15% wjv. In the presence of some divalent metal ions, such as
`Ca2+ or Mg2
`+, the synergistic effect may be reduced or lost
`altogether. The addition of disodium edetate to phenylmercuric
`nitrate(3) and thimerosal (3, 4) has also been reported to reduce
`the antimicrobial efficacy of the preservative. Edetic acid and
`iodine form a colorless addition compound which is bacter(cid:173)
`icidal.
`Dissociation constant:
`PKal = 2.00;
`pKa2 = 2.67;
`pKa3 = 6.16;
`pKa4 = 10.26.
`Melting point: melts above 220°C, with decomposition.
`Solubility: soluble in solutions of alkali hydroxides; soluble 1 in
`500 of water.
`
`11. Stability and Storage Conditions
`Although edetic acid is fairly stable in the solid state, edetate
`salts are more stable than the free acid, which decarboxylates if
`heated above 150°C. Disodium edetate dihydrate loses water
`of crystallization when heated to 120°C. Edetate calcium
`disodium is slightly hygroscopic and should be protected from
`moisture.
`Aqueous solutions of edetic acid or edetate salts may be
`sterilized by autoclaving, and should be stored in an alkali-free
`container.
`Edetic acid and edetates should be stored in well-closed
`containers in a cool, dry, place.
`
`\ \
`
`+
`
`LUPIN EX1028, Page 1
`
`

`
`Edetic Acid 177
`
`12. Incompatibilities
`Edetic acid and edetates are incompatible with strong
`oxidizing agents, strong bases and polyvalent metal ions such
`as copper, nickel and copper alloy.
`Edetic acid and disodium edetate behave as weak acids,
`displacing carbon dioxide from carbonates and reacting with
`metals to form hydrogen.
`Other incompatibilities include the inactivation of certain
`types of insulin due to the chelation of zinc, and the chelation
`of trace metals in TPN solutions following the addition of
`TPN additives stabilized with disodium edetate. Calcium
`disodium edetate has also been reported to be incompatible
`with amphotericin and with hydralazine hydrochloride in
`infusion fluids.
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Edetic acid and edetates are
`mildly irritant to the skin, eyes and mucous membranes.
`Ingestion, inhalation and contact with the skin and eyes should
`therefore be avoided. Eye protection, gloves and a dust mask
`are recommended.
`
`16. Regulatory Status
`Included in the FDA Inactive Ingredients Guide (otic, rectal
`and topical preparations). Included in nonparenteral medicines
`licensed in the UK.
`See also Section 18.
`
`13. Method of Manufacture
`Edetic acid may be prepared by the condensation of
`ethylenediamine with sodium monochloroacetate in the
`presence of sodium carbonate. An aqueous solution of the
`reactants is heated to about 90°C for ten hours, then cooled,
`and hydrochloric acid added to precipitate the edetic acid.
`Edetic acid may also be prepared by the reaction of
`ethylenediamine with hydrogen cyanide and formaldehyde
`with subsequent hydrolysis of the tetranitrile, or under alkaline
`conditions with continuous extraction of ammonia.
`See Section 18 for information on the preparation of edetate
`salts.
`
`14. Safety
`Edetic acid and edetates are widely used in topical, oral and
`parenteral pharmaceutical formulations. They are also
`extensively used in cosmetics and food products.
`Edetic acid is generally regarded as an essentially nontoxic and
`nonirritant material although it has been associated with dose(cid:173)
`related bronchoconstriction when used as a preservative in
`nebulizer solutions. It has therefore been recommended that
`nebulizer solutions for bronchodilation should not contain
`edetic acid.(S)
`Edetates, particularly disodium edetate and edetate calcium
`disodium, are used in a greater number and variety of
`pharmaceutical formulations than the free acid. Both
`disodium edetate and edetate calcium disodium are poorly
`absorbed from the gastrointestinal tract and are associated
`with few adverse effects when used as excipients in pharma(cid:173)
`ceutical fom1ulations.
`Disodium edetate, trisodium edetate and edetic acid readily
`chelate calcium and can, in large doses , cause calcium
`depletion (hypocalcemia) if used over an extended period or
`if administered too rapidly by intravenous infusion. If used in
`preparations for the mouth, they can also leach calcium from
`the teeth. In contrast, edetate calcium disodium does not
`chelate calcium.
`Edetate calcium disodium is nephrotoxic and should be used
`with caution in patients with renal impairment. Disodium
`edetate should similarly be used with caution in patients with
`renal impairment, tuberculosis and impaired cardiac function .
`The WHO has set an estimated acceptable daily intake for
`disodium edetate in foodstuffs at up to 2.5 mgjkg body(cid:173)
`weight.<6>
`See also Section 19.
`LD 50 (mouse, IP): 0.25 gjkg< 7l
`LD 50 (mouse, oral): 0.03 gj kg
`LD 50 (rat, IP): 0.397 gjkg
`
`17. Pharmacopeias
`Rom and USPNF.
`
`18. Related Substances
`Dipotassium edetate; disodium edetate; edetate calcium
`disodium; sodium edetate; trisodium edetate.
`Dipotassium edetate: C 10H 14K 2NzOs
`Molecular weight: 368.46
`CAS number: [2001-94-7]
`Synonyms: dipotassium edathamil; dipotassium ethylenedia(cid:173)
`minetetraacetate; edathamil dipotassium; edetate dipotassium;
`edetic acid dipotassium salt; EDTA dipotassium; N,N'-1 ,2-
`ethanediylbis[ N-( carboxymethyl)glycine] dipotassium salt;
`ethylenebis(iminodiacetic acid) dipotassium salt; ethylenedia(cid:173)
`minetetraacetic acid dipotassium salt; (ethylenedinitri(cid:173)
`lo)tetraacetic acid dipotassium salt; tetracemate dipotassium.
`Appearance: white crystalline powder.
`Disodium edetate: C10H 14N 2Na20s
`Molecular weight: 336.21
`CAS number:
`[139-33-3] for the anhydrous material;
`[6381-92-6] for the dihydrate.
`Synonyms: disodium edathamil; disodium ethylenediaminete(cid:173)
`traacetate; edathamil disodium; edetate disodium; edetic acid
`dis odium salt; EDTA disodium; N,N' -1 ,2-ethanediylbis[N(cid:173)
`(carboxymethyl)glycine] disodium salt; ethylene(cid:173)
`bis(iminodiacetic acid) disodium salt; ethylenediaminetetraa(cid:173)
`cetic acid disodium salt; (ethylenedinitrilo)tetraacetic acid
`disodium salt; Questa! Di; Sequestrene NA2; tetracemate
`disodium; Versene disodium .
`Appearance: odorless white crystalline powder with a slightly
`acid taste.
`Pharmacopeias: Belg, Br, Eur, Fr, Gr, Hung, Ind, It, Jpn, Mex,
`Neth, Nord, Port, Swiss, Turk, US and Yug.
`Acidity jalkalinity: pH = 4.3-4.7 for a 1% wjv solution in
`carbon dioxide free water.
`Freezing point depression:
`0.14°C (I% wjv aqueous solution)
`Melting point:
`decomposition at 252°C for the dihydrate.
`Refractive index:
`1.335 for a 1% wjv aqueous solution.
`Solubility: practically insoluble in chloroform and , ether;
`slightly soluble in ethanol (95%); soluble I in 11 of water.
`Specific gravity:
`1.004 for a 1% wjv aqueous solution.
`Viscosity (kinematic): 1.03 mm2js (I eSt) for a 1% wjv
`aqueous solution.
`
`LUPIN EX1028, Page 2
`
`

`
`178 Edetic Acid
`
`Method of manufacture: disodium edetate may be prepared by
`the reaction of edetic acid and sodium hydroxide.
`Safety: see also Section 14.
`LDso (mouse, IP): 0.26 g/kg<7l
`LD 50 (mouse, IV): 0.056 gjkg
`LD50 (mouse, oral): 2.05 g/kg
`LD50 Erabbit, IV): 0.047 g/kg
`LD50 (rabbit, oral): 2.3 g/kg
`LD50 (rat, oral): 2 g/kg
`LD50 (rat, SC): 3.735 g/kg
`Regulatory status: GRAS listed. Included in the FDA Inactive
`Ingredients Guide (inhalations, injections, ophthalmic pre(cid:173)
`parations, oral capsules, solutions, suspensions, syrups and
`tablets, rectal, topical and vaginal preparations). Included in
`nonparenteral and parenteral medicines licensed in the UK.
`Comments: in pharmaceutical formulations disodium edetate is
`used as a chelating agent typically at concentrations between
`0.005-0.1% wjv.
`Edetate calcium disodium: C 10H 12CaN2Na20s
`Molecular weight: 374.28
`CAS number:
`[62-33-9] for the anhydrous material;
`[23411-34-9] for the dihydrate.
`Synonyms: 385; calcium disodium edetate; calcium disodium
`ethylenediaminetetraacetate; calcium disodium (ethylenedini(cid:173)
`trilo)tetraacetate; edathamil calcium disodium; edetic acid
`calcium dis odium salt; [[N,N' -1 ,2-ethanediylbis[ N-( carboxy(cid:173)
`methyl)glycinat o]]( 4-)-N,N' ,O,O',ON,-oN']calciate(2-)dis o(cid:173)
`dium; EDTA calcium; ethylenediaminetetraacetic acid calcium
`disodium chelate; [( ethylenedinitrilo )tetraacetato] calciate(2-)
`disodium; sodium calciumedetate; Versene CA.
`Appearance: white or creamy-white colored, slightly hygro(cid:173)
`scopic, crystalline powder or granules; odorless, or with a
`slight odor; tasteless, or with a faint saline taste.
`Pharmacopeias: Belg, Br, Cz, Egypt, Eur, Fr, Gr, It, Mex,
`Neth, Nord, Port, Swiss, Turk, US and Yug. Also in BP Vet.
`Some pharmacopeias specify that edetate calcium disodium is
`the dihydrate, others that it is the anhydrous material. The
`USP XXII specifies that edetate calcium disodium is a mixture
`of the dihydrate and trihydrate but that the dihydrate
`predominates.
`Acidity/ alkalinity:
`pH = 4-5 for a 1% w/v aqueous solution.
`Density (bulk) : 0. 69 g/ em 3
`Solubility: practically insoluble in chloroform, ether and other
`organic solvents; very slightly soluble in ethanol (95%); soluble
`1 in 2 of water.
`Method of manufacture: edetate calcium disodium may be
`prepared by the addition of calcium carbonate to a solution of
`disodium edetate.
`Safety: see also Section 14.
`LDso (dog, oral): 12 g/kg<7l
`LD 50 (mouse, IP): 4.5 g/kg
`LD 50 (mouse, oral): 10 g/kg
`LD 50 (rabbit, IP): 6 g/kg
`LD50 (rabbit, oral): 7 g/kg
`LD50 (rat, IP): 3.85 g/kg
`LD50 (rat, IV): 3.0 gjkg
`LD50 (rat, oral): 10 g/kg
`Regulatory status: GRAS listed. Accepted for use as a food
`additive in the UK. Included in the FDA Inactive Ingredients
`Guide (injections, oral capsules, solutions, suspensions, syrups
`and tablets).
`Comments: used in pharmaceutical formulations as a chelating
`agent in concentrations between 0.01-0.1% w/v. Usually
`
`edetate calcium disodium is used in pharmaceutical formula(cid:173)
`tions in preference to disodium edetate or sodium edetate to
`prevent calcium depletion occurring in the body. In food
`products, edetate calcium disodium may also be used in flavors
`and as a color retention agent. Edetate calcium disodium
`occurs as the dihydrate, trihydrate and anhydrous material.
`Sodium edetate: C 10H 12N 2Na40 8
`Molecular weight: 380.20
`CAS number: [64-02-8]
`Synonyms: edetate sodium; edetic acid tetrasodium salt; EDT A
`tetrasodi um; N,N' -1 ,2-ethanediylbis[N-( carboxy(cid:173)
`methyl)glycine] tetrasodium salt; ethylenebis(iminodiacetic
`acid) tetrasodium salt; ethylenediaminetetraacetic acid tetra(cid:173)
`sodium salt; (ethylenedinitrilo)tetraacetic acid tetrasodium
`salt; Sequestrene N A4; tetracemate tetrasodium; tetracemin;
`tetrasodium edetate; tetrasodium ethylenebis(iminodiacetate );
`tetrasodium ethylenediaminetetraacetate; Versene.
`Appearance: white crystalline powder.
`Acidity/ alkalinity:
`pH = 11.3 for a 1% w jv aqueous solution.
`Melting point: > 300°C
`Solubility: soluble 1 in 1 of water.
`Safety: see also Section 14.
`LDso (mouse, IP): 0.33 g/kgC7l
`Regulatory status: included in the FDA Inactive Ingredients
`Guide (inhalations, injections, ophthalmic preparations, oral
`capsules and tablets, and topical preparations).
`Comments: sodium edetate reacts with most divalent and
`trivalent metallic ions to form soluble metal chelates and is
`used in pharmaceutical formulations in concentrations
`between 0.01-0.1% w/v.
`Trisodium edetate: C 10H 13N 2Na30 8
`Molecular weight: 358.20
`CAS number: [150-38-9]
`Synonyms: edetate trisodium; edetic acid trisodium salt; EDTA
`trisodium; N,N' -1 ,2-ethanediylbis[N-( carboxymethyl)glycine]
`trisodium salt; ethylenediaminetetraacetic acid trisodium salt;
`( ethylenedinitrilo )tetraacetic acid trisodium salt; Sequestrene
`N A3; trisodium ethylenediaminetetraacetate; Versene-9.
`Appearance: white crystalline powder.
`Acidity/ alkalinity:
`pH = 9.3 for a 1% w/v aqueous solution.
`Melting point: > 300°C
`Method of manufacture: trisodium edetate may be prepared by
`adding a solution of sodium hydroxide to disodium edetate.
`Safety: see also Section 14.
`LD 50 (mouse, IP): 0.3 g/kg(7l
`LD50 (mouse, oral): 2.15 g/kg
`LD50 (rat, oral): 2.15 g/kg
`Regulatory status: included in the FDA Inactive Ingredients
`Guide (topical preparations).
`Comments: more soluble in water than either the disodium salt
`or the free acid. Trisodium edetate also occurs as the
`monohydrate and is used in pharmaceutical formulations as
`a chelating agent.
`Other salts of edetic acid which are commercially available
`include diammonium, dimagnesium, dipotassium, ferric
`sodium and magnesium disodium edetates.
`
`19. Comments
`Therapeutically, a dose of 50 mg/kg body-weight of disodium
`edetate, as a slow infusion over a 24 hour period, with a
`maximum daily dose of 3 g, has been used as a treatment for
`hypercalcemia. For the treatment of lead poisoning, a dose of
`
`)
`
`LUPIN EX1028, Page 3
`
`

`
`Edetic Acid 179
`
`60-80 mgjkg of edetate calcium disodium, as a slow infusion in
`two daily doses, for 5 days, has been used.
`
`20. Specific References
`I. Richards RME, Cavill RH. Electron microscope study of effect of
`benzalkonium chloride and edetate disodium on cell envelope of
`Pseudomonas aeruginosa. J Pharm Sci 1976; 65: 76-80.
`2. Whalley G. Preservative properties of EDTA. Mfg Chern 1991;
`62(9): 22-23.
`3. Richards RME, Reary JME. Changes in antibacterial activity of
`thiomersal and PMN on autoclaving with certain adjuvants. J
`Pharm Pharmacal 1972; 24(Suppl): 84P-89P.
`4. Morton DJ. EDTA reduces antimicrobial efficacy of thiomerosal.
`lnt J Pharmaceutics 1985; 23: 357-358.
`5. Beasley CRW, Rafferty P, Holgate ST. Bronchoconstrictor
`properties of preservatives in ipratropium bromide (Atrovent)
`nebuliser solution. Br Med J 1987; 294: 1197-1198.
`6. FAO/WHO. Toxicological evaluation of certain food additives
`with a review of general principles and of specifications.
`
`Seventeenth report of the joint FAO/WHO expert committee on
`food additives. Tech Rep Ser Wid Hlth Org 1974; No. 539.
`7. Sweet DV, editor. Registry of toxic effects of chemical substances.
`Cincinnati: US Department of Health, 1987.
`
`21. General References
`Chalmers L. The uses of EDTA and other chelates in industry. Mfg
`Chern 1978; 49(3): 79-80, 83.
`Hart JR. Chelating agents in cosmetic and toiletry products. Cosmet
`Toilet 1978; 93(12): 28-30.
`Hart JR. EDTA-type chelating agents in personal care products.
`Cosmet Toilet 1983; 98(4): 54-58.
`Lachman L. Antioxidants and chelating agents as stabilizers in liquid
`dosage fo rms. Drug Cosmet Ind 1968; 102(2): 43-45, 146-149.
`
`22. Authors
`UK: RS Cook; N Yussuf.
`
`LUPIN EX1028, Page 4
`
`

`
`Sodium Metabisulfite
`
`1. Nonproprietary Names
`BP: Sodium metabisulphite
`PhEur: Natrii metabisulfis
`USPNF: Sodium metabisulfite
`
`2. Synonyms
`Disodium disulfite; disodium pyrosulfite; disulfurous acid
`disodium salt; E223; sodium acid sulfite.
`
`3. Chemical Name and CAS Registry Number
`Sodium pyrosulfite [7681-57-4]
`
`4. Empirical Formula
`Na2S20s
`
`Molecular Weight
`190.1
`
`5. Structural Formula
`
`0
`0
`II
`II
`Na+o--s-o-s-o- Na+
`
`6. Functional Category
`Antioxidant.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Sodium metabisulfite is used as an antioxidant in oral,
`parenteral and topical pharmaceutical formulations. Primar(cid:173)
`ily, sodium metabisulfite is used in acidic preparations; for
`alkaline preparations, sodium sulfite is usually preferred, see
`Sections 18 and 19. Sodium metabisulfite also has some
`antimicrobial activity, which is greatest at acid pH, and may be
`used as a preservative in oral preparations such as syrups.
`In the food industry, and in wine production, sodium
`metabisulfite is similarly used as an antioxidant, antimicrobial
`preservative and anti-browning agent. However, at concentra(cid:173)
`tions above about 500 ppm it imparts a noticeable flavor to
`preparations.
`Sodium metabisulfite usually contains small amounts of
`sodium sulfite and sodium sulfate, see Section 18.
`
`Use
`
`Concentration (%)
`
`Antioxidant
`
`O.oi-1.0
`
`8. Description
`Sodium metabisulfite occurs as colorless, prismatic crystals or
`as a white to creamy-white crystalline powder which has the
`odor of sulfur dioxide and an acidic, saline taste. Sodium
`metabisulfite crystallizes from water as a hydrate containing
`7H20 .
`
`9. Pharmacopeia} Specifications
`
`Test
`
`Identification
`Appea rance of solution
`
`PhEur 1993
`+
`+
`
`USPNFXVTI
`+
`
`Sodium Metabisulfite 451
`
`Continued
`
`Test
`
`pH (5% wfv solution)
`Chloride
`Thiosulfate
`Arsenic
`Heavy metals
`Iron
`Assay (as Na2S20s)
`Assay (as S02)
`
`PhEur 1993
`
`USPNFXVII
`
`3.5-5.0
`
`+
`~ 5 ppm
`~ 20 ppm
`~ 20 ppm
`95-100.5%
`
`~ 0.05 %
`~ 0.05%
`~ 3 ppm
`~ 0.002%
`~ 0.002%
`
`65-67.4%
`
`10. Typical Properties
`Acidity/alkalinity: pH = 3.5-5.0 for a 5% wjv aqueous
`solution at 20°C.
`Melting point: sodium metabisulfite melts with decomposition
`at less than 150°C.
`Osmolarity: a 1.38% wjv aqueous solution is iso-osmotic with
`serum.
`Solubility :
`
`Solvent
`
`Ethanol (95% )
`Glycerin
`Water
`
`Solubility at 20°C
`Unless otherwise stated
`
`slightly soluble
`freely soluble
`I in 1.9
`I in 1.2 at 100°C
`
`11. Stability and Storage Conditions
`On exposure to air and llloisture, sodium metabisulfite is
`slowly oxidized to sodium sulfate with disintegration of the
`crystals.Ol Addition of strong acids, to the solid, liberates
`sulfur dioxide.
`In water, sodium metabisulfite is immediately converted to
`sodium (Na +) and bisulfite (HS03-) ions. Aqueous sodium
`metabisulfite solutions also decompose in air, especially on
`heating, and solutions which are to be sterilized by autoclaving
`should therefore be filled into containers in which the air has
`been replaced with an inert gas, such as nitrogen. The addition
`of dextrose to aqueous sodium metabisulfite solutions results
`in a decrease in the stability of the metabisulfite.(2)
`The bulk material should be stored in a well-closed container,
`protected from light, in a cool, dry, place.
`
`12. Incompatibilities
`Sodium metabisulfite reacts with sympathomimetics and other
`drugs which are ortho- or para-hydroxybenzyl alcohol
`derivatives to form sulfonic acid derivatives possessing little
`or no phannacological activity. The most important drugs
`subject to this inactivation are adrenaline and its derivatives.(""})
`In addition, sodium metabisulfite is incompatible with
`chloramphenicol, due to a more complex reaction, (J) and
`5
`inactivates cisplatin in solution/4
`) it is also incompatible with
`•
`phenylmercuric acetate when autoclaved in eye-drop prepara(cid:173)
`tions .<6l
`Sodium metabisulfite may react with the rubber caps of
`multidose vials which should therefore be pre-treated with
`sodium metabisulfite solution.(7)
`
`13. Method of Manufacture
`Sodium metabisulfite is prepared by saturating a solution of
`sodium hydroxide with sulfur dioxide and allowing crystal(cid:173)
`lization to occur; hydrogen is passed through the solution to
`
`LUPIN EX1028, Page 5
`
`

`
`cc
`
`452 Sodium Metabisulfite
`
`exclude air. Sodium metabisulfite may also be prepared by
`saturating a solution of sodium carbonate with sulfur dioxide
`and allowing crystallization to occur, or by thermally
`dehydrating sodium bisulfite.
`
`14. Safety
`Sodium metabisulfite is widely used as an antioxidant in oral,
`topical and parenteral pharmaceutical formulations; it is also
`widely used in food products.
`Although it is extensively used in a variety of preparations,
`sodium metabisulfite, and other sulfites, have been associated
`with a number of severe, or fatal, adverse reactions.<S-IJ) These
`are usually hypersensitivity type reactions and include
`bronchospasm and anaphylaxis. Allergy to sulfite antioxi(cid:173)
`dants is estimated to occur in 5-10% of asthmatics although
`adverse reactions may also occur in non-asthmatics with no
`history of allergy.
`Following oral ingestion, sodium metabisulfite is oxidized to
`sulfate and is excreted in the urine. Ingestion may result in
`gastric irritation due to the liberation of sulfurous acid, while
`ingestion of large amounts of sodium metabisulfite can cause
`colic, diarrhea, circulatory disturbances, CNS depression and
`death. In Europe, the acceptable daily intake of sodium
`meta bisulfite, and other sulfites, used in foodstuffs has been set
`at up to 3.5 mgfkg body-weight, calculated as sulfur dioxide
`(S02) . The WHO has similarly also set an acceptable daily
`intake of sodium metabisulfite, and other sulfites, at up to 7.0
`mgfkg body-weight, calculated as sulfur dioxide (S02).< 14
`)
`LD50 (rat, IV): 0.12 g/kg(IS)
`
`15. llandling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Sodium metabisulfite
`may be irritant to the skin and eyes; eye protection and
`gloves are recommended. In the UK, the long-term (8-hour
`TWA) occupational exposure limit for sodium metabisulfite
`is 5 mgfm3.(1 6)
`
`16. Regulatory Status
`GRAS listed. Accepted as a food additive in Europe. Included
`in the FDA Inactive Ingredients Guide (epidural, IM and IV
`injections, ophthalmic solutions and oral preparations).
`Included in nonparenteral and parenteral medicines licensed
`in the UK.
`
`17. Pharmacopeias
`
`Aust, Belg, Br, Cz, Egypt, Eur, Fr, Hung, Ind, Jpn, Mex,
`Neth, Nord, Turk, USPNF and Yug. Also in BP Vet.
`
`18. Related Substances
`Potassium bisulfite; potassium metabisulfite; sodium bisulfite;
`sodium sulfite.
`Potassium bisulfite: KHS03
`Molecular weight: 120.20
`CAS number: [7773-03-7]
`Synonyms: E228; potassium hydrogen sulfite.
`Potassium metabisulfite: K2S20 s
`Molecular weight: 222.32
`CAS number: [16731-55-8]
`Synonyms: dipotassium pyrosulfite; E224; potassium pyrosul(cid:173)
`fite.
`Appearance: white crystalline powder.
`
`Pharmacopeias: Fr and USPNF.
`Solubility: freely soluble in water; practically insoluble in
`ethanol (95%).
`Sodimn bisulfite: NaHS03
`Molecular weight: 104.07
`CAS number: [7631-90-5]
`Synonyms: E222; sodium hydrogen sulfite.
`Appearance: white crystalline powder.
`Pharmacopeias: Jpn.
`Density: 1.48 gjcm3
`Solubility: soluble 1 in 3.5 parts of water at 20°C, I in 2 parts of
`water at l00°C, and 1 in 70 parts of ethanol (95%).
`Comments: most substances sold as sodium bisulfite contain
`significant, variable, amounts of sodium metabisulfite, since
`the latter is less hygroscopic and more stable during storage
`and shipment. See Section 19.
`Sodimn sulfite: Na2S03
`Molecular weight: 126.06
`CAS number: [7757-83-7]
`Synonyms: anhydrous sodium sulfite; E221; exsiccated sodium
`sulfite.
`Appearance: a white, odorless or almost odorless crystalline
`powder.
`Pharmacopeias: Br, Eur, Fr, Jpn and Mex.
`Acidity/alkalinity: pH = 9 for a saturated aqueous solution at
`20°C.
`Solubility: soluble 1 in 3.2 parts of water; soluble in glycerin;
`practically insoluble in ethanol (95%).
`Comments: see Section 19.
`
`19. Comments
`Sodium metabisulfite is used as an antioxidant at low pH,
`sodium bisulfite at intermediate pH, and sodium sulfite at
`higher pH values.
`
`20. Specific References
`1. Schroeter LC. Oxidation of sulfurous acid salts in pharmaceutical
`systems. J Pharm Sci 1963; 52: 888-892.
`2. Schumacher GE, Hull RL. Some factors influencing the
`degradation of sodium bisulfite in dextrose solutions. Am J
`Hosp Pharm 1966; 23: 245-249.
`3. Higuchi T, Schroeter LC. Reactivity of bisulfite with a number of
`pharmaceuticals. JAm Pharm Assoc (Sci) 1959; 48: 535-540.
`4. Hussain AA, Haddadin M, Iga K. Reaction of cis-platinum with
`sodium sulfite. J Pharm Sci 1980; 69: 364-365.
`5. Garren KW, Repton AJ. Incompatibility of cisplatin and Reglan
`injectable. Int J Pharmaceutics 1985; 24: 91-99.
`6. Collins AJ, Lingham P, Burbridge TA, Bain R. Incompatibility
`of phenylmercuric acetate with sodium meta bisulfite in eye drop
`formulations. J Pharm Pharmacol 1985; 37(Suppl): 123P.
`7. Schroeter LC. Sulfurous acid salts as pharmaceutical antiox(cid:173)
`idants. J Pharm Sci 1961; 50: 891-90!.
`Jamieson DM, Guill MF, Wray BB, May JR. Metabisulfite
`sensitivity: case report and literature review. Ann Allergy 1985;
`54: 115-12!.
`9. Possible allergic-type reactions. FDA Drug Bull 1987; 17: 2.
`10. Tsevat J, Gross GN, Dowling GP. Fatal asthma after ingestion of
`sulfite-containing wine [letter]. Ann Intern Med 1987; 107: 263.
`II. Weiner M, Bernstein IL. Adverse reactions to drug formulation
`agents: a handbook of excipients. New York: Marcel Dekker Inc,
`1989: 314-320.
`12. Fitzharris P. What advances if any, have been made in treating
`sulphite allergy? Br Med J 1992; 305: 1478.
`
`8.
`
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`

`
`Sodium Metabisulfite 453
`
`13. Smolinske SC. Handbook of food, drug, and cosmetic excipients.
`Boca Raton, FL: CRC Press Inc, 1992: 393-406.
`14. FAO/WHO. Evaluation of certain food additives and contami(cid:173)
`nants. Thirtieth report of the joint FAO(WHO expert committee
`on food additives. Tech Rep Ser Wid Hlth Org 1987; No. 751.
`15. Sweet DV, editor. Registry of toxic effects of chemical
`substances. Cincinnati: US Department of Health, 1987.
`16. Health and Safety Executive. EH40/93 occupational exposure
`limits 1993. London: HMSO, 1993.
`
`21. General References
`Halaby SF, Mattocks AM. Absorption of sodium bisulfite from
`peritoneal dialysis solutions. J Pharm Sci 1965; 54: 52-55.
`Wilkins JW, Greene JA, Weller JM. Toxicity of intraperitoneal
`bisulfite. Clin Pharmacal Ther 1968; 9: 328-332.
`
`22. Authors
`USA: JT Stewart.
`
`l \
`
`~.
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`LUPIN EX1028, Page 7